Poster Session 5

S. Escrivá-de-Romaní¹, L. Ollé-Monràs², L. Joval-Ramentol³, E. Álvarez Colomé⁴, M. Arumí¹, A. Rezqallah¹, A. Suñol⁴, J. Jimenez⁵, E. Castillo⁶, R. Fasani⁵, P. Martinez⁵, A. Baizán⁴, M. Oliveira¹, M. Bellet¹, E. Zamora¹, I. Pimentel¹, M. Borrell¹, N. Gómez¹, A. Rodríguez¹, M. Perachino⁷, V. Barberi⁷, M. Gaudio⁷, C. Salvà de Torres⁸, E. Cimbro⁴, R. Dienstmann³, J. Seoane², P. Nuciforo⁵, A. Vivancos⁶, C. Saura¹; ¹Medical Oncology, Breast Cancer Group, Vall d’Hebron University Hospital, Vall d’Hebron Institute of Oncology (VHIO), Barcelona, SPAIN, ²Computational Cancer Biology Group, Vall d’Hebron Institute of Oncology (VHIO), Barcelona, SPAIN, ³Oncology Data Science Group (ODysSey), Vall d’Hebron Institute of Oncology (VHIO), Barcelona, SPAIN, ⁴Medical Oncology, Vall d’Hebron Institute of Oncology (VHIO), Barcelona, SPAIN, ⁵Molecular Oncology Group, Vall d’Hebron University Hospital, Vall d’Hebron Institute of Oncology (VHIO), Barcelona, SPAIN, ⁶Cancer Genomics Group, Vall d’Hebron Institute of Oncology (VHIO), Barcelona, SPAIN, ⁷Medical Oncology, Breast Cancer Group, Vall d’Hebron Institute of Oncology (VHIO), Barcelona, SPAIN, ⁸Medical Oncology, Vall d’Hebron University Hospital, Vall d’Hebron Institute of Oncology (VHIO), Barcelona, SPAIN.

BACKGROUND: Analyses of P circulating tumor DNA by NGS panels is an emerging useful tool for identifying tumor genomic alterations in BC. There is scarce data about the concordance of genomic alterations found at the same time point in T and P samples of pts with HER2-positive mBC. MATERIALS AND METHODS: This is a single institution study of a consecutive cohort of HER2-positive mBC pts receiving anti-HER2 therapies. Tumor T and P samples were collected prospectively after obtaining consent. Genomic alterations were analyzed retrospectively using NGS with the VHIO300 panel for T (includes 421 genes) and the VHIO360 panel for P samples (includes 74 genes). HER2 expression in T samples was evaluated using Immunohistochemistry (IHC) and in situ hybridization (ISH) following the 2013 ASCO/CAP guidelines. To test the concordance of paired T/P samples between the NGS panels, only the 73 common genes were included. General linear models, Pearson and Spearman correlations were used to associate numerical variables. RESULTS: 107 consecutive pts were included in the study, of which 39 pts had synchronous paired T/P samples. Out of these 39 pts, a total of 42 T/P pairs were available. T samples were analyzed with VHIO300 panel and IHC/ISH, while P samples were tested with VHIO360. Concordance in the presence or absence of ERBB2 amplification status between P and T was coincident in 30 out of 42 pairs (71%) showing a statistically significant correlation with copy number. As a reference, in T samples alone, the concordance between ERBB2 amplification detected by two different methodologies, NGS and by IHC/ISH, resulted positive in 35 out of 42 samples (83%). T and P shared at least one pathogenic or likely pathogenic mutation in 32 out of 42 pairs (76%) where these variants were present. The overall agreement between genotype status (mutant/ wild-type) for all genes was 78.5%. The number of detected mutations per sample varied from 0 – 6. For variants of uncertain significance (VUS), 8 of 38 pairs (21%) shared altered variants in both samples. The average percentage of altered shared genes was 35%. The range of VUS variants detected per sample varied from 0 – 14. For amplifications 26 pairs (65%) out of 40 shared at least one altered gene in both samples. The average percentage of concordant T/P pairs with regards to amplified genes was 60.8%. The range of copies detected per sample varied from 0 – 9. Concordance of genomic alterations found in paired T/P samples is summarized in the table. CONCLUSIONS: A high concordance rate for ERBB2 amplification was detected by NGS in T and P paired samples, as well as in T samples using different approaches, NGS and IHC/ISH. Concordance was high between T and P with regards to pathogenic and likely pathogenic mutations, moderate for amplifications other than ERBB2, and overall low for VUS.

B. Xu¹, F. Ma¹, M. Yan², W. Li³, Q. Ouyang⁴, Z. Tong⁵, Y. Teng⁶, Y. Wang⁷, S. Wang⁸, C. Geng⁹, T. Luo¹⁰, J. Zhong¹¹, Q. Zhang¹², Q. Liu¹³, X. Zeng¹⁴, T. Sun¹⁵, Q. Mo¹⁶, S. Zhou¹⁷, Y. Cheng¹⁸, J. Cheng¹⁹, X. Wang²⁰, J. Nie²¹, J. Yang²², X. Wu²³, X. Wang²⁴, H. Li²⁵, G. Yao²⁶, Y. Fan²⁷, J. Lin²⁷, X. Zhu²⁷; ¹Department of Medical Oncology, Cancer Hospital Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, CHINA, ²Department of Breast Disease, Henan Breast Cancer Center, The Affiliated Cancer Hospital of Zhengzhou University & Henan Cancer Hospital, Zhengzhou, CHINA, ³Department of Oncology, The First Hospital of Jilin University, Changchun, CHINA, ⁴Breast Internal Medicine Department, Hunan Cancer Hospital, The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, CHINA, ⁵Department of Breast Oncology, Tianjin Medical University Cancer Institute & Hospital, Tianjin, CHINA, ⁶Department of Breast Internal Medicine, The First Hospital of China Medical University, Shenyang, CHINA, ⁷Breast Surgery, Shandong Cancer Hospital & Institute, Jinan, CHINA, ⁸Department of Internal Medicine, Sun Yat-sen University Cancer Center, Guangzhou, CHINA, ⁹Breast Center, The Fourth Hospital of Hebei Medical University and Hebei Tumor Hospital, Shijiazhuang, CHINA, ¹⁰Department of Medical Oncology of Cancer Center, West China Hospital, Sichuan University, Chengdu, CHINA, ¹¹Medical Oncology, The First Affiliated Hospital of Guangxi Medical University, Nanning, CHINA, ¹²Ward One of Mammary Department, Harbin Medical University Cancer Hospital, Harbin, CHINA, ¹³Breast Tumor Center, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, CHINA, ¹⁴Breast Cancer Center, Affiliated Cancer Hospital of Chongqing University, Chongqing, CHINA, ¹⁵Breast Internal Medicine Department, Liaoning Cancer Hospital & Institute, Shenyang, CHINA, ¹⁶Breast Surgery, Guangxi Medical University Affiliated Tumor Hospital, Nanning, CHINA, ¹⁷Department of Breast Oncology, The First Affiliated Hospital of USTC West District, Hefei, CHINA, ¹⁸Department of Thoracic Oncology, Jilin Cancer Hospital, Changchun, CHINA, ¹⁹Oncology Center Breast Department, Union Hospital, Tongji Medical College, Huazhong University of Science & Technology, Wuhan, CHINA, ²⁰Breast Medicine, Zhejiang Cancer Hospital, Hangzhou, CHINA, ²¹Breast Surgery, Yunnan Cancer Hospital, Kunming, CHINA, ²²Department of Medical Oncology, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, CHINA, ²³Department of Breast Oncology, Hubei Cancer Hospital, Wuhan, CHINA, ²⁴Department of Medical Oncology, Henan Key Laboratory of Cancer Epigenetics, Cancer Hospital, The First Affiliated Hospital, College of Clinical Medicine, Medical College of Henan University of Science and Technology, Luoyang, CHINA, ²⁵Key Laboratory of Carcinogenesis and Translational Research, Department of Breast Oncology, Peking University Cancer Hospital and Institute, Beijing, CHINA, ²⁶Department of Breast, Southern Medical University Nanfang Hospital, Guangzhou, CHINA, ²⁷Department of Clinical Development, Jiangsu Hengrui Pharmaceuticals Co., Ltd., Shanghai, CHINA.

Background: PHILA, a randomized, double-blind, placebo-controlled phase 3 trial (NCT03863223), assessed the efficacy and safety of pyrotinib plus trastuzumab and docetaxel (PyroHT) as first-line therapy in HER2-positive metastatic breast cancer. PyroHT significantly prolonged progression-free survival (PFS) and improved overall survival (OS) compared with placebo plus trastuzumab and docetaxel (HT), with manageable safety (Xu et al., BMJ 2023; Xu et al., SABCS 2024). Here, we report updated survival results after a median follow-up of 45.5 months.Methods: Patients (pts) with untreated HER2-positive metastatic breast cancer were enrolled across 40 centers in China and randomized (1:1) to receive either oral pyrotinib (400 mg once daily) or placebo plus intravenous trastuzumab (8 mg/kg loading dose, then 6 mg/kg) and docetaxel (75 mg/m²) on day 1 of each 21-day cycle. The primary endpoint was investigator-assessed PFS.Results: From May 2019 to January 2022, 590 pts were randomized and received treatment (PyroHT n=297; HT n=293). As of May 30, 2025, the median follow-up was 46.5 months (IQR 36-55) for PyroHT and 44.6 months (IQR 31-53) for HT. In the PyroHT group, 75 pts (25.3%) were still receiving study treatment, compared with 19 (6.5%) in the HT group. Following treatment discontinuation, 174 pts (58.6%) in the PyroHT group and 229 pts (78.2%) in the HT group received post-discontinuation therapies. Although cross-over was not allowed, the proportions of pts receiving pyrotinib, trastuzumab, pertuzumab, or anti-HER2 antibody-drug conjugate (incl. T-DM1, T-DXd, SHR-A1811) after study treatment discontinuation in each group were 18.5% vs. 51.9%, 26.3% vs. 25.6%, 15.5% vs. 14.0%, and 22.6% vs. 28.0%, respectively. At data cutoff, 85 deaths (28.6%) occurred in the PyroHT group and 108 (36.9%) in the HT group. OS was superior in the PyroHT group compared to the HT group (HR 0.74, 95% CI 0.56-0.98; nominal 1-sided P=0.0188). The median OS was not reached in either group. OS rates were 79.6% in the PyroHT group and 72.1% in the HT group at 3 years, 72.9% and 63.5% at 4 years, 65.7% and 58.5% at 5 years, respectively. As reported previously, consistent and prolonged benefit of investigator-assessed PFS in the PyroHT group was observed (HR 0.44, 95% CI 0.36-0.54; nominal 1-sided P<0.0001). The PFS rates were 40.4% in the PyroHT group and 9.7% in the HT group at 3 years, 31.9% and 7.6% at 4 years, 29.2% and 4.3% at 5 years, respectively. Additionally, the benefits in PFS with PyroHT were consistent across nearly all analyzed subgroups. For pts with prior (neo)adjuvant trastuzumab, median PFS was 62.8 months (95% CI 19.2-not evaluable) in the PyroHT group (n=46) vs 10.4 months (95% CI 6.4-13.2) in the HT group (n=42). Among pts who developed brain metastases, the median time to onset was 16.6 months (IQR 13-28) with PyroHT (n=34) compared to 9.1 months (IQR 8-14) with HT (n=30). Safety data cutoff was April 30, 2024. The incidence of all adverse events decreased considerably after docetaxel discontinuation. In the PyroHT group, the incidence of any grade diarrhea decreased from 98.4% (245/249) to 79.9% (199/249), and grade 3 diarrhea incidence declined from 46.2% (115/249) to 16.1% (40/249). No grade 4 or 5 diarrhea was reported.Conclusions: The long-term analysis confirms that the previously observed improvements in OS and PFS with PyroHT compared to HT in the first-line treatment of HER2-positive metastatic breast cancer were maintained after 45.5 months of median follow-up. Notably, with PyroHT, 5-year OS rate remained at 66% and nearly 30% of pts remained progression-free at 5 years. PyroHT treatment delayed time to onset of brain metastasis. It reinforces dual anti-HER2 regimen (pyrotinib plus trastuzumab) as an established therapeutic strategy for this patient population.

N. Masuda¹, S. Saji², Y. Kojima³, M. Kitada⁴, H. Tada⁵, T. Iwasa⁶, K. Koizumi⁷, H. Shigematsu⁸, Y. Sagara⁹, T. Okuno¹⁰, Y. Hasegawa¹¹, E. Tokunaga¹², T. Shien¹³, U. Toh¹⁴, T. Kuwayama¹⁵, M. Shimoda¹⁶, H. Hasegawa¹⁷, S. Morita¹⁸, T. Yamashita¹⁹; ¹Department of Breast Surgery, Graduate School of Medicine, Kyoto University, Kyoto, JAPAN, ²Department of Medical Oncology, Fukushima Medical University, Fukushima, JAPAN, ³Division of Breast Surgical Oncology, Department of Surgery, Showa Medical University Hospital, Tokyo, JAPAN, ⁴Department of Breast Disease Center, Asahikawa Medical University Hospital, Hokkaido, JAPAN, ⁵Division of Breast and Endocrine Surgery, Faculty of Medicine, Tohoku Medical and Pharmaceutical University, Miyagi, JAPAN, ⁶Department of Medical Oncology, Kindai University Hospital, Osaka, JAPAN, ⁷Department of Breast Surgery, Hamamatsu University Hospital, Shizuoka, JAPAN, ⁸Department of Breast Surgery, Hiroshima University Hospital, Hiroshima, JAPAN, ⁹Department of Breast and Thyroid Surgical Oncology, Social Medical Corporation Hakuaikai, Sagara Hospital, Kagoshima, JAPAN, ¹⁰Department of Breast Surgery, Kobe City Nishi-Kobe Medical Center, Hyogo, JAPAN, ¹¹Department of Breast Surgery, Hachinohe City Hospital, Aomori, JAPAN, ¹²Department of Breast Oncology, NHO Kyushu Cancer Center, Fukuoka, JAPAN, ¹³Department of Breast and Endocrine Surgery, Okayama University Hospital, Okayama, JAPAN, ¹⁴Department of Breast Surgery, Kurume University Hospital, Fukuoka, JAPAN, ¹⁵Department of Breast Surgery, Tokyo Metropolitan Cancer and Infectious Diseases Center Komagome Hospital, Tokyo, JAPAN, ¹⁶Department of Breast and Endocrine Surgery, Hyogo Medical University Hospital, Hyogo, JAPAN, ¹⁷Medical HQs, Eisai Co., Ltd., Tokyo, JAPAN, ¹⁸Department of Biomedical Statistics and Bioinformatics, Graduate School of Medicine, Kyoto University, Kyoto, JAPAN, ¹⁹Department of Breast Surgery and Oncology, Kanagawa Cancer Center, Kanagawa, JAPAN.

Background The randomized open-label phase 3 JBCRG-M06/EMERALD study (NCT03264547) was the first to show the non-inferiority of eribulin (E) to taxane (T) (docetaxel [DTX] or paclitaxel [PTX]) when combined with dual HER2 blockade as first-line chemotherapy for HER2+ locally advanced or metastatic breast cancer (LABC/mBC) (doi: 10.1200/JCO-24-01888). In the primary analysis results, median progression-free survival (PFS) was 14.0 and 12.9 months (mo) in the E and T groups, respectively (hazard ratio, 0.95). Although median treatment duration was longer with E (28.1 weeks) than with DTX or PTX (18.1 and 20.5 weeks, respectively), incidences of adverse events (AEs) were similar between the E and T groups. While DTX and PTX have some pharmacological similarities, their distinct properties may result in differences in therapeutic outcomes. We report the results of a post-hoc analysis in which outcomes were analyzed by type of T used and compared with those when E was used. Methods Patients (pts) with HER2+ LABC/mBC were randomized to receive E (1.4 mg/m² on days 1 and 8) or T (DTX 75 mg/m² on day 1 or PTX 80 mg/m² on days 1, 8, and 15), intravenously in a 21-day cycle, each with trastuzumab + pertuzumab. In the T group, the choice between DTX and PTX was determined by the attending physician, but it had to be declared in advance at the time of enrolment. The Kaplan-Meier method was used to assess survival outcomes, and the log-rank test for intergroup comparisons. Waterfall and swimmer plots were used to assess outcomes based on type of T used. Results Of the total 446 pts, 224 received E and 222 received T (DTX, n = 186; PTX, n = 36) (intention-to-treat population); 224 in the E group and 218 in the T group (DTX, n = 184; PTX, n = 34) received at least one dose of the study drug (safety analysis population). Baseline characteristics were well balanced between the groups. In the T group, pts treated with DTX or PTX had no differences in age or ECOG performance status. Survival outcomes were similar between pts who received DTX or PTX (Table 1A). Incidences of AEs were generally similar between the E and T groups, regardless of type of T used; however, a higher incidence of peripheral sensory neuropathy was noted with PTX whereas it was lower with DTX, compared with E. Additionally, the incidence of neutropenia tended to be lower with DTX (Table 1B). Conclusions In our trial comparing T and E combined with dual HER2 blockade as first-line treatment for HER2+ LABC/mBC, DTX and PTX were used to treat 84% and 16% of pts, respectively. No differences in efficacy (i.e. non-inferiority results) were observed based on type of T used. While AEs were generally similar between the E and T groups, regardless of type of T used, a higher incidence of peripheral sensory neuropathy was noted with PTX compared with E or DTX.

G. Rinnerthaler¹, S. P. Gampenrieder², A. Pichler³, W. Herz⁴, R. Pusch⁵, C. Dormann⁵, C. Suppan¹, M. Sandholzer⁶, T. Winder⁷, S. Heibl⁸, L. Scagnetti⁹, C. A. Schmitt¹⁰, A. F. Zabernigg¹¹, D. Egle¹², C. Hager¹³, P. Pichler¹⁴, F. Roitner¹⁵, J. Andel¹⁶, K. Strasser-Weippl¹⁷, R. Bartsch¹⁸, V. Castagnaviz², M. Hubalek¹⁹, M. Knauer²⁰, C. F. Singer²¹, R. Greil²²; ¹Division of Oncology, Department for Internal Medicine, Medical University Graz, Graz, AUSTRIA, ²Department of Internal Medicine III, Paracelsus Medical University Salzburg, Salzburg, AUSTRIA, ³Internal Medicine – Department for Haemato-Oncology, LKH Hochsteiermark, Leoben, AUSTRIA, ⁴Department of Surgery, Breast Health Center, LKH Hochsteiermark, Leoben, AUSTRIA, ⁵Internal Medicine I, Ordensklinikum Linz Barmherzige Schwestern – Elisabethinen, Linz, AUSTRIA, ⁶Department of Internal Medicine II, Academic Teaching Hospital Feldkirch, Feldkirch, AUSTRIA, ⁷Department of Internal Medicine III, Academic Teaching Hospital Feldkirch, Feldkirch, AUSTRIA, ⁸Department of Internal Medicine I, Klinikum Wels-Grieskirchen GmbH, Wels, AUSTRIA, ⁹Department of Internal Medicine IV, Klinikum Wels-Grieskirchen GmbH, Wels, AUSTRIA, ¹⁰Department for haematology and internal oncology, Kepler University Hospital Linz, Linz, AUSTRIA, ¹¹Department of Internal Medicine, County Hospital Kufstein, Kufstein, AUSTRIA, ¹²Department of Gynaecology, Medical University Innsbruck, Innsbruck, AUSTRIA, ¹³Breast Center, Breast Center Dornbirn, Dornbirn, AUSTRIA, ¹⁴Department for Internal Medicine 1, University Hospital St.Pölten, St. Pölten, AUSTRIA, ¹⁵Department of Internal Medicine II, Hospital Braunau, Braunau am Inn, AUSTRIA, ¹⁶Department of Internal Medicine II, Pyhrn-Eisenwurzen Klinikum Steyr, Steyr, AUSTRIA, ¹⁷Department of Medicine I, Clinic Ottakring, Vienna, AUSTRIA, ¹⁸Department of Medicine I, Division of Oncology, Medical University of Vienna, Vienna, AUSTRIA, ¹⁹Breast Health Center Schwaz, Department of Gynecology, Schwaz, AUSTRIA, ²⁰Breast Center, Tumor and Breast Center Eastern Switzerland, St. Gallen, SWITZERLAND, ²¹Department of Obstetrics and Gynecology and Comprehensive Cancer Center, Medical University of Vienna, Vienna, AUSTRIA, ²²Austrian Group Medical Tumor Therapy, AGMT gemeinnützige GmbH, Vienna, AUSTRIA.

Background: Based upon the CLEOPATRA trial, a combination of docetaxel plus trastuzumab and pertuzumab (THP) has been the standard treatment for patients with metastatic HER2-positive breast cancer. However, this standard has recently been challenged by the results of the DESTINY-Breast09 study, which compared trastuzumab-deruxtecan (T-DXd) plus pertuzumab with THP. In this analysis, we aimed to develop a risk model based on known parameters that identifies patients with a long first-line (1L) therapy duration, as these patients may not need 1L T-DXd therapy. Patients and Methods: The AGMT_MBC-Registry is a nationwide, multicenter, ongoing retrospective and prospective registry for metastatic breast cancer (MBC) patients in Austria. Patients with HER2-positive breast cancer treated with a 1L chemo, trastuzumab plus pertuzumab combination were included in this analysis. Time to next treatment (TTNT) was defined as the interval from initiation of 1L to the initiation of the next subsequent treatment line. To identify prognostic factors associated 1L TTNT a multivariable Cox proportional hazards model was performed. Clinical, demographic, and tumor-related covariates – including metastatic sites, age, hormone-receptor (HR) status, and tumor grade – were included in the analysis. Variable selection was performed using a bidirectional stepwise approach based on the Akaike Information Criterion. Patients with missing values were excluded. A risk score was derived from the linear predictor of the Cox model. Survival-optimized cut-off points were identified using maximally selected rank statistics to stratify patients into low-, intermediate-, and high-risk groups. Hazard ratios (HRs) with 95% confidence intervals (CIs) are reported. Time-to-event analyses were performed using Kaplan-Meier estimates, with group-specific survival probabilities reported at 12, 18, and 36 months. Results: As of March 11, 2025, the registry included 3,094 patients, and 218 patients with HER2-positive MBC were available for this analysis. Median age at diagnosis of MBC was 58 years (range 26-85) and 62% had hormone receptor (HR) positive disease. Bone (57%), liver (43%), and lung metastases (35%) were the most common metastatic sites; brain, pleural, and peritoneal metastases were rare (<5%). At diagnosis, 63% had de novo MBC, 31% had recurrence ≥24 months, and 6% <24 months after surgery. The final multivariable Cox model identified the presence of brain (HR 2.22, p = 0.038), pleural metastases (HR 3.41, p = 0.001), disease-free survival < 24 months (HR 1.98, p=0.046), and older age (HR 1,01 per year, p = 0.043) as significant predictors for a shorter TTNT. Lung metastasis (HR 1.36, p = 0.089) showed a trend toward shorter treatment duration. Based on the risk score, patients were stratified into low- (27%, n = 56), intermediate- (62%, n = 127), and high-risk groups (10%, n = 21). Compared to the low-risk group, TTNT was shorter in the intermediate-risk group (HR 1.79, 95% CI 1.17-2.74; p = 0.007) and in the high-risk group (HR 5.39, 95% CI 2.95-9.86; p < 0.001). In the high-risk group, treatment continuation rates were 45% (95% CI 28-73%) at 12 months, 17% at 18 months, and 6% at 36 months, respectively. In the intermediate-risk group, corresponding rates were 74% (95% CI 67-82%), 63%, and 36%; and in the low-risk group, 84% (95% CI 74-94%), 65%, and 50%, respectively. Conclusion: This real-world analysis identified distinct clinical subgroups of patients with HER2-positive MBC who are at low risk for early 1L treatment discontinuation under the current standard CLEOPATRA regimen. The proposed risk model enables prognostic stratification and may help identify patients who do or do not need an alternative 1L approach, such as T-DXd-based combinations. External validation of the score in independent cohorts is warranted.

J. Albanell¹, J. García-Sáenz², B. Bermejo³, A. Stradella⁴, Y. Izarzugaza⁵, A. Barnadas⁶, E. Alba⁷, J. Alonso-Romero⁸, S. López-Tarruella⁹, F. Henao-Carrasco¹⁰, S. Zazo¹¹, F. Moreno¹², M. Martínez-Martínez¹³, A. Vethencourt⁴, H. Callata-Carhuapoma⁵, J. Herranz¹⁴, R. Caballero¹⁵, M. Portela¹⁵, F. Rojo¹⁶; ¹Medical Oncology, Hospital del Mar-Hospital del Mar Research Institute ; CIBERONC-ISCIII; GEICAM Spanish Breast Cancer Group, Barcelona, SPAIN, ²Medical Oncology, Hospital Clínico San Carlos (HCSC), Instituto de Investigación Sanitaria (IdISSC); CIBERONC-ISCIII; GEICAM Spanish Breast Cancer Group, Madrid, SPAIN, ³Medical Oncology, Hospital Clínico Universitario de Valencia;Biomedical Research Institute INCLIVA; GEICAM Spanish Breast Cancer Group, Valencia, SPAIN, ⁴Medical Oncology, Breast Unit, Catalan Institute of Oncology-Hospital Universitari de Bellvitge-Bellvitge Research Institute (IDIBELL); GEICAM Spanish Breast Cancer Group, Hospitalet de Llobregat, SPAIN, ⁵Medical Oncology, Hospital Universitario Fundación Jiménez Díaz; GEICAM Spanish Breast Cancer Group, Madrid, SPAIN, ⁶Medical Oncology, Hospital de la Santa Creu i Sant Pau; GEICAM Spanish Breast Cancer Group, Barcelona, SPAIN, ⁷Medical Oncology, Hospital Universitario Virgen de la Victoria; GEICAM Spanish Breast Cancer Group, Málaga, SPAIN, ⁸Medical Oncology, Hospital Clínico Universitario Virgen de la Arrixaca, (IMIB-Arrixaca), Universidad de Murcia; GEICAM Spanish Breast Cancer Group, El Palmar, SPAIN, ⁹Medical Oncology, Hospital General Universitario Gregorio Marañón, Instituto de Investigación Sanitaria Gregorio Marañón (IiSGM), Universidad Complutense; GEICAM Spanish Breast Cancer Group, Madrid, SPAIN, ¹⁰Medical Oncology, Hospital Universitario Virgen Macarena; GEICAM Spanish Breast Cancer Group, Sevilla, SPAIN, ¹¹Medical Oncology, Hospital Universitario Fundacion Jimenez Diaz; GEICAM Spanish Breast Cancer Group, Madrid, SPAIN, ¹²Medical Oncology, ospital Clínico San Carlos (HCSC), Instituto de Investigación Sanitaria (IdISSC); GEICAM Spanish Breast Cancer Group, Madrid, SPAIN, ¹³Medical Oncology, Hospital Clínico Universitario de Valencia. Biomedical Research Institute INCLIVA; GEICAM Spanish Breast Cancer Group, Valencia, SPAIN, ¹⁴Statics department, GEICAM Spanish Breast Cancer Group, Madrid, SPAIN, ¹⁵Translational, GEICAM Spanish Breast Cancer Group, Madrid, SPAIN, ¹⁶Pathology, Hospital Universitario Fundacion Jimenez Diaz; CIBERONC-ISCIII; GEICAM Spanish Breast Cancer Group, Madrid, SPAIN.

Background: T-DM1 remains a relevant therapeutic option for patients with HER2-positive metastatic breast cancer (HER2+ MBC), particularly for those who have previously received trastuzumab and taxane-based therapies. However, despite its clinical utility, the mechanisms underlying both primary and acquired resistance to T-DM1 remain largely uncharacterized, limiting the ability to optimize treatment strategies and identify patients most likely to benefit from this therapy. The aim was to characterize the mechanisms of resistance to T-DM1 in the KATIA study.Methods: The KATIA study (NCT03829306) was a prospective, multicenter study in progressive/recurrent HER2+ MBC patients treated with second-line T-DM1. Tumor and plasma samples were collected from 32 (100%) patients. Genomic profiling was performed on pre-treatment baseline (BL) metastatic tumors (n=18, 56%), and on liquid biopsies at BL (n=20, 62,5%) and at disease progression (n=12, 37,5%) using the FoundationOne CDx and FoundationOne liquid CDx assays (324-gene NGS panels; Foundation Medicine). Additionally, we analyzed a 77-gene NGS panel on circulating tumor DNA (AVENIO ctDNA Expanded Kit V2, Roche, n=31, 97%). HER2, Ki67, Estrogen and Progesterone Receptors (ER and PR) status and the tumor immune microenvironment markers (PD-L1, PD1, CD3, CD8, tumor-infiltrating lymphocytes) were analyzed on BL tumors (n=26, 81%) by immunohistochemistry (IHC). The Kaplan-Meier method estimated median progression free survival (PFS) and overall survival (OS). Hazard ratios (HR) with 95% confidence intervals (CIs) were calculated using Cox proportional hazards regression models and the p-values adjusted for multiple comparisons by the Bonferroni method.Results: Tumor BL mutations in CCDN1, FGF4 or FGF19 predicted better mPFS (CCDN1: 8.61 vs. 3.65 m., HR 0.19; 95% CI 0.04-0.92, p=0.039; FGF4: 8.77 vs. 3.84 m., HR 0.1; 95% CI 0.01-0.79, p=0.0298; FGF19: 8.61 vs. 3.65m., HR 0.19; 95% CI 0.04-0.92, p=0.039). On the contrary, GNAS mutations showed a trend towards worse mOS (6.67 vs. 17.45 m., HR 4.63; 95% CI 0.42-51.09, p=1). Tumor burden ctDNA analyses revealed that the presence of ≥3 BL mutations showed a trend towards worse mOS (14.23 vs. 22.87 m., HR 2.85; 95% CI 0.91-10.01, p=0.1032). BL ctDNA mutations in PIK3CA/TP53 (the most frequent mutated genes) also showed a trend towards worse mOS (14.55 vs. 22.87 m., HR 4.78; 95% CI 0.56-40.89, p=1), as well as mutations detected in the following signaling pathways: receptor tyrosine kinases (RTKs: 14.55 vs. 22.87 m., HR 3.15; 95% CI 0.62-16, p=1) and DNA damage response/TP53 (DDR/TP53: 14.55 vs. 22.87 m., HR 4.98; 95% CI 0.59-42.32, p=1). Similar results were observed for mutations detected in these pathways at the time of disease progression. Conclusions: Baseline tumor mutations in CCDN1, FGF4 or FGF19 genes were significantly associated with longer PFS in HER2+ MBC patients treated with second line T-DM1, suggesting their potential role as predictive biomarkers of treatment benefit.

A. Ravichandran¹, M. Hennessy², J. Q. Freeman³, S. Poland², W. Guo², R. Nanda²; ¹Internal Medicine Residency Program, University of Chicago Medicine, Chicago, IL, ²Section of Hematology & Oncology, Department of Medicine, University of Chicago, Chicago, IL, ³Department of Public Health Sciences, University of Chicago, Chicago, IL.

Background: Outcomes for patients with de novo metastatic human epidermal growth factor receptor 2 (HER2)-positive breast cancer have dramatically improved due to advances in HER2-directed therapy, yet significant disparities persist, with Black and Hispanic patients presenting with more advanced stage disease and experiencing worse survival outcomes compared to White patients. Studies suggest racial and ethnic minorities experience longer delays in treatment initiation, however large, comprehensive analyses of the impact of sociodemographic and clinical factors at the national level in the U.S. remain limited. Methods: We retrospectively identified patients diagnosed with de novo metastatic HER2-positive breast cancer between 2010 and 2022 using the National Cancer Database (NCDB). Clinical and sociodemographic characteristics were collected and compared across racial and ethnic groups. We categorized systemic therapy as chemotherapy alone or chemotherapy plus HER2-directed therapy. Treatment receipt and time to treatment initiation were evaluated by race/ethnicity. Multivariable linear regression was performed to examine sociodemographic differences in time to initiation of systemic and localized (i.e., radiotherapy) therapies, respectively. Beta coefficients reflected adjusted differences in treatment timing, with 95% confidence intervals (95% CI) reported. Results: A total of 27,972 patients with de novo metastatic HER2-positive breast cancer were included. Mean age was 58.8 years; 69.0% were White, 17.5% Black, 7.8% Hispanic, and 4.6% Asian/Pacific Islander (per self-report). At initial presentation, 9.5% had brain metastases, and 58.2% had visceral metastases. At the time of diagnosis, Black and Hispanic patients were younger, more often uninsured or Medicaid-insured, and more likely to reside in lower-education, lower-income areas (p<0.001). While overall 88.5% of patients received a combination of chemotherapy and HER2-directed therapy, significant delays in treatment initiation were observed across all treatment modalities in minority groups. For systemic therapy, mean initiation times for Asian/Pacific Islander, White, Black, and Hispanic patients were 46.2 days, 47.2 days, 54.6 days, and 57.2 days, respectively (p<0.001). Time to systemic therapy was significantly reduced in patients with visceral metastases, while brain metastases were associated with earlier radiation initiation (median 28 days to initiation in patients with brain metastases vs. 116 days in patients without brain metastases, p<0.001). Adjusted analyses revealed that on average, Hispanic ethnicity was associated with a 7.3 day (95% CI: 3.2-11.4) delay in starting systemic therapy and 23.0 day (95% CI: 9.0-36.9) delay for radiotherapy initiation. Compared to White patients, Black patients had a 5.7 day (95% CI: 2.9-8.6) delay in starting systemic therapy and Asian/Pacific Islander patients had a 21.0 day (95% CI: 4.9-37.2) delay in starting radiotherapy. Lower education levels, lack of insurance, or having Medicaid/Medicare were also independent predictors of delayed initiation of systemic therapy, but interestingly not radiotherapy. Conclusion: In this U.S. national sample of patients with de novo metastatic HER2-positive breast cancer, substantial disparities persist in timely treatment initiation, particularly among Black and Hispanic patients, even after controlling for sociodemographic and clinical factors. Delays in this setting may adversely affect survival outcomes, highlighting the urgency of improving equitable access to care. Efforts must focus on enhancing health literacy, expanding insurance coverage, and improving care coordination infrastructure in disadvantaged communities.

R. Sanchez-Bayona¹, S. Cobo², M. Kubeczko³, J. Soberino⁴, M. Rey⁵, B. Pycinski⁶, E. Chmielik⁷, J. Montes¹, F. Pardo⁸, V. Sirenko⁵, P. Galván⁹, A. Lesniak³, M. Oczko-Wojciechowska¹⁰, I. Monge¹¹, M. Gonzalez¹², I. Garcia-Fructuoso¹², F. Schettini¹², G. Villacampa¹³, T. Pascual¹², L. Paré⁸, F. Brasó-Maristany⁹, E. Ciruelos¹, A. Prat¹⁴, M. Jarzab³; ¹Medical Oncology, Hospital Universitario 12 de Octubre. Instituto de Investigacion Sanitaria Hospital 12 de Octubre (imas12), Madrid, SPAIN, ²Bioestatistics, Fundació de Recerca Clínic Barcelona – IDIBAPS, Barcelona, SPAIN, ³Breast Cancer Center, Maria Sklodowska-Curie National Research Institute of Oncology, Gliwice, POLAND, ⁴Medical Oncology, IOB- QuirónSalud, Barcelona, SPAIN, ⁵Medical Oncology, Fundació de Recerca Clínic Barcelona – IDIBAPS, Barcelona, SPAIN, ⁶Medical Oncology, Silesian University of Technology, Faculty of Biomedical Engineering, Zabrze, POLAND, ⁷Tumor Pathology Department, Maria Sklodowska-Curie National Research Institute of Oncology, Gliwice, POLAND, ⁸Diagnostic, REVEAL Genomics, Barcelona, SPAIN, ⁹Translational Genomics and Targeted Therapies in Solid Tumors Lab, Fundació de Recerca Clínic Barcelona – IDIBAPS, Barcelona, SPAIN, ¹⁰Department of Clinical and Molecular Genetics, Maria Sklodowska-Curie National Research Institute of Oncology, Gliwice, POLAND, ¹¹Department of Hospital Pharmacy, Hospital Clinic of Barcelona, Barcelona, SPAIN, ¹²Medical Oncology, Hospital Clinic of Barcelona, Barcelona, SPAIN, ¹³Statistics Unit, REVEAL Genomics, Barcelona, SPAIN, ¹⁴Medical Oncology, Hospital Clinic of Barcelona. Translational Genomics and Targeted Therapies Group, IDIBAPS, Barcelona, SPAIN.

Background: The Central nervous system (CNS) is a frequent and clinically significant site of progression in advanced HER2-positive (HER2+) breast cancer. Identifying patients at high risk for CNS progression could inform more personalized surveillance and therapeutic strategies. Prior work has demonstrated the prognostic value of the HER2DX ERBB2 mRNA score in this setting (NPJ Breast Cancer 2025; SABCS 2024). In addition, the HER2DX metastatic prognostic score—an integrated model combining ERBB2 with additional molecular signatures—was developed to predict overall survival (SABCS 2025, submitted). Here, we report the development and validation of the HER2DX CNS progression score, a distinct genomic tool specifically designed to predict the risk of brain metastasis.Methods: Transcriptomic data were analyzed from 215 patients with HER2-positive advanced breast cancer treated with first-line trastuzumab, pertuzumab, and chemotherapy (THP), including 93 cases from Spain and 122 from Poland. All tumor samples were profiled using the standardized HER2DX gene expression platform. Biological features associated with CNS progression were explored in the combined cohort, and a genomic score was developed using key signatures. Coefficients were derived in the Spanish cohort, and the final score was validated in the Polish cohort. Associations with CNS progression and overall survival were estimated using Cox models and Kaplan-Meier curves.Results: In the combined cohort (n=215), the median follow-up was 37.1 months. A total of 53 patients (24.8%) developed brain metastases. No significant differences in CNS progression rates (27.2% and 23.0%) or time to CNS progression (hazard ratio [HR] 0.90, 95% CI 0.51-1.56, p=0.70) were observed between cohorts. Clinical variables associated with CNS progression included younger age and having ≥3 metastatic sites. In contrast, hormone receptor status, HER2 IHC (3+ vs other), menopausal status, biopsy site (primary vs. metastatic), bone disease, and best overall response to THP were not associated with brain metastasis.HER2DX assay identified 3 main genomic patterns associated with CNS progression: (1) HER2DX ERBB2 expression and lower time to CNS progression, (2) HER2DX luminal score and longer time to CNS progression, and (3) a new HER2DX immune-related signature associated with longer time to CNS progression. In the Spanish set, the 3-year cumulative incidence of CNS progression was 42.8% in the HER2DX CNS progression high-risk group vs. 24.9% in the intermediate-risk group vs. 15.5% in the low-risk groups (HR between low vs high 0.32, 0.11-0.90, p=0.032); in the Polish set, the 3-year cumulative incidence of CNS progression was 39.2% in the HER2DX CNS progression high-risk group vs. 13% in the intermediate-risk group vs. 4.3% in the low-risk groups (HR between HER2DX low vs high groups of 0.11, 0.02-0.83, p=0.033). Importantly, the HER2DX CNS progression score was not associated with PFS or OS, confirming its specificity for CNS progression. Conversely, the HER2DX metastatic prognostic score (submitted to SABCS 2025) was not associated with CNS progression, and the two scores were uncorrelated (Pearson r=-0.049).Conclusions: The HER2DX CNS progression score is a novel, biology-informed genomic tool that independently predicts brain metastasis in HER2+ advanced breast cancer treated with first-line THP. These findings support its potential integration into clinical workflows to personalize CNS surveillance and treatment strategies.

G. Griguolo¹, M. Bottosso¹, G. Landa¹, G. Bonomi¹, F. Miglietta¹, M. Guarascio¹, M. La Commare¹, F. Zanghì¹, C. Giorgi², C. Falci², C. Hodgdon³, M. Dieci¹, V. Guarneri¹; ¹Department of Surgery, Oncology and Gastroenterology – University of Padova, Oncology 2, Istituto Oncologico Veneto IRCCS, Padova, ITALY, ²Oncology 2, Istituto Oncologico Veneto IRCCS, Padova, ITALY, ³GRASP, GRASP, Baltimore, MD.

Background: According to recent EANO-ESMO guidelines, proactive brain imaging can be considered in asymptomatic patients (pts) with HER2+ metastatic breast cancer (mBC), due to high risk of developing brain metastases (BMs), with the aim of detecting brain involvement before the development of impactful symptoms. However, no clear evidence to guide the use of a specific radiological technique and timing for brain screening is currently available. After changes in EANO-ESMO guidelines, several oncologists in Italy have started to pragmatically include brain evaluation in CE CT scans performed to re-evaluate HER2+ mBC (traditionally only including thorax/abdomen). However, we lack data regarding the potential impact of this strategy in reducing the frequency of symptomatic BM diagnosis. We here retrospectively assess the impact of brain screening using CE CT scans on incidence of symptomatic BMs in HER2+ mBC pts. Methods: All consecutive pts newly diagnosed with HER2+ mBC and treated with trastuzumab-pertuzumab plus taxane at a single center (2014-2024) were retrospectively identified. Pts with symptomatic BMs at first mBC diagnosis or lacking complete imaging data regarding the first 2 years from mBC diagnosis were excluded. Pts were classified as having undergone brain screening if at least one CE brain CT scan per year was performed in absence of neurological symptoms during the first 2 years following mBC diagnosis, by clinical practice of treating oncologist. Results: Overall, 148 pts were identified: 73 underwent brain screening during the 2-year observation period and 75 did not. Both subgroups represented similar clinicopathological features at mBC diagnosis, including Karnofsky Performance Status (KPS). As expected, patients who underwent brain screening were diagnosed more recently and had a significantly shorter median follow-up from mBC diagnosis (3.0 versus 5.9 years, p<0.001). Median number of brain CT scans per year in asymptomatic pts (during the first 2 years) was 2.0 (IQR 1.2-2.5) and 0.0 (IQR 0.0-0.5) in the screening and non-screening groups, respectively. Thirty pts (20.3%) developed BMs during the first 2 years. Cumulative incidence of BMs at 2-years was significantly higher in pts undergoing screening (vs not) (30.6% vs 12.3%, Gray’s p=0.004). However, cumulative incidence of symptomatic BMs at 2-years was significantly lower in pts undergoing screening (vs not) (0% vs 9.5%, Gray’s p=0.012). Moreover, pts undergoing screening presented a significantly more conserved performance status (KPS 90-100 for 71.4% of pts vs 11.1%, respectively; p=0.002) and a numerical trend toward a lower number of BMs at BM diagnosis (52.4% diagnosed with >3 BMs vs 88.9%, p=0.057). No significant difference in locoregional and systemic treatments administered after BM diagnosis was observed, although whole-brain radiotherapy (WBRT) was less frequently used in pts undergoing screening (14.3% vs 44.4%, p=0.073). Median OS from BM diagnosis was numerically longer in pts undergoing screening (28.6 vs 7.5 months, p=0.192). Conclusions: Brain screening with CT scans is associated with a significantly lower incidence of symptomatic BMs and with a significantly more conserved KPS at BM diagnosis in this retrospective real-world cohort of HER2+ mBC pts treated with pertuzumab-trastuzumab and taxane. These findings support the use of proactive brain imaging for pts with HER2+ mBC. Confirmatory prospective studies are needed to optimize surveillance timing and radiological techniques in this setting.

T. Sanglier¹, I. Gravestock¹, J. Leone², M. Secrest³, C. Tchakoute³, E. Restuccia⁴, F. Montemurro⁵, M. Shivhare⁶, A. Knott⁷, P. Lambert³, D. Martinez⁸, P. Luhn⁹, X. Garcia de Albeniz Martinez¹⁰, S. Tolaney², N. Lin², S. Sammons²; ¹Real World Data Science, F. Hoffmann-La Roche Ltd, Basel, SWITZERLAND, ²Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, ³Real World Data Science, Genentech, Inc., South San Francisco, CA, ⁴Product Development Oncology, F. Hoffmann-La Roche Ltd, Basel, SWITZERLAND, ⁵Product Development Oncology, HER2 positive breast cancer franchise, F. Hoffmann-La Roche Ltd, Basel, SWITZERLAND, ⁶HER2+ Franchise, Roche Products Limited, Welwyn Garden City, UNITED KINGDOM, ⁷Product Development, Clinical Science Oncology, Roche Products Limited, Welwyn Garden City, UNITED KINGDOM, ⁸RTI-HS, RTI Health Solutions, Barcelona, SPAIN, ⁹Real World Data Oncology, Genentech, Inc., South San Francisco, CA, ¹⁰Epidemiology, RTI Health Solutions, Barcelona, SPAIN.

Background: Maintenance endocrine therapy (mET) is increasingly used as part of the post-chemotherapy treatment for HER2-positive, hormone receptor-positive metastatic breast cancer (HER2+, HR+ mBC). However, the impact of mET on delaying brain metastases (BM) and other clinical outcomes is unclear. As the time from taxane completion to mET initiation can vary considerably, standard cohort methods with fixed index dates can lead to immortal time and selection bias. This study estimates the effect of different mET treatment strategies (TS) on BM-free survival (BMFS), overall survival (OS), and real-world progression-free survival (rwPFS) in patients (pts) with HER2+, HR+ mBC without BM. Methods: The study used the Flatiron Health database (January 2011-September 2024). mET included aromatase inhibitors, selective estrogen receptor degraders or modulators, and ovarian function suppression. Our target trial compared four TS in pts with HER2+, HR+ mBC who had completed ≥5 cycles of 1L HER2-targeted therapy + taxane (baseline was last taxane administration): Arm 1: mET initiation within 3 months (mo) of baseline; Arm 2: no mET initiation within 3 mo of baseline (initiation was possible afterwards); Arm 3: no mET initiation within 60 mo of baseline; and Arm 4: mET initiation between 4-6 mo of baseline. In all TS, CDK4/6 inhibitor use was not permitted and pts who initiated 2L treatment/had a BMFS/OS/rwPFS event were excluded from the TS. In the target trial emulation (TTE), pts were assigned to all TS with which their baseline data were compatible, creating four clones (TS were not distinguishable at baseline), and were censored upon deviation from the assigned TS. BMFS, OS, rwPFS were measured up to 60 mo from last taxane administration (LTA); risk differences and risk ratios were estimated via pooled logistic regression adjusted for baseline confounders (de novo vs. recurrent disease, disease-free interval, treatment at an academic center, Roche Prognostic Score, last HR test being negative despite prior positive tests). Estimates were bounded with percentile-based 95% confidence intervals (CI) estimated via bootstrapping. Sensitivity analyses included changes in grace period, time discretization, functional form of time, censoring of early death events, and simulation of uniform initiation of TS. Results: The TTE (N = 784) evaluated 391 pts who received ET within 3 mo and 393 pts who did not receive ET within 3 mo. At the time of taxane completion, baseline characteristics were generally balanced between pt groups, except ET pts were more likely to be treated in an academic center (25.8% vs. 17.3%) and less likely to have a negative latest HR test (3.6% vs. 12.7%). The difference in the risk of death (95% CI) comparing Arm 1 vs. Arm 3 was -3.2% (-5.6, -0.8) at 12 mo and -6.5% (-10.9, -1.7) at 24 mo (negative estimates favor Arm 1). The corresponding risk differences for rwPFS were -6.8% (-16.0, 0.9) and -10.1% (-20.3, -1.9), and for BMFS, -2.0% (-8.9, 4.7) and -4.7% (-13.0, 2.8). Treatment effect estimates were less precise beyond 36 mo due to loss to follow-up. Similar estimates were found against other TS, although the limited number of pts with data compatible with Arm 4 yielded imprecise estimates. Conclusions: Early mET within 3 mo of LTA was associated with improved clinical outcomes in pts with HER2+, HR+ mBC (although the limited number of BMFS events and modest estimates prevent making any firm conclusions). The TTE framework for comparative effectiveness studies with flexible treatment initiation helps align real-world data with randomized clinical trials, supporting better design of real-world data studies including comparisons of TS that can inform clinical practice.

S. Reganti¹, R. Choksi², F. Kudrik³, D. Patt⁴, S. Reddy¹, S. Rosenfeld⁵, D. Parris⁶, G. Rahimi⁶, A. Rui⁶, M. Gart⁶, C. Wall⁶, B. Wang⁶, P. Varughese⁶, J. Donegan⁶, L. Morere⁶, R. Geller⁶, J. Scott⁶, V. Gorantla²; ¹Medical Oncology, Cancer Care Specialists, Reno, NV, ²Medical Oncology, University of Pittsburgh Medical Center (UPMC), Pittsburgh, PA, ³Medical Oncology, South Carolina Oncology Associates, Columbia, SC, ⁴Medical Oncology, Texas Oncology, Austin, TX, ⁵Medical Oncology, Highlands Oncology Group (HOG), Fayetteville, AR, ⁶PrecisionQ, IntegraConnect, West Palm Beach, FL.

Background: Trastuzumab deruxtecan (T-DXd) is an antibody-drug conjugate (ADC) approved for the treatment of metastatic HER2-positive (HER2+) breast cancer in the second-line of therapy or later and has shown significant improvements in progression-free and overall survival (OS) in this population. However, T-DXd is also associated with gastrointestinal toxicities, including nausea and vomiting, which can adversely affect quality of life and treatment adherence. While antiemetic guidelines recommend the use of combination prophylaxis for agents with moderate to high emetogenic potential, there is limited evidence on whether antiemetic strategies themselves impact treatment duration and survival outcomes in oncology patients (pts) receiving T-DXd. This real-world study investigates the potential association between antiemetic regimen choice and OS in metastatic HER2+ breast cancer pts initiating T-DXd therapy. Methods: The IntegraConnect PrecisionQ de-identified electronic health record database, consisting of >3 million cancer pts across >500 care sites, was used to conduct a retrospective cohort study of 540 pts with metastatic HER2+ breast cancer who initiated trastuzumab deruxtecan between December 20, 2019 and October 31, 2024. Pts were stratified by their antiemetic regimen within 7 days of T-DXd initiation: Group 1 (n=251) received 5HT3 receptor antagonist + dexamethasone and Group 2 (n=289) received NK1 receptor antagonist + 5HT3 receptor antagonist + dexamethasone. Real-world overall survival (rwOS) and time to treatment discontinuation or death (TTD) were assessed using Kaplan-Meier analysis starting from the time of T-DXd initiation. Multivariable Cox proportional hazards models were used to adjust for potential confounders including age at diagnosis, race, Eastern Cooperative Oncology Group (ECOG) performance status, and line of therapy. Results: Baseline demographics were balanced between groups. Median age at diagnosis was 54 years for Group 1 and 55 years for Group 2; median age at T-DXd initiation was 61 years for Group 1 and 62 years for Group 2. Both groups were predominantly White (60.2% in Group 1 and 66.4% in Group 2). Median TTD (16.0 vs. 11.0 months (log-rank P< 0.01) and median rwOS (35.7 vs. 19.2 months (log-rank P<0.01) were significantly longer in Group 2 (NK1-based regimen) compared to Group 1 (5HT3 + dexamethasone). The probability of remaining on treatment at 12, 24, and 36 months was higher in Group 2: 12 months: 63% vs. 48%, 24 months: 38% vs. 20%, 36 months: 27% vs. 8%. Similarly, estimated survival at 12, 24, and 36 months was higher in Group 2: 12 months: 83% vs. 71%, 24 months: 60% vs. 42%, 36 months: 48% vs. 29%. On multivariable analysis, receipt of the NK1-containing regimen was associated with a 40% reduced risk of discontinuation or death (hazard ratio: 0.60, 95% CI: 0.45-0.80; P<0.01) compared to the 5HT3 + dexamethasone group, independent of other covariates. Poorer ECOG performance status was associated with increased likelihood of discontinuing T-DXd and worse survival. Conclusion: Among pts with metastatic HER2+ breast cancer treated with T-DXd, the use of a 3-drug antiemetic regimen including a NK1 receptor antagonist + 5HT3 receptor antagonist + dexamethasone was associated with significantly longer treatment persistence which seems to translate to improved OS compared with a 2-durg antiemetic regimen of a 5HT3 receptor antagonist + dexamethasone. These findings suggest that optimization of supportive care strategies may have survival implications and merit further evaluation/prospective validation.

V. Gorantla¹, R. Choksi¹, F. Kudrik², D. Patt³, S. Reddy⁴, S. Reganti⁴, S. Rosenfeld⁵, G. Cioffi⁶, T. Sura⁶, D. Parris⁶, A. Rui⁶, M. Gart⁶, C. Wall⁶, B. Wang⁶, P. Varughese⁶, J. Donegan⁶, L. Morere⁶, R. Geller⁶, J. Scott⁶, R. Mahtani⁷; ¹Medical Oncology, University of Pittsburgh Medical Center (UPMC), Pittsburgh, PA, ²Medical Oncology, South Carolina Oncology Associates, Columbia, SC, ³Medical Oncology, Texas Oncology, Austin, TX, ⁴Medical Oncology, Cancer Care Specialists, Reno, NV, ⁵Medical Oncology, Highlands Oncology Group (HOG), Fayetteville, AR, ⁶PrecisionQ, IntegraConnect, West Palm Beach, FL, ⁷Medical Oncology, Miami Cancer Institute, Baptist Health South Florida, Miami, FL.

Background: Brain metastases (BrM) are a frequent and clinically challenging manifestation of HER2-positive (HER2+) metastatic breast cancer (mBC), affecting up to 50% of patients (pts) over the course of their disease. Current guidelines recommend trastuzumab deruxtecan (T-DXd) as the preferred second-line therapy for HER2+ mBC overall, while the combination of tucatinib, trastuzumab, and capecitabine (TTC) remains an important option for pts with active or progressing BrM disease due to its proven intracranial activity. However, there is a lack of real-world data comparing treatment outcomes with these regimens specifically among pts with BrM involvement. This study evaluates real-world time to next treatment (TTNT) in pts with prior HER2+ therapy and documented BrM treated with second-line T-DXd vs TTC. Methods: We used the IntegraConnect PrecisionQ de-identified electronic health record database, which includes data on over 3 million cancer pts across more than 500 care sites, to identify individuals with HER2+ mBC who received either T-DXd or TTC as second-line therapy on or after January 1, 2020. Eligible pts had documented BrM prior to initiating second-line treatment. HER2+ status was inferred based on receipt of at least one HER2-targeted therapy during first-line metastatic treatment. Individuals who received T-DXd in their first-line of metastatic therapy were excluded from the analysis. The index date was defined as the start of second-line therapy with either TTC or T-DXd. Descriptive statistics were used to summarize demographic and clinical characteristics by treatment group, including age at index date, race, ethnicity, health insurance, BMI, ECOG performance status, estrogen receptor status, first-line metastatic regimen (grouped as ado-trastuzumab emtansine, trastuzumab (H) +pertuzumab (P) + taxane, endocrine therapy +/- HP, or other regimens), and presence of liver, bone, or lung metastases. TTNT was analyzed using Kaplan-Meier survival curves, with median estimates reported. Multivariable Cox proportional hazards regression was used to evaluate the association between treatment and TTNT, adjusting for the aforementioned demographic and clinical covariates. Hazard ratios (HRs) and corresponding 95% confidence intervals (CIs) are presented. Results: A total of 255 pts met study eligibility, of whom 138 (54%) received T-DXd as second-line therapy. Pts treated with T-DXd were slightly older than those who received TTC (median age: 58 vs 55 years; Wilcoxon p=0.026). A lower proportion of pts in the T-DXd group were classified as overweight (BMI 25-30) compared to the TTC group (17% vs 29%; chi-square p=0.026). No other significant differences in demographic or clinical characteristics were observed between treatment groups. Median TTNT was significantly longer among pts who received T-DXd compared to TTC (17 vs 11 months; log-rank p=0.006). This difference remained significant after adjustment for demographic and clinical covariates, with T-DXd associated with a 48% reduced likelihood of requiring subsequent therapy (HR: 0.52; 95% CI: 0.37-0.74; p<0.001). Conclusions: In this real-world analysis of pts with prior HER2+ therapy and documented BrM, second-line treatment with T-DXd was associated with significantly longer TTNT compared to TTC among pts with BrM. These findings may help inform treatment decisions in this high-risk population. However, interpretation is limited by the retrospective design, potential selection bias, and the use of treatment patterns to infer HER2 status. Most importantly, granular clinical data on BrM, including prior local therapies (radiation and/or surgery) and CNS-specific outcomes, were unavailable. Further prospective studies are needed to validate these findings.

H. Lv¹, S. Wang², Y. Song³, L. Niu¹, M. Zhang¹, Z. Liu¹, J. Wu¹, X. Sun¹, Y. Cui¹, J. Wang¹, Y. Feng¹, H. Sun¹, J. Huang², J. Zhang², L. Wang¹, M. Lv³, H. Zeng¹, S. Chen¹, M. Yan¹; ¹Department of Breast Disease, Henan Breast Cancer Center, Affiliated Cancer Hospital of Zhengzhou University, Zhengzhou, CHINA, ²Cancer Center, Sun Yat-sen University, Guangzhou, CHINA, ³Breast Disease Center, The Affiliated Hospital of Qingdao University, Qingdao, CHINA.

Background: While novel HER2-targeted agents (including TKIs and ADCs) have demonstrated intracranial activity in HER2 positive (HER2 +) metastatic breast cancer (MBC) with active brain metastases (BM), effective management of TKI- and/or ADC-refractory disease remains an ongoing clinical challenge. Building on preclinical evidence of utidelone’s superior blood-brain barrier penetration and bevacizumab’s established anti-edema effects, we conducted this phase II study (NCT05357417) evaluating the combination in TKI-progressed HER2+ BM patients. Methods: This multicenter, two-cohort, single-arm phase II trial (NCT05357417) enrolled adult patients (≥18 years) with breast cancer who had brain metastases, either radiotherapy-naïve or with documented progression following prior radiotherapy. The results from HER2-negative cohort (U-BOMB study) have been completed and published [Yan M, et al. JAMA Oncol, 2025 Jun 26; e251694]. Here we present the preliminary findings from HER2-positive cohort (U-BOMB-HER) of patients with HER2-positive breast cancer who developed progressive brain metastases following treatment failure with trastuzumab and TKI . Patients received utidelone (30 mg/m² IV on days 1-5) plus bevacizumab (15 mg/kg IV on day 1) every 3 weeks until disease progression or intolerance. The primary endpoint was central nervous system (CNS) objective response rate (CNS-ORR) as assessed by Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1), with secondary endpoints including CNS disease control rate (CNS-DCR), progression-free survival (PFS), CNS-PFS, overall survival (OS) and safety.Results: From May 2022 to April 2025, 50 evaluable patients were enrolled (median age 52.0 years; range 32-68) with a median of 3 prior lines of therapy (range 0-9). Baseline characteristics included: 1 brain metastasis (n=14), 2 metastases (n=10), and ≥3 metastases (n=26). The cohort comprised 56.0% (28/50) radiotherapy-naïve patients and 44.0% (22/50) with post-radiotherapy progression, with 52.0% (26/50) having prior anti-HER2 ADC exposure (including 4 patients treated with ≥2ADCs with different payloads).Among 50 response-evaluable patients, the CNS objective response rate (CNS-ORR) was 54.0% (95% CI 39.3-68.2%), with a disease control rate of 92.0% (46/50; 95% CI 80.8-97.8%). For all 50 patients, median progression-free survival (PFS) was 8.6 months (95% CI 7.0-10.2) at data cutoff (June 30, 2025; median follow-up 14.0 months), with median overall survival (OS) of 11.0 months (95% CI 8.4-13.6).Treatment emergent adverse events (TEAEs) of any grade included peripheral neuropathy (96.0%), leukopenia (58.0%), ALT/AST elevation (52.0%), neutropenia (50.0%), anemia (42.0%), hypertension (42.0%), and proteinuria (38.0%). Grade 3 AEs occurred in peripheral neuropathy (6.0%), neutropenia (16.0%), leukopenia (8.0%), thrombocytopenia (4.0%), hypertension (12.0%), anemia (2.0%), and GGT elevation (2.0%). No grade ≥4 treatment-related AEs were observed. Conclusions: ​Preliminary findings from the U-BOMB-HER study indicate that utidelone plus bevacizumab demonstrates clinically meaningful CNS activity, along with a manageable safety profile, in patients with HER2-positive breast cancer brain metastases, refractory to trastuzumab and TKI. ClinicalTrials.gov: NCT05357417.

F. André¹, E. Hamilton², S. Loi³, C. Anders⁴, P. Schmid⁵, E. Artamonova⁶, R. Villanueva-Vázquez⁷, J. Pedrini⁸, D. Doval⁹, S. C. Chen¹⁰, S. Boston¹¹, A. Konpa¹², M. Markowska¹³, G. Fabbri¹⁴, K. Jhaveri¹⁵; ¹Department of Medical Oncology, Gustave Roussy, Paris-Saclay University, Villejuif, FRANCE, ²Breast Cancer and Gynecologic Cancer Research, Sarah Cannon Research Institute, Nashville, TN, ³Breast Unit, Peter MacCallum Cancer Centre, Melbourne, VIC, AUSTRALIA, ⁴Division of Medical Oncology, Duke Cancer Institute, Durham, NC, ⁵Centre for Experimental Cancer Medicine, Barts Cancer Institute, Queen Mary University of London, London, UNITED KINGDOM, ⁶Department of Chemotherapy, N N Blokhin National Medical Research Center of Oncology, Moscow, RUSSIAN FEDERATION, ⁷Breast Cancer Unit – Early Drug Development Unit, ICO L’Hospitalet, Barcelona, SPAIN, ⁸Department of Mastologia, Nossa Senhora da Conceição Hospital, Porto Alegre, BRAZIL, ⁹Breast and Thoracic Services, Rajiv Gandhi Cancer Institute and Research Centre, Delhi, INDIA, ¹⁰Division of General Surgery, Department of Surgery, Linkou Chang Gung Memorial Hospital, Taoyuan City, TAIWAN, ¹¹Late Development Oncology, Oncology R&D, AstraZeneca, Gaithersburg, MD, ¹²Late Development Oncology, Oncology R&D, AstraZeneca, Warsaw, POLAND, ¹³Late Oncology Statistics, Oncology R&D, AstraZeneca, Warsaw, POLAND, ¹⁴Translational Medicine, Oncology R&D, AstraZeneca, Boston, MA, ¹⁵Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY.

Background: T-DXd is approved for the treatment of adult pts with HER2+ mBC who have received a prior anti-HER2-based regimen. Recent results from the planned interim analysis of the Phase 3 DESTINY-Breast09 study demonstrated a statistically significant and clinically meaningful improvement in progression-free survival (PFS) by blinded independent central review for T-DXd + pertuzumab versus standard of care (taxane + trastuzumab + pertuzumab) in first-line (1L) HER2+ mBC (median 40.7 vs 26.9 months; hazard ratio 0.56 [95% CI 0.44, 0.71]). The T-DXd monotherapy module remains blinded until final PFS analysis. DESTINY-Breast07 (NCT04538742; initiated prior to DESTINY-Breast09) was a Phase 1b/2 multicenter, open-label, modular study exploring the safety, tolerability, and antitumor activity of T-DXd ± other anticancer agents in HER2+ mBC. Results presented are from the final analysis of the dose-expansion phase assessing T-DXd ± pertuzumab as 1L treatment in HER2+ mBC. Methods: Eligible pts had locally assessed HER2+ (immunohistochemistry [IHC] 3+ or IHC 2+ / in situ hybridization-positive) mBC. No prior therapy for mBC was allowed and a disease-free interval of ≥12 months from (neo)adjuvant therapy was required. Pts were stratified by hormone receptor status (positive [estrogen or progesterone receptor ≥1%] vs negative), disease status (recurrent vs de novo), and PD-L1 expression (positive [IHC ≥1%] vs negative). Pts received T-DXd 5.4 mg/kg intravenously (IV) every 3 weeks (Q3W) as monotherapy or in combination with pertuzumab 420 mg IV Q3W, with an 840-mg loading dose. Primary endpoints were safety and tolerability; secondary endpoints included objective response rate (ORR), duration of response, and PFS, per RECIST 1.1 by investigator, as well as time to progression on subsequent therapy (PFS2) by investigator, and overall survival (OS). Results: At final data cutoff (January 31, 2025), 75 pts in the T-DXd module and 50 pts in the T-DXd + pertuzumab module had received study treatment; demographics and disease characteristics were well balanced. Median follow up was 37.1 months with T-DXd and 38.6 months with T-DXd + pertuzumab. Median total treatment duration was 26.8 months in the T-DXd module, and 27.6 months for T-DXd and 26.0 months for pertuzumab in the T-DXd + pertuzumab module. Confirmed ORR (80% CI) was 78.7% (71.4, 84.7) with T-DXd and 84.0% (75.3, 90.5) with T-DXd + pertuzumab. At 36 months, 65.5% and 69.4% of pts remained in response in the T-DXd and T-DXd + pertuzumab modules, respectively. At study completion, median PFS and median OS were not reached for either module. The 80% CI lower limit for median PFS was 40.2 months for T-DXd + pertuzumab; all other CI limits were not evaluable. PFS rate (80% CI) at 24 months was 71.4% (63.5, 77.8) with T-DXd and 67.8% (58.2, 75.7) with T-DXd + pertuzumab. Grade ≥3 adverse events (AEs) occurred in 57.3% (n=43/75) and 62.0% (n=31/50), and serious AEs in 21.3% (n=16/75) and 28.0% (n=14/50), of pts in the T-DXd and T-DXd + pertuzumab modules, respectively. Adjudicated drug-related interstitial lung disease / pneumonitis events occurred in 11 (14.7%; Grade 1, n=3; Grade 2, n=8) pts who received T-DXd and 7 (14.0%; Grade 2, n=6; Grade 3, n=1) who received T-DXd + pertuzumab. Additional data by subgroup, including biomarker analyses, will be presented. Conclusion: In this Phase 1b/2 DESTINY-Breast07 study, safety profiles for T-DXd and pertuzumab were generally consistent with the known profiles of each agent. Encouraging clinical activity was demonstrated in pts who received either T-DXd monotherapy or T-DXd + pertuzumab as a 1L treatment for HER2+ mBC; results from the T-DXd + pertuzumab module are consistent with the interim findings from the Phase 3 DESTINY-Breast09 study.

S. Mehta¹, L. Stevens², R. Shah¹, M. Garretson¹, S. Pasha², C. Brown-Bickerstaff², L. Herms², M. Danso³; ¹US Medical Affairs, Daiichi Sankyo, Inc., Basking Ridge, NJ, ²Real-World Research, Ontada, Boston, MA, ³Sarah Cannon Research Institute, Virginia Oncology Associates, Norfolk, VA.

Background: A novel antibody drug conjugate, trastuzumab deruxtecan (T-DXd), has demonstrated unparalleled clinical benefit in DESTINY-Breast clinical trials for HER2+ metastatic breast cancer (mBC). However, limited data exists on the clinical benefit of T-DXd in minority racial/ethnic patient groups in the US. This study assessed real-world patient characteristics, treatment patterns, and outcomes among patients (pts) with HER2+ mBC treated with T-DXd in the US community oncology setting by racial/ethnic group. Methods: This retrospective chart review study utilized the iKnowMed electronic health record and included pts who initiated T-DXd for HER2+ mBC (index event) between Jan 1, 2020 and Apr 30, 2024, had ≥1 post-index visit and had documented race/ethnicity as Black and/or Hispanic (BH cohort) or White and non-Hispanic (Wt cohort). Pts were followed until last patient contact or death on or before Apr 30, 2024. To balance key baseline characteristics across cohorts, BH pts were propensity score matched to Wt pts with exact matching according to line of therapy (LOT), adjustment for age category, and a caliper width of 0.25 standard deviations. Patient characteristics, treatment patterns, real-world Objective Response Rate (rwORR, complete/partial response) and incidence of adverse events of interest while on treatment were summarized descriptively for both cohorts. Time to treatment discontinuation (TTD), time to next treatment (TTNT), and real-world progression-free survival (rwPFS) from index were estimated using the Kaplan-Meier method. Results: A total of 162 pts were included, with 81 in each cohort. Mean age at index was 56.3 years (BH 56.3; Wt 56.2) and all pts all were female except for 1 BH male. A higher proportion of pts in the BH cohort were residing in the South region (59.3% vs. 37.0%), had visceral only metastasis (65.4% vs. 58.0%) and HR- status (27.2% vs. 22.2%) than in the Wt cohort. More pts in the BH cohort (49.4%) received T-DXd in 3L+ setting than in the Wt cohort (43.2%). The rwORR was 63.0% and 67.9% in the BH and Wt cohort, respectively. Among the BH pts (median follow-up: 15.2 months [mo]), median (95% CI) rwPFS was 16.6 mo (9.9-21.4), TTD was 12.5 mo (9.7-14.9), and TTNT was 18.3 mo (13.1-22.9). Similarly, among Wt pts (median follow-up: 13.6 mo), median (95% CI) rwPFS was 14.7 mo (9.8-17.4), TTD was 12.2 mo (9.7-16.8), and TTNT was 18.4 mo (13.2-21.1). The rates of adverse events of interest were as follows: nausea (BH 50.6%; Wt 70.4%), fatigue (BH 45.7%; Wt 64.2%), vomiting (BH 21.0%; Wt 27.2%), diarrhea (BH 24.7%; Wt 35.8%), neutropenia (BH 13.6%; Wt 7.4%), alopecia (BH 2.5%; Wt 11.1%), and interstitial lung disease/pneumonitis (BH 7.4%; Wt 4.9%). During follow-up, 30.9% of BH pts and 33.3% of Wt pts initiated subsequent treatment beyond index. Among these pts (BH n = 25; Wt n = 27), trastuzumab emtansine-based (BH 16.0%; Wt 18.5%) and T-DXd-based (BH 16.0%; Wt 14.8%) regimens were most frequently used in the LOT immediately following index. Conclusion: Among US minority racial/ethnic groups (Blacks and/or Hispanics) under-represented in prior HER2+ mBC clinical studies, T-DXd demonstrated real-world clinical benefit and tolerability similar to that observed in White non-Hispanic pts. Interpretation of findings should consider limitations inherent to the retrospective design, including residual and unmeasured confounding, and potential information bias stemming from differential symptom reporting, clinical monitoring, and documentation practices across racial/ethnic groups. Nonetheless, these findings support the effectiveness of T-DXd across diverse populations and underscore the importance of inclusive data to inform clinical decision-making and advance equitable breast cancer management and care delivery across racial/ethnic groups.

T. C. Haddad¹, V. J. Suman², R. R. Roa³, B. J. Ernst⁴, R. Lupu⁵, T. Vander Steen⁵, M. H. Solanki⁵, M. Keeney⁵, D. W. Northfelt⁴, K. S. Anderson⁴, T. J. Hobday¹, S. Chumsri³, J. E. Hoppenworth¹, J. L. Carroll¹, K. V. Giridhar¹, C. C. O’Sullivan¹, R. A. Leon-Ferre¹, M. P. Goetz¹; ¹Department of Oncology, Mayo Clinic, Rochester, MN, ²Department of Quantitative Health Sciences, Mayo Clinic, Rochester, MN, ³Division Hematology/Oncology, Mayo Clinic, Jacksonville, FL, ⁴Division Hematology/Oncology, Mayo Clinic, Phoenix, AZ, ⁵Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN.

Background: Fatty Acid Synthase (FASN) is a key lipogenic enzyme co-regulated with HER2 and highly expressed in ER+ and HER2+ BC. Its targeting downregulates HER2 expression. Our preclinical studies revealed that FASN inhibition can sensitize or restore sensitivity to trastuzumab, paclitaxel and ET in HER2+ BC models. Denifanstat (deni, formerly TVB-2640) is a novel FASN inhibitor that demonstrated promising clinical activity and safety in a prior phase I trial as either monotherapy or in combination with paclitaxel. The primary objective of this study was to evaluate the objective tumor response rate (ORR) of deni plus trastuzumab (H) in combination with paclitaxel (T) or ET. Methods: Two independent, phase II clinical trials were initiated to assess the efficacy and safety of deni plus H in combination with T (Cohort A) or ET (Cohort B). Key inclusion criteria included HER2+ MBC resistant to HER2-directed therapy, measurable disease, unlimited ET, ≤6 prior chemotherapy or antibody drug conjugate regimens, and confirmation of HER2+ MBC on a pre-registration biopsy. Deni was administered 100 mg/m² orally once daily. HP or H plus ET (fulvestrant or aromatase inhibitor) was administered at standard dose and schedule. Blood was collected on Cycle 1 Day 1 (C1D1), C1D8 and C2D1 for serum FASN analysis. An additional MBC tumor biopsy was collected on C2D1 for correlative studies. A 2-stage Simon design with a safety-run in was used to test the null hypothesis that the true ORR is at most 5% against the alternative it is at least 20%. With a sample size of 32 patients (pts) per cohort, if ≥4 responses are seen, this design has a 90% chance of rejecting the true ORR is <5% when the true ORR is ≥20% at a 0.10 level of significance. The decision to close both trials to enrollment early was multifactorial. Results: From August 2017 – February 2024, 33 pts with HER2+ MBC pre-registered, among which 17 were eligible and 16 were evaluable (15 pts in Cohort A and 1 pt in Cohort B). The most common reason for ineligibility was HER2-negative status on central review of the pre-registration biopsy. Median age was 57 years (range 35-80). All pts were non-Hispanic and 13 (81.3%) were White. Median prior lines of therapy was 5 (range 0 – 11). In Cohort A, there were 5 partial responses; thus, the primary endpoint was met with the ORR estimated to be 33.3% (90% CI: 14.2-57.7%). The median PFS time was 7.0 months (95 %CI: 3.7 – 11.3), and median OS was 25.7 months (95%CI: 10.2 – NE). No dose limiting toxicities were observed during the C1 safety run-in (6 pts). In Cohort A, 7 (46.7%) developed a grade 3 or 4 adverse event (AE) attributed to combination therapy. Grade ≥2 AEs regardless of attribution occurring in ≥20% of all pts included anemia, fatigue, neutropenia, palmar plantar erythrodysesthesia (PPE), and peripheral neuropathy. Treatment was discontinued due to progression (12; 80%) or AE (3; 20% – pneumonitis; neuropathy; PPE). In Cohort B, the pt maintained stable disease through 8 cycles with grade 3 ALT increase, and she remained alive 31.2 months post-registration. Median C1D1 FASN level was 32.7 ng/mL (IQR: 18.7 – 49.6 ng/mL). There was minimal association between C1D8 and C2D1 FASN levels and time to disease progression (C1D8 n=9, Spearman rank correlation coefficient (r_s) = 0.040; C2D1 n=13, r_s = -0.019). Analyses of changes in MBC tumor expression of FASN, phospho-AKT, and phospho-S6 are in progress. Conclusion: Deni combined with HP provided clinical antitumor activity in pts with HER2+ MBC resistant to trastuzumab. Expected paclitaxel-associated AEs were observed. Nearly half of pts experienced a grade 3 or 4 AE attributed to the combination therapy, and 20% stopped treatment due to AE. Further study of deni, H plus ET is necessary to draw safety and efficacy conclusions.

Y. Liu, S. Huang, Y. Dang, M. L. Disis; Cancer Vaccine Institute, University of Washington, Seattle, WA.

DNA-Based HER2 Vaccine Induces Broader and More Durable T-Cell Responses Than Peptide Vaccine in Advanced HER2-Positive Breast CancerYing Liu, Sydney Huang, Yushe Dang, and Mary L. Disis. UW Cancer Vaccine Institute, University of Washington, Seattle, WABackground: Patients with HER2-overexpressing breast cancer often exhibit reduced immunity to the HER2 antigen. Therapeutic vaccines can enhance cytotoxic T cell responses against tumor-associated antigens, enabling selective tumor destruction. Both peptide- and DNA-based platforms have been explored for vaccine delivery, but direct comparisons of their safety and immunogenicity remain limited. We hypothesize that DNA-based vaccines may generate more robust and durable HER2-specific immunity than other vaccine platforms due to prolonged antigen expression from persistent plasmid presence in host tissues.Methods: We retrospectively analyzed 66 patients from a phase 1 DNA-vaccine trial and 38 from a phase 2 peptide-vaccine trial, all with stage III or IV HER2-positive breast cancer and either no evidence of disease or stable bone-only disease at enrollment. Both vaccines targeted HER2 intracellular domain (ICD) epitopes. Immunogenicity was assessed via IFN-γ ELISpot assays on cryopreserved PBMCs stimulated with HER2 ICD or extracellular domain (ECD) peptides as an indicator of epitope spreading. Changes in T-cell responses from baseline to peak post-vaccination were evaluated using the Wilcoxon test, and between-trial differences using the Mann-Whitney test. Patients were stratified by baseline HER2 immunity and immunologic responder status. Adverse events were recorded per NCI CTCAE v4.0. Results: The magnitude of T-cell immunity achieved to the HER2 ICD varied between the two modes of vaccination and was dependent on whether patients had preexisting immunity to HER2 when entering the study. Patients receiving the DNA vaccine showed significant increases in HER2 ICD immunity regardless of preexisting HER2 immunity (p=0.005 with, p<0.001 without), while those receiving the peptide vaccine showed elevated responses only in patients without preexisting immunity (p<0.001; p=0.76 with immunity). Both vaccines induced intramolecular epitope spreading, that is a broadening of the immune response to the HER2 ECD, representing the induction of endogenous immunity. DNA-vaccine recipients showed significant ECD immune responses both in those with (p=0.03) and without (p<0.001) baseline HER2 immunity. In contrast, peptide-vaccine recipients showed increased ECD immunity only in those without baseline immunity (p=0.04; p=0.33 with immunity). The DNA group had higher ECD immunity at baseline (p=0.02) and post-vaccination (p=0.005). The elevation in T-cell immunity from baseline to peak post-vaccination was comparable between vaccine types for both HER2 ICD (p=0.37) and ECD (p=0.13), including among responders (p=0.35 for ICD, p=0.44 for ECD). However, among non-responders, DNA-vaccine recipients demonstrated greater increases in both HER2 ICD (p=0.005) and ECD (p=0.04) immunity. One grade 3 ALT elevation occurred in the DNA-vaccine trial; no grade 3–5 events were observed in the peptide-vaccine trial. Conclusion: Both DNA- and peptide-based HER2 vaccines were well tolerated and capable of inducing HER2-specific T-cell responses in patients with advanced HER2-positive breast cancer. However, the DNA vaccine elicited broader and more consistent immune activation, including stronger epitope spreading to HER2 ECD and greater responses among patients without preexisting immunity. Notably, DNA-vaccine recipients demonstrated enhanced immunity even among non-responders, suggesting a more robust platform for overcoming baseline immune tolerance.

Z. Chen, P. Huang, H. Zhou, J. Chen; Breast Medical Oncology, Zhejiang Cancer Hospital, Hangzhou, CHINA.

Title: Dalpiciclib Plus Pyrotinib Plus Letrozole for Patients with Estrogen Receptor-Positive and HER2-Positive Metastatic Breast Cancer (DAPLET) Abstract:Background: Estrogen receptor-positive and HER2-positive breast cancer accounts for approximately 10-15% of breast cancers. Standard metastatic regimens combining trastuzumab-based HER2-targeted therapy with chemotherapy show limited efficacy in this subtype. In SYSUCC-002 trial, trastuzumab plus endocrine therapy was not inferior to trastuzumab plus chemotherapy therapy in first-line HER2+HR+ metastatic breast cancer, suggesting the possibility of omission of chemotherapy. The CDK4/6 pathway may be involved in HER2-targeted therapy resistance due to the HER2-ER signaling cross-talk and thus CDK4/6 inhibitor may become a strategy for patients with HER2+ER+ breast cancer. Pyrotinib, an irreversible pan-HER tyrosine kinase inhibitor, shows synergistic activity with CDK4/6 blockade in preclinical models. Building on this rationale, we evaluated a novel, chemotherapy-free regimen of pyrotinib, dalpiciclib, and letrozole in patients with HER2+ER+ metastatic breast cancer.Methods: Eligible patients had ER+HER2+ metastatic breast cancer, defined as ER≥1%, and HER2 positivity (immunohistochemistry 3+ or in situ hybridization positive). Patients should previously receive at most one systemic treatment containing trastuzumab for metastatic breast cancer. Patients with stable brain metastases and no clinical symptoms could be enrolled. Eligible patients received pyrotinib (320 mg orally once daily, every 4 weeks), dalpiciclib (125 mg orally once daily on days 1-21 of a 4-week cycle), and letrozole (2.5 mg orally once daily, every 4 weeks) until disease progression or intolerable toxicity. Pre/peri-menopausal patients received GnRH agonist. Radiographic evaluation was conducted every two cycles. The primary endpoint was objective response rate (ORR). In SYSUCC-002 trial, the ORR of trastuzumab plus endocrine arm was 37.2%, thus we hypothesized ORR of 55% in this trial. Using Simon’s optimal two-stage design, at the significance level of type I error rate at 0.05 and power of 0.8, a total of 22 patients was accrued in stage I. If there were more than 9 responses among these evaluable 22 patients, the study would enter stage II. The registration number of this trial was NCT07014410.Results: Between February 2023 and March 2025, 18 patients were enrolled. The median age was 54.5 years (range, 34-71). Ki67 expression at baseline included 12 patients (66.7%) with ≥30%. Of these 18 patients, 12 (66.7%) previously received trastuzumab, of whom 6 patients (33.3%) injecting with trastuzumab at metastatic stage. As of June 20, 2025, 16 of 18 patients had evaluable radiographic data (two patients withdrew from the study within two cycles because of intolerable toxicity). In these evaluable 16 patients, 11 patients achieved confirmed responses (1 complete response, 10 partial responses), yielding an ORR of 68.9% (95% confidence interval [CI], 41-88%). Despite inadequate patients in stage I, outstanding efficacy result indicated the study could enter stage II. The most common grade 3 adverse events were white blood cell count decreased (61.1%) and neutropenia (50.0%). No grade≥4 events were reported.Conclusions: This chemotherapy-free, trigeminy-targeted regimen demonstrated promising antitumor activity and manageable toxicity in first or second line HER2+ER+ metastatic breast cancer. The data supported this regimen as a potential alternative to standard chemotherapy-based approaches in this subtype. Efficacy of this regimen needs to be further evaluated in Simon stage II.

C. M. Sabotta¹, F. Liao², M. J. Shea², S. Nanda², L. Qin², P. S. Steeg³, M. F. Rimawi⁴, C. Gutierrez², C. Osborne⁴, S. G. Hilsenbeck⁴, J. Veeraraghavan⁴, R. Schiff⁴; ¹Lester and Sue Smith Breast Center, Baylor College of Medicine, Houston, TX, ²Lester and Sue Smith Breast Center, Dan L. Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, TX, ³Women’s Malignancies Branch, Center for Cancer Research National Cancer Institute, Bethesda, MD, ⁴Lester and Sue Smith Breast Center, Dan L. Duncan Comprehensive Cancer Center, and Dept of Medicine, Baylor College of Medicine, Houston, TX.

Background: HER2-positive (HER2+) breast cancer (BC) is an aggressive subtype with 30-50% incidence of brain metastases in metastatic patients. The HER2-selective tyrosine kinase inhibitor (TKI) tucatinib (Tuca) and the pan-HER TKI neratinib (Nrb), mostly used in the late line setting, are effective, including in treating brain metastases. The new antibody drug conjugate T-DXd is also highly effective in the brain metastatic setting. It is crucial to understand the mechanisms of resistance to these brain permeable anti-HER2 therapies. Materials and Methods: GFP/Luc tagged SUM190-BR3 (SUM190Br), a brain-tropic derivative of the HER2+/ER- inflammatory SUM190 cell model (harboring the PIK3CA H1047R mutation), was used (PMID: 27245829). A long-term highly Tuca resistant (TucaR) derivative of this line was developed through exposure to increasing doses of Tuca up to 1uM. Characterization of these resistant and naïve cells was performed by Western blot (WB), DNA-seq, and RNA-seq. Drug efficacy studies involved methylene blue-based cell growth and IC₅₀ assays, and included the Akt inhibitor (i), capivasertib (Capi, 1uM), T-DXd (5ug/mL), and the EGFR-specific TKI gefitinib (Gef, 1uM) or monoclonal antibody cetuximab (Cetux, 10ug/mL). To characterize the in vivo tumorigenicity and metastatic capacity of our resistant model, immunocompromised mice were injected with cells via subcutaneous or intracardiac routes and monitored for primary tumor growth and metastasis by bioluminescence imaging. Results: Interestingly, the naïve SUM190Br cells are intrinsically resistant to Tuca (IC₅₀>600nM), but not Nrb (IC₅₀<60nM). Capi is effective as a single agent in the TucaR model (p<.0001). WB analysis of the TucaR model showed substantially elevated levels of total EGFR and modestly elevated HER2, as well as increased phosphorylation of EGFR and HER2, suggesting pathway reactivation at time of resistance vs. short-term Tuca treated naïve cells. Further, DNA and RNA-seq analysis showed high EGFR at the mRNA level with no change in copy number. As we previously showed in other HER2+ TucaR models such as BT474 (with acquired EGFR amplification), the SUM190Br TucaR cells remain sensitive to Nrb. Likewise, EGFRi together with Tuca was effective in overcoming resistance in this TucaR model. T-DXd is highly effective in metastatic BC, but high EGFR expression has been shown to reduce its efficacy (PMID: 39437778). Both Gef and Cetux improve the efficacy of T-DXd in our models, but Cetux is selectively effective against the TucaR model. Moreover, our preliminary in vivo results show that the highly aggressive TucaR model grows as xenografts, keeps brain tropism via intracardiac injection, and metastasizes via subcutaneous injection. Conclusions: Our findings suggest the role of high EGFR and PIK3CA mutations in resistance to Tuca, which warrants additional preclinical and clinical investigation. This underscores the importance of understanding if PIK3CA mutations are associated with reduced Tuca sensitivity and the testing of new mutant specific PIK3CAi or other PI3K/Akt pathway inhibitors. Our brain tropic TucaR cell and mouse models will be useful to understanding resistance in the brain metastatic setting, and future work will test the most promising treatments in vivo. The recent DESTINY-Breast09 trial points to the promise of T-DXd in combination with the monoclonal antibody pertuzumab as the new first line for metastatic BC. Since high-EGFR is suggested to play a potential role in reducing T-DXd efficacy, our ongoing and future work seeks to understand if the new T-DXd plus pertuzumab combination will be effective compared to T-DXd plus EGFRi in treating HER2+ BC with high EGFR.

M. Eysha¹, M. Elchouemi², W. Zhang ³, R. del Toro-Mijares⁴, A. Asad⁵, A. Elkhanany⁶; ¹Department of Medicine, Texas tech University health science center, El Paso, TX, ²Department of Medicine, Texas Tech University Health Science Center El Paso,, Houston, TX, ³Department of Medicine, Duke University Medical Center, Durham, NC, ⁴Department of Medicine, Texas Tech Health El Paso, El Paso, TX, ⁵Department of Medicine, UTMB John Sealy School of Medicine, Galveston, TX, ⁶Department of Medicine, Baylor College of Medicine, Houston, TX.

Background: CLEOPATRA trial, adding Pertuzumab to Docetaxel and Trastuzumab improved median overall survival (OS) from 40.8 to 57.1 months and remains guideline-defining for first-line HER2-positive metastatic breast cancer (MBC), albeit with risks of myelosuppression and long-term neurotoxicity. In HR⁺ HER2⁺ MBC, few studies presented good outcomes with addition of endocrine therapy (ET) and CDK4/6 inhibitors without chemotherapy (PERTAIN, SYSUCC-002, PERNETTA, BR 18-2 MINI). Robust real-world survival data comparing chemotherapy-free versus taxane-induction strategies in this subgroup are lacking. Methods: TriNetX Global Collaborative Network (152 sites, 2008-2024) was queried for adults (≥18 y) with incident HR⁺ HER2⁺ MBC treated with Trastuzumab (± Pertuzumab) plus ET. Patients receiving ≥1 dose of paclitaxel or docetaxel within 6 months of diagnosis before the first HER2-targeted dose constituted the induction cohort (IND, n = 365 pre-match); others served as controls (CTRL, n = 498). One-to-one propensity-score matching (caliper 0.10) on 13 demographics/comorbidities yielded 323 well-balanced pairs (N = 646); after matching all standardized differences were < 0.10 except male sex (3 % vs 0 %). Ten-year OS was the primary endpoint. Secondary outcomes were grade-coded neutropenia, sepsis, heart failure, emergency-department (ED) visits and intensive-care-unit (ICU) admission. Survival analysis done with univariate Kaplan Meier and Cox models. Results: Of 7184 HR⁺ HER2⁺ MBC cases, 2114 received first-line Trastuzumab (± Pertuzumab) + ET; 863 met prespecified criteria (365 IND, 498 CTRL); 646 remained after 1:1 matching. Matched cohorts were well balanced, with median age 52 years, 96 % female, 59 % White, 22 % Black. All baseline standardized differences < 0.10 (except male sex 3 % vs 0 %). Median follow-up was 1578 vs 1151 days (IND vs CTRL). Ten-year OS was 64.3 % in IND vs 53.1 % in CTRL (absolute gain 11.2 %; HR 0.64, 95 % CI 0.47-0.85, P = 0.002). Ten-year mortality fell from 31.9 % to 24.1 % (absolute risk reduction 7.8 %; NNT = 13). Survival curves diverged by 12 months and remained parallel. Induction increased neutropenia (25.7 % vs 13.9 %; HR 1.88, P < 0.001) and ED visits (63.5 % vs 51.7 %; HR 1.24, P = 0.009); with median time to first ED visit shortened from 1084 to 678 days in the IND group. Serious events were comparable: sepsis 17.6 % vs 14.9 % (P = 0.34), heart failure 18.0 % vs 16.4 % (P = 0.60), ICU admission 16.1 % vs 16.4 % (P = 0.92). Conclusions: In contrast to some signals from chemotherapy-free regimens in PERTAIN, SYSUCC-002 and PERNETTA, this real-world study shows that a short taxane induction in HR⁺ HER2⁺ MBC before trastuzumab-ET confers a 36 % relative and 11 % absolute 10-year OS advantage; one extra life saved per thirteen treated; at the cost of predictable, manageable myelosuppression and higher acute-care use without excess cardiotoxicity, sepsis or ICU need. This data strengthens guideline endorsements of chemotherapy-containing first-line regimens and asks for careful discussion if upfront de-escalation is considered, as well as provides a benchmark for ongoing chemo-sparing strategies utilized in other trials (DESTINY-Breast09, DEMETHER, etc.). Selection and lead-time bias are possible but were mitigated by robust propensity matching.

D. Jaber¹, S. Marini¹, N. Raptis¹, N. K. Heater², Y. Ma², S. Warrior², L. Flaum², R. Stein², P. Robinson², H. Liu², Y. Zhang², R. Chen², Q. Zhang², L. C. Platanias², W. Gradishar², P. U. Kumthekar², J. Lu²; ¹Internal Medicine, McGaw Medical Center of Northwestern University, Chicago, IL, ²Hematology-Oncology, Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Chicago, IL.

Background: Patients with HER2-positive (HER2+) metastatic breast cancer (MBC) are at increased risk for developing central nervous system (CNS) metastases, presenting a significant clinical challenge and a major cause of morbidity and mortality in this population. Circulating tumor cells (CTCs) offer a noninvasive tool for disease monitoring; however, the prognostic significance of CTC subtypes in the context of CNS involvement remains unclear. This study examines the association between CTC subtypes and CNS progression and outcomes in patients with HER2+ MBC and detectable HER2+ CTCs. Methods: This retrospective cohort study examined patients with MBC who had CTCs collected from blood samples between 2016-2024 under an IRB-approved protocol (NU16B06) at Northwestern University Robert H. Lurie Comprehensive Cancer Center. CTC enumeration was performed via CELLTRACKS (Menarini). Patients with CTC samples collected within 6 months prior to radiographic detection of CNS metastases, defined as parenchymal brain metastases (PBM) or leptomeningeal disease (LMD), were included. Early CNS disease was defined as detection of CNS metastases within 12 months of metastatic diagnosis. Patients with at least one HER2+ CTC were analyzed. The relative proportion of CTCs was assessed by including both HER2+ and non-HER2+ CTC counts in multivariable models to capture the distinct contributions of each subtype. Results: 26 patients with HER2+ CTCs who developed CNS metastases were identified. The median age at diagnosis of CNS metastases was 54 years (interquartile range [IQR]: 46-64); 18 (75%) were White, 4 (17%) African American, and 2 (8.3%) Asian. At radiographic detection, 21 (80.8%) had PBM, 3 (11.5%) had LMD, and 2 (7.7%) had both. Median total CTC count was 15 (IQR: 5-108), and median HER2+ CTC count was 6 (IQR: 2-59). Following CNS detection, 13 (50%) received HER2-targeted therapy, 8 (31%) received non-HER2 therapy, and 5 (19%) received no therapy. Median overall survival (OS) was 13.0 months with HER2-targeted therapy versus 7.0 months with non-HER2 therapy (p=0.32), while median progression-free survival (PFS) was 2.6 vs. 2.0 months, respectively (p=0.98). After adjusting for extracranial disease burden, receipt of radiation, and CTC counts, HER2-targeted therapy was not associated with differences in OS (HR 0.50, 95% CI 0.16-1.50, p=0.2) or PFS (HR 1.89, 95% CI 0.55-6.47, p=0.3). Similarly, after multivariable adjustment, HER2+ CTC count was not associated with OS (HR 1.006 per CTC, 95% CI 0.99-1.02, p=0.5) or PFS (HR 0.997 per CTC, 95% CI 0.98-1.01, p=0.7), and non-HER2+ CTC count was not associated with OS (1.007 per CTC, 95% CI 0.10-1.02, p=0.2) or PFS (HR 1.004 per CTC, 95% CI 0.99-1.02, p=0.4). After multivariable adjustment, HER2+ CTC count was not associated with early (12 months) CNS progression (OR 1.00, 95% CI 0.97-1.03, p=0.9), whereas higher non-HER2+ CTC count was significantly associated with early CNS progression (OR 1.02 per CTC, 95% CI 1.00-1.07, p=0.041). Conclusion: In this real-world cohort of patients with HER2+ CTCs and CNS metastases, higher non-HER2+ CTC burden, included to capture total CTC burden while isolating the effects of HER2+ CTCs, was associated with early CNS progression. HER2+ CTC counts and HER2-targeted therapy were not associated with survival or progression outcomes. These findings suggest that CTC heterogeneity, particularly the presence of non-HER2+ subpopulations, may reflect a biologically aggressive or treatment-resistant phenotype in patients with HER2+ MBC and CNS involvement. The lack of association between HER2+ CTCs and outcomes may reflect the limited cohort size and treatment heterogeneity, highlighting the need for larger studies to clarify the prognostic value of HER2+ CTC burden in this population.

J. S. Frenel¹, A. de Nonnevile², C. Guerin-Charbonnel³, J. Zeghondy⁴, L. Mathiot¹, A. Mailliez⁵, F. Poumeaud⁶, N. Isambert⁷, M. Arnedos⁸, F. Le Du⁹, L. Galland¹⁰, R. Kabirian¹¹, S. Guiu¹², L. Poestch¹³, E. Deluche¹⁴, F. Cherifi¹⁵, F. Dalenc⁶, E. Volant¹, B. Pistilli⁴, T. San¹⁶, T. Bachelot¹⁷, A. Patsouris¹⁸, F. Bocquet¹⁹, L. Larrouquere¹⁷, D. Loirat²⁰; ¹Medical Oncology, Institut de Cancerologie de L’Ouest, Saint-Herblain, FRANCE, ²Medical Oncology, Institut Paoli Calmette, Marseille, FRANCE, ³Statistics, Institut de Cancerologie de L’ouest, Saint-Herblain, FRANCE, ⁴Medical Oncology, Gustave Roussy, Villejuif, FRANCE, ⁵Medical Oncology, Centre Oscar Lambert, Lille, FRANCE, ⁶Medical Oncology, Oncopole, Toulouse, FRANCE, ⁷Medical Oncology, CHU Poitiers, Poitiers, FRANCE, ⁸Medical Oncology, Centre Bergonie, Bordeaux, FRANCE, ⁹Medical Oncology, Centre Eugène Marquis, Rennes, FRANCE, ¹⁰Medical Oncology, Centre Georges-Francois Leclerc, Saint-Herblain, FRANCE, ¹¹Medical Oncology, Institut Curie, Paris, FRANCE, ¹²Medical Oncology, Institut de Cancer Montpellier, Monptellier, FRANCE, ¹³Medical Oncology, Polyclinique Bordeaux Nord Aquitaine, Bordeaux, FRANCE, ¹⁴Medical Oncology, CHU de Limoges, Limoges, FRANCE, ¹⁵Medical Oncology, Centre Francois Baclesse, Caen, FRANCE, ¹⁶Medical Oncology, CORT37, Chambray les tours, FRANCE, ¹⁷Medical Oncology, Centre Leon Berard, Lyon, FRANCE, ¹⁸Medical Oncology, Institut de Cancerologie de L’ouest, Angers, FRANCE, ¹⁹Data Factory and analytics, Institut de Cancerologie de L’ouest, Saint-Herblain, FRANCE, ²⁰Medical Oncology, Institut Curie, PARIS, FRANCE.

Background: Trastuzumab deruxtecan (T-DXd) is currently the standard second-line therapy for HER2-positive metastatic breast cancer (MBC). Recent results from the DESTINY-Breast09 (DB-09) trial suggest it may soon be considered for first line setting. However, optimal treatment sequences after T-DXd remain unclear. Currently, data regarding the efficacy of the combination of tucatinib, trastuzumab, and capecitabine (TTC) administered as second- or third-line therapy after T-DXd is limited. Materials and Methods: We conducted a cohort study across 17 French cancer centers. Eligible patients had HER2-positive MBC and received TTC as second- or third-line therapy in the metastatic setting after prior treatment with T-DXd. The primary endpoint was progression-free survival (PFS). Secondary endpoints included time to next treatment (TTNT), overall survival (OS), objective response rate (ORR). Results: Between July 2021 and June 2025, 103 patients were enrolled. The median age at TTC initiation was 54.6 years (range: 21.0-86.0), 42.7% had de novo metastatic disease and 55.3% had brain metastases. Prior (neo)adjuvant chemotherapy and anti-HER2 therapy were administered to 55.3% of patients, while 88.3% had received pertuzumab as treatment for metastatic disease. Most patients (91.3%) progressed on T-DXd, while 8.7% discontinued due to toxicity or other reasons. The median duration of prior T-DXd therapy was 8.0 months (range: 0.7-37.2). TTC was administered as second-line therapy in 8.7% and third line in 91.3%, immediately following T-DXd in all cases. After a median follow-up of 12.7 months (95% CI: 11.0-17.0), 74 patients (71.8%) had discontinued TTC due to disease progression, 26 patients (25.2%) remained on treatment, and 3 patients (3.0%) discontinued TTC because of toxicity. Median PFS with TTC was 4.7 months (95% CI: 3.5-5.7), median TTNT was 6.6 months (95% CI: 4.8-9.6), and median OS was 12.3 months (95% CI: 10.5-19.5). Among the 96 RECIST-evaluable patients, 9.4% achieved a complete response, 20.8% had a partial response, 27.1% showed stable disease, and 42.7% experienced progressive disease as best response. Patients treated with T-DXd for >18 months (n=15) had a median PFS of 6.9 months (95% CI: 4.8-NR) and a median TTNT of 8.9 months (95% CI: 5.9-NR) compared to to a median PFS of 3.9 months (95% CI: 3.2-5.3) and a median TTNT of 5.5 months (95% CI: 4.2-9.6) in those treated with T-DXd for ≤ 18 months (n=88). Patients with brain metastases had a median PFS of 5.0 months (95% CI: 3.8-7.4) and a median TTNT of 8.5 months (95% CI: 5.5-11.7). For those without brain metastases, median PFS was 3.5 months (95% CI: 2.7-6.8) and median TTNT was 4.8 months (95% CI: 3.4-9.6). Following TTC progression, 60 patients received further therapy, with a median PFS of 2.7 months (95% CI: 2.5-3.9). Conclusion: In this multicenter French cohort, TTC showed clinically meaningful activity as a second- or third-line therapy in HER2-positive MBC patients previously treated with T-DXd, especially among long-responders (PFS>18 months) to T-DXd. Final updated results will be presented at the meeting.

M. Kubeczko¹, S. Cobo², R. Sanchez-Bayona³, B. Pycinski⁴, J. Soberino⁵, E. Chmielik⁶, E. Sanfeliu⁷, M. Rey⁸, F. Pardo⁹, A. Aguirre⁸, O. Castillo⁸, A. Lesniak¹, M. Oczko-Wojciechowska¹⁰, E. Carcelero¹¹, B. Adamo¹², M. Vidal¹², M. Bergamino¹³, J. Maues¹⁴, G. Villacampa¹⁵, L. Pare⁹, E. Ciruelos¹⁶, A. Prat¹⁷, M. Jarzab¹, F. Braso-Maritany¹⁸; ¹Breast Cancer Center, Maria Sklodowska-Curie National Research Institute of Oncology, Gliwice, POLAND, ²Breast Cancer Center, Institut d’Investigacions Biomèdiques August Pi i Sunyer, Barcelona, SPAIN, ³Unidad de Cáncer de Mama y Ginecológico, Hospital Universitario 12 de Octubre, Madrid, SPAIN, ⁴Faculty of Biomedical Engineering, Silesian University of Technology, Zabrze, POLAND, ⁵Breast Cancer Unit, IOB-QuirónSalud, Barcelona, SPAIN, ⁶Tumor Pathology Department, Maria Sklodowska-Curie National Research Institute of Oncology, Gliwice, POLAND, ⁷Department of Medicine, Translational Genomics and Targeted Therapies in Solid Tumors, August Pi i Sunyer Biomedical Research Institute (IDIBAPS); Hospital Clinic Barcelona; University of Barcelona, Barcelona, SPAIN, ⁸Translational Genomics and Targeted Therapies in Solid Tumors, Cancer Institute and Blood Disorders, Hospital Clinic; Translational Genomics and Targeted Therapies in Solid Tumors, August Pi I Sunyer Biomedical Research Institute (IDIBAPS), Barcelona, SPAIN, ⁹Reveal Genomics, Reveal Genomics, Barcelona, SPAIN, ¹⁰Department of Clinical and Molecular Genetics, Maria Sklodowska-Curie National Research Institute of Oncology, Gliwice, POLAND, ¹¹Pharmacy Department, Hospital Clinic Barcelona, Barcelona, SPAIN, ¹²Department of Medical Oncology, Hospital Clinic of Barcelona; Translational Genomics and Targeted Therapeutics in Solid Tumors, August Pi i Sunyer Biomedical Research Institute (IDIBAPS); SOLTI Breast Cancer Research Group, Barcelona, SPAIN, ¹³Medical Oncology Department, Hospital Clinic Barcelona, Barcelona, SPAIN, ¹⁴GRASP, GRASP, Baltimore, MD, ¹⁵Statistics Unit, Vall d’Hebron Institute of Oncology, Cellex Centre; SOLTI Breast Cancer Research Group, Barcelona, SPAIN, ¹⁶Medical Oncology Department Breast Cancer Unit, Hospital Universitario 12 de Octubre; HM CIOCC; SOLTI Breast Cancer Research Cooperative Group, Madrid, SPAIN, ¹⁷Cancer Institute and Blood Diseases, Hospital Clínic Barcelona; Translational Genomics and Targeted Therapies in Solid Tumors, August Pi I Sunyer Biomedical Research Institute; University of Barcelona; Reveal Genomics; SOLTI Cancer Research Group, Barcelona, SPAIN, ¹⁸Translational Genomics and Targeted Therapies in Solid Tumors, Hospital Clinic Barcelona; August Pi i Sunyer Biomedical Research Institute (IDIBAPS), Barcelona, SPAIN.

Background: The HER2DX genomic test is a standardized, quantitative assay with demonstrated prognostic value in first-line advanced HER2+ breast cancer treated with trastuzumab, pertuzumab, and chemotherapy (THP). Here, we validated the test in an independent cohort (n=122) and explored its association with long-term outcomes in a combined real-world population (n=215). Methods: HER2DX testing was performed on baseline tumor tissue from 122 consecutive patients with advanced HER2+ breast cancer treated with first-line THP at the Breast Cancer Center, Maria Sklodowska-Curie National Research Institute of Oncology, Gliwice (Poland). In addition, we evaluated a 93-patient real-world cohort from Spain (NPJ Breast Cancer 2025) with updated survival data in order to create a combined cohort. The assay was conducted at a central laboratory in Barcelona, blinded to clinical outcomes. Outcomes were assessed using pre-established ERBB2 mRNA score cutoffs. Multivariable Cox models were adjusted for clinicopathological variables. Prognostic value was also assessed in the subgroup of patients achieving a response (partial or complete) to first-line THP. An improved version of the test, called HER2DX metastatic prognostic score (HER2DX-mets-score), which combines the HER2DX ERBB2 score with additional molecular signatures, was trained in the Spanish cohort and validated in the Polish cohort. Results: In the Polish cohort (n=122), the mean age was 59.2 years (range: 36-85.7), 72.1% of patients presented with de novo metastatic disease, and 59% had hormone receptor-positive tumors. The overall response rate was 68.9%, the median progression-free survival (PFS) was 28.4 months (95% CI 17.9-42.9), and the median overall survival (OS) was 51.1 months (95% CI 43.8-87.6). Patients in the high ERBB2 mRNA group had significantly improved outcomes compared to those in the combined medium/low groups: PFS (hazard ratio [HR] 0.57; 95% CI 0.35-0.92; p=0.02) and OS (HR 0.48; 95% CI 0.28-0.83; p=0.009). In the combined cohort (n=215), the prognostic value of the ERBB2 score was confirmed. Patients in the high ERBB2 group had significantly longer PFS (median 33.8 months, 95% CI 25.6-52.5) and OS (median not reached) compared to those in the medium/low group (median PFS 12.5 months, 95% CI 9.79-25; median OS 37.1 months, 95% CI 25.4-47.9), with HRs of 0.50 (95% CI 0.35-0.71; p<0.001) for PFS and 0.36 (95% CI 0.23-0.54; p<0.001) for OS. The objective response rate (ORR) was significantly higher in the High HER2DX ERBB2 group (84.4%) compared to the Low group (52.0%; p <0.001). In multivariable models, the ERBB2 score remained independently prognostic. Among patients with a response to THP, those with high ERBB2 scores had a median PFS of 33.9 months (95% CI 26.9-61) and median OS not reached, compared to 17.6 months (95% CI 10.3-42.9) and 37.1 months (95% CI 25.4-51.1) in the medium/low group, respectively. Notably, in the subgroup of patients with fewer than three metastatic sites, those with high ERBB2 scores experienced a median PFS of 51.7 months (95% CI 28.6-NA) and a median OS that was not reached, compared to 20.3 months (95% CI 10.4-41.5) and 42.4 months (95% CI 27.6-55.8) in the medium/low group. HER2DX-mets-score outperformed the ERBB2 score alone in both cohorts; detailed results will be presented at the conference. Conclusions: The HER2DX ERBB2 mRNA score provides robust, independent prognostic information in patients treated with first-line THP for advanced HER2+ breast cancer. The test may help identify individuals who could be managed with chemotherapy followed by maintenance HP, while others may require treatment intensification. These findings suggest a potential role for the HER2DX ERBB2 score, and its improved version, HER2DX metastatic prognostic score, in informing more personalized treatment strategies.

P. R. POHLMANN¹, N. Chen², J. A. Mouabbi³, N. Jahan⁴, M. Rampurwala⁵, A. Discacciati⁶, M. Eklund⁶, A. Chapple⁷, G. L. Hirst⁸, S. Venters⁹, L. Brown-Swigart⁹, E. Petricoin III¹⁰, A. D. Borowsky¹¹, L. J. van ‘t Veer⁹, A. L. Delson¹², S. M. Asare¹³, S. Jaffari¹⁴, P. Henderson¹⁵, D. Tripathy³, L. J. Esserman⁸, H. S. Rugo¹⁶, R. Nanda², E. Stringer-Reasor⁴, D. Yee¹⁷, F. Meric-Bernstam¹⁸, D. A. Potter¹⁹; ¹Breast Medical Oncology and Investigational Cancer Therapeutics (joint appointment), University of Texas MD Anderson Cancer Center, Houston, TX, ²Department of Medicine, University of Chicago, Chicago, IL, ³Breast Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, TX, ⁴Division of Hematology and Oncology, University of Alabama at Birmingham O’Neal Comprehensive Cancer Center, Birmingham, AL, ⁵Hematology and Medical Oncology, UChicago Medicine Center for Advanced Care Orland Park, Orland Park, IL, ⁶Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, SWEDEN, ⁷Statistics, Quantum Leap Healthcare Collaborative, San Francisco, CA, ⁸Department of Surgery, University of California San Francisco, San Francisco, CA, ⁹Department of Laboratory Medicine, University of California San Francisco, San Francisco, CA, ¹⁰Center for Applied Proteomics and Molecular Medicine, George Mason University, Manassas, VA, ¹¹Department of Pathology and Laboratory Medicine, University of California Davis, Sacramento, CA, ¹²Breast Science Advocacy Core, Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, CA, ¹³Program Management, Quantum Leap Healthcare Collaborative, San Francisco, CA, ¹⁴QLHC, QLHC, San Francisco, CA, ¹⁵Collaborations, Quantum Leap Healthcare Collaborative, San Francisco, CA, ¹⁶Breast Medical Oncology, City of Hope Cancer Center, Duarte, CA, ¹⁷Departments of Medicine and Pharmacology (joint appointment), Masonic Cancer Center, University of Minnesota, Minneapolis, MN, ¹⁸Department of Investigational Cancer Therapeutics, University of Texas MD Anderson Cancer Center, Houston, TX, ¹⁹Department of Medicine, Masonic Cancer Center, University of Minnesota, Minneapolis, MN.

BackgroundDespite advances in therapies such as trastuzumab deruxtecan (T-DXd) for HER2-expressing metastatic breast cancer, the disease remains incurable, underscoring a critical unmet need. Evorpacept (evo) is a high-affinity CD47-blocker with an inactive IgG Fc region designed to enhance antibody-dependent cellular phagocytosis. Here, we report results from a phase Ib trial of evo + T-DXd in patients (pts) with advanced HER2-expressing (HER2+/HER2low) breast cancer [NCT05868226].MethodsPRE-ISPY Phase I/Ib trial is an open-label platform study evaluating therapies in the advanced disease setting to identify promising regimens for rapid transition into I-SPY2, K-SPY or other trials. This multicenter study arm included 30 pts with previously treated, T-DXd naïve, advanced/metastatic HER2+/HER2low breast cancer. Part 1 dose finding contained 2 cohorts (A and B) of 10 patients each evaluating 2 doses of evo 30 mg/kg and 45 mg/kg combined with standard doses of T-DXd 5.4 mg/kg IV Q3W. Part 2 expansion (cohort C) enrolled additional 10 patients at RP2D. The primary objectives were to establish safety, Recommended Phase 2 Dose (RP2D) and antitumor activity (Overall Response Rate, ORR) in HER2+/HER2low mBC pts. PFS, Disease Control Rate (DCR), evo PK and ADA, CD47 levels, were secondary endpoints. ResultsAs of May 30^th 2025, enrollment was complete with 30 pts (n=10 in each cohort A, B and C). Median follow-up was 6.6 months (4.6 in HER2+ vs 7.4 in HER2low), with 11 pts remaining on treatment at data cutoff. Median age (range) was 54 (30-76) yrs; 14 (47%), 8 (27%) and 2 pts (7%) had a history of liver, lung and brain metastasis, respectively; and 28 patients had measurable disease at enrollment. By local HER2 assessment, 7/10 (70%) pts in cohort A and 13/20 (65%) pts in cohorts B/C had HER2low mBC diagnosis, respectively. 13/30 (43%) of pts had 3 or more prior treatment lines in the advanced setting. There were no DLTs. The RP2D was evo 45 mg/kg and T-DXd 5.4 mg/kg IV Q3W. Among all 30 pts, treatment-emergent adverse events (TEAE) of any grade occurring in the most participants were nausea (73%), fatigue (67%), diarrhea (53%) and anemia (50%). Most of these events were Grade 1 or 2 in severity. Overall, 14 participants (47%) experienced Grade 3 events (anemia, hemolytic anemia, decreased counts of neutrophils, lymphocytes and platelets, dental caries, portal hypertension, fatigue, mastitis, back pain, hypokalemia, syncope, embolism, dyspnea, and pneumonia). Four pts experienced 8 total SAEs: grade 3 hemolytic anemia, grade 4 thrombocytopenia¸ grade 3 pneumonia, portal hypertension, embolism, mastitis, and grade 2 pyrexia, each event occurring once. All SAEs were resolved except for portal hypertension. There were no grade 5 TEAEs. One AE of special interest was described (grade 2 decreased left ventricular ejection fraction). There was one grade 1 ILD/pneumonitis. Dose reductions were made for 4 participants; one included a temporary dose hold. The confirmed ORR (cORR) was 33.3% (95% CI 17.9%-52.9%) and the DCR was 73.3% (95% CI 53.8%-87.0%). In HER2+ mBC pts, cORR was 40% (95% CI 13.7%-72.6%) and the DCR was 90% (95% CI 54.1%-99.4%). In the HER2low pts (n=20), cORR was 30% (95% CI 12.8%-54.3%) and DCR was 65% (95% CI: 40.9%-83.7%). Median progression free survival (mPFS) was 8.6 months, with a mPFS of 5.6 months in HER2low (13/20 events) and not yet reached in HER2+ (2/10 events). Updated data and correlatives will be provided at the Symposium. Conclusions In this phase I study, Evo + T-DXd demonstrated a manageable safety profile comparable with T-DXd alone and evidence of antitumor activity in pretreated HER2+/HER2low mBC. There were no new safety signals.

I. Alvarez¹, Á. Guerrero-Zotano², J. Cruz-Jurado³, S. Antolín⁴, E. Galve⁵, C. Rodríguez⁶, M. Hernández⁷, A. Tibau⁸, C. Falo⁹, J. Chacón¹⁰, A. Miguel¹¹, Á. Rodríguez-Lescure¹², E. Adrover¹³, M. Margelí-Vila¹⁴, R. Andrés¹⁵, S. Servitja¹⁶, M. Merino¹⁷, I. González¹⁸, J. Alonso-Romero¹⁹, R. Villanueva²⁰, M. Echarri²¹, A. Antón-Torres²², S. Varela²³, M. Ruíz-Borrego²⁴, J. Guerra²⁵, M. Corbellas²⁶, M. Escudero²⁷, S. Bezares²⁷, F. Rojo²⁸, S. López-Tarruella²⁹; ¹Medical Oncology, Unidad de Cáncer de Guipúzcoa – Osakidetza; GEICAM Spanish Breast Cancer Group, San Sebastián, SPAIN, ²Medical Oncology, Fundación Instituto Valenciano de Oncología (FIVO); GEICAM Spanish Breast Cancer Group, Valencia, SPAIN, ³Medical Oncology, Hospital Universitario de Canarias; GEICAM Spanish Breast Cancer Group, Santa Cruz de Tenerife, SPAIN, ⁴Medical Oncology, Complejo Hospitalario Universitario A Coruña (CHUAC); GEICAM Spanish Breast Cancer Group, A Coruña, SPAIN, ⁵Medical Oncology, Hospital Universitario de Basurto; GEICAM Spanish Breast Cancer Group, Bilbao, SPAIN, ⁶Medical Oncology, Hospital Universitario de Salamanca-IBSAL; GEICAM Spanish Breast Cancer Group, Salamanca, SPAIN, ⁷Medical Oncology, Hospitalario Universitario de Gran Canaria Dr. Negrín; GEICAM Spanish Breast Cancer Group, Las Palmas, SPAIN, ⁸Medical Oncology, Hospital de la Santa Creu i Sant Pau; GEICAM Spanish Breast Cancer Group, Barcelona, SPAIN, ⁹Medical Oncology, ICO Hospitalet; GEICAM Spanish Breast Cancer Group, Barcelona, SPAIN, ¹⁰Medical Oncology, Hospital Universitario de Toledo; GEICAM Spanish Breast Cancer Group, Toledo, SPAIN, ¹¹Medical Oncology, ALTHAIA Xarxa Asistencial de Manresa; GEICAM Spanish Breast Cancer Group, Barcelona, SPAIN, ¹²Medical Oncology, Hospital General Universitario de Elche; GEICAM Spanish Breast Cancer Group, Elche, SPAIN, ¹³Medical Oncology, Hospital General Universitario de Albacete; GEICAM Spanish Breast Cancer Group, Albacete, SPAIN, ¹⁴Medical Oncology, ICO-Badalona. B-ARGO (Badalona Applied Reasearch Group in Oncology); GEICAM Spanish Breast Cancer Group, Badalona, SPAIN, ¹⁵Medical Oncology, Hospital Clinico Universitario Lozano Blesa; GEICAM Spanish Breast Cancer Group, Zaragoza, SPAIN, ¹⁶Medical Oncology, Hospital del Mar-Hospital del Mar Research Institute ; GEICAM Spanish Breast Cancer Group, Barcelona, SPAIN, ¹⁷Medical Oncology, Hospital Universitario Infanta Sofía; GEICAM Spanish Breast Cancer Group, San Sebastián de los Reyes, SPAIN, ¹⁸Medical Oncology, Hospital Son Llátzer; GEICAM Spanish Breast Cancer Group, CR/ De Manacor, Km 4, SPAIN, ¹⁹Medical Oncology, Hospital Clínico-Universitario Virgen de la Arrixaca-IMIB; GEICAM Spanish Breast Cancer Group, Murcia, SPAIN, ²⁰Medical Oncology, Hospital de Sant Joan Despi Moises Broggi; GEICAM Spanish Breast Cancer Group, Sant Joan Despí, SPAIN, ²¹Medical Oncology, Hospital Universitario Severo Ochoa; GEICAM Spanish Breast Cancer Group, Madrid, SPAIN, ²²Medical Oncology, Hospital Universitario Miguel Servet; GEICAM Spanish Breast Cancer Group, Zaragoza, SPAIN, ²³Medical Oncology, Hospital Universitario Lucus Augusti; GEICAM Spanish Breast Cancer Group, Lugo, SPAIN, ²⁴Medical Oncology, Hospital Universitario Virgen del Rocío; GEICAM Spanish Breast Cancer Group, Sevilla, SPAIN, ²⁵Medical Oncology, Hospital Universitario Fuenlabrada; GEICAM Spanish Breast Cancer Group, Fuenlabrada, SPAIN, ²⁶Medical Oncology, Hospital Universitario Dr. Peset; GEICAM Spanish Breast Cancer Group, Valencia, SPAIN, ²⁷Medical Oncology, GEICAM Spanish Breast Cancer Group, San Sebastián de los Reyes, SPAIN, ²⁸Medical Oncology, Fundación Jiménez Díaz; GEICAM Spanish Breast Cancer Group, Madrid, SPAIN, ²⁹Medical Oncology, Hospital General Universitario Gregorio Marañón; CIBERONC-ISCIII; GEICAM Spanish Breast Cancer Group, Madrid, SPAIN.

Background: Breast cancer (BC) is a heterogeneous disease with distinct subtypes, each having different prognosis and treatment responses. RegistEM aims to understand the distribution of subtypes in advanced BC (ABC) and their clinical implications. Significant advances have led to better median overall survival (OS) in patients (pts) with HER2+ BC. Targeted anti-HER2 therapies have changed the management and prognosis of HER2+ ABC, although there is a lack of data from long-term responders (LTRs).Methods: ABC pts, either recurrent early BC (EBC) or de novo metastatic (dnMBC), diagnosed from Jan-16 to Dec-19, were enrolled in this ambispective non-interventional cohort study. Biological samples from primary tumors, metastatic lesions, and blood were collected. This subanalysis aims to better characterize LTRs among pts with HER2+ ABC receiving 1^st-line (1L) or 2^nd-line (2L) anti-HER2 targeted therapies. We defined LTR as pts who did not progress to 1L therapy for more than 35 months (mo.), or for more than 16 mo. in 2L therapy. BC subtype was assessed by immunohistochemistry (IHC) with or without in situ hybridization (ISH) in the most recent tumor sample before 1L therapy. In the current analysis, 1,900 pts from 38 GEICAM sites were included (database ongoing, cut-off date Mar 17, 2025).Results: 341/1,900 (18%) pts had HER2+ ABC, 133(39%) were considered as LTR and 197 (58%) as non-LTR (NLTR), 11 pts were excluded due to lack of information or not receiving systemic treatment for ABC. At ABC diagnosis, median age was 56 years (interquartile range 48-69), all pts were female (70% postmenopausal), 68 (51%) LTR and 77 (39%) NLTR had dnMBC (p=0.0881). Hormone receptors positive (HR+) were observed in 92 (69%) LTR and 122 (62%) NLTR. HER2 status was confirmed by IHC 3+ in 89 (67%) LTR and 140 (71%) NLTR, and ISH amplified in 55 (41%) LTR and 81 (41%) NLTR. A different pattern of metastatic spread was observed between LTR and NLTR (p<0.01; χ² test): visceral (58% vs. 76%), bone without visceral (27% vs. 16%), and only soft tissue (15% vs. 8%), respectively. Tumor burden with ≤2 locations was present in 57 (50%) LTR and 96 (49%) NLTR. Most frequent metastatic locations were lymph nodes (53%) and bone (51%), similar in both groups; more NLTR had liver (30% vs. 40%), lung (28% vs. 35%), pleura (2% vs. 11%), and brain (4% vs. 9%). Neo-/adjuvant therapy was given to 61 (95%) LTR and 112 (94%) NLTR with EBC, mainly chemotherapy (CT)/anti-HER2 (34% LTR vs. 38% NLTR), CT/endocrine therapy (ET)/anti-HER2 in 30% LTR, and CT in 22% NLTR, with 55 and 48 mo. as median time to ABC in LTR and NLTR, respectively. The most common 1L therapies in both groups were CT/biological therapy (BT) (33% LTR vs. 48% NLTR) and CT/ET/BT (50% LTR vs. 28% NLTR); BT was mainly anti-HER2 and antiangiogenics, and ET, aromatase inhibitors (AI). 2L-therapy was given to 57% LTR and 72% NLTR. Most common 2L therapies were BT (50% LTR and 59% NLTR), ET/BT (mainly AI plus anti-HER2) in LTR (29%), and CT/BT (anti-HER2 in 89%) in NLTR (20%). At database cut-off date and after a median follow-up of 46 mo, 1L median PFS (mPFS) was significantly longer in LTR patients: 50 mo. (95% confidence interval [CI]: 42-64) LTR compared to 12 mo. (95% CI: 10-13) in NLTR pts. No PFS event on 1L was seen in 52 (39%) LTR and 13 (7%) NLTR. 2L mPFS (95% CI) was 23 mo. (19-30) LTR vs. 5 (4-7) NLTR. Death was reported in 31/133 (23%) LTR and 149/197 (76%) NLTR, mainly because of PD (65% LTR vs. 77% NLTR). Median (95% CI) OS from ABC diagnosis was not reached in LTR and 34 mo. (31-38) NLTR.Conclusions: In our cohort, pts with HER2+ ABC classified as LTR more frequently had bone or soft tissue-only metastases compared to visceral disease. No significant differences were observed between LTR vs NLTR in terms of HR, HER2-IHC score (3+ vs. 2+), oligo- vs. non-oligometastatic presentation, or dnMBC vs recurrent EBC disease.

M. Inoue-Choi¹, B. Adeyemi², J. Schmidt³, L. Luo⁴, A. Ali⁵; ¹Oncology Outcomes Research, AstraZeneca, Gaithersburg, MD, ²US Medical Affairs, Oncology Business Unit, AstraZeneca, Gaithersburg, MD, ³GMA/Payer Biometrics, Oncology R&D, AstraZeneca, Cambridge, UNITED KINGDOM, ⁴Oncology Data & Analytics, AstraZeneca, Gaithersburg, MD, ⁵Department of Hematology and Oncology, Cleveland Clinic Foundation, Case Western Reserve University Cleveland, Cleveland, OH.

Background: The current guideline-recommended 1L standard of care (SOC) for HER2+ mBC is taxane, trastuzumab, and pertuzumab (THP) followed by maintenance therapy after initial response; however, many patients may not receive SOC in routine clinical practice. This study describes demographics, disease characteristics, and long-term treatment outcomes in US patients treated with SOC or other treatments for 1L HER2+ mBC. Methods: This retrospective observational study used the nationwide Flatiron Health database of derived and de-identified electronic health records. Patients aged ≥18 years with HER2+ mBC who received 1L treatment for mBC from January 2015 to February 2024 (excluding clinical trial drugs), with confirmatory HER2+ biomarker test results before initiation of 1L treatment, were included. Demographic and clinical characteristics were captured on the index date (start of 1L treatment). Patients were followed until death or last activity date on or before end of study (September 2024). SOC was defined as THP followed by maintenance trastuzumab/pertuzumab after response (with concurrent endocrine therapy for hormone receptor-positive [HR+] disease). Study outcomes included real-world time from initiation of 1L treatment to initiation of 3L treatment or death (rwTTNT2) and real-world time from initiation of 1L treatment to disease progression after initiation of 2L treatment or death (rwPFS2). Results: Overall, 3277 patients were included; 1L SOC was received by 35.5% (n=1164) of patients, with mean (standard deviation) age at index date of 58.7 (12.4) years, compared with 61.4 (14.1) years for other regimens (see Table for further characteristics). Of the 64.5% (n=2113) of patients who received other regimens, 17.1% (n=362) received HER2-targeted monotherapy and 36.8% (n=778) HER2-targeted combination therapy. Recurrent disease and HR+ status were observed in a greater proportion of patients treated with other regimens than with SOC. During follow up, 32.9% of patients treated with 1L SOC were observed to receive 3L treatment, 26.5% died, and 40.6% were censored before 3L. In patients receiving other regimens at 1L, these proportions were 37.1%, 33.3%, and 29.6%, respectively. Median rwTTNT2 (95% CI) was prolonged in patients treated with 1L SOC versus other regimens (30.1 [27.4, 33.6] vs 17.4 [16.1, 19.0] months). Median rwPFS2 (95% CI) was also prolonged in patients treated with 1L SOC (26.1 [24.2, 28.0] months) versus other regimens (18.9 [17.7, 19.9] months). Conclusion: Among patients with HER2+ mBC, receipt of guideline-recommended SOC (vs not) in the 1L setting was associated with substantially prolonged long-term outcomes. However, disease characteristics at treatment initiation may have influenced treatment regimen choice and impacted long-term outcomes.

H. Wildiers¹, N. Harbeck², E. Ciruelos³, G. Jerusalem⁴, V. Müller⁵, N. Niikura⁶, G. Viale⁷, R. Bartsch⁸, C. Kurzeder⁹, M. Higgins¹⁰, R. Connolly¹¹, S. Baron-Hay¹², M. Gión¹³, V. Guarneri¹⁴, G. Bianchini¹⁵, S. Escrivá-de-Romaní¹⁶, M. Prahladan¹⁷, S. Anand¹⁸, N. Toms¹⁷, R. Antony¹⁹, N. Lin²⁰; ¹Department of General Medical Oncology, University Hospitals Leuven, KU Leuven, Leuven, BELGIUM, ²Breast Center, Department of Gynecology and Obstetrics, Comprehensive Cancer Center Munich, LMU University Hospital, Munich, GERMANY, ³Breast Cancer Unit, Hospital Universitario 12 de Octubre, Madrid, SPAIN, ⁴Department of Medical Oncology, CHU Liège and Liège University, Liège, BELGIUM, ⁵Department of Gynecology and University Breast Center, University Medical Center Hamburg-Eppendorf, Hamburg, GERMANY, ⁶Department of Breast Oncology, Tokai University School of Medicine, Isehara City, Kanagawa Prefecture, JAPAN, ⁷Department of Pathology and Laboratory Medicine, IEO European Institute of Oncology IRCCS, Milan, ITALY, ⁸Division of Oncology, Department of Medicine 1, Medical University of Vienna, Vienna, AUSTRIA, ⁹Breast Center, University Hospital Basel, Basel, SWITZERLAND, ¹⁰UCD Cancer Trials Cluster, St. Vincent’s University Hospital, Dublin, IRELAND, ¹¹Cancer Research @ UCC, University College Cork, Cork, IRELAND, ¹²Department of Medical Oncology, Royal North Shore Hospital, Sydney, NSW, AUSTRALIA, ¹³IOB-Madrid, Beata María Ana Hospital, Madrid, SPAIN, ¹⁴Department of Surgery, Oncology and Gastroenterology, University of Padova, Padova, ITALY, ¹⁵Department of Medical Oncology, IRCCS Ospedale San Raffaele, Milan, ITALY, ¹⁶Medical Oncology Department, Vall d’Hebron Institute of Oncology and Vall d’Hebron University Hospital, Barcelona, SPAIN, ¹⁷Global Medical Affairs, Oncology R&D, AstraZeneca, Cambridge, UNITED KINGDOM, ¹⁸Biostatistics, Oncology R&D, AstraZeneca, Gaithersburg, MD, ¹⁹Global Medical Affairs, Oncology R&D, AstraZeneca, Gaithersburg, MD, ²⁰Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA.

Background: T-DXd demonstrated substantial and durable overall and intracranial clinical activity in DESTINY-Breast12. In pts with BM, 12-month progression-free survival (PFS) and central nervous system (CNS) PFS rates were 61.6% and 58.9%, respectively, and CNS objective response rate (ORR) was 71.7% (79.2% in pts with stable and 62.3% in pts with active BM). In the cohort of pts without BM, efficacy of T-DXd was in line with previous data, and there were no new safety signals. To date, T-DXd has shown clinical benefit irrespective of HR status, most recently in first-line HER2+ mBC in DESTINY-Breast09. In a post-hoc analysis of DESTINY-Breast12, outcomes by HR status in pts with BM were explored. Methods: Pts ≥18 years old with HR-positive (HR+) or HR-negative (HR−) HER2+ mBC whose disease had progressed after ≤2 previous lines of therapy were eligible; BM were required to be stable or active (untreated/treated progressing) and not in need of immediate local therapy. All pts received intravenous T-DXd 5.4 mg/kg every 3 weeks. Efficacy outcomes were analyzed by baseline HR status using the Kaplan-Meier technique for PFS. Results: In total, 262 pts with baseline BM were included in this analysis, of whom 165 (63.0%) had HR+ disease. Among pts with BM, the median age (range) was 52.0 (30-80) years in the HR+ subgroup and 54.0 (28-86) years in the HR− subgroup (n=97). Median follow up for PFS at data cutoff (February 8, 2024) was 13.1 months in both subgroups. Median PFS was not calculable for either HR subgroup. The 12-month PFS and CNS PFS, as well as CNS ORR, were indicative of consistent responses with T-DXd regardless of HR subgroup; confirmed ORRs, including in pts with measurable disease at baseline, indicated activity of T-DXd in pts with HR+ and HR− tumors (Table). The median total treatment duration (range) was 12.0 (0.7-26.9) months in the HR+ subgroup and 11.1 (0.1-26.8) months in the HR− subgroup. Adverse events of any grade in pts occurred with a similar overall incidence in both HR subgroups; the most common Grade ≥3 events were neutropenia (12.1%), anemia (7.3%), and fatigue (6.7%) in the HR+ subgroup, and neutropenia (11.3%), decreased neutrophil count (8.2%), and anemia (7.2%) in the HR− subgroup. Interstitial lung disease / pneumonitis occurred in 26 (Grade 5, n=3) and 16 (Grade 5, n=3) pts in the HR+ and HR− subgroups, respectively. Results by HR subgroup in the cohort without BM (data not presented) were consistent with those from the cohort with BM. Conclusion: T-DXd demonstrated consistent intracranial activity and safety in pts with BM, regardless of HR status. These data reinforce the utility of T-DXd as a second-line treatment regardless of HR status in pts with HER2+ mBC.

*n=125 (HR+) and n=72 (HR−); †based on n=84 (HR+) and n=53 (HR−) with measurable disease at baseline

J. Chien¹, E. Neuberger², S. Simon³, K. Watkins², G. Curigliano⁴, B. Li², S. Stergiopoulos², M. Czachorowski⁵, H. Itakura⁶; ¹Helen Diller Family Comprehensive Cancer Center, UCSF, San Francisco, CA, ²Pfizer Inc., Pfizer Inc., New York, NY, ³Pfizer S.L.U., Pfizer S.L.U., Madrid, SPAIN, ⁴European Institute of Oncology, IRCCS, and Department of Oncology and Hemato-Oncology, University of Milano La Statale, Milano, ITALY, ⁵Pfizer Ltd., Pfizer Ltd., Surrey, UNITED KINGDOM, ⁶Medicine – Med/Oncology, Stanford University School of Medicine, Stanford, CA.

Background: US and EU treatment guidelines currently recommend tucatinib in combination with trastuzumab and capecitabine (TTC) in third-line (3L) for patients with human epidermal growth factor receptor 2-positive (HER2+) metastatic breast cancer (MBC), and in second-line (2L) for those patients with brain metastases (BM). More recently, trastuzumab deruxtecan (T-DXd) has become the recommended 2L treatment option and may be considered as first-line treatment for patients with rapid progression after (neo)adjuvant therapy. Previous real-world studies in patients receiving TTC after T-DXd have reported median time to next treatment (TTNT) of 6 months and median overall survival (OS) of 13 months; however, these study populations included later line treatment, a small sample size, and did not solely include TTC immediately following T-DXd, limiting applicability to current clinical practice. This study aimed to describe real-world outcomes in patients with HER2+ MBC in the US who were treated with TTC in 2L, 3L and fourth-line (4L) immediately following T-DXd. Methods: We conducted a retrospective cohort analysis of patients with HER2+ MBC receiving TTC therapy using the Flatiron Health electronic health record (EHR)-derived deidentified longitudinal database. This US nationwide database, containing patient-level structured and unstructured data curated using natural language processing with machine learning and technology-enabled abstraction, includes >720,000 patients with breast cancer. Patients included were diagnosed with HER2+ MBC (January 2017 to July 2024), treated with TTC in 2L, 3L or 4L immediately following T-DXd, and were not enrolled in clinical trials. Patients were assessed from the start of TTC (index date) to death, last medical activity, or end of available study follow-up (January 2025), whichever came first. Primary outcomes included, but were not limited to, TTNT and OS in all patients. Exploratory analyses will assess TTNT and OS in patients stratified by BM status, duration of T-DXd treatment, and hormone receptor status. Descriptive statistics were used for patient characteristics, and outcomes were evaluated using Kaplan-Meier analyses. Results: In total, 92 patients with HER2+ MBC received TTC immediately following T-DXd. Overall, median (95% CI) TTNT was 8.6 (5.7-11.6) months and median (95% CI) OS was 19.5 (12.0-26.1) months (Table). Exploratory outcomes will be presented in future analyses. Conclusion: Patients with HER2+ MBC benefit from TTC immediately after treatment with T-DXd, demonstrating its clinically meaningful activity in a contemporaneous post-T-DXd setting. These results reinforce the effectiveness of tucatinib, with longer TTNT and OS than in previous real-world studies, in a population more applicable to current clinical practice.

S. Im¹, J. Cortes², S. Kim³, G. Curigliano⁴, G. Buscacio de Sousa⁵, S. E. Nagai⁶, T. Sun⁷, J. Ignacio Delgado Mingorance⁸, P. Stephens⁹, V. Kaklamani¹⁰, F. Puglisi¹¹, C. Levy¹², H. Iwata¹³, S. A. Hurvitz¹⁴, S. Nakatani¹⁵, Z. Liang¹⁶, S. Ashfaque¹⁷, A. Egorov¹⁸, E. P. Hamilton¹⁹; ¹Department of Internal Medicine, Seoul National University Hospital, Cancer Research Institute, Seoul National University College of Medicine, Seoul, KOREA, REPUBLIC OF, ²Department of Oncology, International Breast Cancer Center (IBCC), Pangaea Oncology, Quironsalud Group, Barcelona, SPAIN, ³Department of Oncology, Asan Medical Center, University of Ulsan, Seoul, KOREA, REPUBLIC OF, ⁴Department of Oncology and Hemato-Oncology, European Institute of Oncology, IRCCS, University of Milano, Milano, ITALY, ⁵Department of Breast Cancer, Instituto Americas, Rio de Janeiro, BRAZIL, ⁶Department of Breast Oncology, Saitama Cancer Center, Saitama, JAPAN, ⁷Department of Oncology, Cancer Hospital of Dalian University of Technology, Shenyang, CHINA, ⁸Servicio de Oncología Médica, Hospital Universitario de Badajoz, Badajoz, SPAIN, ⁹Exeter Oncology Centre, Royal Devon and Exeter Hospital, Exeter, UNITED KINGDOM, ¹⁰Department of Medicine, Breast Oncology Program, UT Health San Antonio, MD Anderson Cancer Center, San Antonio, TX, ¹¹Department of Medicine (DMED), University of Udine, Department of Medical Oncology, National Cancer Institute, Centro di Riferimento Oncologico (CRO), Udine, Aviano, ITALY, ¹²Department of Medical Oncology, Centre François Baclesse, Caen, FRANCE, ¹³Department of Advanced Clinical Research and Development, Nagoya City University, Graduate School of Medical Sciences, Nagoya, JAPAN, ¹⁴Clinical Research Division (FHCC) and Division of Hematology/Oncology, Department of Medicine (UW), Fred Hutchinson Cancer Center and University of Washington, Seattle, WA, ¹⁵Department of Clinical Science, Daiichi Sankyo Co., Ltd., Tokyo, JAPAN, ¹⁶Department of Biostatistics & Data Management, Daiichi Sankyo, Basking Ridge, NJ, ¹⁷Department of Clinical Safety, Daiichi Sankyo, Basking Ridge, NJ, ¹⁸Department of Global Oncology Clinical Development, Daiichi Sankyo Oncology France, Rueil-Malmaison, FRANCE, ¹⁹Department of Oncology, Sarah Cannon Research Institute, Nashville, TN.

Background In DESTINY-Breast03 (NCT03529110), T-DXd demonstrated a statistically significant and clinically meaningful improvement in progression-free survival (PFS) and overall survival (OS) over T-DM1 in pts with HER2+ mBC previously treated with trastuzumab and a taxane. Here, we report the 5-year follow-up analysis of efficacy and safety. Methods DESTINY-Breast03 is a randomized, multicenter, open-label, phase 3 study. Pts were randomly assigned (1:1) to receive either T-DXd 5.4 mg/kg or T-DM1 3.6 mg/kg intravenously every 3 weeks. Exploratory analyses (investigator assessed) at 5 years included OS, PFS, PFS2 (time from randomization to disease progression on the next line of therapy or death), confirmed objective response rate (cORR), duration of response (DoR), and safety. Results In all, 524 pts were randomly assigned (261 to T-DXd and 263 to T-DM1), with the last pt enrolled on June 23, 2020. As of the data cutoff (DCO), June 27, 2025, median (m; range) duration of follow-up was XX.X mo (XX.X-XX.X) for T-DXd and XX.X mo (XX.X-XX.X) for T-DM1; XX pts (XX.X%) in the T-DXd group and XX pts (XX.X%) in the T-DM1 group remained on treatment. The most common reasons pts discontinued study treatment were progressive disease (PD; [XX.X%]) and adverse events (AEs; [XX.X%]) with T-­DXd, and PD (XX.X%) and AEs (XX.X%) with T-DM1. XX pts (XX.X%) in the T-DXd group and XX pts (XX.X%) in the T-DM1 group received subsequent therapy of physician’s choice. Median treatment duration (range) was XX.X mo (XX.X-XX.X) with T-DXd and XX.X mo (XX.X-XX.X) with T-DM1. mOS (95% CI) was XX.X mo (XX.X-XX.X) with T-DXd and XX.X mo (XX.X-XX.X) with T-DM1 (hazard ratio [HR], X.XX [95% CI, X.XX-X.XX], using a Cox regression model with treatment as the only covariate). The OS (95% CI) rate at 5 years was XX.X% (XX.X-XX.X%) with T-DXd vs XX.X% (XX.X-XX.X%) with T-DM1. mPFS (95% CI) was XX.X mo (XX.X-XX.X) with T-DXd vs XX.X mo (XX.X-XX.X) with T-DM1 (HR, X.XX [95% CI, X.XX-X.XX]). The PFS (95% CI) rate at 5 years was XX.X% (XX.X-XX.X%) with T-DXd vs XX.X% (XX.X-XX.X%) with T-DM1. mPFS2 (95% CI) was XX.X mo (XX.X-XX.X) with T-DXd vs XX.X mo (XX.X-XX.X) with T-DM1. Rates of treatment-emergent adverse events (TEAEs) were consistent with the prior DCO. Adjudicated drug-related interstitial lung disease (ILD)/pneumonitis occurred in XX.X% of pts treated with T-DXd (X new events [grade X] since last DCO) and XX.X% of pts with T-DM1 (X new events [grade X]), with no grade 4/5 events in either group. Updated data are shown in the Table. Conclusions The final analysis of DESTINY-Breast03 confirms the superior efficacy of T-DXd over T-DM1 in pts with HER2+ mBC whose disease had progressed following prior treatment with trastuzumab and a taxane. The safety profile of T-DXd remains manageable, with no new safety signals observed with longer follow-up.

R. Song, Y. Fan, B. Xu, B. Lan, F. Ma; Medical Oncology, Chinese Academy of Medical Sciences and Peking Union Medical College – National Cancer Center, Cancer Hospital, Beijing, CHINA.

Objective: Human epidermal growth factor receptor (HER2)-targeted tyrosine kinase inhibitors (TKIs) have transformed the treatment landscape for HER2-positive metastatic breast cancer (MBC). Previous studies demonstrated the robust antitumor activity of TKIs in both first-line and later-line settings. Nevertheless, the benefits of maintaining TKI-based regimens after resistance remain uncertain. Based on real-world data, this study comprehensively assessed the clinical value of cross-line TKI application and investigated key factors influencing efficacy, aiming to provide insights for TKI administration in the advanced stage. Methods: This real-world study consecutively enrolled HER2-positive MBC patients receiving TKI-based regimens at 3 institutions (including the National Cancer Center, China) from October 2014 to April 2024. Inclusion criteria included patients who received at least two lines of TKI-based therapy in the advanced settings. Patients receiving cross-line TKI therapy not due to disease progression and with incomplete clinical records were excluded. The primary endpoint was progression-free survival (PFS). Results: A total of 132 patients with HER2-positive metastatic breast cancer who received two or more lines of TKI-based regimens were enrolled, with 49 receiving three lines and 19 receiving four lines of TKI therapy. The median age of all patients was 52 years. In patients receiving two lines of TKI therapy (N = 132), second-line PFS (PFS2) was significantly shorter than first-line (median PFS (mPFS): 5.5 vs. 9.0 months; hazard ratio (HR) 2.048; 95% confidence interval (CI) 1.588 – 2.640; P < 0.001). Multivariate Cox regression analysis identified PFS1 ≥ 6 months as an independent predictor of prolonged PFS2 (HR 0.492; 95% CI 0.333 – 0.728; P < 0.001). Among patients receiving TKI as the sole HER2-targeted agent (TKI with/without chemotherapy or endocrine therapy) (N = 70), the addition of chemotherapy in the second-line setting was associated with a significantly longer PFS2 compared to chemotherapy-free regimens (mPFS: 6.4 vs. 2.2 months; HR 0.404; 95% CI 0.208 – 0.787; P = 0.005). Similarly, patients who switched to a different TKI agent experienced a longer PFS2 than those who continued the original TKI regimen (mPFS: 6.8 vs. 4.5 months; HR 0.581; 95% CI 0.356 – 0.948; P = 0.025). Importantly, patients who switched from lapatinib to pyrotinib had a significantly longer PFS2 compared to those who continued pyrotinib in the second-line setting (mPFS: 7.0 vs. 4.1 months, HR 0.523, 95%CI 0.298 – 0.917, P < 0.001). Further analysis of patients receiving three lines of TKI therapy (N = 49) showed that PFS3 was shorter than PFS2 and PFS1 (mPFS: 4.1, 6.2, and 9.1 months, respectively; P < 0.001, P for trend < 0.0001). Notably, patients with high HER2 expression (immunohistochemistry 3+ vs. 2+ and fluorescence in situ hybridization positive, HR 0.282; 95% CI 0.117 – 0.680; P = 0.005) and PFS1 > 9.1 months (HR 0.549; 95% CI 0.306 – 0.988; P = 0.045) were associated with markedly longer PFS3. In the second- and third-line TKI settings, PFS did not significantly differ between regimens using TKI as the sole anti-HER2 agent and those combining TKI with another anti-HER2 agent (antibody or antibody-drug conjugate) (P > 0.05). Conclusions: This study indicated that cross-line anti-HER2 TKI therapy confers sustained PFS benefits in HER2-positive MBC. Notably, patients with longer frontline PFS and those who switched TKI agents exhibited superior survival outcomes in subsequent treatment lines. Further prospective studies are warranted to confirm these findings.

Y. Liu, S. Guohong, R. Ran, J. Hanfang, S. Bin, X. Liang, Z. Jiayang, Z. Ruyan, L. Huiping; Department of Breast Oncology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Beijing, CHINA.

Background: Based on anti-HER2 therapy, the combination of CDK4/6 inhibitors proved to be a potential regimen, which can simultaneously inhibit the crosstalk between the ER and HER2 pathways. PATINA study showed a meaningful prolonged PFS after a chemo-based induction therapy when added Palbociclib to the maintaining treatment, same kind of de-chemo treatment which also achieve better efficacy is still expected to be the initial regimen during metastatic setting.Methods: CABC016 is a phase II, single-arm, prospective cohort study (NCT05969184), assessing palbociclib combine with anti-HER2 antibody and endocrine therapy (ET) to treat HR+/HER2+ metastatic breast cancer (MBC). Patients are treated with palbociclib at a dose of 125 mg daily on days 1 – 21 of a 28 – day cycle, plus trastuzumab (H, trastuzumab or inetetamab) or trastuzumab plus pertuzumab (HP) intravenously on day 1 of each 21-day cycle. ET options included aromatase inhibitor (AI), tamoxifen or fulvestrant depend on endocrine sensitivety, with ovarian suppression required for premenopausal patients. The primary endpoint is investigator-assessed progression-free survival (PFS); key secondary endpoints were safety, response rate (ORR), disease control rate (DCR), and survival (OS).Result Analysis cutoff date is June 21, 2025. Enrolled 47 eligible MBC patients with a median age of 56 (32 – 74). 72.3% and 68.1% have >50% ER and >30% Ki – 67 expression. 72.3% patients had visceral and 17.0% had stable brain disease. At least one prior chemotherapy regimen was administered in 70.2% of patients, of whom 46.8% have been treated with taxane. The mPFS of ITT population is 16.5 m(95%CI, 11.3 – 21.9), with 19.3 m (95%CI, 15.5 – 22.5) of median follow – up. The mOS is 34.9 m(95%CI, 29.1 – 40.6), which is immature. Further analysis found that patients who were ET-naïve during metastatic setting had better mPFS (22.0 m[95%CI, 16.3 – 27.6], n = 26) than who had been treated by ET (8.3 m[95%CI, 3.2 – 13.5], n = 21) (P < 0.001). mPFS is longer in the front lines than late lines (mPFS of 1, 2 and 3 or more prior ET is 11.1 m[95%CI, 3.2 – 19.0; n = 12], 4.8 m[95%CI, 3.7 – 6.1; n = 7] and 1.5 m[95%CI, 0.3 – 2.7; n = 2], respectively (P < 0.001). At a median of 3 lines of this cohort, mPFS is better in 1st- line treatment (18.9 m[95%CI, 12.5 – 25.5; n = 17]) than in second/third – line (15.8 m[95%CI, 9.9 – 21.7; n = 18]), than fourth or later(up to 12 lines)treatment (7.7 m[95%CI, 1.5 – 13.9; n = 12]) (P = 0.008). In front line (line 1-3) patients, mPFS is even longer in ET-naïve patients (24.1 m[95%CI, 18.6 – 29.6], n = 23]) than those under ET treated (7.0 m[95%CI, 3.3 – 10.8], n = 12). No significant difference in mPFS was observed between the inetetamab (13.9 m[95%CI, 9.3 – 18.5; n = 26]) and trastuzumab (14.5 m[95%CI, 7.4 – 21.6; n = 21]) (P = 0.28), or H and HP (11.3month[95%CI, 6.0 – 16.5] vs. 18.1m[95%CI, 11.0 – 25.1; P = 0.418). The ORR of ITT population is 34.1%, included 1 CR, and DCR is 87.8%. While in ET-naïve setting, the ORR rise to 45.5%, and DCR rise to 95.5%. For patients with stable brain disease, the longest survival reached 34.6 months, no significant difference in mPFS was observed between patients with or without brain disease (P= 0.293), with a 50% ORR and 62.5% DCR, respectively. The overall safety profile was manageable. The most common grade 3-4 AEs were neutropenia (44.2%) and thrombocytopenia (20.9%). Dose reduction of palbociclib (from 125mg to 100mg) had occurred in 18 patients (38.3%) because of myelotoxicity. No patient fell out because of AEs.Conclusion: This mini cohort study showed palbociclib plus ET plus anti-HER2 antibody could be one of the optimal initial treatment options for metastatic setting of HR+/HER2+ breast cancer, especially for early use during ET-based regimen, even for stable brain disease.

V. Valero, Z. WANG, R. BASSETT, R. K. MURTHY, P. POHLMANN, D. TRIPATHY, A. RAGHAVENDRA; BREAST MEDICAL ONCOLOGY, MD ANDERSON CANCER CENTER, HOUSTON, TX.

Clinical Outcomes of Trastuzumab Emtansine (T-DM1) Following Trastuzumab Deruxtecan (T-DXd) inMetastatic Breast Cancer: A Single-Center Experience Background: HER2-positive metastatic breast cancer (MBC) remains an oncological challenge afterdisease progression to pertuzumab-trastuzumab, and fam-trastuzumab deruxtecan. Data on treatmentoutcomes with T-DM1 following progression on trastuzumab deruxtecan (T-DXd) remain limited. This study evaluates the clinical outcomes of patients with HER2-positive MBC who received T-DM1 post-T-DXd. Methods: Demographics and clinical characteristics were summarized for the whole cohort who received T-DM1 after T-DXd. Continuous variables were summarized using medians and ranges, while categorical variables were summarized using frequencies and percentages. Overall survival (OS), defined as the time from the date of receiving T-DM1 to the date of death or last follow-up, progression-free survival (PFS),defined as the time from the date of receiving T-DM1 to the date of first documented disease progression or death, whichever occurred first, and time to progression (TTP), defined as the time from the date of receiving T-DM1 to the date of disease progression, were evaluated using the Kaplan-Meier method, and differences in survival curves were compared using the log-rank test. Cox proportional hazards regression models assessed associations between survival outcomes and clinical variables. The overall response rate was calculated based on the proportion of patients experiencing progressive or stable disease. A p-value <0.05 was considered significant. Analyses were performed using R version 4.2.2.Results: All 22 patients were female with a median age of 55.5 years. Median OS was 13.54 months (95% CI:8.74-NE), median PFS was 2.14 months (95% CI: 1.35-2.69), and median TTP was 2.20 months (95% CI: 1.38-2.69). HER2-low expression was associated with shorter OS (HR: 3.05), PFS (HR:4.30), and TTP (HR: 5.30). Overall response rate was 91%, with 68% showing progressive disease and 23% stable disease. No significant associations were identified between best response and other clinical variables. Conclusions: This study provides real-world evidence of the limited clinical efficacy of T-DM1 following resistant to T-DXd in HER2-positive MBC. Further research is warranted to develop novel therapeutic agents in this subgroup of patients and also to develop strategies to avoid resistant to T-DXd.Keywords: Fam-trastuzumab deruxtecan, Trastuzumab emtansine, metastatic breast cancer, outcomes, Antibody-drug conjugates, metastatic breast cancer

Y. Liu¹, J. Bahia², C. Haghighi¹, S. Vinayak¹, J. S. Childs¹, M. L. Disis¹; ¹Cancer Vaccine Institute, University of Washington, Seattle, WA, ²Division of General Internal Medicine, University of Washington, Seattle, WA.

Incidence of the development of brain metastases in patients with advanced stage HER2+ breast cancer who have previously received a HER2 directed cancer vaccine. Ying Liu, Jaspreet Bahia, Candace B Haghighi, Shaveta Vinayak, Jennifer S. Childs, and Mary L. Disis. UW Cancer Vaccine Institute, University of Washington, Seattle WA Background: HER2-positive breast cancer, characterized by the overexpression of the HER2 protein, has been associated with an aggressive disease course, higher rates of recurrence, and poorer prognosis compared to HER2-negative breast cancer and accounts for approximately 15-20% of all breast cancer cases. The introduction of HER2-targeted therapies has transformed the treatment of HER2+ breast cancer and significantly improved survival rates. A major challenge for patients is the development of brain metastases, which can occur in up to 30–50% of patients with breast cancer. Patients with HER2+ breast cancer have a higher risk of developing brain metastases. Immune system cells, specifically T-cells, are one of the few modalities that are capable of crossing the blood brain barrier and may offer an immunologic approach to the prevention of brain metastases in high risk patients. We have been immunizing HER2+ breast cancer patients with HER2 directed vaccines for over 2 decades and sought to determine the impact of HER2-targeted cancer vaccines on the development of brain metastases compared to historical controls. In addition, we will explore the link between the clinical outcomes of patients and the level of immunity they achieved after HER2 specific immunization. Methods: We conducted a retrospective review of 146 patient medical records of advanced stage (III or IV) breast cancer patients, with a HER2+ breast cancer diagnosis confirmed by either IHC 3+ or FISH amplification, who had received a HER2 directed vaccine from one of four clinical trials conducted at the University of Washington, Cancer Vaccine Institute. Patients were followed for the development of brain metastases from the time of initiation of vaccination for at least 5 years. The diagnosis of brain metastases was based on surgical and pathological reports or radiology records and clinical notes from the medical record. IRB approval was obtained prior to initiation of the study. Results: Of the 146 patients with retrospective data, 12 patients had documented brain metastases prior to trial enrollment and were excluded from further evaluation. Of the remaining 134 patients who had no brain metastases at enrollment and subsequently received HER2-targeted vaccines, 21 developed brain metastases, yielding a cumulative incidence (CI) of 15.7%. Stratified by hormone receptor (HR) status, the incidence was 16.9% in HR+/HER2+ patients (n = 13) and 14.5% in HR-/HER2+ patients (n = 8). When compared to a recent historical control cohort of 18,075 real-world patients from the U.S. Flatiron Health database, which reported a 60-month CI of brain metastases of 22.7% in HR+/HER2+ and 33.6% in HR-/HER2+ subgroups, our findings suggest a 26% relative reduction of brain metastases in HR+/HER2+ patients and a 57% reduction in HR-/HER2+ patients. Conclusion: HER2 directed vaccination could have a protective effect on the development of brain metastases in patients with advanced stage HER2+ breast cancer. Phase II trials are planned to prospectively evaluate the vaccine in this setting.

G. Pfeiler, F. Heinzl, C. Leser, D. Gschwantler-Kaulich, C. Singer, S. Kostic, A. Golescu, C. Deutschmann; Department of Obstetrics and Gynecology, Medical University of Vienna, Vienna, AUSTRIA.

BackgroundTimely genetic testing in HER2-negative metastatic breast cancer (mBC) patients is important to identify BRCA mutations and allow optimal treatment options including Poly(ADP-ribose)polymerase inhibitors (PARPi) and platinum salts. Yet, testing rates have been reported unsatisfactory. Evaluation of the implementation of genetic testing in a real-world setting is important to reveal and subsequently target potential inadequacies and risk factors that are associated with a low testing rate. MethodsWe performed a retrospective analysis including all HER2- mBC patients treated at the Department of Obstetrics and Gynecology of the Medical University of Vienna, Austria, starting from 10.4.2019 (date of EMA approval of Olaparib for gBRCAmut HER2- mBC). The primary objective of the study was to evaluate the rate of HR+/HER2- mBC patients treated at a single academic center in Austria that were recommended to undergo genetic testing by the treating physicians. The secondary objective of the study was to identify factors that were associated with a higher likelihood of having undergone genetic testing. We performed descriptive statistics as well as logistic regression analysis using R version 4.3.2. Results47.6% (109 of 229) of HER2- mBC patients and therefore with an indication for genetic testing had been recommended to undergo genetic testing by the treating physicians. Of these informed patients, 89.0% (97 of 109) underwent genetic testing, of which 11.6% (11 of 95) had a BRCA mutation and were eligible for targeted treatment. In multivariate analysis younger age (p-value: 0.0007), HR+/HER2- subtype (p-value: 0.0000) and positive family history for breast and ovarian cancer (p-value: 0.0001) were significantly associated with the conduct of genetic counseling.ConclusionThe present study showed low genetic counseling rates of HER2- mBC patients in a real-world academic setting especially in patients without specific risk factors for hereditary breast cancer. Informed patients showed a high willingness to undergo genetic testing. Genetic testing revealed targetable mutations in over 10% of tested patients and allowed additional treatment options.

W. Jacot¹, F. Bidard², R. Colin-Chevalier³, S. Guiu¹, S. Renault⁴, G. Lossaint⁵, J. Pierga², L. Cayrefourcq⁶, F. Fiteni⁷, C. Alix-Panabières⁶; ¹Department of Medical Oncology, Institut du Cancer de Montpellier, Montpellier, FRANCE, ²Department of Medical Oncology, Institut Curie, Paris and Saint Cloud, Paris, FRANCE, ³Department of Biometry, Institut du Cancer de Montpellier, Montpellier, FRANCE, ⁴Circulating Tumor Biomarkers Laboratory, Inserm CIC-BT 1428, Department of Translational Research, Institut Curie, Paris, FRANCE, ⁵Department of Clinical Research and Innovation, Institut du Cancer de Montpellier, Montpellier, FRANCE, ⁶Laboratoire Cellules Circulantes Rares Humaines, University Medical Centre of Montpellier, Montpellier, FRANCE, ⁷Department of Medical Oncology, University Medical Centre of Nimes, Nimes, FRANCE.

Background: Trastuzumab deruxtecan (T-DXd) has become the standard second-line treatment of HER2-overexpressing metastatic breast cancer (HER2⁺ MBC). However, to date, no reliable circulating biomarker has been identified to anticipate the resistance or sensitivity to this compound, and to better understand the underlying mechanisms of resistance / sensitivity. We evaluated in a prospective cohort the respective value of circulating tumor cell (CTC) levels, as well as CTC HER2 immunostaining and its heterogeneity, before and early during therapy as a tool to evaluate the prognosis of HER2⁺ MBC patients. Methods: We prospectively enrolled patients with HER2⁺ MBC receiving T-DXd across three French clinical centers (NCT04025541). Peripheral blood samples were collected at three timepoints: prior to treatment initiation (T₁), before the second treatment cycle (T₂), and at the time of confirmed disease progression (T₃). CTCs were detected using the CellSearch® system. For each detected CTC, both enumeration and quantitative assessment of HER2 expression by immunofluorescence were performed. HER2 staining intensity and intra-patient heterogeneity were evaluated using the ACCEPT image analysis algorithm, enabling characterization of HER2-positive CTCs (HER2⁺ CTCs). Progression-free survival (PFS) was modeled based on longitudinal trajectories of HER2⁺ CTC levels using shared random effects joint models. Results: A total of 60 evaluable patients were enrolled between June 2021 and February 2025. As of the data cutoff (July 1, 2025), with a median follow-up of 17.2 months (95% CI: 11.6-21.7 months), 28 patients had experienced disease progression. CTCs were detectable at baseline (T₁) in 20 patients (33.3%) and at the second timepoint (T₂) in 4 patients (6.6%). No baseline clinical or pathological variables were found to be significantly associated with CTC positivity at T₁. Neither the baseline presence of CTCs (with a median PFS of 13.6 months [7.5 – 25.4] vs. 17.1 [8.9 – NA], p=0.4, for the CTC+ (≥1 detected cell) and CTC- populations, respectively) nor the longitudinal evolution model were associated with PFS. HER2⁺ CTCs were detected in 7 patients (11.6%). Among CTC-positive cases, no statistically significant correlation was observed between the number of CTCs and the presence of HER2⁺ CTCs. Notably, HER2⁺ CTCs were exclusively identified in patients whose tumor tissue exhibited HER2 3+ expression. While not significant (p=0.2), the HER2⁺ CTC population presented a PFS twice longer compared to the HER2⁺ CTC-negative population (25.3 [8.1 – NA] vs. 13.6 months [8.7 – 21.7], respectively, HR=0.48), even if the HER2⁺ CTC population was more heavily pretreated (median of 3 previous cytotoxic treatments in the MBC setting compared to 1 for the HER2⁺ CTC-negative group, p=0.01). The longitudinal evolution model was not associated with PFS. Conclusions: Detection of HER2⁺ CTCs appears to be a rare event in HER2⁺ MBC. However, their presence may help identify a subset of patients who derive greater benefit from T-DXd. Larger studies and evaluation of additional circulating biomarkers, such as ctDNA, are warranted.

F. Kemik¹, T. K. Sahin², H. Ozcelik³, A. Sezer⁴, G. Basaran⁵, S. Biter⁶, D. Erdem⁷, S. Tunbekici⁸, A. Oruc⁹, A. K. Guren¹⁰, K. Kaban¹¹, M. B. Aykan¹², O. B. Ekinci¹³, I. Deliktas Onur¹⁴, A. Kalem¹⁵, O. Altunok¹⁶, M. Seyyar¹⁷, B. Guney¹⁸, O. Akdogan¹⁹, M. Yazici²⁰, N. Majidova²¹, B. Koylu¹, C. I. Kikili¹, N. Demir¹, D. Tunali¹, S. Lacin¹, D. Tural¹, A. Bilici³, E. Bayram⁶, E. Goker⁸, M. Araz⁹, I. V. Bayoglu¹⁰, N. Molinas Mandel¹¹, N. Karadurmus¹², E. Celik¹³, O. Ates¹⁴, H. Yesil Cinkir¹⁵, M. Yimaz¹⁶, R. U. Gursu¹⁸, O. Yazici¹⁹, D. Cabuk²⁰, D. C. Guven², F. Selcukbiricik¹, S. Aksoy², S. Gunduz¹; ¹Department of Medical Oncology, Koc University School of Medicine, Istanbul, TURKEY, ²Department of Medical Oncology, Hacettepe University Cancer Institute, Ankara, TURKEY, ³Department of Medical Oncology, Istanbul Medipol University, Istanbul, TURKEY, ⁴Department of Medical Oncology, Başkent University, Adana, TURKEY, ⁵Medical Oncology Department, Faculty of Medicine, Acıbadem University, Istanbul, TURKEY, ⁶Department of Medical Oncology, Faculty of Medicine, Çukurova University, Adana, TURKEY, ⁷Department of Medical Oncology, Samsun Medical Park Hospital, Samsun, TURKEY, ⁸Department of Medical Oncology, Ege University, Izmir, TURKEY, ⁹Department of Medical Oncology, Necmettin Erbakan University School of Medicine, Konya, TURKEY, ¹⁰Department of Medical Oncology, Marmara University Faculty of Medicine, Istanbul, TURKEY, ¹¹Department of Medical Oncology, American Hospital, Istanbul, TURKEY, ¹²Department of Medical Oncology, Health Science University, Gulhane School of Medicine, Ankara, TURKEY, ¹³Department of Medical Oncology, Prof. Dr. Cemil Taşcıoğlu City Hospital, University of Health Sciences, Istanbul, TURKEY, ¹⁴Department of Medical Oncology, Health Sciences University Dr Abdurrahman Yurtaslan Ankara Oncology Education and Research Hospital, Ankara, TURKEY, ¹⁵Department of Medical Oncology, Gaziantep University, Gaziantep, TURKEY, ¹⁶Department of Medical Oncology, Bakirkoy Dr Sadi Konuk Training and Research Hospital, Istanbul, TURKEY, ¹⁷Department of Medical Oncology, Gaziantep City Hospital, Gaziantep, TURKEY, ¹⁸Department of Medical Oncology, Istanbul Training and Research Hospital, Istanbul, Istanbul, TURKEY, ¹⁹Department of Medical Oncology, Gazi University School of Medicine, Ankara, TURKEY, ²⁰Department of Medical Oncology, Kocaeli University, Kocaeli, TURKEY, ²¹Department of Medical Oncology, VM Medical Park Maltepe Hospital, Istanbul, TURKEY.

Introduction: Trastuzumab deruxtecan (T-DXd) has emerged as a highly effective antibody-drug conjugate for patients with HER2-positive metastatic breast cancer, particularly following progression on prior HER2-directed therapies. However, the clinical relevance of prior exposure to another HER2-targeted ADC, trastuzumab emtansine (T-DM1), on the efficacy of subsequent T-DXd remains unclear. Clarifying this sequencing effect is essential for optimizing treatment strategies in the advanced disease setting. Methods: This multicenter, retrospective cohort study evaluated patients with HER2-positive metastatic breast cancer who received T-DXd therapy. The primary objective was to assess the impact of prior exposure to another antibody-drug conjugate, T-DM1, on progression-free survival (PFS) following T-DXd treatment. Eligible patients were identified from institutional records across 21 oncology centers in Turkey, and clinical, pathological, and treatment data were collected. PFS was defined as the time from initiation of T-DXd to radiologic or clinical disease progression or last follow-up. Cox proportional hazards regression was used to estimate hazard ratios for progression. Results: A total of 199 patients were included, with a mean age of 45.8 ± 12.0 years (range: 21-83). T-DXd was administered at a median line of 3 (range: 1st-9th line). The majority of patients received T-DXd as a third (29.2%) or fourth-line therapy (25.6%). The median follow-up was 8.3 months, and the mean follow-up was 10.5 months (95% CI: approximately 9.5-11.5). Comorbidities were present in 31.2% of patients, and 57.3% were premenopausal. ER and PR positivity rates were 65.3% and 47.7%, respectively. HER2 status was IHC 3+ in 75.9% and IHC 2+/ISH+ in 24.1%. Prior to T-DXd, 67.3% of patients received T-DM1. Disease progression after T-DXd occurred more frequently in patients previously treated with T-DM1 (47.0% vs. 13.8%, p<0.001). In the univariate analysis, prior exposure to T-DM1 was significantly associated with a higher risk of progression under T-DXd treatment (HR = 3.03, 95% CI: 1.51-6.10, p = 0.002). Consistent with this finding, progression-free survival (PFS) was significantly shorter in the T-DM1-pretreated group compared to the T-DM1-naive group (p = 0.001, log-rank test). The median PFS was 12.1 months (95% CI: 7.7-16.5) in the T-DM1 group, whereas the median was not reached in the T-DM1-naive group during the study period. Conclusion: Prior exposure to T-DM1 was associated with significantly shorter progression-free survival and a higher risk of disease progression following T-DXd treatment in patients with HER2-positive metastatic breast cancer. These findings highlight the potential impact of treatment sequencing on T-DXd efficacy and underscore the need for personalized therapeutic strategies in the advanced setting.

A. SyBing¹, E. Garcia², J. Meyer³, M. Miller⁴, X. Li⁴, V. Kumar⁵, A. Topletz-Erickson¹; ¹Clinical Pharmacology & Translational Sciences, Pfizer, San Diego, CA, ²Pharmacometrics & Systems Pharmacology, Pfizer, San Diego, CA, ³Clinical Bioanalytics, Pfizer, San Diego, CA, ⁴Late Stage Clinical Development – Breast, Oncology, Pfizer, San Diego, CA, ⁵Pharmacokinetics, Dynamics, and Metabolism, Pfizer, San Diego, CA.

Background: Disitamab vedotin (DV) is a human epidermal growth factor receptor 2 (HER2) targeting antibody drug conjugate (ADC) with a monomethyl auristatin E (MMAE) payload via a maleimidocaproyl-valine-citrulline (MC-VC) linker. MMAE is primarily metabolized in vitro by cytochrome P450 3A4 (CYP3A4) and is a substrate of P-glycoprotein (P-gp). A clinical drug-drug interaction (DDI) study previously showed that ketoconazole, a strong CYP3A4 and P-gp inhibitor, increased unconjugated MMAE exposure 1.34-fold following brentuximab vedotin (BV) treatment in patients with CD30+ hematologic malignancies¹. Thus, current recommendations for concomitant use of MMAE-conjugated ADCs and a strong CYP3A4 inhibitor are limited to close monitoring for adverse events. However, it’s unclear whether a similar trend of increased exposure holds true for other MMAE-conjugated ADCs. In this study, unconjugated MMAE PK following DV administration was characterized with and without tucatinib, a strong CYP3A4 inhibitor and a known P-gp inhibitor currently approved for previously treated HER2 expressing metastatic breast cancer, to assess the impact of tucatinib-mediated CYP3A4 and P-gp inhibition on unconjugated MMAE PK. Methods: C5731004/SGNDV-004 (NCT06157892) is a phase 1b/2 open-label, multicenter study designed to identify the maximum tolerated dose (MTD) and/or optimal dose of DV when administered in combination with tucatinib in participants with HER2+ (IHC 3+ or IHC 2+/ISH+) and HER2-low (IHC 1+ or IHC 2+/ISH-) expressing locally advanced or metastatic breast cancer (LA/mBC) and locally advanced or metastatic gastric cancer and gastroesophageal junction adenocarcinoma (LA/mGC/GEJC). Participants in the dose escalation phase of SGNDV-004 received DV (1.25 mg/kg or 1.50 mg/kg IV Q2W) starting Cycle 1 Day 1 and tucatinib (TUC, 300 mg PO BID) starting Cycle 1 Day 8. Unconjugated MMAE PK blood samples were collected on Days 1, 2, 3, and 8 in Cycle 1 (DV alone) and Cycle 2 (DV+TUC). Unconjugated MMAE plasma concentrations were analyzed using validated high performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS). The DDI assessment was made using unconjugated MMAE PK parameters following DV administration including plasma area under the concentration-time curve up to Day 8 (AUC_0-168h) and maximal concentrations (C_max) in Cycle 2 (test) relative to Cycle 1 (reference) and were calculated using PKNCA (R v4.3.1, PKNCA v0.10.2). Results: PK data were available for 6 patients at 1.25 mg/kg and 3 patients at 1.50 mg/kg. The geometric mean (geometric CV%) of Cycle 1 and Cycle 2 dose-normalized MMAE AUC_0-168h values were 232.2 (83%) and 275.7 (101%) ng*hr/mL/(mg/kg), respectively. The geometric mean (geometric CV%) of Cycle 1 and Cycle 2 dose-normalized MMAE C_max values were 1.87 (88%) and 2.40 (94%) ng/mL/(mg/kg), respectively. Geometric mean ratios (CI_90%) for Cycle 2/Cycle 1 MMAE AUC_0-168h and C_max were 1.18 (1.05-1.35) and 1.28 (1.17-1.40), respectively. Conclusions: Unconjugated MMAE exposure following DV administration of 1.25 mg/kg or 1.5 mg/kg Q2W was increased <1.3-fold in the presence of tucatinib in participants with HER2 expressing LA/mBC or LA/mGC/GEJC, translating to an overall weak DDI impact. References1.Han TH, Gopal AK, Ramchandren R, Goy A, Chen R, Matous JV, Cooper M, Grove LE, Alley SC, Lynch CM, O’Connor OA. CYP3A-mediated drug-drug interaction potential and excretion of brentuximab vedotin, an antibody-drug conjugate, in patients with CD30-positive hematologic malignancies. J Clin Pharmacol. 2013 Aug;53(8):866-77. doi: 10.1002/jcph.116. Epub 2013 Jun 10. PMID: 23754575; PMCID: PMC3777854.

L. Niu¹, X. Liang², S. Wang³, S. Zhang⁴, Z. Lv⁵, H. Li⁶, Y. Zhao⁷, Y. Yin⁸, Y. Song⁹, G. Sun¹⁰, B. Zhao¹¹, L. Cai¹², Q. Ouyang¹³, C. Geng¹⁴, H. Yao¹⁵, X. Wu¹⁶, Z. Chen¹⁷, Z. Jiang¹⁸, H. Li², M. Yan¹; ¹Department of Breast Disease, Henan Breast Cancer Centre, The Affiliated Cancer Hospital of Zhengzhou University and Henan Cancer Hospital, Zhengzhou, CHINA, ²Department of Breast Oncology, Peking University Cancer Hospital & Institute, Beijing, CHINA, ³Department of Medical Oncology, State Key Laboratory of Oncology in South China Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, CHINA, ⁴Department of Breast Cancer, Fifth Medical Center of Chinese PLA General Hospital, Beijing, CHINA, ⁵Cancer Center, The First Hospital of Jilin University, Changchun, CHINA, ⁶Department of Breast Medical Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, CHINA, ⁷Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, CHINA, ⁸Department of Oncolog, Jiangsu Province Hospital, Nanjing, CHINA, ⁹Breast Center B Ward, The Affiliated Hospital of Qingdao University, Qingdao, CHINA, ¹⁰Department of Breast and Thyroid Surgery, Affiliated Tumor Hospital of Xinjiang Medical University, Xinjiang, CHINA, ¹¹Department of Breast Cancer, The Clinical Research Center of Breast Tumor and Thyroid Tumor in Xinjiang Uygur Autonomous Region, Affiliated Tumor Hospital of Xinjiang Medical University, Xinjiang, CHINA, ¹²Department of Medical Oncology, Harbin Medical University Cancer Hospital, Heilongjiang, CHINA, ¹³Department of Breast Medicine, Hunan Cancer Hospital,The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, CHINA, ¹⁴Department of Breast Center, The Fourth Hospital of Hebei Medical University, Shijiazhuang, CHINA, ¹⁵Department of Medical Oncology, Breast Tumor Center, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, CHINA, ¹⁶Department of Breast Surgery, Hubei Cancer Hospital, Tongji Medical College, Huazhong University of Science and Technology, Hubei Provincial Clinical Research Center for Breast Cancer, Wuhan Clinical Research Center for Breast Cancer, Wuhan, CHINA, ¹⁷Department of Breast Medical Oncology, Cancer Hospital of the University of Chinese Academy of Sciences (Zhejiang Cancer Hospital), Hangzhou, CHINA, ¹⁸Department of Breast Oncology, The Fifth Medical Center of Chinese PLA General Hospital, Beijing, CHINA.

Background The combination of pyrotinib and capecitabine has shown promising efficacy in patients with HER2-positive metastatic breast cancer and brain metastases (BMs). However, it remains uncertain whether the timing of local radiotherapy affect overall survival (OS) on the basis of this systemic regimen. The purpose of our study is to investigate the impact on OS of the addition of brain radiotherapy to the treatment with pyrotinib and capecitabine in patients with HER2-positive breast cancer BMs in a real-world clinical practice setting. MethodsThis is a multicenter, retrospective-prospective, real-world study conducted across 41 centers in China (NCT05359120). Patients diagnosed with HER2-positive breast cancer and BMs, with complete diagnostic and treatment records available in hospital electronic medical record systems were eligible for this study. Enrolled patients were categorized into three cohorts based on the radiotherapy status while undergoing systemic treatment: those who were radiotherapy-naïve (Cohort A), those who received whole-brain radiotherapy (WBRT) and/or stereotactic radiosurgery (SRS) within three months of initiating systemic treatment (Cohort B), and those who received systemic treatment more than three months after radiotherapy (Cohort C). Systemic treatment was defined as pyrotinib (no less than 240 mg once daily) combined with capecitabine (no less than 50% of 1000 mg/m² twice daily on days 1-14 of each 21-day cycle) until disease progression or unacceptable toxicity. The endpoints included OS and progression-free survival(PFS). Here we present the results of Cohort A and B. ResultsFrom September 2018 to January 2024, a total of 287 female patients were enrolled in the study. In Cohort A, 27.4% (37/135) of patients presented with symptomatic BMs, while 52.5% (64/122) in Cohort B. Additionally, a greater percentage of patients in Cohort A (88.9%) had active BMs compared to those in Cohort B (61.5%).As of May 6, 2025, the median follow-up duration was 35.9 months (95% CI: 34.3-37.5) in Cohort A and 45.3 months (95% CI: 41.9-48.6) in Cohort B. The median OS was 35.4 months (95% CI: 31.4-39.4) in Cohort A and 37.3 months (95% CI: 27.4-47.2) in Cohort B, with no statistically significant difference between the two groups (p = 0.793). Similarly, the median progression-free survival (PFS) was comparable between Cohort A and Cohort B, at 15.0 months (95% CI: 11.7-18.3) and 15.5 months (95% CI: 12.1-18.9), respectively (p = 0.073). ConclusionTo our knowledge, this is the largest study of pyrotinib plus capecitabine in HER2-positive breast cancer patients with BMs. No significant difference was observed in OS or PFS between the two groups: priority systemic therapy with pyrotinib plus capecitabine until disease progression or unacceptable toxicity, or systemic therapy concurrently with radiotherapy. Therefore, future studies should further elucidate the characteristics of patients most likely to benefit from specific systemic-local treatment combinations and enabling personalized therapeutic strategies for HER2-positive breast cancer patients with BMs. These findings warrant prospective clinical investigation. Research Sponsor: None.

C. Okoye¹, C. Emeasoba², O. Ntukidem³, L. Odion-Omonhimin⁴; ¹Internal Medicine, Northeast Georgia Medical Center, Gainesville, GA, ²Internal Medicine, UAMS Northwest, Fayeteville, AR, ³Internal Medicine, Trinity Health Ann Arbor, Ypsilanti, MI, ⁴Internal Medicine, Southern Regional Medical Center, Riverdale, GA.

BackgroundESR1 (estrogen receptor) mutations are a common mechanism of acquired resistance to first-line aromatase inhibitor (AI) therapy in HR-positive, HER2-negative advanced breast cancer. These mutations often emerge during combined AI plus CDK4/6 inhibitor treatment, making tumors insensitive to estrogen deprivation. The SERENA-6 trial is built on the rationale that serial plasma ctDNA monitoring can detect emergent ESR1 mutations before radiographic progression. Early identification of an ESR1 mutation allows preemptive switching from the AI to the novel oral SERD camizestrant (while continuing the same CDK4/6 inhibitor) to target resistant clones. The goal is to extend control of ER-driven tumor growth and delay the need for chemotherapy.MethodsSERENA-6 (NCT04964934) is a global, double-blind, randomized phase III trial in postmenopausal women with HR+/HER2- advanced breast cancer on first-line AI+CDK4/6i therapy. Patients underwent serial plasma ctDNA testing (every 2-3 months) during stable disease. When a new ESR1 mutation was detected (before any clinical progression), 315 patients were randomized 1:1 to either continue the AI (plus placebo) or switch to camizestrant 75 mg once daily (plus placebo AI), with all patients remaining on their original CDK4/6 inhibitor. The primary endpoint was investigator-assessed progression-free survival (PFS). Key secondary endpoints included overall survival, time to second progression event (PFS2), chemotherapy-free survival, patient-reported outcomes (including quality of life), and safety.ResultsAt the planned analysis, median PFS was significantly longer in the camizestrant arm than in the control arm (16.0 vs. 9.2 months; HR = 0.44; 95% CI 0.31-0.60; P < 0.0001). This corresponds to a 56% relative reduction in risk of progression or death. The 1-year and 2-year PFS rates were markedly higher with camizestrant (60.7% and 29.7%) versus continued AI (33.4% and 5.4%). Patients who switched to camizestrant also experienced a clinically meaningful delay in symptom deterioration: the median time to clinically significant worsening of quality-of-life was 23.0 months vs 6.4 months for those who remained on AI. Camizestrant was well tolerated; adverse events were consistent with its known profile. Very few patients required treatment discontinuation, and no new safety signals emerged. A mild ocular effect, photopsia, was noted in some patients, but it did not affect vision or daily function.ConclusionThe SERENA-6 findings demonstrate that real-time molecular profiling with ctDNA to guide early therapeutic switching can substantially improve outcomes in endocrine-resistant HR+ breast cancer. Preemptive replacement of the AI with camizestrant upon molecular progression more than doubled median PFS, extended quality-adjusted survival, and deferred progression by targeting ESR1-mutant clones. These results support a new paradigm of personalized endocrine therapy: intervening at the first molecular sign of resistance to prolong endocrine benefit and delay chemotherapy.

Z. Sarfraz¹, V. Podder², K. Vazquez³, F. Akkoc Mustafayev¹, M. Jaramillo¹, K. A. Qidwai¹, M. Ganiyani¹, V. Andion Camargo¹, R. Mahtani⁴, M. Ahluwalia¹; ¹Medical Oncology, Miami Cancer Institute, Baptist Health South Florida, Miami, FL, ²Gynecologic Oncology, Mount Sinai Medical Center, Miami, FL, ³Research, Miami Cancer Institute, Baptist Health South Florida, Miami, FL, ⁴Breast Medical Oncology, Miami Cancer Institute, Baptist Health South Florida, Miami, FL.

Background: Trastuzumab deruxtecan (T-DXd), a novel antibody-drug conjugate (ADC), has shown promising intracranial efficacy in breast cancer (BC) patients with brain metastases (BM). This meta-analysis evaluates the intracranial activity and systemic efficacy of T-DXd in patients with metastatic BC and BM. Methods: A systematic search was conducted from inception until May 6, 2025, across PubMed, Cochrane Library, and oncology conference abstracts (ASCO, ESMO, SABCS, and EANO). Eligible studies included clinical trials and cohort studies reporting outcomes for BC patients with BM receiving T-DXd. Random-effects meta-analysis models with Freeman-Tukey transformations were used for pooling proportions (intracranial clinical benefit rate [IC-CBR], intracranial objective response rate [IC-ORR], and 12-month systemic overall survival [OS]). Systemic progression-free survival (PFS) was pooled using a random-effects inverse-variance model. For PFS, means and standard deviations (SDs) were extracted when available or estimated from medians and IQRs using the Wan et al. (2014) method: mean = (Q1 + median + Q3)/3 and SD = (Q3 − Q1)/1.35, adjusted for sample size. Heterogeneity was assessed using the I² statistic, with values ≤25% considered low, 26-75% moderate, and >75% high. Registration: osf.io/swghm. Results: Of the 489 screened records, 14 studies were included; 1 was a randomized controlled trial, 6 were prospective single-arm trials, and 7 were retrospective cohort studies, including real-world data from early access programs. Median patient age was 56.3 years; 97.3% had HER2-positive BC, and 2.7% HER2-low. Prior cranial radiotherapy was administered in 61%, with concurrent radiotherapy at T-DXd initiation in 1.4%. Median follow-up duration was 12.9 months (IQR: 11-15). T-DXd was administered uniformly at 5.4 mg/kg IV every three weeks, with protocol-specified dose reductions allowed. Pooled IC-CBR was 81% (95% CI: 69-91%, p<0.001), indicating strong intracranial clinical efficacy, with low heterogeneity (I²=18.6%). IC-ORR was 62% (95% CI: 51-74%, p<0.001), suggestive of substantial intracranial tumor responses. Moderate heterogeneity was noted (I²=71.8%). The pooled mean systemic PFS was 12.6 months (95% CI: 7.1-18.1, I²=99.8%, p<0.001). Pooled 12-month OS was 81% (95% CI: 66-93%, p<0.001), highlighting favorable survival outcomes despite high heterogeneity (I²=86.5%). Conclusion: T-DXd demonstrates robust intracranial activity and 12-month survival in breast cancer patients with brain metastases. The pooled IC-CBR of 81% notably exceeds historical benchmarks reported with T-DM1 or chemotherapy, which typically range from 30-50% in this population. Prospective studies are needed to refine patient selection and optimize therapeutic sequencing.

T. Ackbarali¹, K. Jones², A. Bardia³, S. Hurvitz⁴; ¹Hematology/Oncology Team, Medlive, Lake Worth, MA, ²Hematology/Oncology Team, Medlive, Needham, MA, ³Division of Hematology and Oncology, University of California, Los Angeles, Santa Monica, CA, ⁴Division of Hematology and Oncology, Fred Hutchinson Cancer Center, Bellevue, WA.

BACKGROUND: A significant change in practice has occurred in breast cancer based on an improved understanding of HER2 expression existing on a broader spectrum than previously known. Despite the availability of personalized treatments for patients with metastatic breast cancer (mBC) based on their HER2-expression status, many patients who express HER2 are not receiving the optimal, tailored treatment for their disease. This is largely due to a lack of clarity surrounding HER2 testing, integration of HER2-targeted therapies across all subtypes of breast cancer, and management of unique adverse events (AEs) associated with novel HER2-targeting therapies. An interactive, case clinic was designed for oncology clinicians to engage in applying the latest guideline-recommended treatment approaches for mBC to close these gaps and ensure patients receive optimal therapy. METHODS: The branched-learning curriculum was comprised of two 30-minute tracks evaluating best practices in the management of HER2-positive and HER2-low breast cancer. The education launched on Medlive.com in September 2024 and will remain available for 12 months. Following a pre-assessment, learners selected their initial preferred track, which included several concise and easy-to-digest modules framed by clinical cases. Faculty experts provided rationales for each decision-point option before moving on to the next module. Discussions ensued on factors influencing treatment selection, guidelines and clinical evidence, treatment-sequencing strategies, and strategies for adverse-event management. Pre-post assessment data through case decisions for HER2+ (track 1) vs HER2-low MBC (track 2)will be presented. RESULTS: To date, more than 1,300 clinicians have engaged with the education program, 74% of whom were MD/DO and 81% designating their specialty as oncology. Given a choice of selecting tracks, 91% initiated the education in track 1 and 89% of all learners completed both tracks. An approximate 16% improvement was seen across all knowledge and competence questions for intended learners (pathology and oncology speciaties) with higher gains – upwards of 50% – demonstrated for confidence treating HER2-low MBC vs HER2+ MBC. The reported intended changes in clinical practice included: • Greater personalized treatment sequencing based on patient-specific characteristics (36%)​ • Higher frequency of use of novel HER2-targeted agents in 2^nd-line therapy (29%)​ • Implementing stricter monitoring for AEs associated with HER2-targeted therapies (27%)​ • Rigorous testing for HER2-low expression in patients with MBC (25%)​ • Increasing referrals for clinical trials of novel HER2-targeted agents (20%) ​ Pre-test variability in responses indicated that some learners were unclear on when additional testing is warranted, likely due to inconsistent application of updated HER2 testing protocols in clinical practice. CONCLUSIONS: The post-test gains indicate an improved ability to differentiate between available ADCs, with greater recognition of novel therapies as the preferred next-line therapy in HER2-low disease due to its targeted mechanism against HER2, even at low levels. However, the persistent gap suggests an opportunity to reinforce how HER2 expression levels influence ADC selection and where other ADCs may fit into later-line treatment. Improvements were seen in testing protocols, treatment application, and AE management, for relevant populations likely to benefit. These outcomes demonstrated the impact of this education initiative focusing on point-of-care decisions. Support was provided by an independent educational grant from Daiichi Sankyo, Inc. and AstraZeneca Pharmaceuticals.​​

G. E. Heinrich; Gynocological Oncology, Practice for gynecological oncology, Fürstenwalde, GERMANY.

“LONGTERM” – Long-Term Response (>18 Months) in Metastatic HER2-Positive Breast Cancer: A Retrospective Analysis of Patients Diagnosed Between 2010 and 2020 in the German BNGO NetworkHeinrich G., Nuti P., Busch S., Olbermann A., Ruhmland B., Urban H., Lenk I., Kreiss-Sender J., Lorenz R., Baerens D.-T., Förster F., Wierick E., Großmann C., Wolf C., Altmann F., Uleer C., Müller A., Massinger-Biebl H., Apel K., Schubert R., Oskay-Özcelik G., Fiege J., Hielscher C., Steinfeld-Birg D.BackgroundProgression-free survival (PFS) and overall survival (OS) have significantly improved in patients with HER2-positive metastatic breast cancer (mBC) due to advances in targeted therapies. The current standard first-line treatment includes dual antibody therapy with trastuzumab and pertuzumab combined with chemotherapy, as established in the CLEOPATRA trial. This real-world data (RWD) analysis, conducted by the German Association of Private Practice-Based and Outpatient Gynecologic Oncologists (BNGO), retrospectively examined patients with a PFS >18 months.MethodsThis multicenter, retrospective, non-interventional RWD analysis included patients newly diagnosed with HER2-positive metastatic or inoperable breast cancer between January 1, 2010, and July 31, 2019. Data collection occurred between March 1, 2022, and December 31, 2023, using existing site documentation. Data were pseudonymized and entered into standardized electronic case report forms (eCRFs) via a common electronic data capture (EDC) system. Patients were included if they had HER2 IHC 3+ and/or ISH positivity and a PFS of at least 18 months following first-line therapy.Inclusion Criteria– First diagnosis of metastatic or inoperable disease between 01.01.2010 and 31.07.2020- HER2 IHC 3+ and/or ISH-positive at first metastatic diagnosis or in the primary tumor if unknown in metastases- PFS >18 months, assessed clinically or radiologically (RECIST 1.1)- Receipt of anti-HER2 therapy as first-line treatmentExclusion Criteria– No documented HER2+ status in metastases or primary tumor- Disease progression within 18 months of diagnosisResultsOf 111 patients from 24 sites, 95 were eligible. Median age at diagnosis was 61.1 years. Of these, 58.9% had prior early-stage HER2+ disease, 33.7% were de novo metastatic, and 7.4% showed HER2 receptor conversion. ER and PR positivity were recorded in 72.6% and 58.9% of patients, respectively. Table 1 summarizes the distribution of metastatic sites at diagnosis.Chemotherapy combined with anti-HER2 therapy was administered in 74.7% of cases, with trastuzumab used in 98.9% and pertuzumab in 66.3%. Endocrine therapy was given in 63.2% of patients, often sequentially. At the end of follow-up, 69.5% of patients remained under therapy, 14.7% had died, and 2.1% were lost to follow-up.ConclusionThis RWD analysis provides insight into the evolving treatment patterns and outcomes of long-term responders with HER2-positive metastatic breast cancer. All patients received anti-HER2 therapy, most commonly the trastuzumab-pertuzumab combination. Hormone receptor-positive patients often received sequential endocrine therapy. The findings reflect adherence to international guidelines (ASCO, NCCN, AGO) and highlight the role of national networks such as BNGO in generating meaningful real-world oncology data.

J. BOUZIANE¹, P. Loap², S. Allali², L. Escalup³, J. Pierga⁴, Y. Kirova²; ¹Radiation Oncology, CHU HASSAN II , Fez, Morocco, Fez, MOROCCO, ²Radiation Oncology, Institut Curie, Paris, Paris, FRANCE, ³Pharmacy, Institut Curie, Paris, Paris, FRANCE, ⁴Medical Oncology, Institut Curie, Paris, Paris, FRANCE.

Background: Metastatic breast cancer, particularly HER2-positive disease, remains a therapeutic challenge and is often associated with poor prognosis. While anti-HER2 therapies such as trastuzumab have improved outcomes, trastuzumab deruxtecan (T-DXd), an antibody-drug conjugate, has shown promising efficacy even in heavily pretreated patients. Clinical trials, including DESTINY-Breast, have demonstrated significant improvements in progression-free survival (PFS) and overall survival (OS). However, the safety and efficacy of combining T-DXd with radiotherapy (RT) have yet to be fully evaluated. This study aims to assess the outcomes of this combination in patients with HER2-positive and HER2-low metastatic breast cancer.Methods: We conducted a retrospective study including patients treated between November 2020 and January 2024. Patients with HER2-positive and HER2-low metastatic breast cancer who received concurrent trastuzumab der uxtecan and radiotherapy were identified. Data on patient demographics, treatment regimens, radiation doses, toxicity profiles, efficacy and treatment discontinuations were collected. Data on tumor response were collected through imaging examinations, and follow-up was conducted from the last day of radiotherapy until death or the last examination, and toxicities were graded using CTCAE V5.0. Results: The studied population includes 33 patients with HER2-positive and HER2-low metastatic breast cancer who underwent concurrent treatment with trastuzumab deruxtecan and radiotherapy. The median follow-up was 14 months. Treatment details indicated that trastuzumab deruxtecan was administered at the recommended dose across various treatment modalities. Of the patients evaluated, 39.4% achieved partial remis sion, while 9.1% attained complete remission. Additionally, 39.4% experienced stable disease, and 12.1% faced disease progression necessitating a change in therapy. Safety assessment revealed that acute toxicities were mainly associated with systemic treatment. Survival analysis showed 11 deaths (33.3%) during the follow-up period, with a median overall survival of 26 months and median progression-free survival of 12 months.Conclusion: The combination of trastuzumab deruxtecan with radiotherapy in HER2-positive and HER2-low metastatic breast cancer demonstrates promising efficacy with a manageable safety profile. Further studies are warranted to fully elucidate the potential synergistic effects of this treatment regimen and its impact on patient outcomes.

H. Yan, M. Toki, H. Kristeleit; Medical Oncology, Guy’s and St Thomas’ NHS Foundation Trust, London, UNITED KINGDOM.

Background: Treatment options for HER2 positive MBC are increasing and trastuzumab deruxtecan (T-DXd) is now used in earlier lines of treatment, having shown superiority to trastuzumab emtansine (T-DM1) in DESTINY-Breast03 and to THP in DESTINY-Breast09. Uncertainty remains on the optimal sequencing of these drugs and their impact on OS with concerns raised regarding the generalisability of reported progression free survival (PFS) and treatment attrition rates in these trials. In this series, we report treatment attrition rates and PFS for patients starting 1^st line chemotherapy between 2019 and 2024. Methods: Electronic health records were searched for patients with HER2 positive advanced breast cancer starting 1^st line treatment between 01/01/19 and 31/12/24. Dates to calculate PFS and OS as well as attrition rates were extracted for each line of therapy. Results: 143 women commenced treatment during the study period. Median age was 51.6 years at time of first breast cancer diagnosis and 55.2 years at time of metastatic disease. 82 patients had de-novo metastatic disease, invasive disease-free survival in the remainder was 46.6 months. Observed median PFS for THP (23.0 months) appeared comparable to the THP arms of CLEOPATRA (18.7 months)​¹​ and DESTINY-Breast09 (26.9 months)​²​. T-DM1 (9.0 months) performed similarly to the EMILIA (9.6 months) study​^3​ and better than the control arm of DESTINY-Breast03 (6.8, CI 5.6-8.2 months)​⁴​. T-DXd was used in 11 patients in the 2nd line setting and 16 patients in the 3rd line setting and in this small series performed considerably worse (11.7 months) than in DESTINY-Breast03 (28.8 months)​4​ and DESTINY-Breast02 (17.8 months)​⁵​, but was comparable to other real-world experience (12.3 months)​⁶​. With median follow-up of 27.6 months, 44 patients have died, and median OS has not been reached. 15 (34%) events were due to CNS progression and two (7%) patients treated with T-DXd experienced grade 5 pulmonary toxicity. Attrition rates mirrored published findings.​⁷​ In subgroup analysis, ER+ patients had a longer median PFS than ER- although this was not statistically significant (26.1 vs 19.9 months, p = 0.26). Notably, patients with HER2 2+ (ISH+) had shorter median PFS compared to those with HER2 3+ (10.5 vs 27.9 months, p = 0.0089). Conclusion: Guy’s Cancer serves one of the most ethnically diverse populations in the world. In this retrospective real-world study, 1^st and 2^nd line PFS was similar to published phase 3 studies. Although T-DXd appeared to perform better than T-DM1 in our population, it fell short of the outcomes seen in the DESTINY studies. However, due to the small number of patients treated with T-DXd and the short follow-up our confidence intervals are wide. High attrition rates and death from CNS disease in 1/3 of patients supports the earlier use of T-DXd in this population.

K. H. Tesfamariam, X. Hu, I. Longa Rizzo, E. S Villodre, L. TH Phi, J. Song, S. Krishnamurthy, Y. Gong, W. Priebe, W. A. Woodward, B. G. Debeb; Breast Medical Oncology, MD Anderson Cancer Center, Houston, TX.

sEcad-STAT3/NFκB axis in inflammatory breast cancer progression Kiros H. Tesfamariam^1,6,*, Xiaoding Hu^1,6,*, Isabella Longa Rizzo^1,6, Emilly S Villodre^1,6, Lan TH Phi^1,6, Juhee Song², Savitri Krishnamurthy^3,6, Yun Gong³, Waldemar Priebe⁴, Wendy A Woodward^5,6, Bisrat G. Debeb^1,6 Departments of ¹Breast Medical Oncology, ²Biostatistics, ³Pathology, ⁴Experimental Therapeutics^{, 5}Breast Radiation Oncology, and ⁶MD Anderson Morgan Welch Inflammatory Breast Cancer Clinic and Research Program, The University of Texas MD Anderson Cancer Center, Houston TX. (* Equal contributors) Abstract Background: Inflammatory breast cancer (IBC) is a rare and aggressive subtype of breast cancer, accounting for 2-5% of all cases. It is characterized by rapid progression and a high propensity for distant metastasis, including to the brain. We showed that elevated serum levels of soluble E-cadherin (sEcad), an 80 kDa ectodomain fragment, are independently correlated with poor survival and increased incidence of brain metastasis in IBC patients. sEcad overexpression also promoted brain metastasis growth in IBC xenograft models. RNA-seq analyses revealed activation of STAT3 and NFκB signaling in sEcad-overexpressing cells. Given the interaction between sEcad and Protein Disulfide Isomerase A4 (PDIA4), we hypothesize that sEcad promotes metastasis in IBC through PDIA4-dependent activation of STAT3 and NF-κB signaling pathways. Methods: Using lentiviral transduction, we stably overexpressed sEcad in the IBC cell lines SUM149 and MDA-IBC3. Protein expression and phosphorylation states of STAT3 and NFκB were validated by immunoblotting. Functional assays, including colony formation, migration, and invasion, were conducted to assess the impact of sEcad overexpression and PDIA4 knockdown using shRNA constructs. Pharmacological inhibition studies with STAT3 and NFκB pathway inhibitors (WP1066 and ATL) were conducted to evaluate pathway dependencies. To test the in vivo efficacy of these inhibitors on brain metastasis, SUM149-sEcad cells were injected via the intracardiac route into SCID/Beige mice. Molecular docking simulations using the Glowworm Swarm Optimization algorithm for protein-protein interactions, as well as a deep learning model based on diffusion algorithms for protein-ligand interactions, were used to assess binding interactions among sEcad, PDIA4, STAT3, and the inhibitors. Results: Overexpression of sEcad in SUM149 and MDA-IBC3 cells significantly increased phosphorylation of STAT3 and NFκB, and enhanced proliferation, colony formation, migration, and invasion. Knockdown of PDIA4 in sEcad-overexpressing cells reversed these effects and reduced pSTAT3 and pNFκB levels, highlighting PDIA4’s critical role in mediating sEcad-driven signaling. Both STAT3 and NFκB pathway inhibitors, either alone or in combination, reduced cell proliferation and colony formation in sEcad-high cells in a dose- and time-dependent manner. Moreover, treatment with brain-permeable inhibitors of STAT3 and NFκB reduced metastatic burden in an IBC brain metastasis model (p=0.03). Finally, molecular docking studies confirmed energetically favorable interactions between sEcad and PDIA4 (swarm 110; score: 38.6), as well as effective binding of PDIA4 with ATL (RMSD: 1.8 Å) and WP1066 (RMSD: 1.3 Å). Conclusion: Our findings demonstrate that sEcad is a key driver of aggressive oncogenic features in IBC through PDIA4-dependent activation of STAT3 and NFκB pathways. Targeting the sEcad-STAT3/NFκB signaling axis represents a promising therapeutic strategy for IBC.

Y. Horimoto¹, M. Oshi², A. Yamada², Y. Ueki³, R. Semba³, R. Wu¹, H. Kusama¹, T. Kawate¹, F. Murakami³, T. Ishikawa¹, G. Kutomi³, J. Watanabe³; ¹Breast Surgery and Oncology, Tokyo Medical University, Tokyo, JAPAN, ²Gastroenterological Surgery, Yokohama City University Graduate School of Medicine, Yokohama, JAPAN, ³Breast Oncology, Juntendo University Faculty of Medicine, Tokyo, JAPAN.

PURPOSE: In metastatic breast cancer (MBC) treatment, HER2 expression is a key factor in determining the indication for trastuzumab deruxtecan (T-DXd). While HER2 mutations have been identified as therapeutic biomarkers for T-DXd in several solid tumors, their clinical relevance in breast cancer has received little attention. Consequently, the impact of HER2 mutations on the efficacy of T-DXd in MBC remains unclear. METHODS: We retrospectively examined 25 Japanese women with HER2-low MBC treated with T-DXd from January 2022 to October 2024. Tumor tissue from primary or metastatic sites was analyzed for four HER2 kinase domain mutations (L755S, D769Y, V777L, and V842I) using droplet digital PCR. These mutations were selected for their potential functional relevance in solid tumors based on recent studies. Treatment efficacy was assessed by time to treatment discontinuation (TTD), and its association with each mutation was examined. Subgroup analysis was performed based on the number of mutations (single vs. multiple). RESULTS: Clinicopathological characteristics are summarized in the Table. The frequencies of the four HER2 kinase domain mutations were as follows: L755S (64%), D769Y (32%), V777L (8%), and V842I (92%), with notable variation by mutation site. Tumors harboring D769Y tended to have a higher Ki67 labeling index (p = 0.027), suggesting increased proliferation activity. Patients with the L755S mutation had a shorter median TTD than those without the mutation (32 vs. 41 weeks), suggesting a potential association with reduced sensitivity to T-DXd. No apparent differences in TTD were observed for D769Y, V777L, or V842I mutations. Patients with multiple (≥ 2) mutations had a significantly shorter median TTD than those with a single mutation (30 vs. 52 weeks). CONCLUSION: Specific HER2 kinase domain mutations may influence the response to T-DXd in HER2-low MBC. This is the first study to report the frequencies of these four mutations and to assess mutation-specific differences in treatment duration using real-world data.

A. Konieczna¹, M. Holanek², M. Pieniazek³, J. Zubrowska⁴, A. Polakiewicz-Gilowska⁵, R. Soumarova⁶, H. Studentova⁷, A. Mlodzinska¹, K. Winsko-Szczesnowicz⁸, M. Lisik-Habib⁹, A. Pekala⁹, D. Krejci¹⁰, J. Sustr¹¹, I. Kolarova¹², I. Kolouskova², I. Danielewicz¹³, M. Szymanik-Resko¹³, T. Ciszewski¹⁴, L. Rusinova¹⁵, B. Czartoryska-Arlukowicz⁸, A. Lacko³, M. Jarzab⁵, R. Pacholczak-Madej¹⁶, Z. Bielcikova¹⁷, M. Malejcikova¹⁸, M. Puskulluoglu¹⁹; ¹Department of Breast Cancer and Reconstructive Surgery, Maria Sklodowska-Curie National Research Institute of Oncology-National Research Institute, Warszawa, POLAND, ²Department of Comprehensive Cancer Care, Masaryk Memorial Cancer Institute, and Faculty of Medicine, Masaryk University, Brno, CZECH REPUBLIC, ³Department of Oncology, Breast Unit Clinical Oncology Day Care Department, Wroclaw Medical University, Lower Silesian Comprehensive Cancer Center, Wroclaw, POLAND, ⁴Department of Clinical Oncology, Holy Cross Cancer Center, Kielce, POLAND, ⁵Breast Cancer Center, Maria Sklodowska-Curie National Research Institute of Oncology, Gliwice, POLAND, ⁶Department of Oncology, Third Faculty of Medicine, Charles University, University Hospital Kralovske Vinohrady, Prague, CZECH REPUBLIC, ⁷Department of Oncology, Faculty of Medicine and Dentistry, Palacky University and University Hospital, Olomouc, CZECH REPUBLIC, ⁸Department of Clinical Oncology, M. Sklodowska-Curie Bialystok Oncology Center, Bialystok, POLAND, ⁹Department of Proliferative Diseases, Nicolaus Copernicus Multidisciplinary Centre for Oncology and Traumatology, Lodz, POLAND, ¹⁰Department of Oncology, First Faculty of Medicine, Charles University in Prague, and Bulovka University Hospital, Prague, CZECH REPUBLIC, ¹¹Department of Oncology and Radiotherapy, Faculty of Medicine in Pilsen, Charles University, and University Hospital Pilsen, Plzen, CZECH REPUBLIC, ¹²Department of Oncology and Radiotherapy, Faculty of Medicine in Hradec Kralove and University Hospital in Hradec Kralove, Charles University, Hradec Kralove, CZECH REPUBLIC, ¹³Oddzial Onkologii i Radioterapii, Szpitale Pomorskie sp. z o.o., Gdynia, POLAND, ¹⁴Department of Metabolic Diseases and Immuno-oncology, Medical University of Lublin, Lublin, POLAND, ¹⁵Department of Oncology, Stefan Kukura Hospital Michalovce, Michalovce, SLOVAKIA, ¹⁶Department of Gynecological Oncology, Maria Sklodowska-Curie National Research Institute of Oncology, Krakow Branch, Krakow, POLAND, ¹⁷Department of Oncology, First Faculty of Medicine, Charles University, and General University Hospital, Prague, CZECH REPUBLIC, ¹⁸II. Oncology Clinic of LFUK, National Cancer Institute, Bratislava, SLOVAKIA, ¹⁹Department of Clinical Oncology, Maria Sklodowska-Curie National Research Institute of Oncology, Krakow Branch, Krakow, POLAND.

Background: Patients over 65 years constitute a substantial subset of those diagnosed with metastatic triple-negative breast cancer (mTNBC), yet are frequently underrepresented in clinical trials due to comorbidities, frailty, and polypharmacy. Sacituzumab govitecan (SG), approved for pretreated mTNBC, demonstrated comparable efficacy and tolerability in this age group in the ASCENT trial. However, real-world data remain limited. This multinational study investigates the safety and effectiveness of SG in patients aged >65 years treated in routine clinical practice. Materials and Methods: We retrospectively analyzed clinical data from female patients receiving SG across 18 oncology centers in Slovakia, Poland, and the Czech Republic between August 2021 and May 2025. Patients were stratified by age at SG initiation (≤65 vs. >65 years). Baseline characteristics, treatment patterns, and adverse events (graded according to CTCAE v5.0) were compared. Clinical information was extracted retrospectively from routine medical records. The analysis included progression-free survival (PFS; time from SG initiation to progression or death), overall survival (OS; time from SG initiation to death from any cause), objective response rate (ORR), and disease control rate (DCR) as clinical endpoints. Tumor responses were evaluated according to RECIST 1.1. Univariate Cox regression models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs). P < 0.05 was considered statistically significant. Results: Among 303 patients included, 76 (25.1%) were >65 years. Only 10 of them (13.2%) underwent geriatric assessment as part of routine clinical practice. Older patients had received a higher number of prior palliative systemic therapies (median 2 [IQR 1-2] vs. 1 [IQR 1-2], p=0.039). Visceral metastases (77.5% vs. 60.5%, p=0.006) and central nervous system (CNS) metastases (11.5% vs. 2.6%, p=0.038) were more frequent in the younger group. A reduced starting dose of SG (≤8 mg/kg at cycle 1 day 1) was used in 13.2% of older and 7.5% of younger patients (p=0.204). Adverse event-related dose reductions occurred in 46.1% of individuals >65 and 34.8% ≤65 (p=0.106). Delays in SG administration were observed in 71.1% and 60.4%, respectively (p=0.125). Grade ≥3 neutropenia occurred in 42.1% vs. 45.8% (p=0.733). No other significant differences in toxicity were detected. Median number of full SG cycles was similar across age groups (7 [IQR 3-12] vs. 6 [IQR 3-10], p=0.240). ORR was 30.3% vs. 30.8% (p>0.999), and DCR was 72.4% vs. 61.7% (p=0.122). Survival analyses demonstrated that patients >65 years achieved significantly longer PFS and OS compared to younger individuals (median PFS: 5.42 vs. 4.07 months; HR=0.716; 95% CI: 0.534-0.960; p=0.026; and median OS: 12.81 vs. 10.91 months; HR=0.691; 95% CI: 0.485-0.985; p=0.041, respectively). Conclusions: Older women with mTNBC treated with SG in routine clinical practice achieved significantly longer PFS and OS than younger patients, despite similar treatment exposure, toxicity, and response rates. These findings challenge the assumption that age alone predicts poorer outcomes and support SG use in selected older individuals. However, only 13.2% of patients >65 years underwent formal geriatric assessment, suggesting a possible selection bias toward clinically fit individuals. The observed survival advantage may also reflect lower rates of CNS and visceral metastases or less aggressive tumor biology. Our findings emphasize the need for individualized treatment decisions based on clinical fitness rather than age and support broader integration of geriatric assessment into routine oncology practice. Prospective studies are warranted to clarify the biological and clinical drivers of age-related outcome differences.

J. Ahn, J. Zambelas, D. Chen, M. Vasquez, W. Dong, H. Zhao, S. Wong; Systems Medicine and Bioengineering (SMAB), Houston Methodist, Houston, TX.

Background: Brain metastasis from triple-negative breast cancer (TNBC) is highly aggressive and remain difficult to treat, with a disproportionate burden among African American patients, especially in Texas. Chronic psychological stress, anxiety, or depression affecting more than 50% of cancer patients, disrupts neurotransmitter homeostasis and has been increasingly implicated in promoting cancer progression and metastasis. Among stress-associated neurotransmitters, serotonin (5-HT) levels are markedly elevated both under chronic stress and with selective serotonin reuptake inhibitor (SSRI) use, and can exacerbate brain metastasis. In this study, we investigate the mechanistic contribution of serotonin-HTR2B signaling to stress-induced brain metastatic progression in TNBC, using spatial transcriptomics and functional analysis. Methods: We conducted a comprehensive analysis of neurotransmitter-related gene expression using both single-cell RNA-seq (scRNA-seq) and bulk transcriptomic data from TNBC brain metastases and brain-tropic cell lines. Chronic restraint stress models were used to study metastasis development following inoculation with 4T1-BR or MDA-MB231-BR cells. Visium spatial transcriptomics was performed on brain tissue sections to spatially resolve transcriptional alterations within the metastatic niche under stress conditions. Functional validation included CRISPR -Cas9-mediated knockout (KO) of HTR2B in TNBC cell lines and in vivo bioluminescence imaging to monitor metastatic burden. Clinical datasets (GSE12276, n=204; TNBC cohort n=422) were analyzed to examine HTR2B expression levels and their association with patient survival outcomes. Results: TNBC brain metastases and brain-seeking cell lines showed widespread neurotransmitter-related gene upregulation. In vivo, chronic restraint stress significantly accelerated brain metastasis formation (p=0.022) and increased anxiogenic behaviors in mice. Spatial transcriptomic analysis revealed serotonin-HTR2B signaling enriched at the tumor-microenvironment interface in stressed mice, with activation of ERK/MAPK, PI3K/AKT, and STAT signaling pathways. CRISPR-mediated knockout of HTR2B resulted in a ~60% reduction in brain metastatic burden under stress conditions (p < 0.01), without affecting in vitro proliferation. Exogenous serotonin modestly increased in vitro growth but likely promotes metastasis via microenvironmental interactions. High tumor HTR2B expression was associated with shorter brain metastasis-free survival (p=0.012) and distant metastasis-free survival (p=0.013). Conclusions: Chronic stress promotes TNBC brain metastasis through activation of serotonin-HTR2B signaling, creating a pro-metastatic niche. Ongoing studies aim to identify specific stromal and immune cell populations responding to this signaling axis, using spatial transcriptomics-guided multiplex imaging. This work addresses a critical knowledge gap in understanding how stress reshapes the brain metastatic microenvironment. Collectively, these findings highlight serotonin-HTR2B as a promising therapeutic target to mitigate brain metastasis risk in stressed cancer patients.

F. Kudrik¹, R. Choksi², V. Gorantla², S. Reddy³, S. Reganti³, S. Rosenfeld⁴, G. Cioffi⁵, E. Alwon⁵, D. Parris⁵, A. Rui⁵, M. Gart⁵, C. Wall⁵, B. Wang⁵, P. Varughese⁵, J. Donegan⁵, L. Morere⁵, R. Geller⁵, J. Scott⁵, D. Patt⁶; ¹Medical Oncology, South Carolina Oncology Associates, Columbia, SC, ²Medical Oncology, University of Pittsburgh Medical Center (UPMC), Pittsburgh, PA, ³Medical Oncology, Cancer Care Specialists, Reno, NV, ⁴Medical Oncology, Highlands Oncology Group (HOG), Fayetteville, AR, ⁵PrecisionQ, IntegraConnect, West Palm Beach, FL, ⁶Medical Oncology, Texas Oncology, Austin, TX.

Background: Treatment options for metastatic triple-negative breast cancer (mTNBC) are limited, but antibody-drug conjugates (ADCs) such as sacituzumab govitecan (SG) have shown improved survival outcomes compared to single-agent chemotherapies. However, individuals undergoing this treatment are at an increased risk of neutropenia. Furthermore, updates to the package insert recommend primary prophylaxis with granulocyte-colony stimulating factor (G-CSF) for at-risk patients (pts). This study evaluated the impact of prophylactic G-CSF use on time to treatment discontinuation (TTD) and real-world overall survival (rwOS) among individuals with mTNBC who received SG. Methods: The IntegraConnect PrecisionQ de-identified electronic health record database, consisting of >3 million cancer pts across >500 care sites, was used to identify individuals with mTNBC that initiated SG between 4/22/2020 and 4/9/2025. Eligibility criteria included age ≥18 years at diagnosis and ≥2 documented visits. Prophylactic G-CSF was defined as any G-CSF use within 8 days following initiation of SG. Pts were excluded from the analysis if there was documentation of neutropenia (neutrophil count <1500/µL), discontinuation of SG, death, or censoring within 8 days of SG initiation. Demographic and clinical characteristics, including age at SG initiation, race, and Eastern Cooperative Oncology Group (ECOG) performance status, were assessed overall and stratified by prophylactic G-CSF use. Gray’s test was performed to assess cumulative incidence of neutropenia, adjusted for the competing risk of death, and 4-month estimates are reported. Kaplan-Meier survival curves were evaluated to assess TTD and rwOS by prophylactic G-CSF. To assess for the time-varying effect of prophylactic G-CSF use on TTD and rwOS, time-stratified multivariable Cox proportional hazards regression was performed with time-interval-specific effects (0-4 months, 4+ months) for prophylactic G-CSF use, and adjusted for additional demographic and clinical characteristics (age, race, ECOG status). Hazard ratios (HR) and 95% confidence intervals (CI) are reported. Results: Overall, 685 pts with mTNBC treated with SG were identified in the PrecisionQ database that met the study criteria. Most identified as White (67%), 41% had an ECOG status of 1, and 88% did not receive prophylactic G-CSF. Median age at SG initiation was 60 years (interquartile range [IQR]: 53, 69). Age, race, and ECOG status did not significantly differ by prophylactic G-CSF use. At 4 months, cumulative incidence of neutropenia was significantly higher among those who did not receive prophylactic G-CSF (42% vs. 30%, Gray’s test p=0.002). Median TTD and rwOS did not significantly differ by prophylactic G-CSF use. From 0-4 months, pts who did not receive prophylactic G-CSF were >2 times more likely to die compared to those who received prophylactic G-CSF within the first 8 days of SG initiation (HR: 2.37; 95% CI: 1.22-4.59 p=0.011). This impact was attenuated after 4 months (HR: 1.02, 0.79-1.50, p=0.4), indicating a time-varying effect of prophylactic G-CSF use on rwOS after SG initiation. There was no significant difference observed in TTD in either time-interval. Conclusions: Prophylactic use of G-CSF had a significant initial impact on rwOS among pts with mTNBC receiving SG. While prophylactic use of G-CSF did not confer a significant survival benefit after 4 months, the upfront effect warrants clinical consideration and integration into early treatment practices. These findings also indicate the need for further research assessing the impact of continued G-CSF use on overall survival.

S. Shen¹, V. Solomon¹, D. Williams¹, C. White¹, Y. Chen¹, M. Meem¹, I. Warren¹, P. Drullinsky¹, S. Schweber¹, R. Wang¹, M. Gorsky¹, A. Gucalp¹, J. Shen¹, R. Sanford¹, A. Widman¹, M. Robson¹, L. Norton¹, T. Traina¹, D. Graham², R. Mahtani³, N. M. Iyengar⁴; ¹Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, ²Medicine, Hackensack Meridian Health, Hackensack, NJ, ³Medicine, Baptist Health, Miami, FL, ⁴Medicine, Winship Cancer Institute at Emory University, Atlanta, GA.

Background: The prognosis for metastatic triple negative breast cancer (metTNBC) remains poor and novel therapeutic strategies are urgently needed. Insulin resistance & obesity are independent predictors of worse survival in metTNBC. Moreover, Homeostatic Model Assessment for Insulin Resistance (HOMA-IR) and related metabolic markers often worsen significantly during chemotherapy. Methionine aminopeptidase 2 (MetAP2/p67) is an enzyme involved in angiogenesis and regulation of metabolic hormones that is overexpressed in breast cancer. In a phase I study of evexomostat, a MetAP2 inhibitor, 80% of patients with advanced solid tumors had stable disease and improvements in fasting insulin, adiponectin, and VEGF-C. The primary objective of this phase 2 study is to assess the efficacy of evexomostat on insulin resistance in combination with standard of care eribulin in metTNBC. Here, we report results from the safety run-in phase and exploratory biomarker changes. Methods: This is a multicenter phase 2 randomized controlled trial of evexomostat + eribulin (NCT05570253). Key eligibility include metTNBC, baseline HbA1c >5.5% and/or BMI ≥30, and ≤2 prior treatment lines in the metastatic setting. In the safety run-in period, 15 patients received evexomostat 49 mg/m² Q2 weeks + eribulin 1.4 mg/m² on D1&8 of a 21-day cycle. The safety threshold was defined as ≥4/15 patients experiencing serious adverse events (SAEs) not resolving within 14 days. The primary endpoint of the randomized phase is change in HOMA-IR at 12 weeks. Secondary endpoints include objective response rate (ORR) and safety and tolerability. Patients were considered evaluable if they received ≥1 dose of evexomostat. Change in HOMA-IR and other markers was analyzed using Wilcoxon signed rank test. Results: Among the 15 patients in the safety run-in phase, 2/15 experienced SAEs, both of which were grade 3 anemia. The most common any-grade AE was anemia (9/15, 60%). AEs of grade ≥3 were reported in 11 patients; the most frequent grade ≥3 AE was decreased neutrophil count. Accordingly, the safety stopping rule was not triggered and the trial advanced to the randomization phase. Exploratory analyses from baseline to week 12 demonstrated significant changes in LDL cholesterol, adiponectin, leptin, resistin, VEGF-D, and sFRP-5 (p=0.016, 0.009, 0.021, 0.016, 0.027, and 0.012 respectively; see Table). There was no increase in HOMA-IR (p>0.9). Among 12 patients evaluable for response; ORR was 17% and clinical benefit rate was 67%. Conclusions: Evexomostat + eribulin safety was confirmed and the trial advanced to the randomization phase including a placebo-controlled arm with eribulin. Preliminary biomarker results indicate that insulin resistance was unchanged, and favorable changes were seen in other metabolic markers.

S. N. Powell¹, A. J. Khan¹, R. Delsite¹, N. Riaz¹, J. S. Reis-Filho²; ¹radiation oncology, memorial sloan kettering cancer center, New York, NY, ²pathology, memorial sloan kettering cancer center, New York, NY.

Purpose/objectives: Women with recurrent triple-negative breast cancer (TNBC) who have recurrent disease have a poor prognosis. We know that recurrent TNBC has a high rate of homologous recombination deficiency (HRD). HRD cells are sensitive to cisplatin and radiation therapy (RT) independently, but their combination may enhance the sensitivity of HRD tumors. Materials/Methods: From April 2015 to September 2022, we enrolled 50 patients with locally recurrent or metastatic TNBC to a phase II trial (NCT02422498) of weekly cisplatin (25mg/m²) x12 and concurrent RT (50-60 Gy in 25 fractions or 37.5-48 Gy in 15 fractions). The primary end-point was the imaging response at 4-8 weeks after completion of therapy. Imaging response was a >50 reduction in the cross-sectional area of the index lesion. Fresh biopsies of all recurrent tumor masses were obtained in order to assess RAD51 function in viable cells, using ex-vivo irradiation for RAD51 foci in single cell suspensions from the tumor specimens. Tumors were categorized as HRD or HR-proficient (HRP) using the criteria established (PMID 28299801). All tumors with available material were subjected to whole genome sequencing (WGS) and categorized as HRD by criteria published recently (PMID 37587346).Results: The median age of enrolled patients was 50 (range 31-70). All patients had received at least two prior systemic therapies. 39 had local recurrence on the chest wall or regional nodes, with 25 having additional metastatic disease. 11 patients had only metastatic disease, with radiotherapy given to the dominant and painful site of disease. 1 patient was later determined to not have TNBC and was excluded from analysis. 42 of 49 patients had successful evaluation of HRD status, with 7 patients failing due to an inadequate cellular specimen on a limited core biopsy and the lack of any prior DNA for WGS. Of the 42 currently evaluated patients, 23 were HRD and 19 were HRP. For the patients with HRD tumors, the imaging response rate to cisplatin and RT was 78% (n=18, of which 10 showed a complete imaging response). In contrast, for HRP tumors the response rate was 21% (n=4, of which none showed a complete imaging response). The response of HRD tumors without radiotherapy, but to cisplatin alone was 24% (n=5) and only 1/15 HRP tumor showed a response to cisplatin alone. For the tumors where we had both RAD51 foci and WGS (n=29) the correlation of HRD calling was 27/29, with the two discordant tumors having evidence of BRCA2 reversion. HRD tumors were both sporadic biallelic and unknown germline at the time of recruitment to the study. Only 2 tumors were HRD without any detectable mutation in HR genes, suggesting that target gene mutation is the predominant cause of HRD. Further details of the whole genome signatures will be presented, with a mixture of BRCA1-like and BRCA2-like tumors observed (PMID 37587346). Although the study did not extend beyond the intitial treatment and response evaluation, follow-up durability of response was observed in the complete imaging responders.Conclusions: HRD status as determined by RAD51 focus formation or by WGS for genomic scars is the major determinant of imaging response of the index lesion (receiving cisplatin and RT). Even though these patients were heavily pre-treated, the imaging response and clinical benefit rate was reassuringly high for HRD patients, many of whom were non-germline cases. This trial supports the use of modern HRD testing as a method for selecting patients for HRD-directed therapies in future clinical trials. The incidence of HRD in recurrent TNBC is well above 50%, suggesting that many patients may benefit from newer agents for exploiting HRD in the future.

J. Knight-Shefner¹, R. M. O’Regan², E. Sampene³, O. Danciu⁴, K. Hoskins⁴, M. E. Burkard⁵, M. T. West¹, V. Carreno¹, I. Fernandez¹, K. B. Wisinski¹, M. N. Sharifi¹; ¹Medicine, University of Wisconsin Carbone Cancer Center, Madison, WI, ²Hematology and Oncology, University of Rochester, Rochester, NY, ³Biostatistics, University of Wisconsin, Madison, WI, ⁴Hematology and Oncology, University of Illinois Cancer Center, Chicago, IL, ⁵Medicine, University of Iowa Holden Cancer Center, Iowa City, IA.

Background: Triple-negative breast cancer (TNBC) is a heterogenous disease encompassing different intrinsic molecular subtypes. Outcomes remain poor for those with advanced disease despite recent advancements in immunotherapy and antibody-drug conjugates. The androgen receptor (AR) is a luminal nuclear hormone steroid receptor in the same family as the estrogen receptor and progesterone receptor. Although dependent on assay and cutoff used, about 25-35% of TNBC have AR protein expression detectable by immunohistochemistry (IHC). Preclinical data suggest the luminal androgen receptor (LAR) molecular subtype of TNBC is dependent on AR signaling and is particularly susceptible to CDK 4/6 inhibition. Thus, AR has emerged as a therapeutic target via androgen blockade in AR+ TNBC. We hypothesized that the combination of ribociclib, a CDK 4/6 inhibitor, and bicalutamide, an androgen receptor inhibitor, will demonstrate clinical benefit for patients with advanced AR+ TNBC. Methods: In this single arm, non-randomized phase I/II study, patients with AR+ TNBC were treated with combination ribociclib and bicalutamide. AR+ was defined as >0% in phase I and ≥10% in phase II. Up to 3 prior lines of systemic therapy for metastatic disease were allowed. Dose escalation was by 3+3 design with fixed bicalutamide at 150 mg daily and ribociclib (1) 400 mg QD on days 1-21, (2) 400 mg on days 1-28, and (3) 600 mg on days 1-21. A Simon two stage design was utilized with a planned total of 25 patients, including phase I patients treated at the recommended phase II dose (RP2D). The primary efficacy endpoint was clinical benefit rate (CBR) at 16 weeks. Secondary objectives were progression free survival (PFS), objective response rate (ORR), overall survival (OS), duration of response (DOR), and safety/tolerability. Additionally, a circulating tumor cell (CTC) AR gene signature was explored. The study was concluded early due to low enrollment. Results: 21 patients were enrolled. Median age was 56 (range 37-75 yrs) and all patients were female. 76% of patients were non-Hispanic white, 19% Black, and 5% unknown. AR positivity was between 2-95%. In the phase I dose escalation, the RP2D was determined to be the standard doses of each agent: ribociclib 600 mg daily on days 1-21 of the 28-day cycle and bicalutamide 150 mg daily. Of the 19 patients with available adverse event data, the most common treatment-emergent adverse events included: leukopenia 79% (47% grade 3), neutropenia 74% (47% G3, 16% G4), lymphopenia 47% (11% G3), fatigue 47%, thrombocytopenia 37% (11% G3), anemia 37% (5% G3), nausea 37%, AST elevation 26% (5% G3), ALT elevation 21%, constipation 21%, hot flashes 21%, creatinine elevation 16%. Two patients experienced a grade 3 infection: one with urinary tract infection and one with skin infection. 18/21 patients were evaluable for efficacy, which included both the phase I and phase II cohorts. The CBR at 16 weeks was 27% (5/18 patients, 95% CI [0.097, 0.535]; p-value 0.0481). There was a PR in 1 patient. OS, PFS, ORR, and DOR will be presented, as well as efficacy in patients treated at RP2D. AR-V7 was detected in baseline CTC samples in 2 out of the first 11 patients in the cohort, neither of whom achieved disease control at 16 weeks. CTC analysis for the remaining patients is ongoing and will be reported. Conclusions: Although the study did not complete accrual, there were 5 patients with AR+ TNBC treated with ribociclib and bicalutamide combination therapy who achieved disease control at 16 weeks. Further, the AR V7 CTC gene signature may be an emerging biomarker of treatment response to AR and CDK 4/6 inhibition. Future investigation of biomarkers beyond tissue AR IHC staining could be investigated to improve patient selection.

X. Wang¹, Y. Zhang¹, A. Petrilla², S. McElwee³, B. Momani³, J. Dinoso⁴, B. Stwalley⁵, C. Lai⁶, A. Brufsky⁷; ¹Global Value and Access, HEOR, Gilead Sciences, Inc, Foster City, CA, ²HEOR, Norstella, Boston, MA, ³RWD, Norstella, Boston, MA, ⁴Global Medical Affairs, Gilead Sciences, Inc, Foster City, CA, ⁵US Medical Affairs, Gilead Sciences, Inc, Foster City, CA, ⁶Clinical Development, Gilead Sciences, Inc, Foster City, CA, ⁷Division of Hematology/Oncology Breast Cancer Center, Clinical Investigation, UPMC Hillman Cancer Center, Pittsburgh, PA.

Introduction: Patients with la/m TNBC have poor prognosis and limited effective treatment options. Clinical guidelines recommend testing for biomarkers, including PD-L1 expression, to inform clinical decision making and eligible treatments. This study describes treatment patterns and clinical outcomes in patients with la/m TNBC treated in US community and academic health systems. Methods: This observational, cohort study used deidentified person-level NorstellaLinQ EMR/lab and supplemental claims data. Patients were required to have diagnosis of la/m TNBC followed by initiation of 1L mTNBC anti-cancer treatment between 1/1/ 2020 and 12/31/2023. Patients were followed from initiation of 1L treatment (index date) until earliest of death, end of EMR, or end of study period (12/31/2024). Patients were stratified by PD-L1 status closest to the index date. Tumor PD-L1 status were assessed using the PD-L1 assays in EMR laboratory results or evidence of PD-L1 tumor status in unstructured clinical notes. Clinical outcomes included real-world time on treatment (rwTOT) and real-world time to next treatment (rwTTNT). Results: A total of 724 patients met criteria for analysis (PD-L1 Negative: 163, PD-L1 Positive: 398, Unknown/did not receive IO in la/m setting: 163). Mean(sd) age at index: 59(13) years. Demographics were comparable across PD-L1 Negative/Positive subgroups. Less than 5% of study patients were exposed to IO therapy in (neo)adjuvant setting. Among all patients, there were over 30 distinct 1L treatment agent-based regimens observed. Among patients with PD-L1 negative tumors, most common 1L regimens were chemotherapy monotherapy (“chemo mono”) (73.6%) and chemotherapy + immunotherapy (chemo + IO) (17.2%)). Among patients with PD-L1 positive tumors, most common 1L regimens were chemo + IO (60.6%) and chemo mono (31.7%). Approximately 34% of study patients cycled through at least 3 LOTs during the study period. rwTOT and rwTTNT were described in Table 1. Conclusions: In this real-world study of US patients with la/m TNBC and confirmed PD-L1 status, there is variability in 1L, 2L and 3L regimens. The majority of the PD-L1 positive cohort received 1L chemo (+/- IO) followed by chemo + IO or ADCs in 2L/3L. Negative PD-L1 cohort was largely prescribed 1L chemo followed by ADCs or chemo in 2L/3L, while there is a proportion of patients who used chemo+ IO combination therapy that is higher than previously published literature. The proportion of patients receiving subsequent LOTs was low, highlighting the need for new and efficacious frontline treatment options.

E. Hamilton¹, D. A. Aysel¹, M. Yan², C. Wang³, H. Yang⁴, J. Shi⁵, W. Xie⁶, H. Wang⁷, Y. Sun⁸, X. Sun⁹, B. Zhang⁹, Q. Yang¹⁰, Z. Jia⁹, H. Mu⁹, S. Tillmanns¹¹, Y. Barbachano¹², J. Furlanetto¹³, T. Sun¹⁴; ¹SCRI Oncology Partners, Sarah Cannon Research Institute, Nashville, TN, ²Department of Breast Disease, Henan Breast Cancer Center, The Affiliated Cancer Hospital of Zhengzhou University & Henan Cancer Hospital, Zhengzhou, CHINA, ³Cancer Institute and Hospital, Tianjin Medical University, Tianjin, CHINA, ⁴Department of Medical Oncology, Affiliated Hospital of Hebei University, Baoding, CHINA, ⁵Department of Internal Medicine, Linyi Cancer Hospital, Linyi, CHINA, ⁶Department of Breast & Bone and Soft Tissue Tumor, Guangxi Medical University Cancer Hospital, Nanning, CHINA, ⁷Department of Breast & Bone and Soft Tissue Tumor, Guangxi Medical University Cancer Hospital,, Nanning, CHINA, ⁸Cancer Hospital of Shandong First Medical University, Cancer Hospital of Shandong First Medical University, Jinan, CHINA, ⁹Clinical Development, Duality Biologics, Shanghai, CHINA, ¹⁰Research and Development, Duality Biologics, Shanghei, CHINA, ¹¹Clinical Development, BioNTech SE, Mainz, GERMANY, ¹²Biostatistics, BioNTech UK Ltd, London, UNITED KINGDOM, ¹³Medical Safety, BioNTech SE, Mainz, GERMANY, ¹⁴First Ward of Breast Medicine, Liaoning Cancer Hospital and Institute, Shenyang, CHINA.

Background DB-1305/BNT325 is a novel investigational ADC with a humanized TROP2 IgG1 monoclonal antibody linked to a DNA topoisomerase I inhibitor via a cleavable linker. Early clinical data showed a manageable safety profile and encouraging activity across tumor types, particularly in ovarian cancer (Marathe, ESMO 2023 & Rubinstein, SGO 2025). This study evaluated DB-1305/BNT325 in pts with previously treated mTNBC. Methods In the dose expansion part of this Phase 1/2 trial, pts with mTNBC (w/o prior sacituzumab govitecan) received DB-1305/BNT325. The primary endpoints were objective response rate (ORR), based on investigator assessment per RECIST 1.1, and safety. Secondary endpoints included disease control rate (DCR), duration of response (DOR) and progression-free survival (PFS). Results As of March 31, 2025, 26 pts with TNBC had received ≥1 dose of DB-1305/BNT325, with 6 pts still on treatment. The cohort is fully enrolled. Median age was 49 years (range: 29-77); most pts were Asian (92.3%) and had ECOG PS 1 (65.4%). Most common metastases sites were bone (50%), lung (38.5%), and liver (34.6%). The median number of prior lines of treatment was 2 (range: 2-6), including immunotherapy in 8 (30.8%), platinum-based chemotherapy in 19 (73.1%), and bevacizumab in 5 (19.2%) pts. Efficacy data (summarized in the table) is available for all 26 pts after a median follow-up of 9.3 months. Treatment-emergent and treatment-related adverse events (TRAEs) occurred in all 26 pts, with Grade ≥3 in 9 (34.6%) pts. TRAEs led to dose reduction in 5 pts (19.2%) and discontinuation in 1 pt (3.8%, due to anemia). No TRAEs resulted in death. The most common TRAEs were stomatitis (any grade: 69.2%, Grade ≥3: 7.7%), anemia (any grade: 53.8%, Grade ≥3: 11.5%), nausea (any grade 46.2%, Grade ≥3: 0%), decreased neutrophil (any grade: 46.2%, Grade ≥3: 0%) and white blood (any grade: 46.2%, Grade ≥3: 3.8%) cell count. Updated analyses from the cohort will be presented. Conclusions The data suggest an encouraging efficacy and manageable safety profile of DB-1305/BNT325 in pts with pretreated TNBC, with only 1 patient discontinuing treatment due to TRAE. DB1305/BNT325 is now being evaluated in combination with BNT327, an investigational anti-PD-L1 x VEGF-A bispecific antibody in pts with TNBC.

M. V. Dolezal¹, V. G. Abramson², N. Chittoria³, S. Ehsani⁴, R. G. Pestell⁵, H. S. Rugo⁶, H. Rui⁷, D. L. Adams⁸, J. Meidling⁹, M. Lataillade⁹, J. P. Lalezari⁹; ¹Department of Medicine, Stanford University School of Medicine, Stanford, CA, ²Department of Medicine, Vanderbilt-Ingram Cancer Center, Nashville, TN, ³Department of Medicine, University of Utah Huntsman Cancer Institute, Salt Lake City, UT, ⁴Department of Medicine, University of Arizona Cancer Center, Tucson, AZ, ⁵Department of Medicine, Pennsylvania Cancer and Regenerative Medicine Research Center, Wynnewood, PA, ⁶Department of Medical Oncology & Therapeutics Research, City of Hope Comprehensive Cancer Center, Duarte, CA, ⁷Cancer Biology, Thomas Jefferson University, Philadelphia, PA, ⁸Department of Clinical R&D, Creatv MicroTech, Inc., Monmouth Junction, NJ, ⁹Department of R&D, CytoDyn Inc., Vancouver, WA.

Background. Pretreated patients with metastatic triple-negative breast cancer (mTNBC) have a poor prognosis. In clinical trials among previously treated mTNBC patients the median overall survival (mOS) has been reported as 6.6 months for ≥3rd line chemotherapy, 11.8 months for ≥2nd line sacituzumab govitecan, and 9.9 months for ≥1st line pembrolizumab. It has also been reported that in the real-world, after first line therapy around a third of patients die before receiving 2nd line treatment. Furthermore, there remains an unmet need in the PD-L1 negative mTNBC patient population. It has been shown that >95% of TNBCs are positive for C-C chemokine receptor 5 (CCR5). Leronlimab (LRM) is a humanized monoclonal antibody that blocks CCR5 and reduces TNBC metastasis by >98% in preclinical models. Methods. In a retrospective post hoc analysis, data were pooled from 28 patients with mTNBC from 3 LRM clinical trials (NCT03838367 [N=10]; NCT04313075 [N=16]; NCT04504942 [N=2]). LRM was given subcutaneously weekly at a dose of 350 mg (N=10), 525 mg (N=15), or 700 mg (N=3) in combination with various chemotherapies ± immune checkpoint inhibitors (ICI). PD-L1 staining was measured on cancer-associated macrophage-like cells (CAMLs) and circulating tumor cells (CTCs) prior to and after (≈40 days) LRM treatment. Cox proportional univariate analyses were run to determine Hazard Ratios (HRs) for progression-free survival (PFS) and overall survival (OS) at 48 months. Results. Median age was 48.5 years (range 32-83) with a median of 2 prior metastatic therapies (range 0 to ≥3). Overall, 18% (5/28) of patients had PD-L1 positive tumor staining (CPS≥10%). LRM was well tolerated with no patients withdrawing due to LRM-related adverse events and no dose-limiting toxicities. Overall, mPFS was 3.8 months and mOS was 6.8 months. Survival at 1, 2, 3, and 4 years was 35.7%, 21.4%, 17.9%, and 17.9%, respectively. An upregulation from baseline of PD-L1 was observed in CAMLs/CTCs in 76% (16/21) of patients (7 patients had no post-baseline samples) after any dose of LRM, and in 88% (15/17) of patients receiving the 525 mg or 700 mg doses. Sixteen patients showed a drop in CAMLs/CTCs after initiating LRM while 12 showed an increase. The mOS for patients who showed a drop in CAMLs/CTCs was 17.2 months (95% CI, 9.4–N/A) compared to 3.7 months (95% CI, 1.7–5.6) for those patients who showed an increase in CAMLs/CTCs after LRM treatment (HR: 7.11 [95% CI, 2.5–20.2; p=0.0007]). Further, of the seven patients treated with an ICI with, or after LRM, 5/5 (100%) patients with PD-L1 upregulation remained alive at 4 years, compared to none of the 21 patients (0%) who did not receive an ICI with or after LRM (HR: 4.14 [95% CI, 1.7–10.2; p=0.0041]). Conclusions. In this retrospective pooled analysis of 28 mTNBC patients, LRM was well tolerated. A 4-year OS rate of 17.9% (5/28) in a population with a median of 2 prior metastatic therapies is encouraging. Among a key subgroup, all 5 patients with PD-L1 upregulation who subsequently received ICI remained alive at 4 years possibly indicating a correlation with durable responses. A reduction in CAMLs/CTCs after LRM treatment may relate to improved survival, suggesting its potential as a prognostic biomarker. These findings support the hypothesis that LRM may enhance PD-L1 expression on CAMLs/CTCs, potentially priming tumors for improved responses to ICIs. In an evolving treatment landscape these data warrant prospective evaluation of LRM, particularly in combination with ICIs in mTNBC.

K. A. Ahmed¹, Y. Kim², R. Dowell¹, D. Oliver¹, M. Mills¹, R. Nair³, A. Armaghani⁴, R. Costa⁴, T. O’Connor⁴, G. Rajasekaran Rathnakumar⁴, H. Soliman⁴, A. Soyano⁴, E. Tan-Chiu⁴, P. Forsyth⁵, J. Arrington⁶, H. Yu¹, H. Han⁴; ¹Radiation Oncology, Moffitt Cancer Center, Tampa, FL, ²Biostatistics and Bioinformatics, Moffitt Cancer Center, Tampa, FL, ³Pharmacy, Moffitt Cancer Center, Tampa, FL, ⁴Breast Oncology, Moffitt Cancer Center, Tampa, FL, ⁵Neuro Oncology, Moffitt Cancer Center, Tampa, FL, ⁶Radiology, Moffitt Cancer Center, Tampa, FL.

Background: The prognosis and quality of life for triple negative breast cancer (TNBC) brain metastases remains poor. Sacituzumab govitecan (SG) has shown potential blood brain barrier (BBB) penetration in preclinical and clinical settings with anti-tumor activity in the phase III ASCENT Trial (NCT02574455). Radiotherapy can open the BBB and has been shown to be safe in combination with anti-PD-1 therapy in our previous study (NCT03807765). Combining radiation with the anti-PD-1 monoclonal antibody, zimberelimab, and SG may provide a synergistic anti-tumor approach. Methods: The study is designed as a single-arm, nonrandomized, open-label, phase I/II trial of SG and zimberelimab with stereotactic radiosurgery (SRS) among patients with metastatic TNBC with brain metastases. The primary endpoint is neurologic toxicity defined by CTCAE v5 criteria (phase I) assessed via a 3+3 design. Eligibility includes TNBC patients ≥ 18 years old with brain metastases eligible for SRS with at least one measurable lesion ≥ 0.5 cm per RANO-BM criteria. Treatment is initiated with SRS followed 1 week later by SG on days 1 and 8 (10 mg/kg) with zimberelimab on day 1 (360 mg IV) repeated every 3 weeks. Phase I results are reported, clinical trial information: NCT06238921. Results: Three patients were enrolled between December 2024 through April 2025. Median age was 56 (range: 49-57) with a baseline KPS of 90 in 2 patients and 70 in 1 patient. Median lines of prior systemic therapy in the stage IV setting was 1 (range 0-2). No intracranial dose limiting toxicities were noted. The most common grade ≥ 2 adverse events were neutropenia in 3 patients (100%) (grade 4 in 1 and grade 2 in 2 patients) and grade 2 fatigue in 1 patient. The best RANO-BM intracranial response has been a partial response (PR) in 3 patients (100%). The best irRECIST systemic response has been a PR (n=1), stable disease (n=1), and progressive disease (n=1). Two patients continue study therapy currently. No deaths have occurred. Conclusions: Results from the phase I portion reveals safety of a combined approach. Efficacy continues to be assessed in the phase II portion.

S. M. Doss, P. Raval; Department of Medicine, Medical College of Georgia, Augusta, GA.

Background: Prior studies of metastatic triple-negative breast cancer (TNBC) have generally categorized multiple metastatic sites broadly as “multiple” or have focused on single-organ involvement, limiting the ability to counsel patients on prognosis for specific metastatic groups. To assist oncologists in these discussions, we analyzed how site-specific patterns of distant metastasis affected survival and treatments received for de-novo stage IV TNBC using a large, real-world national registry. Methods: Using the National Cancer Database (NCDB), we identified women over age 40 who were diagnosed with de-novo stage IV TNBC between 2010 and 2020. Metastatic groups were classified as brain only, lung only, liver only, or combinations of these sites at diagnosis. We focused only on brain, lung, and liver involvement because bone metastases are known to have a more favorable prognosis. Median overall survival (OS) and six-month and one-year survival rates were calculated using Kaplan-Meier analysis. Multivariate Cox regression analyzed associations between metastatic group and two-year OS after adjustment for age, comorbidity index, race/ethnicity, facility type, and diagnosis year. Treatment patterns were summarized for each metastatic group. Results: We identified 119,373 women with stage IV breast cancer, of whom 13,345 (11.2%) had TNBC. After excluding patients with missing variable data, 7,448 women comprised the final cohort for analysis. Median OS by metastatic group ranged from 3.6 months (brain + liver) to 12.7 months (lung only). In ascending order, one-year OS rates were 13.1% for brain + lung + liver, 17.3% for brain + liver, 29.2% for brain + lung, 30.8% for brain only, 34.0% for lung + liver, 47.6% for liver only, and 51.8% for lung only. In multivariate Cox regression, compared to brain only, patients with metastases to lung only (adjusted hazard ratio [aHR] 0.55, 95% confidence interval [CI] 0.49-0.61, p<0.001) and liver only (aHR 0.69, 95% CI 0.62-0.77, p<0.001) had increased two-year OS, while patients with metastases to brain + liver (aHR 1.67, 95% CI 1.37-2.03, p<0.001) and brain + lung + liver (aHR 1.72, 95% CI 1.47-2.01, p<0.001) had worse OS. Chemotherapy receipt ranged from 57.0% (brain + liver) to 75.7% (liver only). Radiation was most common in patients with CNS involvement, ranging from 60.6% (brain + liver) to 69.9% (brain + lung). Surgery to the primary breast site was rare, highest in lung only (27.1%) and lowest in brain + liver (6.3%). Conclusions: Sites of distant metastasis at diagnosis strongly influenced survival and treatment choice in stage IV TNBC. Patients with lung-only metastases showed the highest OS, while those with brain and/or liver involvement had markedly worse OS. These results can help guide clinicians and patients in counseling, expectations, and treatment planning for stage IV TNBC.

T. Wang¹, W. Zhao², J. Xiao¹, J. Zhou¹, X. Shi², Q. Li², Z. Jiang¹; ¹Department of Oncology, The Fifth Medical Center of Chinese PLA General Hospital, Beijing, CHINA, ²Department of Oncology, Beijing Gobroad Hospital, Beijing, CHINA.

Background: The advent of novel antibody-drug conjugates (ADCs) has greatly changed the treatment landscape of advanced HER2-negative breast cancer. Preclinical studies have showed potential synergistic effect between ADCs and immunotherapies, while the clinical evidence remains limited. Our phase 2, multi-cohort, open-label, non-controlled trial (NCT06433609), was designed to evaluate the efficacy and safety of ADCs with distinct targets combined with PD-L1 inhibitor adebrelimab in pts with pretreated advanced HER2-negative breast cancer. Here, we present the preliminary results of TROP2-ADC SHR-A1921 combined with adebrelimab in pts with advanced triple negative breast cancer (TNBC). Methods: Pts with HER2-negative advanced breast cancer who had experienced disease recurrence or progression on or after at least one line of systematic therapy were eligible for this trial. Prior PD-1/L1 inhibitors were allowed. Eligible pts with advanced TNBC enrolled in Cohort 2 received SHR-A1921 (3 mg/kg IV on day 1, Q3W) and adebrelimab (1200mg IV on day 1, Q3W). The primary endpoint was objective response rate (ORR) per investigator based on RECIST v1.1. Secondary endpoints included disease control rate (DCR), clinical benefit rate (CBR), duration of response (DoR), progression-free survival (PFS), overall survival (OS) and safety. Results: Between Sept. 6th, 2024 and Dec. 31st, 2024, 15 pts were enrolled in Cohort 2. The median age was 52 years (range, 29-70), and pts had the median one (range, 0-8) prior treatment at the advanced setting. Eleven pts (73.3%) had ECOG PS of 1, eight (53.3%) were PD-L1-positive (CPS≥1) and 13 (86.7%) had visceral metastases, with 8 (53.3%) having ≥3 metastatic sites. With a median follow-up of 5.5 mo (range, 1.2-8.9), all of pts had at least one efficacy assessment. The confirmed ORR was 46.7% (95% confidence interval [CI], 21.2-73.4) with a median DoR of 4.6 mo. CBR was 46.7% (95%CI, 21.2-73.4), and DCR was 86.7% (95%CI, 59.5-98.3). Of note, among 6 pts with PD-L1-negative diseases, 2 pts achieved PR and 1 pt achieved PR to be confirmed. Nine PFS events were observed, and the median PFS was 5.1 mo (95%CI 3.1-NA). Two pts died after disease progression, and the median OS was unmatured. Treatment-related adverse events (TRAEs) occurred in all pts, and mostly were of grade 1-2. Grade≥3 TRAEs occurred in 2 pts (13.3%), including one (6.7%) grade 3 stomatitis and one (6.7%) grade 3 lymphocyte decreased. Eight pts experienced dose reduction of SHR-A1921 due to TRAEs. No dose discontinuation and no death due to AE was reported. Conclusion: The combination of SHR-A1921 and adebrelimab demonstrated promising anti-tumor efficacy and manageable safety in pretreated TNBC pts regardless of PD-L1 status, warranting further investigations in this population. Our exploration of ADCs combined with adebrelimab in HER2-negative advanced breast cancer is still ongoing.

J. Zubrowska¹, M. Holanek², M. Pieniazek³, A. Polakiewicz-Gilowska⁴, R. Soumarova⁵, H. Studentova⁶, A. Konieczna⁷, A. Mlodzinska⁷, K. Winsko-Szczesnowicz⁸, M. Lisik-Habib⁹, A. Pekala⁹, D. Krejci¹⁰, J. Sustr¹¹, I. Kolarova¹², I. Danielewicz¹³, M. Szymanik-Resko¹³, T. Ciszewski¹⁴, L. Rusinova¹⁵, B. Czartoryska-Arlukowicz⁸, A. Lacko³, M. Jarzab⁴, R. Pacholczak-Madej¹⁶, I. Lugowska¹⁷, Z. Bielcikova¹⁸, M. Malejcikova¹⁹, M. Puskulluoglu²⁰; ¹Department of Clinical Oncology, Holy Cross Cancer Center, Kielce, POLAND, ²Department of Comprehensive Cancer Care, Masaryk Memorial Cancer Institute, and Faculty of Medicine, Masaryk University, Brno, CZECH REPUBLIC, ³Department of Oncology, Breast Unit Clinical Oncology Day Care Department, Wroclaw Medical University and Lower Silesian Comprehensive Cancer Center, Wroclaw, POLAND, ⁴Breast Cancer Center, Maria Sklodowska-Curie National Research Institute of Oncology, Gliwice, POLAND, ⁵Department of Oncology, Third Faculty of Medicine, Charles University, University Hospital Kralovske Vinohrady, Prague, CZECH REPUBLIC, ⁶Department of Oncology, Faculty of Medicine and Dentistry, Palacky University and University Hospital, Olomouc, CZECH REPUBLIC, ⁷Department of Breast Cancer and Reconstructive Surgery, Maria Sklodowska-Curie National Research Institute of Oncology-National Research Institute, Warszawa, POLAND, ⁸Department of Clinical Oncology, M. Sklodowska-Curie Bialystok Oncology Center, Bialystok, POLAND, ⁹Department of Proliferative Diseases, Nicolaus Copernicus Multidisciplinary Centre for Oncology and Traumatology, Lodz, POLAND, ¹⁰Department of Oncology, First Faculty of Medicine, Charles University in Prague, and Bulovka University Hospital, Prague, CZECH REPUBLIC, ¹¹Department of Oncology and Radiotherapy, Faculty of Medicine in Pilsen, Charles University, and University Hospital Pilsen, Plzen, CZECH REPUBLIC, ¹²Department of Oncology and Radiotherapy, Faculty of Medicine in Hradec Kralove and University Hospital in Hradec Kralove, Charles University, Hradec Kralove, CZECH REPUBLIC, ¹³Oddzial Onkologii i Radioterapii, Szpitale Pomorskie sp. z o.o., Gdynia, POLAND, ¹⁴Department of Metabolic Diseases and Immuno-oncology, Medical University of Lublin, Lublin, POLAND, ¹⁵Department of Oncology, Stefan Kukura Hospital Michalovce, Michalovce, SLOVAKIA, ¹⁶Department of Gynecological Oncology, Maria Sklodowska-Curie National Research Institute of Oncology, Krakow Branch, Krakow, POLAND, ¹⁷Centre of Excellence for Precision Oncology, Maria Sklodowska-Curie National Research Institute of Oncology (NIO-PIB), Warsaw, POLAND, ¹⁸Department of Oncology, First Faculty of Medicine, Charles University, and General University Hospital, Prague, CZECH REPUBLIC, ¹⁹II. Oncology Clinic of LFUK, National Cancer Institute, Bratislava, SLOVAKIA, ²⁰Department of Clinical Oncology, Maria Sklodowska-Curie National Research Institute of Oncology, Krakow Branch, Krakow, POLAND.

Background: Triple-negative breast cancer (TNBC) is an aggressive form of breast cancer (BC) characterized by rapid clinical progression. Further lines of palliative systemic therapy typically offer diminishing benefit and increasing toxicity. Unlike hormone receptor-positive BC, TNBC lacks low-toxicity, long-term treatment options. In heavily pretreated patients, the decision to continue systemic therapy is particularly challenging. In the absence of robust evidence and amid growing expectations for individualized, patient-centered care, clinicians must rely on judgment to determine when to shift focus to palliative care. Timely recognition of the end-of-life (EOL) phase is essential to avoid overtreatment, reduce harm, and ensure care aligns with patient goals. The aim of this study was to assess the timing of the final oncologist visit relative to death in heavily pretreated women with advanced TNBC. We also analyzed systemic treatment status and palliative care involvement at that time and explored clinical factors associated with this interval. Materials and Methods: This multinational ambispective cohort study included women with advanced TNBC who received ≥2 lines of palliative systemic therapy and died between June 20, 2022, and June 20, 2025. Data from 17 centers in Poland, the Czech Republic, and Slovakia were extracted from medical records. The primary endpoint was the interval (in days) between the final oncologist visit and death. Collected variables included age at last visit, number of prior chemotherapy lines, performance status (PS), systemic treatment continuation, and palliative care involvement prior to last visit. Analyses were performed in R (v4.3.3), with significance set at p < 0.05. Results: A total of 183 women were included. The median age at death was 53.6 years (range: 28.6-86.5). The median number of previous palliative chemotherapy lines was 4 (range: 2-12), and the median interval between the last oncologist consultation and death was 17 days (range: 0-410). At the final visit, systemic treatment was ongoing in 53 patients (29.5%), and palliative care involvement prior to the last visit was documented in 89 patients (49%). The median interval between the final oncologist consultation and death among patients continuing systemic therapy was 27 days (range: 2-194). PS at the last visit was 0-1 in 36 patients (20%), 2 in 38 (21%), 3 in 65 (36%), and 4 in 35 (19%). A significantly longer interval between the last visit and death was observed in patients with better performance status 0-1 vs ≥2 (p<0.001). No significant difference was observed with respect to palliative care involvement (p=0.849). Conclusions: These findings highlight the need for earlier recognition of clinical decline and more proactive integration of palliative care in patients with advanced TNBC. Avoiding non-beneficial systemic therapy near the EOL may support care focused on symptom relief, patient autonomy, and quality of life. Given the particularly poor prognosis of metastatic TNBC, ensuring timely access to appropriate EOL care has become a recognized priority at the European level, including within the Network of Expertise on Complex and Poor Prognosis Cancers (NoE PPC), as part of broader efforts to address inequalities and improve outcomes for this high-risk population. Structured EOL planning remains a critical gap in international real-world practice and requires urgent attention in this context.

T. A. Traina¹, E. Serra², J. Bedard², M. Levesque-Leroux², P. Gagnon-Sanschagrin², A. Guérin², S. Guenther³, G. Joseph⁴, V. Guan⁴, J. Salcedo⁴; ¹Department of Medicine, Evelyn H. Lauder Breast Center, Memorial Sloan Kettering Cancer Center, New York, NY, ²-, Analysis Group ULC, Montréal, QC, CANADA, ³Global Medical Affairs, BioNTech SE, Mainz, GERMANY, ⁴Health Economics & Outcomes Research, BioNTech US Inc, Cambridge, MA.

Background: Patients with PD-L1-negative locally recurrent inoperable or metastatic triple-negative breast cancer (lr/m TNBC) have limited treatment options and typically receive first-line (1L) chemotherapy in clinical practice. Real-world evidence on patient outcomes, particularly real-world progression-free survival (rwPFS) from 1L treatment initiation in PD-L1-negative lr/m TNBC, remains scarce. Additional data are needed to better understand clinical outcomes in this population and support evidence-based treatment decision-making. Methods: A retrospective cohort of adults (≥18 years old) receiving 1L treatment for PD-L1-negative lr/m TNBC was identified in Komodo Research Data (01/2016-12/2023), a large claims database that covers approximately 30% of the United States (US) population. Patients with lr/m TNBC were identified using an algorithm developed with medical expert guidance that required systemic treatment initiation within 3 months of a biopsy and no observed surgery in the 12 months following the biopsy. Triple-negative and PD-L1 statuses were inferred from treatments received in the lr/m setting. Demographics were described on the date of 1L treatment initiation, and comorbidities were assessed during the preceding 12 months. Real-world proxies of progression were also defined with medical expert guidance and included death, hospice admission, initiation of a second line of systemic treatment, or initiation of radiotherapy. Among patients who initiated 1L treatment ≥6 months before the end of data availability, the Kaplan-Meier method assessed rwPFS from 1L treatment initiation until the first real-world proxy of progression or end of follow-up, defined as the earliest of end of continuous health plan enrollment or end of data availability. Results: A total of 929 patients with lr/m TNBC were identified in this study. The median (interquartile range [IQR]) age at 1L initiation was 59 (51-66) years. Most patients were female (98.6%). Among those with a recorded race (69.3%), 60.1% were White, 26.4% were Black or African American, and 9.2% were Hispanic or Latino. Most patients had commercial insurance (64.9%), followed by Medicare (26.7%) and Medicaid (8.4%). The most frequent comorbidities prior to 1L treatment initiation were liver disease (26.8%), chronic obstructive pulmonary disease (22.7%), diabetes (22.0%), and peripheral vascular disease (13.6%). Median (IQR) follow-up from 1L initiation was 10.3 (5.7-20.1) months. The most common 1L treatments in the lr/m TNBC setting included cyclophosphamide+doxorubicin-based regimens (28.1%), followed by capecitabine (12.7%), paclitaxel (10.4%), carboplatin+paclitaxel (9.4%), and carboplatin+gemcitabine (8.6%), with frequent use of non-NCCN-guideline-preferred regimens. Among the 910 patients with sufficient follow-up to assess rwPFS, 703 (77.3%) had an indicator of progression following 1L initiation. Median (95% confidence interval [CI]) rwPFS was 4.7 (4.5-5.2) months. rwPFS rates (95% CI) were 69.0% (65.9%-71.9%) at 3 months, 41.7% (38.4%-45.0%) at 6 months, 22.6% (19.7%-25.6%) at 12 months, and 18.3% (15.5%-21.2%) at 18 months. The observed indicators of progression were, in order of frequency, initiation of a second line of systemic treatment (43.8%), death (25.5%), initiation of radiotherapy (18.1%), and hospice admission (12.7%). Conclusions: In US clinical practice, patients with PD-L1-negative lr/m TNBC experience rapid disease progression following initiation of 1L treatment, with a median time to progression of less than 5 months. These findings underscore a critical unmet need for effective 1L treatment options with tolerable safety profiles to improve outcomes in this patient population.

T. Luo¹, C. Zhuang¹, Y. Song¹, P. He¹, D. Zheng¹, X. Yan¹, X. Zhong¹, T. Tian¹, B. Wei², Y. Xie¹, J. Chen¹, Q. Lv¹; ¹Institute of Breast Health Medicine, Breast Center, Department of Medical Oncology, Cancer Center, West China Hospital, Sichuan University, China, Chengdu, CHINA, ²Department of pathology, West China Hospital, Sichuan University, China, Chengdu, CHINA.

Background: Triple-negative breast cancer (TNBC) is characterized by limited treatment options and poor prognosis, with chemotherapy serving as the primary treatment approach. Immunotherapy and targeted therapy have become critical strategies for improving prognosis in patients with TNBC, but real-world adoption remains unclear. This study aimed to characterize first-line (1L) treatment and clinical outcomes in patients with advanced TNBC (aTNBC) in Western China.Methods: This retrospective study enrolled aTNBC patients initiating first-line therapy (2018-2023) in West China Hospital. Descriptive statistics summarized treatment adoption and patient characteristics.The primary endpoint was overall survival (OS), progression-free survival (PFS), and time to next treatment or death (TTNTD).Results: A total of 282 patients with aTNBC were included, with a median age of 51 years (range, 22-80). The mOS was 22.0 months(95% CI, 19.6-25.1), mPFS was 7.8 months(95% CI, 7.1-9.0) and mTTNTD was 8.3 months(95% CI, 7.2-9.4) among patients. Patients aged 40-65 years had significantly longer OS (p=0.04). Patients with recurrent metastatic TNBC demonstrated significantly prolonged PFS (p=0.04) and TTNTD (p=0.04) compared to those with de novo metastatic TNBC; however, no statistically significant difference in OS was observed. Patients with a treatment-free interval (TFI) exceeding 12 months demonstrated significantly longer OS (p<0.001). Ipsilateral chest metastasis was associated with shorter OS(p=0.005), while primary breast recurrence correlated with reduced PFS (p=0.02) and TTNTD (p=0.02) in locoregional recurrence patients. Patients who developed distant metastasis exhibited significantly shorter OS (p=0.04), PFS (p=0.002), and TTNTD (p=0.002); notably, those with liver or lung metastasis as the first metastatic site showed particularly poor prognosis (liver PFS (p<0.001) and TTNTD (p=0.002); lung OS (p=0.02), PFS (p=0.003) and TTNTD (p<0.001)). PD-L1 testing (22C3 assay) was performed in 20.6% (58/282) of patients, yielding a 50.0% positivity rate (29/58, CPS ≥1), among whom 8 received immune checkpoint inhibitors (ICIs) in 1L treatment. 17 patients received ICIs without established PD-L1 biomarker eligibility (either PD-L1-negative or untested status). Pathogenic germline BRCA1/2 mutations were identified in 19 of 83 tested patients (22.9%), among whom only 5 received PARP inhibitor in 1L treatment. Additionally, ADC-based therapy was administered to 9 patients in the 1L treatment. Conclusions: In Western China, 1L treatment for aTNBC predominantly relies on chemotherapy with limited ICI and targeted therapy due to economic and logistical barriers. Future expanding access to immunotherapy and targeted therapy in Western China is clinically imperative to address current care disparities.

J. Żubrowska¹, M. Kubeczko², M. Pieniążek³, A. Polakiewicz-Gilowska², M. Malejčíková⁴, A. Konieczna⁵, M. Holánek⁶, I. Kolářová⁷, R. Soumarová⁸, H. Študentová⁹, A. Młodzińska⁵, K. Winsko-Szczęsnowicz¹⁰, M. Lisik-Habib¹¹, A. Pękala¹¹, D. Krejčí¹², J. Šustr¹³, I. Danielewicz¹⁴, M. Szymanik-Resko¹⁴, T. Ciszewski¹⁵, L. Rusinova,¹⁶, A. Rudzińska¹⁷, B. Czartoryska-Arłukowicz¹⁰, A. Łacko¹⁸, M. Jarząb², R. Pacholczak-Madej¹⁹, Z. Bielčiková²⁰, M. Püsküllüoğlu²¹; ¹Department of Clinical Oncology, Holy Cross Cancer Center, Kielce, POLAND, ²Breast Cancer Center, Maria Sklodowska-Curie National Research Institute of Oncology, Gliwice, POLAND, ³1. Department of Oncology 2. Breast Unit Clinical Oncology Day Care Department, 1. Wrocław Medical University, 2. Lower Silesian Comprehensive Cancer Center, Wrocław, POLAND, ⁴II. Oncology Clinic of LFUK, National Cancer Institute, Bratislava, SLOVAKIA, ⁵Department of Breast Cancer and Reconstructive Surgery, Maria Sklodowska-Curie National Research Institute of Oncology, Warsaw, POLAND, ⁶Department of Comprehensive Cancer Care, Faculty of Medicine, Masaryk University, and Masaryk Memorial Cancer Institute, Brno, CZECH REPUBLIC, ⁷Department of Oncology and Radiotherapy, Faculty of Medicine in Hradec Kralove and University Hospital in Hradec Kralove, Charles University, Hradec Králové, CZECH REPUBLIC, ⁸Department of Oncology, Third Faculty of Medicine, Charles University, University Hospital Kralovske Vinohrady, Prague, CZECH REPUBLIC, ⁹Department of Oncology, Faculty of Medicine and Dentistry, Palacky University and University Hospital, Olomouc, CZECH REPUBLIC, ¹⁰Department of Clinical Oncology, M. Skłodowska-Curie Bialystok Oncology Center, Białystok, POLAND, ¹¹Department of Proliferative Diseases, Nicolaus Copernicus Multidisciplinary Centre for Oncology and Traumatology, Lodz, POLAND, ¹²Department of Oncology, First Faculty of Medicine, Charles University in Prague, and Bulovka University Hospital, Prague, CZECH REPUBLIC, ¹³Department of Oncology and Radiotherapy, Faculty of Medicine in Pilsen, Charles University, and University Hospital Pilsen, Plzen, CZECH REPUBLIC, ¹⁴Oddział Onkologii i Radioterapii, Szpitale Pomorskie sp. z o.o., Gdynia, POLAND, ¹⁵Department of Metabolic Diseases and Immuno-oncology, Medical University of Lublin, Lublin, POLAND, ¹⁶Department of Oncology, Stefan Kukura Hospital Michalovce, Michalovce, SLOVAKIA, ¹⁷Department of Clinical Oncology, Maria Sklodowska-Curie National Research Institute of Oncology, Krakow, POLAND, ¹⁸1. Department of Oncology 2. Breast Unit Clinical Oncology Day Care Department, Maria Sklodowska-Curie National Research Institute of Oncology, Wrocław, POLAND, ¹⁹Department of Gynecological Oncology, Maria Sklodowska-Curie National Research Institute of Oncology, Krakow, POLAND, ²⁰Department of Oncology, First Faculty of Medicine, Charles University, and General University Hospital, Prague, CZECH REPUBLIC, ²¹Department of Clinical Oncology, Maria Sklodowska-Curie National Research Institute of Oncology, Kraków, POLAND.

Background Patients with metastatic triple-negative breast cancer (mTNBC) have limited treatment options and poor outcomes in later lines. Sacituzumab govitecan (SG) has shown benefit in this setting, including among those previously treated with programmed death-1 (PD-1) inhibitors. In the ASCENT trial, outcomes were numerically worse in patients with prior immunotherapy. As SG is used after progression on first-line chemoimmunotherapy with the PD-1 inhibitor pembrolizumab, concerns arise about its efficacy in this subgroup. Several biological and clinical mechanisms could support the hypothesis that prior anti-PD-1 therapy might influence SG efficacy, including selection of resistant clones, immune remodeling, functional decline, absence of mechanistic synergy, and acquired resistance to SN-38. This study evaluates SG outcomes according to prior use of pembrolizumab-based first-line treatment in Poland, the Czech Republic, and Slovakia. Materials and Methods We conducted a retrospective analysis of patients with mTNBC treated with SG across 18 oncology centers between August 2021 and May 2025. Patients were stratified by prior exposure to first-line palliative chemoimmunotherapy with pembrolizumab, as defined by KEYNOTE-355 criteria. Baseline data included prior treatment history, metastatic burden, and starting dose of SG. Outcomes assessed were progression-free survival (PFS), overall survival (OS), objective response rate (ORR), and disease control rate (DCR), with tumor response evaluated per RECIST 1.1. Safety was analyzed based on adverse events (AEs) graded by CTCAE v5.0. Comparisons were performed using non-parametric and exact tests, and survival was analyzed using univariate Cox models with p<0.05 considered significant. Results Of the 302 evaluable women, 38 (12.6%) had previously received first-line anti-PD-1-based therapy. Baseline characteristics were similar between the groups. The median number of prior lines of palliative systemic therapy was 1 (IQR 1-2; range 1-7 in the anti-PD-1 group vs. 1-10 in the chemotherapy group; p=0.158). Brain metastases were present in 5/38 (13.2%) vs. 23/264 (8.7%) (p=0.372), and visceral metastases in 33/38 (86.8%) vs. 188/264 (71.2%) (p=0.066). A reduced starting dose of SG (≤8 mg/kg) was administered in 2/38 patients (5.3%) previously treated with first-line anti-PD-1 therapy and in 25/264 (9.5%) of others (p=0.550). Median OS was 10.74 months in the anti-PD-1 group and 11.43 months in the chemotherapy group (HR=1.30; 95% CI: 0.836-2.021; p=0.244). Median PFS was 3.22 vs. 4.44 respectively (HR=1.14; 95% CI: 0.782-1.662; p=0.497). ORR was 28.9% (11/38) in the anti-PD-1 group vs. 31.1% (82/264) in the chemotherapy group (p=0.939), while DCR was 60.5% (23/38) vs. 64.8% (171/264) (p=0.742). The median number of full SG cycles was 4 (IQR 2.25-9) in the anti-PD-1 group vs. 6 (IQR 3-11) (p=0.124). Toxicity profiles were similar. Grade ≥3 neutropenia occurred in 12/38 (31.6%) in the anti-PD-1 group and 124/264 (47.0%) in the chemotherapy group (p=0.137). Dose reductions due to AEs were required in 15/38 (39.5%) vs. 99/264 (37.5%) (p=0.956), and treatment delays occurred in 24/38 (63.2%) vs. 167/264 (63.3%) (p=1.000). Conclusions This real-world analysis provides insight into SG use after first-line pembrolizumab-based chemoimmunotherapy in mTNBC. While no clear reduction in efficacy or safety was observed, the impact of prior anti-PD-1 exposure remains clinically relevant. In light of the growing adoption of perioperative pembrolizumab and the anticipated shift of SG into earlier treatment lines, the impact of prior immunotherapy on SG performance should be further explored across diverse mTNBC settings and disease trajectories.

S. Loi¹, G. Werutsky², Y. Park³, S. Loibl⁴, G. Curigliano⁵, D. Eiger⁶, J. Spiridigliozzi⁷, A. K. Dubey⁸, J. Cheng⁹, S. M. Tolaney¹⁰; ¹Division of Cancer Research, Peter MacCallum Cancer Centre, Melbourne, AUSTRALIA, ²Medical Oncology, Breast Cancer Program, Latin American Cooperative Oncology Group, Porto Alegre, BRAZIL, ³Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, KOREA, REPUBLIC OF, ⁴N/A, German Breast Group (GBG) and Centre for Haematology and Oncology, Neu-Isenburg, GERMANY, ⁵Department of Oncology and Hemato-Oncology, University of Milano and European Institute of Oncology IRCCS, Milan, ITALY, ⁶Clinical Development | Late Oncology Team 2, Bristol-Myers Squibb, Princeton, NJ, ⁷Department of Oncology Clinical Development, Bristol-Myers Squibb, Princeton, NJ, ⁸Global Biometrics and Data Sciences, Bristol-Myers Squibb, Princeton, NJ, ⁹Research and Development, SystImmune , Inc., Redmond, WA, ¹⁰Division of Breast Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA.

Background: The epidermal growth factor receptor (EGFR) and human epidermal growth factor receptor (HER) 3 are well-established oncogenic drivers frequently overexpressed in advanced cancers, including triple-negative breast cancer (TNBC) and HER2-negative BC. Their prevalence and critical role in tumor progression make these receptors suitable targets for iza-bren. Iza-bren is a potentially first-in-class antibody-drug conjugate (ADC) composed of an EGFR×HER3 bispecific antibody, conjugated to a novel topoisomerase 1 inhibitor payload (Ed-04) via a cleavable stable linker. Iza-bren has shown promising clinical activity and a manageable safety profile in early-phase clinical trials across various solid tumors, including pre-treated metastatic BC. Methods: IZABRIGHT-Breast01 (NCT06926868) is an open-label, randomized phase 2/3 trial evaluating the efficacy and safety of iza-bren vs chemotherapy of investigator’s choice (paclitaxel, nab-paclitaxel, capecitabine, or carboplatin plus gemcitabine) in patients with previously untreated, locally advanced, recurrent inoperable or metastatic TNBC or estrogen receptor (ER)-low, HER2-negative BC who are ineligible for approved anti-programmed death-1/programmed death ligand 1 (PD-[L]1)-based treatment combinations or endocrine therapy-based treatments, respectively. Key inclusion criteria include ≥ 18 years of age, ECOG performance status 0-1, measurable disease by RECIST v1.1, and either histologically or cytologically confirmed locally advanced, recurrent inoperable, or metastatic TNBC or ER-low, HER2-negative BC. Additional eligibility criteria include recent tumor biopsy collected (≤ 6 months), brain MRI or CT scan ≤ 28 days pre-randomization, and eligibility for ≥ 1 chemotherapy option. Key exclusion criteria include known germline BRCA 1/2 mutation with PARP inhibitor as best treatment option, untreated symptomatic CNS metastases, known bleeding disorders or conditions affecting bone marrow reserve, history of interstitial lung disease or pneumonitis, and prior therapy with iza-bren or any other ADC targeting EGFR and/or HER3 or containing a topoisomerase 1 inhibitor payload. In phase 2, patients will be randomized 1:1:1 to receive iza-bren at dose 1 (arm A1) or dose 2 (arm A2) on days 1 and 8 of each 3-week cycle, or chemotherapy of investigator’s choice (arm B). After a dose is selected, the study will proceed to phase 3 to confirm efficacy and safety with the selected dose of iza-bren. In phase 3, patients will continue to be randomized 1:1 into arms A and B. Randomization will be stratified by early recurrence (6-12 months after last treatment with curative intent) vs late recurrence (> 12 months) vs de novo disease presentation (no prior early-stage breast cancer), hormone receptor status (ER-low [1%-10%] and/or progesterone receptor [PgR]-low [1%-10%] vs negative [ER and PgR < 1%]), and intended chemotherapy (taxanes [nab-paclitaxel or paclitaxel] vs capecitabine vs carboplatin plus gemcitabine). Treatment will continue until disease progression or unacceptable toxicity. The primary endpoint is progression-free survival (PFS) per blinded independent central review using RECIST v1.1. The key secondary endpoint is overall survival. Other secondary endpoints include investigator-assessed PFS, objective response, disease control rate, duration of response, time to response, time to subsequent treatment, PFS after next line of treatment, safety, and health-related quality of life.

H. H. Li, J. L. Zhang, D. D. Zhou, S. J. Sun, Y. S. Gao; Department of Breast Medical Oncology, Shandong First Medical University and Shandong Academy of Medical Sciences, Shandong Cancer Hospital and Institute, Jinan, CHINA.

Objective: Triple-negative breast cancer (TNBC) is the most challenging subtype of breast cancer due to its high heterogeneity, aggressive metastatic potential, and lack of effective targeted therapies and predictive biomarkers. Although btg2 has been implicated as a tumor suppressor in tumorigenesis and cancer progression, its specific role in TNBC invasion and metastasis remains unclear. This study aims to elucidate the mechanism through which btg2 regulates the invasion and metastasis of TNBC by modulating the degradation of becn1. Methods: Using the TCGA database, we analyzed btg2 expression levels and their prognostic significance in TNBC, which we further validated through IHC staining of clinical TNBC samples. Functional assays, including cell viability, colony formation, transwell assays, as well as mouse xenograft experiments, were performed to assess the impact of btg2 on TNBC cell proliferation, migration, and invasion. To elucidate the underlying mechanism, we employed mass spectrometry (MS), co-immunoprecipitation (Co-IP), and immunofluorescence confocal microscopy to examine the interaction between btg2 and becn1. Additionally, Western blotting, qPCR, cycloheximide chase, and ubiquitination assays were conducted to determine how btg2 regulates becn1 protein stability and ubiquitination, including the potential involvement of rnf123 in btg2-mediated becn1 degradation. Results: btg2 was significantly downregulated in TNBC tissues, and this downregulation correlated with poor prognosis. Functional studies demonstrated that btg2 suppressed TNBC cell proliferation, colony formation, migration, and invasion, findings further corroborated by xenograft tumor models. Mechanistically, btg2 increased becn1 levels by inhibiting its proteasomal degradation. Specifically, btg2 expression reduced becn1 ubiquitination, prolonged its half-life, and activated autophagy. Furthermore, we discovered that btg2 stabilizes becn1 by binding to rnf123, thereby blocking rnf123-mediated ubiquitination of becn1. Conclusions: Our findings demonstrate that btg2 interacts with the E3 ligase rnf123 to suppress becn1 ubiquitination and proteasomal degradation, leading to autophagy activation and inhibition of TNBC invasion and metastasis. These results highlight btg2 as a potential diagnostic marker and therapeutic target for TNBC.

R. Shukla¹, K. Ormiston¹, G. Sarathy¹, S. Dhekne¹, D. Quiroga¹, S. Gupta², D. Stover¹, P. Giglio³, C. Rolfo¹, E. Shankar¹; ¹Internal Medicine, The Ohio State University, columbus, OH, ²Urology, The Case Western Reserve University, Cleveland, OH, ³Neurology, The Ohio State University, columbus, OH.

Background: Triple-negative breast cancer (TNBC) is an aggressive disease and lacks effective therapies due to tumor heterogeneity, resistance, and poor immune infiltration. There is a critical need to develop novel and less toxic therapies to improve TNBC survival outcomes. Treatment with Enhancer of Zeste Homolog 2 (EZH2) inhibitors have shown improved efficacy suggesting that these inhibitors play a pivotal role in TNBC progression. We have previously demonstrated that combined treatment with GSK126, an EZH2 inhibitor and dopamine D1 receptor agonist (A77636) exhibit higher efficacy in inhibiting tumor growth and metastasis of TNBC cells both in vitro and in vivo. Here, we examined the immune phenotype/function by which EZH2 and A77636 combination reprogram the TNBC microenvironment. Methods: Female NSG mice (4-6 weeks old) were orthotopically injected with MDA-MB-231 cells into the mammary fat pads. Once tumors became palpable, mice were randomized into four treatment groups (n = 8 per group): Vehicle control, GSK126 (2 mg/kg body weight), A77637 (50 mg/kg body weight), and the combination of GSK126 and A77637. Treatments were administered intraperitoneally once per week for four weeks. Tumor size was measured weekly using calipers, and tumor volume was calculated using the formula: (length × width²)/2. At the end of the treatment period, mice were euthanized. Tumors were excised and weighed. Tumor tissue, bone, blood, and spleen were harvested for flow cytometry analysis. Results: The combination of GSK126 and A77636 demonstrated a synergistic antitumor effect, significantly reducing both tumor weight and volume compared to vehicle or single-agent treatments. Tumor weight was significantly lower in the combination group compared to vehicle (mean difference = 0.278 g, 95% CI: 0.109-0.446, p = 0.0018). Similarly, tumor volume was significantly reduced in the combination group relative to vehicle (mean difference = 101 mm³, 95% CI: 51.7-151, p < 0.0001). This combinatorial treatment also led to a marked reduction in monocyte populations within both the peripheral blood and tumor microenvironment. EZH2 expression was significantly decreased in tumor-associated monocytes and neutrophils in the combination group. Kinetic analysis of tumor-infiltrating monocytes revealed a biphasic response: initial recruitment of pro-inflammatory Ly6C^hi monocytes followed by a transition to anti-inflammatory Ly6C^lo monocytes. Notably, the combination therapy significantly reduced Ly6C^hi monocyte infiltration compared to the vehicle control (0.32 vs. 0.92, representing a 65% decrease; p = 0.0138). In contrast, it increased Ly6C^lo monocyte levels relative to vehicle control (2.5 vs. 1.5), showing a 1.67-fold increase, (p = 0.5126) compared to single-agent and single-dose treatments. Furthermore, the combination group showed a trend toward increased production of the anti-inflammatory cytokine IL-10, while reduction of pro-inflammatory cytokine IL-1β production in both Ly6C^hi and Ly6C^lo monocyte. Conclusion: These findings demonstrate that dual targeting of EZH2 and A77636 not only suppresses TNBC tumor growth but also reprograms the tumor immune repertoire by shifting monocyte dynamics toward an anti-inflammatory phenotype, offering a promising strategy to overcome resistance and improve therapeutic outcomes. (This work is supported by DOD: W81XWH2010065, for Eswar Shankar)

F. Kudrik¹, R. Choksi², D. Patt³, S. Reddy⁴, S. Reganti⁴, S. Rosenfeld⁵, S. W. Champaloux⁶, A. Shrivastava⁶, D. Parris⁶, A. Rui⁶, M. Gart⁶, C. Wall⁶, B. Wang⁶, P. Varughese⁶, J. Donegan⁶, L. Morere⁶, R. Geller⁶, J. Scott⁶, V. Gorantla²; ¹Medical Oncology, South Carolina Oncology Associates, Columbia, SC, ²Medical Oncology, University of Pittsburgh Medical Center (UPMC), Pittsburgh, PA, ³Medical Oncology, Texas Oncology, Austin, TX, ⁴Medical Oncology, Cancer Care Specialists, Reno, NV, ⁵Medical Oncology, Highlands Oncology Group (HOG), Fayetteville, AR, ⁶PrecisionQ, IntegraConnect, West Palm Beach, FL.

Background: Triple negative breast cancer is a less common, aggressive subtype that lacks the expression of estrogen and progesterone receptors as well as HER2, making standard endocrine and HER2-directed therapies ineffective. Current NCCN guidelines recommend germline BRCA testing for all patients (pts) with metastatic breast cancer to identify candidates for poly (ADP-ribose) polymerase (PARP) inhibitors. In addition, PD-L1 testing, defined as a combined positive score (CPS) ≥10, guides utilization of pembrolizumab in combination with chemotherapy. Taken together, biomarker testing is an important component in guiding care. The study describes patterns and timing of BRCA and PD-L1 testing among pts with mTNBC who initiated therapy. Methods: Pts with metastatic triple-negative breast cancer (mTNBC) who initiated therapy on or after January 1, 2021, were identified from the IntegraConnect PrecisionQ database, which includes electronic health records from over 3 million de-identified pts in the U.S. Metastatic status and biomarker information were verified through manual chart review, including extraction from unstructured clinical notes, genomic reports and pathology reports. The review captured hormone receptor and HER2 status, as well as documentation of BRCA and PD-L1 testing. Descriptive analyses compared testing rates by demographics, ECOG status, recurrent vs de novo presentation, and treatment patterns. Results: Overall, 720 curated pts were identified as having mTNBC and initiated a line of therapy on or after 1/1/2021 (date initiated minimum 1/1/2021; maximum 3/5/2025). Of the 720 pts, 651 (90%) received a BRCA genetic test, yet just 61% (n=437) were tested prior to the mTNBC therapy initiation date and among those 71% (N =311) received Germline testing. Out of the 651 pts who received a BRCA test, germline testing was recorded in 463 pts (71%), somatic testing in 536 pts (82%) and both types of tests were identified in 361 pts (55%). Prior to mTNBC therapy initiation, 42% (n=303) were tested for PD-L1 and 83% (N=600) were tested for PD-L1 at any time. The mean age for pts at treatment initiation date differed for those who received a BRCA test at any time compared to those who did not receive a BRCA test (mean age at treatment initiation date: BRCA tested 60 years old versus BRCA Not tested: 63 years old). Distribution of ECOG scores did not differ by PD-L1 or BRCA testing status at time of treatment of mTNBC. BRCA testing was similar across racial groups, but PD-L1 testing was lower in the African American population (68% vs. 76%). Out of all the PD-L1 CPS tested pts (N=384), a positive result, defined as a CPS that was ≥10, occurred in 49% (N=188) of cases and a negative result occurred in 51% (N=196) of cases. Among those who received a PD-L1 test after initiation of therapy, the median time to test was 29 days (interquartile range 10-151 days). Pts with recurrent disease had similar testing rates compared to those with de novo disease for both BRCA (89% vs. 91%) and PD-L1 (74% vs. 73%) testing. In the pts who tested positive for BRCA and negative for PD-L1 (n=36), PARP inhibitors were used in a subsequent line of therapy for 19 pts (53%). In the pts with a PD-L1 CPS ≥10 prior to mTNBC treatment initiation and did not receive pembrolizumab in the neo-adjuvant or adjuvant setting (n=166), pembrolizumab was utilized in 92 pts (55%). Conclusions: Out of all pts who were tested, only 42% of pts received PD-L1 testing and 61% received BRCA testing prior to initiating first-line treatment for mTNBC. Further opportunities for timely testing should be explored to optimize treatment choice.

K. Graciano¹, C. Liu¹, B. Ning¹, H. Guo², J. Xu¹; ¹Genetics, University of Alabama at Birmingham, Birmingham, AL, ²Pathology, University of Alabama at Birmingham, Birmingham, AL.

Triple-negative breast Cancer (TNBC) accounts for around 15-20% of all breast cancers and is associated with poor long-term outcomes. It remains the most challenging subtype to treat because of its aggressive phenotype and limited treatment options. Aurora Kinases are overexpressed in multiple types of solid tumors, including breast cancer. Our preliminary studies discovered that AURKB expression disproportionally increased in African American TNBC patients more than in European American TNBC patients. Aurora kinase inhibitors, such as alisertib (MLN8237), have demonstrated early signals of efficacy with a manageable safety profile for the treatment of patients with locally advanced or metastatic breast cancer (NCT02860000). However, they did not show significant efficacy in TNBC unless combined with chemotherapy. EZH2, a histone methyltransferase and catalytic subunit of Polycomb Repressive Complex 2 (PRC2), has a broad role in cell stemness, and its overexpression promotes the development of many cancers, including TNBC. Multiple independent studies have identified EZH2 as an attractive drug target in TNBC. Several EZH2 inhibitors, which inhibit the methyltransferase activity of EZH2, have been approved for the treatment of sarcoma and follicular lymphoma in clinical settings. However, EZH2 inhibitors are ineffective at inhibiting TNBC cell growth. We unexpectedly discovered that Aurora Kinases interact with and phosphorylate EZH2, and inhibition of Aurora Kinases upregulates the chromatin silencing marker H3K27me3. Moreover, combined inhibition of EZH2 and Aurora kinases shows a synergistic antitumor effect in TNBC. Phosphorylation of EZH2 by Aurora Kinase could retain EZH2 in the cytosol, leading to a functional shift from a PRC2 complex-dependent activity to a potential non-canonical EZH2 pro-metastatic function. Furthermore, RNA-seq analysis of the TNBC cells treated with Aurora Kinases inhibitors (AKi) Barasertib (AZD1152) and/or EZH2 PROTAC degrader MS177 reveals that AKi inhibits the expression of a panel of genes, which EZH2 degrader also regulates. Combinatory treatment leads to a synergistic effect on this panel of gene expression, which is critical for cell apoptosis, proliferation, and metabolism in TNBC cells. To summarize, we discovered Aurora Kinases have a less-studied, non-canonical oncogenic function, which acts in parallel with the canonical cell division activity to produce more aggressive tumor metastasis phenotypes seen in TNBC. This non-canonical function highly depends on EZH2-mediated cancer cell apoptosis, proliferation, invasion, and metastasis, which differs from the well-known cell division function of Aurora Kinases, regulating chromosomal alignment, segregation, and cytokinesis during mitosis.

R. Caputo¹, C. Martinelli¹, M. Piezzo¹, G. Buono¹, V. Di Lauro¹, R. Buonaiuto¹, A. Verrazzo¹, D. Cianniello¹, M. V. Bonomo², F. Pantano³, S. Scagnoli², S. Cocco¹, G. R. Ricciardi⁴, F. Giotta⁵, L. S. Stucci⁶, N. Staropoli⁷, S. Turano⁸, M. V. Sanò⁹, P. Trasacco¹⁰, L. Orlando¹¹, L. Del Mastro¹², A. Fabi¹³, M. De Laurentiis¹, A. Botticelli²; ¹Department of Breast and Thoracic Oncology, Istituto Nazionale Tumori-IRCCS “Fondazione G. Pascale”, Naples, ITALY, ²Department of Radiological, Oncological and Pathological Sciences, Policlinico Umberto I-Sapienza University of Rome, Rome, ITALY, ³Department of Medical Oncology, Fondazione Policlinico Universitario Campus Bio-Medico, Rome, ITALY, ⁴Department of Onco-hematology, Papardo Hospital, Messina, ITALY, ⁵Medical Oncology, IRCCS Istituto Tumori “Giovanni Paolo II”, Bari, ITALY, ⁶Medical Oncology, Policlinico Hospital of Bari, Bari, ITALY, ⁷Department of Experimental and Clinical Medicine, Magna Graecia University, Azienda Ospedaliera Universitaria R. Dulbecco Catanzaro, Catanzaro, ITALY, ⁸Department of Oncohematology, Azienda Ospedaliera di Cosenza, Cosenza, ITALY, ⁹Medical Oncology, Istituto Clinico Humanitas, Misterbianco, Catania, ITALY, ¹⁰Department of Clinical Medicine and Surgery, University of Naples “Federico II”, Naples, ITALY, ¹¹Medical Oncology, “Antonio Perrino” Hospital, Brindisi, ITALY, ¹²Department of Medical Oncology, IRCCS Ospedale Policlinico San Martino, Genoa, ITALY, ¹³Precision Medicine in Senology, Scientific Directorate – Department of Women and Child Health, Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, ITALY.

Background: Sacituzumab Govitecan (SG), an antibody-drug conjugate (ADC) targeting TROP2, has demonstrated significant improvements in progression-free survival (PFS) and overall survival (OS) compared to standard chemotherapy in previously treated patients with metastatic triple-negative breast cancer (mTNBC). However, drug-drug interactions (DDIs), particularly in real-world settings, may influence the pharmacological activity of anticancer agents, potentially affecting both treatment efficacy and toxicity. Drug-PIN® (Personalized Interactions Network) is a tool designed to detect DDIs and integrate them with demographic, clinical, and biochemical patient data. In this multicenter retrospective analysis, we aim to evaluate the impact of clinical toxicites and DDIs on treatment outcomes in patients receving SG in a real world context.Methods: Toxicities, drug-drug interactions (DDIs), and clinical outcomes—including PFS and OS— in patients with mTNBC treated with SG in routine clinical practice were retrospectively collected from 11 Italian centers, as part of the NCT02284581 multicenter study. DDIs were assessed using the Drug-PIN® platform, which generated a Drug-PIN® score and assigned each patient to a Drug-PIN® tier: green (no clinically significant DDIs), and yellow to red (increasing DDI severity). Patients with relevant DDIs (tiers yellow to red) were compared to those without significant interactions (tier green). PFS and OS were estimated using the Kaplan-Meier method. The association between Drug-PIN® classification and clinical outcomes was assessed through multivariate logistic regression.Results: A total of 123 pts were included. Patient’s characteristics are reported in table 1. Median time from diagnosis of mBC to SG start was 17 months (range 0- 117). Among pts taking any medications, 20 pts (16.3%) had a relevant DDIs. Median rwPFS was 5.0 months in pts without any DDIs and 2.8 months in patients with DDIs [HR 1.89 (1.14-3.15) p 0.0138]. Using a multivariate model, both Drug-PIN tier [green vs other; HR 2.18 (1.3-3.5); p 0.0015] and presence of brain metastases at baseline [HR 1,62 (1,07-2,47) p 0,022] resulted as independent predictor of shorter PFS. Median OS was numerically higher but not statistically significant (p 0.098) in pts without DDIs [7.57 months vs 5.3 months [HR 1.69 (0.91-3.15)]. No significant association among DDIs and the report of common treatment related toxicity or dose reduction was detected.Conclusion: In our real-world cohort, a low rate of clinically relevant DDIs was observed. While DDIs were associated with shorter PFS, no differences in toxicity or dose modifications emerged. Further investigations are needed to assess the potential impact of DDIs in mBC pts treated with ADCs.

R. Caputo¹, M. Piezzo¹, C. Martinelli¹, G. Di Mauro², V. Granata³, M. Pagliuca⁴, A. Botticelli⁵, F. Pantano⁶, F. Giotta⁷, A. Diana⁸, L. S. Stucci⁹, N. Staropoli¹⁰, S. Turano¹¹, E. Bajardi¹², G. Pernice¹³, M. V. Sanò¹⁴, A. Caltavituro¹⁵, L. Orlando¹⁶, S. Scagnoli⁵, C. De Angelis⁴, A. Fabi¹⁷, G. Buono¹, M. De Laurentiis¹; ¹Department of Breast and Thoracic Oncology, Istituto Nazionale Tumori-IRCCS “Fondazione G. Pascale”, Naples, ITALY, ²School of Specialization in Medical Oncology, University of Messina, Naples, ITALY, ³Divisions of Radiology, Istituto Nazionale Tumori-IRCCS “Fondazione G. Pascale”, Naples, ITALY, ⁴Clinical and Translational Oncology, Scuola Superiore Meridionale, Naples, ITALY, ⁵Department of Radiological, Oncological and Pathological Sciences, Policlinico Umberto I-Sapienza University of Rome, Rome, ITALY, ⁶Department of Medical Oncology, Fondazione Policlinico Universitario Campus Bio-Medico, Rome, ITALY, ⁷Medical Oncology, IRCCS Istituto Tumori “Giovanni Paolo II”, Bari, ITALY, ⁸Medical Oncology Unit, Ospedale del Mare, Naples, ITALY, ⁹Medical Oncology, Policlinico Hospital of Bari, Bari, ITALY, ¹⁰Department of Experimental and Clinical Medicine, Magna Graecia University, Azienda Ospedaliera Universitaria R. Dulbecco Catanzaro, Catanzaro, ITALY, ¹¹Department of Oncohematology, Azienda Ospedaliera di Cosenza, Cosenza, ITALY, ¹²Medical Oncology, Casa di Cura La Maddalena, University of Palermo, Palermo, ITALY, ¹³Medical Oncology, Fondazione Istituto Giglio, Cefalù, ITALY, ¹⁴Medical Oncology, Istituto Clinico Humanitas, Misterbianco, Catania, ITALY, ¹⁵Department of Clinical Medicine and Surgery, University of Naples “Federico II”, Naples, ITALY, ¹⁶Medical Oncology, “Antonio Perrino” Hospital, Brindisi, ITALY, ¹⁷Precision Medicine in Senology, Scientific Directorate – Department of Women and Child Health, Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, ITALY.

Background: Central nervous system (CNS) metastases, including brain metastases (BMs) and leptomeningeal disease (LMD), occur in approximately 20%-40% of patients (pts) with breast cancer during the course of their disease. Triple-negative breast cancer (TNBC) is associated with a high incidence of BMs (up to 34%) and poor survival rates. Sacituzumab Govitecan (SG) has demonstrated significant improvements in progression-free survival (PFS) and overall survival (OS) in pre-treated pts with metastatic TNBC (mTNBC) in the pivotal ASCENT trial. However, data on SG efficacy in pts with TNBC and CNS metastases are limited, as only 32 pts with stable/treated BMs were enrolled in the study, and patients with active BMs or LMD were excluded. This study aimed to provide further insight into the clinical activity of SG in pts with mTNBC and CNS involvement. Methods: Clinical and treatment data of pts with TNBC and BMs who were treated in a real-life setting were retrospectively collected from 14 Italian centers as part of a multicenter, observational study (NCT02284581). CNS treatment response was retrospectively categorized as objective response, stable disease, or progressive disease. Real-world (rw)PFS, rwOS, and CNS-specific progression-free survival (CNS-PFS) were described using the Kaplan-Meier method and reported with a 95% confidence interval. Survival outcomes between groups were compared by log-rank tests. Analysis was carried out with R software (version 4.5.1). Results: A total of 54 pts were included in the analysis. Of these, 46 (85.2%) had treated/stable CNS metastases, 4 (7.4%) had active CNS metastases, and 4 (7.4%) had LMD. The median age at SG initiation was 54 years (range: 31-75). The median time from mTNBC diagnosis to CNS metastasis was 12 months, and the median time from CNS metastasis diagnosis to SG initiation was 5 months. Pts had received a median of 2 prior lines of therapy before CNS involvement. At a median follow-up of 18.2 months, the median rwPFS was 3.75 months (95% CI, 3.06-7.89 months) and the median rwOS was 9.49 months (95% CI, 6.21-15.3). The CNS objective response rate (ORR) was 19.6% among pts with treated/stable BMs, and 25% in both pts with active BMs and those with LMD. The median CNS-PFS in the overall population was 9.26 months (range: 4.8-16.2), with subgroup medians of 12.1 months for stable/treated BMs, 4.8 months for active BMs, and 4.1 months for LMD. The table provides a summary of the efficacy results.Conclusion: To our knowledge, this study represents the largest real-world analysis to date assessing the activity of SG in pts with TNBC and CNS metastases. Our findings are consistent with the efficacy profile observed in the ASCENT trial. These data support the potential role of SG in this difficult-to-treat population, although further studies are warranted to better characterize its activity in pts with mTNBC and CNS involvement.

B. Wang¹, M. Li¹, Y. Xie¹, Z. Yang²; ¹Department of Breast and Urological Medical Oncology, Fudan University Shanghai Cancer Center, Shanghai, CHINA, ²Department of Nuclear Medicine, Fudan University Shanghai Cancer Center, Shanghai, CHINA.

Background:Patients with estrogen receptor (ER)-positive breast cancer may experience ER-negative conversion (ER loss) during disease progression. ¹⁸F-fluoroestradiol positron emission tomography/computed tomography (¹⁸F-FES PET/CT) offers a practical approach for comprehensive ER evaluation across all metastatic sites, allowing early identification of ER conversion—especially valuable for cases where biopsy is technically challenging. This study aimed to compare survival outcomes and clinical characteristics between ER loss and metastatic triple-negative breast cancer (mTNBC) patients, exploring the prognostic implications of dynamic ER changes. Methods:This retrospective study screened 808 patients with ER-positive, HER2-negative breast cancer at initial diagnosis who underwent ¹⁸F-FES PET/CT after diagnosis of recurrent or metastatic disease from 2017 to 2023 at Fudan University Shanghai Cancer Center. Among them, 82 patients with functional ER loss detected by FES-PET at metastatic sites before first-line treatment were identified. 115 contemporaneous standard mTNBC patients with complete medical records were enrolled in control group. Propensity score matching (PSM) was used to balance baseline characteristics (number of metastatic sites, visceral/liver/lung/bone metastasis, taxane therapy history; caliper = 0.1). Results:PSM matched 59 patients per group and baseline clinical characteristics are well-balanced. FES-PET showed 71.7% concordance with IHC. Median progression-free survival (PFS) was significantly shorter in ER loss group compared with mTNBC (6.7 vs 12.0 months, HR=1.55, P=0.042). Objective response rate (ORR) (15.3% vs 37.3%) and disease control rate (DCR) (72.9% vs 84.7%, P=0.044) favored mTNBC, as well. Androgen receptor (AR) expression is available in 25 and 32 patients in ER loss and mTNBC group, respectively, and AR pathway positivity (≥10%) was significantly higher in ER loss group (88.0% vs 25.0%, P<0.0001). 28 of 59 (47.5%) ER loss patients received chemotherapy, and 18 of them received capecitabine based first-line therapy, while 34 of 59 (57.6%) mTNBC patients received platinum-based chemotherapy and 8 of 59 mTNBC patients had PD-1/PD-L1 exposure in first-line therapy. Conclusions:Our study reveals that patients with functional ER loss defined by FES-PET exhibit worse outcomes than mTNBC, potentially attributed to lighter treatment intensity and AR pathway activation. These findings suggest that functional ER-negative conversion, detectable via whole-body FES PET/CT, may identify a distinct high risk subgroup requiring TNBC-level treatment intensification. Future studies should investigate underlying mechanisms and evaluate AR-targeted therapies in this population.

H. Muhammad¹, S. S. Chavan¹, C. Feng¹, SMMART Clinical Trials Program, H. S. Basu¹, W. Huang¹, R. Rajat¹, G. Wilding¹, S. Kummar², G. B. Mills³; ¹AI, PATHOMIQ, Inc., Cupertino, CA, ²Molecular Oncology, Knight Cancer Institute, Oregon Health & Science University, Portland, OR, ³Precision Oncology, Knight Cancer Institute, Oregon Health & Science University, Portland, OR.

Introduction: PARP inhibitors (PARPi) have demonstrated the potential to enhance tumor immunogenicity and sensitize cancer cells to immune checkpoint blockade, as shown in the AMTEC clinical trial. However, identifying PARPi responders and understanding the tumor’s adaptive response remain significant clinical challenges. Advances in multi-omic profiling offer unprecedented resolution into these dynamics, yet the complexity and volume of such data demand sophisticated analytical approaches. By applying AI to histopathology images, we aim to uncover predictive morphogenomic biomarkers of PARPi response, potentially enabling more precise treatment selection and to reveal novel mechanisms of therapeutic adaptation in the tumor and its immune microenvironment. Method: We applied two complementary approaches to identify predictive morphometric and morphogenomic biomarkers in biopsy samples collected during the AMTEC trial. Using the PATHOMIQ Phenotype Atlas, we quantified fold changes in individual morphological phenotypes between matched pre-treatment and on-treatment biopsies to identify morphology-based predictors of treatment response. Using the PATHOMIQ Genoscope, a deep learning model that infers RNA expression from H&E-stained slides, we estimated gene expression profiles directly from histology images. Genes that were significant in univariate Cox modeling were evaluated in multivariate models to identify transcriptomic predictors. Result: To assess phenotypic changes across serial biopsies, we computed fold changes in the prevalence of individual morphological phenotypes between pre-treatment and on-treatment samples. Specific morphometric changes related to desmoplasty and necrosis were significantly associated with progression-free survival (PFS). Their emergence in on-treatment biopsies enabled clear patient stratification, as confirmed by a log-rank test (p < 0.001). Separately, univariate Cox proportional hazards modeling identified 15 genes, predicted directly from H&E images via Genoscope, as significantly associated with PFS. A multivariate model incorporating the top-ranked genes along with FOXC1 demonstrated robust stratification of patient outcomes. Kaplan-Meier estimation using a median-expression cutoff revealed a significant survival difference (p < 0.01, log-rank test). Discussion: These results show that AI-based analysis of H&E slides can identify both morphological and gene expression markers predictive of PARP inhibitor response. The identification of these desmoplastic changes during treatment may signal early resistance and these necrotic changes signal early response, while inferred expression of genes such as FOXC1, a known biomarker, was linked to poor progression-free survival. This morphogenomic approach enables non-destructive, scalable patient stratification and may support real-time treatment adaptation in future studies.

R. Kabirian¹, M. Gendreau¹, F. C. Bidard¹, F. Lerebours², A. Vincent Salomon³, L. Djerroudi³, P. H. Cottu¹, F. Coussy¹, J. Y. Pierga¹, L. Cabel¹, D. Loirat¹; ¹Medical Oncology department, Institut Curie – Institute of Women’s Cancers, Paris, FRANCE, ²Medical Oncology department, Institut Curie – Institute of Women’s Cancers, Saint-Cloud, FRANCE, ³Department of Diagnostic and Theranostic Medicine, Institut Curie – Institute of Women’s Cancers, Paris, FRANCE.

Background: Neoadjuvant pembrolizumab combined with paclitaxel and carboplatin followed by anthracycline and cyclophosphamide has become the standard of care for stage II-III early triple-negative breast cancer (TNBC). However, clinicopathological features and outcomes of metastatic relapse after neoadjuvant chemo-immunotherapy remain poorly documented. Methods: We conducted a retrospective analysis at Institut Curie Hospitals (France) including patients diagnosed with a metastatic relapse between Nomvember 2022 and May 2025, after having received pembrolizumab-based neoadjuvant regimen for early TNBC. Patients’ characteristics at early and metastatic settings were collected, as well as Distant Metastasis-Free Interval (DMFI, from primary diagnosis to metastatic relapse), Progression-Free Survival on 1^st line therapy (PFS1, from the date of metastatic relapse) and Overall Survival (OS, from the date of metastatic relapse). Results: We identified N=32 patients out of 386 patients treated with neoadjuvant pembrolizumab who experienced metastatic relapse following a pembrolizumab-based neoadjuvant regimen. At primary diagnosis, all 32 tumors were TNBC, including N=3 tumors (9%) with low (1-9%) expression of hormone receptors and N=13 tumors (41%) with HER2low status. Strikingly, androgen receptor (AR) expression was apparently enriched, with N=8/22 (36%) primary tumors showing high (≥10%) AR expression. Most primary tumors were of grade 3 (N=25/32, 78%) and stage II (N=20, 63%). Only N=2/29 (7%) patients displayed a germline BRCA1/2 mutation. Following neoadjuvant chemo-immunotherapy, N=30 patients underwent surgery, of whom only N=5 patients (17%) had a pCR (RCB=0). Post-operative treatments were heterogeneous: N=11 patients (37%) received adjuvant pembrolizumab monotherapy, N=9 (30%) received capecitabine monotherapy, N=5 (17%) received a combination of both, N=3 (10%) were included in a clinical trial while N=2 (7%) relapsed before any adjuvant therapy. The median DMFI from initial diagnosis was 16 months, IQR[9-19], and most relapses (N=23, 72%) occurred during or within 6 months after the completion of adjuvant therapy. At relapse, median age was 43 years (IQR[37-50]). Visceral metastases were present in N=22 patients (69%), while brain and bone-only metastases were identified in N=6 (19%) and N=3 (9.4%) patients, respectively. A prior or concurrent local recurrence was observed in N=12 of patients (38%). Although N=13/24 tumors (54%) displayed a high PD-L1 CPS score, only 3 patients (9%) were rechallenged with pembrolizumab and chemotherapy as first line therapy. N=11 patients (34%) received standard chemotherapy, N=16 patients (50%) received sacitumab govitecan (SG) when olaparib and experimental therapy were each administered to N=1 patient (3%). After a median follow-up of 11.2 months, median PFS1 was 3.9 months [95%CI:2.4-5.5]. We found no prognostic impact of disease sites and no survival difference between standard chemotherapy (median PFS1: 3.7mo) and SG (4.1mo). N=15 deaths have been observed, with a median OS of 8.5 months [95%CI: 7.7-NA]. Updated results with longer follow-up will be presented. Conclusions: This real-world cohort of patients with TNBC relapsing after pembrolizumab-based neoadjuvant therapy shows an extremely poor prognosis upon metastatic recurrence, regardless of metastatic site and first line therapy. There remains a critical need to improve treatment strategies in this population.

W. Poon¹, R. Uzma², R. Master³, L. Wang⁴, H. Zhao⁴, A. Veeraraghavan², L. Ridnour⁵, S. J. Lockett⁶, R. Raghunathan⁴, D. A. Wink⁵, S. T. Wong⁴; ¹Department of Medical Sciences, Texas A&M Health Science Center, Bryan, TX, ²Department of Electrical and Computer Engineering, Rice Univeristy, Houston, TX, ³School of Engineering Medicine, Texas A&M University, Houston, TX, ⁴Department of Systems Medicine and Bioengineering, Houston Methodist, Houston, TX, ⁵Center for Cancer Research, National Cancer Institute, Frederick, MD, ⁶Cancer Research Technology Program, Frederick National Laboratory for Cancer Research, Frederick, MD.

Triple-negative breast cancer (TNBC, 15–20% of breast cancers) has poor prognosis, high metastatic potential, and limited treatment options due to the absence of estrogen receptor (ER), progesterone receptor (PR), and HER2 amplification. The tumor microenvironment (TME) plays a key role in driving progression, with inflammatory enzymes such as inducible nitric oxide synthase (NOS2) and cyclooxygenase-2 (COX-2) upregulated in aggressive subtypes. High NOS2 expression in TNBC has been linked to poor overall survival, possibly due to its role in shaping an immunosuppressive microenvironment and activating pro-metastatic signaling cascades. Elevated COX-2 expression is also a hallmark of TNBC, where it facilitates M2 macrophage polarization, regulatory T cell recruitment, and resistance to immune checkpoint blockade. However, their influence on tumor metabolism, lipid accumulation, and collagen dynamics remains unclear. The TME is also spatially heterogeneous, made up of diverse niches that lead to therapy resistance. Microscopy offers insight into these regions, but exogenous dyes hinder translation to live tissues. To overcome this, we employed a label-free, multimodal multiphoton microscopy platform combining second harmonic generation (SHG) for collagen, two-photon autofluorescence (TPAF) for redox metabolism, and coherent anti-Stokes Raman scattering (CARS) for lipid imaging. We examined how NOS2-derived nitric oxide depletion and COX-2 inhibition via indomethacin affect TNBC metabolism, lipid profiles, and collagen architecture. Orthotopic 4T1 TNBC tumors were established in 4 cohorts of BALB/c mice: Group 1 (n=5, wild type (WT) untreated), Group 2 (n=7, WT + indomethacin), Group 3 (n=5, NOS2 knockout (NOS2-/-)), and Group 4 (n=7, NOS2-/- + indomethacin). 12-15 mm diameter tumors were excised, sectioned, and imaged ex vivo. A dual-output ultrafast tunable laser (Insight DeepSee, Santa Clara, USA) was used as the optical source of the label-free multimodal platform. For CARS, TPAF of NADH, TPAF of FAD, and SHG, the following excitation wavelengths were used: 803 nm combined with 1040 nm, 755 nm, 860 nm, and 803 nm. Samples were imaged at 25x magnification (0.94 µm/pixel). Multimodal images of whole slices were acquired and processed using MATLAB. SHG images were quantified by collagen area fraction (CAF), anisotropy parameter, Hough transform-based standard deviation, and Fourier transform-based metrics. Redox ratio was used to assess TPAF images. Size distribution of lipid droplets through CARS was also analyzed. CARS imaging revealed distinct lipid remodeling across both NOS2-NO depletion and indomethacin treatment. NOS2- tumors show a significant increase in large lipid droplets (1,000–10,000 pixels) compared to wild-type, suggesting enhanced lipid accumulation suggesting altered storage or β-oxidation. Indomethacin-treated tumors, independent of NOS2, had a greater share of small lipid droplets (1–10 pixels), reflecting altered lipolysis or turnover. The combined treatment in NOS2- mice further augmented the accumulation of small lipid droplets (p<0.0075), supporting a synergistic effect. Global SHG and TPAF analyses did not reveal significant differences, but initial regional analyses are ongoing to assess collagen structure and metabolic redox states in peritumoral and immune-rich zones. Early inspection suggests disorganized collagen in immune dense regions of NOS2- tumors, potentially facilitating immune cell infiltration.

M. Hofherr; Medical Oncology, Washington University, St. Louis, MO.

Background: The mainstay of triple negative breast cancer (TNBC) continues to be cytotoxic treatment, specifically carboplatin/gemcitabine, carboplatin/paclitaxel or sacituzumab govitecan. The most common adverse effect of these regimens is dose-dependent and dose-limiting neutropenia. Recent meta-analyses of randomized controlled trials (RCTs) have shown a reduction in all-cause mortality in patients receiving prophylactic G-CSF with cytotoxic chemotherapy as well as an association with improved overall survival (OS). However, these meta-analyses did not exclusively look at metastatic breast cancer patients. To the authors knowledge, this is the first real-world evidence study looking at G-CSF use in metastatic triple negative breast cancer. This study investigated the use of prophylactic G-CSF agents to determine if metastatic breast cancer patients receiving intermediate or high-risk chemotherapy regimens remained on treatment longer, resulting in less febrile neutropenia and better outcomes. Methods: In this retrospective, single center study we examined pts with early-stage breast cancer who received and discontinued denosumab or zoledronic acid. IRB approval was obtained. Number and length of treatments, fractures of any kind, and delay in BMA were collected from the electronic medical record using diagnosis codes. The objectives of this study were to describe the rate and severity of neutropenia, febrile neutropenia, progression-free survival (PFS) metastatic TNBC who received carboplatin/gemcitabine, carboplatin/paclitaxel or nab-paclitaxel, and sacituzumab govitecan. Results: A total of 197 patients were included with 79 receiving carboplatin plus gemcitabine, 20 receiving carboplatin plus paclitaxel or nab-paclitaxel, and 98 receiving Sacituzumab govitecan. The primary reason for exclusion was having not received the chemotherapy regimen despite having the treatment plan ordered. The median PFS was 4.9 months (95 % confidence interval [CI], 3.5 – 6.3) in the G-CSF group compared to 2.5 months in the no G-CSF group (95% CI, 2.2 – 3.2). PFS was significantly longer in the G-CSF group than in the no-G-CSF group (hazard ratio for disease progression or death, 0.66; 95% CI, 0.453 – 0.951; p = 0.026). The percentage of patients who were alive and free from progression at 12 months was 26.8% and 20.5% at 24 months. The incidence of febrile neutropenia was higher in the G-CSF group than in the no-G-CSF group (18 and 4 incidences, respectively; p = 0.012). However, when comparing patients who received primary prophylaxis and secondary prophylaxis, those receiving primary prophylaxis had a lower incidence of febrile neutropenia (4 and 14, respectively; p = 0.009). Conclusions: In this study, we found that PFS significantly improved in patients who received G-CSF at any point during their course of the treatment, with carboplatin plus gemcitabine, carboplatin plus paclitaxel or nab-paclitaxel, or Sacituzumab govitecan and patients receiving primary prophylaxis had a lower incidence of febrile neutropenia, treatment plan adjustment, and treatment discontinuation.

P. Suman¹, S. Kakkat¹, B. Kola¹, E. T. Herrera¹, A. Richter², A. Mahadevan², S. Atterberry², K. Sawrie², R. Gupta², D. T. Tambe³, C. Sarkar¹, D. Chakroborty¹; ¹Department of Pathology, USA Health Mitchell Cancer Institute, University of South Alabama, Mobile, AL, ²USA Health Mitchell Cancer Institute, University of South Alabama, Mobile, AL, ³Pharmacology and Mechanical Engineering, University of South Alabama, Mobile, AL.

In the United States, breast cancer (BCa) is the second most common cause of cancer-related death for women and the most commonly diagnosed malignancy. Cancer-associated fibroblasts (CAFs) are a crucial component of the tumor microenvironment (TME) that influences breast cancer progression. By interacting with cancer cells and altering the extracellular matrix (ECM), CAFs actively promote tumor growth and metastasis. In contrast, normal fibroblasts restrict tumor progression. Despite the significant role of CAFs, little is known about the mechanisms underlying the regulation and conversion of normal fibroblasts into CAFs within the TME. Lysine Deficient Protein Kinase 1 (WNK1) is a serine/threonine kinase that is important for maintaining electrolyte balance and tissue homeostasis in the body. It is overexpressed in the BCa microenvironment, particularly in CAFs. This study investigated the role of WNK1 in regulating CAFs in BCa. Studies were conducted using BCa patient tissues, available public data, orthotopic mouse 4T1 tumor models, and in vitro assays to identify the effect of WNK1 on regulating fibroblast functions and BCa progression. WNK1 expression levels were determined in BCa tissues, orthotopic 4T1 BCa mouse embryonic fibroblasts (MEFs), and 4T1 BCa cells using Western blot analysis, RT-PCR, immunofluorescence, and confocal microscopy. Quantitative RT-PCR (qRT-PCR) and flow cytometry were used to identify the molecular changes associated with WNK1 manipulation in MEFs in vitro. Our results indicated that WNK1 is overexpressed in BCa and is associated with a poor prognosis and worse disease outcomes. WNK1 is expressed by both cancer cells and CAFs in tumors; however, WNK1 expression in CAFs was significantly higher. Our in vitro data revealed molecular changes in MEFs, accompanied by the upregulation of WNK1, when these cells were exposed to 4T1 cell-conditioned medium.   Furthermore, significant upregulation in the expression of CAF-specific markers, α-SMA, FAP, and FSP1, along with ECM crosslinking genes and fibronectin, was observed in 4T1 medium-stimulated MEFs, which was significantly repressed in the presence of WNK1 inhibitors. Interestingly, upon overexpression of WNK1 in MEFs through expression plasmid vector, CAF markers and ECM crosslinking genes were found to be expressed significantly higher in WNK-overexpressed MEFs compared to normal MEFs, as indicated by qRT-PCR and flow cytometry analysis.  The findings suggest a critical role for WNK1 in fibroblast-to-CAF transition. Analyzed publicly available datasets also indicated a strong correlation between WNK1 expression and the expression of ECM crosslinking genes in BCa. Taken together, our findings indicate that WNK1 contributes to BCa progression by regulating CAF conversion and the production of ECM proteins. Our results suggest that WNK1 may be a potential therapeutic target in BCa.

J. Padilla¹, Y. Park¹, A. Bansal², A. Banduru³, J. Lee¹; ¹Biochemistry and Molecular Medicine, The George Washington University, Washington, DC, ²School of Medicine and Health Sciences, The George Washington University, Washington, DC, ³College of Arts and Sciences, Case Western Reserve University, Cleveland, OH.

Patients with triple negative breast cancer (TNBC) experience the highest mortality and lowest metastasis-free survival rate amongst all other breast cancer subtypes. TNBC is characterized by absence of hormone receptors; estrogen receptor and progesterone receptor, and HER2 receptor, which limits the effectiveness of targeted therapies, highlighting the need for further study. One key factor, BTB and CNC homology 1 (BACH1), a heme-binding transcription factor, is upregulated in TNBC compared to other breast cancer subtypes. Previous studies have identified BACH1 as a regulator of metastasis in cancers, including TNBC. While much of the focus has been on the intrinsic regulation of BACH1, the impact of the tumor microenvironment (TME), specifically nutrients like lactate, on BACH1 regulation and TNBC metastasis is unknown. Cancer cells rely on heightened glycolysis, leading to excessive lactate production, even in the presence of oxygen. This metabolic shift supports both tumor growth and metastasis. Given the emerging role of lactate as a key signaling molecule, we explored how lactate in the TME directly regulates BACH1 expression and contributes to metastasis of TNBC. In vitro simulation of a lactate rich microenvironment using human and murine TNBC cell lines resulted in increased BACH1 protein expression while mRNA expression remained unregulated. Additionally, lactate accumulation in the microenvironment led to BACH1-dependent increase in invasion and migration of TNBC, while proliferation remained unregulated. To understand the mechanism of lactate mediated upregulation of BACH1, a recently identified posttranslational modification, lysine lactylation (Kla) was investigated utilizing global lactylation analysis and BACH1 specific interactome under lactate rich conditions. These findings represent a novel regulatory mechanism by which lactate in tumor microenvironment contributes to metastasis of TNBC through lactylating BACH1 or its interacting partners. These results suggest that targeting BACH1 stability through lactylation inhibition could serve as a promising approach to limit TNBC metastatic progression, especially in aggressive, therapy-resistant cases.

X. Wang¹, J. Frampton², S. Pathak³, M. Afshari⁴, J. Dinoso⁵, A. Brufsky⁶; ¹Global Value and Access, HEOR, Gilead Sciences, Inc, Foster City, CA, ²Evidence Synthesis, Thermo Fisher Scientific, London, UNITED KINGDOM, ³Evidence Synthesis, Thermo Fisher Scientific, Bengaluru, INDIA, ⁴Clinical Development, Gilead Sciences, Inc, Foster City, CA, ⁵Global Medical Affairs, Gilead Sciences, Inc, Foster City, CA, ⁶Division of Hematology/Oncology, Magee-Womens Hospital and the Hillman Cancer Center, University of Pittsburgh Medical Center, Pittsburg, PA.

Objective: To evaluate current treatment outcomes for patients with inoperable locally advanced or metastatic triple negative breast cancer (LA/mTNBC) whose tumors express programmed death-ligand 1 (PD-L1+) treated in the first line. Methods: Literature databases were searched to June 2024. Randomized trials involving adults with PD-L1+, (combined positive score [CPS] ≥1/immune cells ≥1% or receiving anti-PD-[L]1 therapy) inoperable LA/mTNBC treated in the first line were included. Results: From 4140 records, 50 reporting on eight phase 3, six phase 2 or 1/2 trials were included. The primary endpoint was progression-free survival (PFS) in 9 trials and overall survival (OS) in 5. Median PFS ranged from 3.6-12.2 months. Adding atezolizumab to taxane-based chemotherapies (7.2-7.5 vs. 5.3-6.4 months)—but not gemcitabine-carboplatin or capecitabine (4.2 vs. 3.6 months)—resulted in a significant PFS benefit. Adding pembrolizumab or toripalimab to standard chemotherapy also significantly improved PFS (9.7-10.8 vs. 5.6-6.7 months). There were also statistically significant improvements in PFS with molecular subtyping-based treatments and a numerical improvement in PFS when replacing nab-paclitaxel with sacituzumab govitecan (SG) combined with immunotherapy. Similarly, replacing chemotherapy with SG combined with pembrolizumab significantly increased PFS. Conversely, trials evaluating the addition of oleclumab, nivolumab, or ipatasertib to chemotherapy and/or immunotherapy did not significantly improve PFS. Median OS ranged from 10.7-32.8 months across trials; most showed no significant differences between treatment arms. However, adding atezolizumab (25.4 vs. 17.9 months) or toripalimab (32.8 vs. 19.5 months) to nab-paclitaxel significantly improved OS. Adding pembrolizumab to chemotherapy significantly improved OS only in patients with CPS ≥10 (23.0 vs. 16.1 months). Further trials investigating other immunotherapies added to standard chemotherapy did not significantly improve OS. Overall response rates (ORR) ranged from 23.1%-72.7%. All treatment arms, except nivolumab and toripalimab, resulted in a numerically higher ORR vs. comparator arms; however, statistical significance was rarely assessed and demonstrated only for the addition of atezolizumab to nab-paclitaxel. Overall, patients experiencing a serious adverse event ranged from 16%-44.4%. Conclusions: This review indicates an evolving treatment landscape, with the adoption of regimens with atezolizumab, toripalimab, pembrolizumab, and SG being associated with improved efficacy in patients with PD-(L)1-eligible LA/mTNBC. Specifically, the most recent publication revealed that SG in combination with pembrolizumab being a potential new frontline standard of care.

V. Toragall¹, A. Rester¹, S. Begum², O. Shofolawe-Bakare¹, K. Hulugalla¹, J. Monroe², Y. Gibert³, T. Werfel¹; ¹Biomedical Engineering, University of Mississippi, Oxford, MS, ²Department of Cell and Molecular Biology, Cancer Center and Research Institute, University of Mississippi, Jakson,, MS, ³Department of Cell and Molecular Biology,, University of Mississippi Medical Center, Jackson, MS, USA, Jakson,, MS.

Platelets play a central role in tumor metastasis by promoting circulating tumor cell (CTC) survival, vascular arrest, and extravasation. Thromboxane A2 (TXA2), a key platelet activation mediator, drives these processes via its receptor (TPr). Here, we investigate the therapeutic potential of the TPr antagonist ifetroban to disrupt platelet-tumor cell crosstalk and suppress metastasis in triple-negative breast cancer (TNBC). In vitro, ifetroban significantly reduced platelet activation and binding to MDA-MB-231 cells. Co-culture assays showed U46619 (TPr agonist) increased platelet-tumor cell interactions by 160%, while ifetroban pretreatment reduced binding by 65% (p<0.05). Flow cytometry confirmed decreased CD62P expression (activation marker) in ifetroban-treated platelets, supporting the established antiplatelet effect of TPr blockade. The in vivo zebrafish model results revealed that ifetroban reduced MDA-MB-231 xenograft metastasis without attenuating platelet (CD41+) recruitment. Murine studies demonstrated ifetroban’s efficacy across TNBC models: 4T1 subcutaneous tumor model (1×106 cells) showed higher lung and liver metastatic foci in control animals, while ifetroban treatment (50 mg/kg BW, oral dosing, pretreatment for 2 weeks before tumor induction and continued until the end) resulted in significantly lower (p<0.05) numbers of lung and liver metastases and lower circulating levels of TXA2 metabolite, TXB2. Additionally, a decrease in tumor volume and weight was observed in ifetroban-treated animals, although ifetroban (up to 500 µM) did not show any direct toxic effects on tumor cell lines (MDA-MB-231 and 4T1), suggesting an indirect anticancer effect. Further confirmation came from a xenograft model using Athymic nude mice induced with MDA-MB-231 RFP cells (1×106 cells, subcutaneous injection). The treatment regime was similar (50 mg/kg BW, oral dosing, pretreatment for 2 weeks before tumor induction and continued until the end), and results from in vivo imaging system (IVIS) studies showed a significant (p<0.05) reduction in MDA-MB-231 cell metastasis to the liver and lungs compared to the control. Tumor weight and volume reductions were consistent with previous animal studies, demonstrating ifetroban’s therapeutic efficacy in different TNBC models. Histopathological analysis of lungs and liver confirmed findings in both mouse models. Mechanistically, ifetroban suppressed circulating TXB2 (TXA2 metabolite) and disrupted platelet-mediated CTC protection. Notably, tumor volume/weight reductions occurred without direct tumor cell toxicity, implicating immune-modulatory effects. These findings highlight ifetroban’s ability to target platelet-driven metastatic niches by blocking TXA2-TPr signaling. Our data provide preclinical evidence for repurposing ifetroban as an adjuvant therapy to reduce metastasis in TNBC, offering a novel strategy to counteract platelet-supported metastatic progression.

Y. ZHANG¹, E. Pathak¹, C. Koh¹, J. Lidster¹, J. Yeong², E. Lim³, W. Tam¹; ¹GIS, Genome institute of Singapore, A*STAR, singapore, SINGAPORE, ²IMCB, Institute for Molecular and Cell Biology (IMCB), Agency for Science, Technology and Research (A*STAR), singapore, SINGAPORE, ³Division of Medical Oncology, Division of Medical Oncology, National Cancer Centre Singapore, singapore, SINGAPORE.

The ability to precisely manipulate cancer cell states represents a promising approach to enhance therapeutic response. Our previous work demonstrated that retinoids can reduce tumorigenicity in triple-negative breast cancer (TNBC) models by shifting cells from a mesenchymal to an epithelial state, thereby sensitizing resistant TNBC cells to standard-of-care treatments. Here, we designed a Phase I trial, BEXMET, to investigate whether bexarotene, a retinoid X receptor agonist, can induce epithelial cell state changes and increase sensitivity to capecitabine in patients with metastatic TNBC. This cohort included 12 patients who received bexarotene during a two-week lead-in period, followed by repeated treatment cycles consisting of two weeks of oral capecitabine and one week of bexarotene. Tumor biopsies were collected at four time points: pre-treatment, post-bexarotene lead-in, post-capecitabine (cycle 1), and at disease progression (if applicable). RNA-Seq and multiplex immunohistochemistry were performed on all biopsies. Our results show that bexarotene induced a mesenchymal-to-epithelial transition (MET) in 3 of 9 patients, as indicated by transcriptional and histological markers. These bexarotene responders demonstrated increased sensitivity to capecitabine, evidenced by enrichment of cell death-related gene expression following treatment. Notably, the MET responders exhibited reduced immune cell infiltration and a more epithelial-like phenotype after two weeks of bexarotene treatment. At baseline, these responders tended to have a more mesenchymal and immune-infiltrated tumor profile, suggesting potential predictive biomarkers for response. In conclusion, this study provides early clinical evidence that pharmacologic induction of cell state changes can enhance the efficacy of existing chemotherapies in metastatic TNBC. Targeting cell plasticity may offer a cost-effective and accessible therapeutic strategy for this aggressive breast cancer subtype.

T. Shimoi¹, N. Shibata², M. Kitada³, M. Tsuneizumi⁴, M. Yamamoto⁵, Y. Ozaki⁶, Y. Fujimoto⁷, S. Akiyoshi⁸, N. Hashimoto⁹, M. Yamaguchi¹⁰, Y. Yamamoto¹¹, N. Masuda¹², H. Tada¹³, T. Yamanaka¹⁴, Y. Kikawa¹⁵, T. Taira¹⁶, S. Nakagawa¹⁷, K. Kiyota¹⁸, M. Oba¹⁹, N. Niikura²⁰; ¹Department of Medical Oncology, National Cancer Center Hospital, Tokyo, JAPAN, ²Department of Clinical Oncology, Kansai Medical University Hospital, Osaka, JAPAN, ³Department of Breast Disease Center, Asahikawa Medical University Hospital, Hokkaido, JAPAN, ⁴Department of Breast Surgery, Shizuoka General Hospital, Shizuoka, JAPAN, ⁵Department of Breast Oncology, National Hospital Organization Hokkaido Cancer Center, Hokkaido, JAPAN, ⁶Department of Breast Medical Oncology, Cancer Institute Hospital of JFCR, Tokyo, JAPAN, ⁷Division of Breast Oncology, Saitama Cancer Center, Saitama, JAPAN, ⁸Department of Breast Oncology, National Hospital Organization Kyushu Cancer Center, Fukuoka, JAPAN, ⁹Department of Breast Surgery, Aomori Prefectural Central Hospital, Aomori, JAPAN, ¹⁰Department of Breast Surgery, JCHO Kurume General Hospital, Fukuoka, JAPAN, ¹¹Department of Breast and Endocrine Surgery, Kumamoto University Hospital, Kumamoto, JAPAN, ¹²Department of Breast Surgery, Graduate School of Medicine, Kyoto University, Kyoto, JAPAN, ¹³Department of Surgery, Division of Breast and Endocrine Surgery, Tohoku University Hospital, Miyagi, JAPAN, ¹⁴Department of Breast Surgery and Oncology, Kanagawa Cancer Center, Kanagawa, JAPAN, ¹⁵Department of Breast Surgery, Kansai Medical University Hospital, Osaka, JAPAN, ¹⁶Department of Medical Oncology, Social Medical Corporation Hakuaikai Sagara Hospital, Kagoshima, JAPAN, ¹⁷Biometrics Department, Clinical Development Division, Chugai Pharmaceutical Co., Ltd., Tokyo, JAPAN, ¹⁸Oncology Medical Science Department, Medical Affairs Division, Chugai Pharmaceutical Co., Ltd., Tokyo, JAPAN, ¹⁹Department of Clinical Data Science, Clinical Research & Education Promotion Division, National Center of Neurology and Psychiatry, National Center of Neurology and Psychiatry Hospital, Tokyo, JAPAN, ²⁰Department of Breast and Oncology, Tokai University School of Medicine, Kanagawa, JAPAN.

Background: Atezolizumab plus nab-paclitaxel has been available as a standard treatment for Programmed Death-Ligand 1 (PD-L1)-positive metastatic triple-negative breast cancer (mTNBC) in Japan since 2019, based on the results of the IMpassion130 trial. However, real-world evidence remains insufficient. Moreover, while immune-related adverse events (irAEs) are known to occur not only during treatment but also after discontinuation, detailed characterization of these events is limited. The ATTRIBUTE study was designed to evaluate the safety and effectiveness of atezolizumab plus nab-paclitaxel in a real-world patient population, including those who would have been excluded from the pivotal clinical trial. Methods: This multicenter, prospective observational study was conducted in Japan. Key eligibility criteria included: 1) age ≥20 years, 2) PD-L1-positive mTNBC, 3) planned atezolizumab treatment, 4) no hypersensitivity to atezolizumab, 5) ≤2 prior systemic therapy lines for mTNBC. The primary outcome was the incidence of adverse events as assessed by investigators. Secondary outcomes included progression-free survival (PFS), objective response rate (ORR), clinical benefit rate (CBR), and others. The observation period was set at 2 years from the final patient enrollment, with this report presenting the first analysis data collected 6 months after the final patient enrollment. The protocol was approved by the institutional review board and informed consent was obtained from all patients. Results: A total of 151 patients were enrolled from 79 institutions between February 15, 2021, and April 30, 2024. The safety analysis population comprised 149 patients, and the full analysis set included 148 patients. Baseline characteristics included: median age: 59 years, ECOG PS 0: 75.2%, postoperative recurrence: 73.2%, and history of neoadjuvant/adjuvant therapy: 59.7%. This study included patients who would have been excluded from IMpassion130: ECOG PS ≥2 (4.1%) and history or presence of autoimmune disease (7.4%). The incidence of serious adverse events (SAE) was 16.8%. SAE occurring in ≥1% of patients included pneumonitis (3.4%, n=5), diarrhea (1.3%, n=2), fever (1.3%, n=2), adrenal insufficiency (1.3%, n=2) and heart failure (1.3%, n=2). Two cases of Grade 5 pneumonitis were observed. The incidence of late-onset irAEs (31 days to 6 months after treatment discontinuation) associated with atezolizumab was 2.7%, including reports of adrenal insufficiency, pneumonitis, and palmar-plantar erythrodysesthesia syndrome. The median progression-free survival details will be presented at the meeting. The ORR was 33.6% (95% CI: 25.3-42.7), and the CBR was 37.7% (95% CI: 29.1-46.9). Conclusion: In this first analysis of one of the largest real-world patient populations, no new safety signals were observed for atezolizumab combination therapy compared with previous reports. Further follow-up is ongoing, and findings will be reported at upcoming scientific conferences and publications. Clinical trial identification: UMIN000041747 Funding: Chugai Pharmaceutical Co., Ltd.

A. Arora, S. S. Ghosh; Department of Biosciences and Bioengineering, Indian Institute of Technology Guwahati, Guwahati, INDIA.

Background: Triple-negative breast cancer (TNBC) is an aggressive breast cancer subtype, characterized by the lack of targetable bioreceptors, high chemoresistance, metastasis and limited treatment options. Therefore, identifying novel biological targets and therapeutic avenues is crucial to improve TNBC outcomes. It is known that the plasticity of key signaling pathways like Wnt and MAPK, contributes to TNBC progression and metastasis. In the efforts to identify actionable targets, we performed a high-throughput analysis of TNBC microarray datasets and identified Maternal embryonic leucine zipper kinase (MELK), a component of MAPK pathway, to be significantly upregulated, with high MELK expression correlated with poor overall survival of TNBC patients. Additionally, our bioinformatic and RT-PCR analyses identified Pigment epithelium-derived factor (PEDF), a suppressor of the Wnt pathway through the inhibition of its co-receptor LRP6, to be significantly downregulated in TNBC cells. Building on these findings, our current study aims to target these dysregulated pathways by leveraging drug repurposing approach to target MELK in the MAPK pathway and PEDF recombinant protein therapy to restore Wnt suppression in TNBC. Methods: To inhibit MELK, an FDA-approved drug library was screened utilizing molecular docking, molecular dynamics simulations (MDS), and MMPBSA energy calculations. The top drug candidates were validated for their cellular activity using functional assays, flow cytometry, RT-PCR, and western blot analyses in TNBC cell lines (MDA-MB-231 and MDA-MB-468). The recombinant PEDF (rPEDF) protein was produced in E.coli with His-tag for purification using affinity chromatography and characterized by circular dichroism (CD) and MALDI-TOF biophysical analyses. The effect of rPEDF in EMT-induced TNBC cell lines and free-floating generated 3D spheroid cultures was evaluated by MTT assay, scratch assay, matrigel invasion assay and cellular signaling by RT-PCR, western blot and confocal microscopy. Results: Virtual Screening of a library of 1293 FDA-approved drugs and MDS parameters like RMSD, RMSF and pair distance revealed that the top 10 drugs (binding energy <-67.75 kJ/mol) were strongly stabilized in the kinase domain of MELK. The top two candidates: Netarsudil and Dutasteride, led to a dose-dependent reduction in cell proliferation, migration, G1-phase cell cycle arrest, significant reduction of MELK expression and its target genes, including cyclin B1, cyclin D1, p21 and p27 in TNBC cell lines. In protein therapy, MALDI-TOF confirmed the purified rPEDF had the legitimate 54 kDa molecular weight, and CD demonstrated the protein retained its secondary structure integrity. rPEDF treatment demonstrated anti-proliferative effects in EMT-induced TNBC cells and 3D tumor spheroids along with increased intracellular ROS and mitochondrial membrane depolarization. A significant decrease in colony and sphere formation, invasion and migration ability of TNBC cells was also observed following rPEDF treatment. The reduction in migration ability was corroborated by significant reduction in EMT markers and Wnt signaling proteins: N-cadherin, Vimentin, and β-catenin, underscoring the role of rPEDF in suppressing Wnt pathway-mediated TNBC survival and metastasis. Conclusion: Our findings accentuate the translational potential of repurposed drugs Netarsudil and Dutasteride and rPDEF protein as novel therapeutic agents, effectively targeting the MAPK and Wnt pathways, leading to reduced proliferation and metastasis in TNBC cell lines. By leveraging these approaches, including ongoing in vivo validation, our research aims to bridge the gap between identification of therapeutic targets and development of tailored treatment options, facilitating future clinical investigations in TNBC.

J. L. Christenson, N. S. Spoelstra, K. I. O’Neill, M. M. Williams, J. K. Richer; Pathology, University of Colorado Anschutz Medical Campus, Aurora, CO.

Introduction. During metastasis, tumor cells interact extensively with cells in distant organs. These interactions can interfere or modify the function of the normal cells at metastatic sites to induce a more pro-tumor microenvironment. The lung is one of the most common sites of breast cancer (BC) metastasis, and alveolar epithelial cells are the most common cell type in the lung. My data suggests that the lung alveolar epithelium contributes to metastatic outgrowth, and I hypothesize that BC lung micrometastases activate surrounding lung epithelial cells which, in turn, support the outgrowth of BC metastases within the lung. The overall purpose of these studies is to identify factors secreted by resident lung epithelial cells that could be used as metastasis-specific therapeutic targets and/or agents. Methods. To test this hypothesis, I utilized immunocompetent preclinical metastatic mouse mammary carcinoma models to study lung metastatic outgrowth, the stage most relevant to patients diagnosed with metastatic disease. To quantify lung wound repair, I developed a custom multispectral imaging panel. Single-cell RNA-sequencing (scRNAseq) was performed on mouse lungs with high or low metastatic burden to identify genes in the lung epithelium that produce potentially targetable pro-metastatic factors. No-contact co-culture experiments were used to study reciprocal paracrine interactions between lung type II alveolar epithelial (AT2) and BC cells. Results. A wound repair-related phenotype, characterized by chronic inflammation, developed within the lung microenvironment during metastatic outgrowth, including an increase in the number and activation of AT2 cells surrounding metastases as they grow. Single-cell RNA-sequencing of mouse lungs with a high vs. low metastatic burden showed that metastatic outgrowth significantly changed AT2 gene expression resulting in a modified secretome. No-contact co-culture experiments indicated that TNBC cells directly alter AT2 gene expression, and AT2 secreted factors promoted TNBC growth. I investigated the possible mechanism(s) responsible for these effects and discovered that AT2 pulmonary surfactant protein and lipid levels are altered by BC-derived secreted factors. Interestingly, treatment with the naturally derived calf surfactant Infasurf, which contains native surfactant proteins/lipids and is FDA-approved for use in premature infants, inhibited BC cell proliferation. Conclusion. Low levels of surfactant are commonly associated with pulmonary disease and lung cancer. My BC lung metastasis data suggests that something similar may be occurring in the lungs during metastatic outgrowth. Overall, my studies demonstrate that in addition to directly targeting malignant cells, there is potential to target lung epithelial cells in the metastatic BC microenvironment as well, in order to effectively treat BC lung metastasis.

H. Chou¹, M. Peng², W. Kuo¹, S. Shen¹, C. Yu¹, W. Shen³, C. Yang², H. Kuo⁴, H. Lin⁵, D. F. Lin⁵, M. Wang⁶, N. Sadetsky⁷, Y. Lin², S. Chen¹; ¹Department of General and Breast surgery, Chang Gung Memorial Hospital, Linkou Branch, Taoyuan City, TAIWAN, ²Department of Oncology, Chang Gung Memorial Hospital, Linkou Branch, Taoyuan City, TAIWAN, ³Division of Hematology-Oncology, Department of Internal Medicine, Chang Gung Memorial Hospital, Linkou Branch, Taoyuan City, TAIWAN, ⁴Division of Hematology-Oncology, Department of Internal Medicine, New Taipei Municipal Tucheng Hospital, New Taipei City, TAIWAN, ⁵Medical affairs, Gilead, Taipei, TAIWAN, ⁶Real world evidence, Gilead, Stockley Park, UNITED KINGDOM, ⁷Real world evidence, Gilead, Foster City, CA.

Background Sacituzumab govitecan (SG), a Trop-2-directed antibody-drug conjugate, is approved globally for second-line (2L) or later treatment of unresectable locally advanced or metastatic triple-negative breast cancer (mTNBC) and HR+/HER2- mBC. However, pivotal trials largely included Western populations. Given known ethnic differences in mTNBC biology and treatment responses, evaluating SG’s real world effectiveness and safety in Asians is crucial. SG was approved in Taiwan in Nov 2022 and reimbursed by the National Health Insurance in Feb 2024. This interim analysis from the inSiGht study provides early real-world data in Taiwanese mTNBC patients post-reimbursement. Methods This retrospective analysis included mTNBC patients treated with SG in the 2L setting in Chang Gung Memorial Hospital Breast Cancer Registry (Taipei, Linkou and Tucheng) from Feb 2024 to Apr 2025. Clinical characteristics, treatment outcomes, and adverse events were assessed. Kaplan-Meier estimates on treatment outcomes and subgroup analyses by treatment line were performed. Results Among 42 patients (median age: 56 years); 15 received SG as 2L and 27 as third-line or later (3L+). ECOG 0-1 was reported in 90.5% (2L: 86.7%; 3L+: 92.6%). Visceral metastases were present in 90.5% (2L: 86.7%; 3L+: 92.6%) and brain metastases in 21.4% (2L: 26.7%; 3L+: 18.5%). HER2-low expression was seen in 47.6% (2L: 53.3%; 3L+: 44.4%), and 52.4% were HER2 IHC 0. Prior PD-L1 inhibitor use was reported in 28.6% (2L: 46.7%; 3L+: 18.5%). Median time from mTNBC diagnosis to SG initiation was 11 months (2L: 6.2 months; 3L+: 15 months). Median rwPFS was 5 (95%CI: 2.6, 8.8) months overall. By line of treatment, median rwPFS was 9.0 (95%CI: 2.6, NR) months in 2L and 3.8 (95%CI: 2.3, NR) months in 3L+. Median follow up was 9 months (IQR 6.4, 13.8). The 9-month OS rate (95% CI) was 73% (59- 89%) overall, with higher OS in 2L (92% [79-100%]) vs. 3L+(61% [43-85%]). Among 33 patients with response data, 36.4% achieved partial response (PR), 27.3% had stable disease (SD) and 36.4% showed progression. PR rate was higher in 2L (53.8%) vs. 3L+ (25.0%). Progression occurred more in 3L+ (45.0%) vs. 2L (23.1%). Among patients who discontinued SG, the primary reason was disease progression (79.3%), followed by death (13.8%) and adverse events (6.9%). Notably, none of the 2L patients discontinued due to adverse events. Grade 2 diarrhea occurred in 7.1%, grade 1 in 16.7%. Grade 3 and 4 neutropenia were observed in 4.8% each. Granulocyte colony-stimulating factors use was reported in 23.8% of patients. Conclusion This interim analysis demonstrates the real-world effectiveness and tolerability of SG in Asian patients with mTNBC. Effectiveness outcomes are particularly encouraging when SG is used earlier in the treatment course and are comparable to those observed in the ASCENT trial. These findings support SG’s clinical value in Asian populations, including those with aggressive disease features such as brain and visceral metastases. Further follow up will help confirm these observations as additional data mature.

M. Nelis¹, A. Chichura², L. Zhang³, V. Gadi⁴; ¹Obstetrics and Gynecology Institute, Cleveland Clinic Foundation, Cleveland, OH, ²Surgical Oncology, University of Illinois, Chicago, Chicago, IL, ³Department of Surgery, University of Illinois, Chicago, Chicago, IL, ⁴Division of Hematology & Oncology, University of Illinois, Chicago, Chicago, IL.

Neoadjuvant Chemo-Immunotherapy Yields Survival Comparable to Upfront Surgery inMetaplastic Breast Cancer: A National Cancer Database AnalysisAuthors:Margo Nelis, MD¹Lily Zhang, MS ²Vijayakrishna Gadi, MD, PhD³Anna M. Chichura, MD^4,51. Obstetrics and Gynecology Institute, Cleveland Clinic, Cleveland, OH 44195, USA.2. Biostatistician, Department of Surgery, University of Illinois Chicago, Chicago, IL60612, USA.3. Division of Hematology and Oncology, Department of Medicine, University of IllinoisChicago, Chicago, IL 60612, USA.4. Division of Surgical Oncology, Department of Surgery, University of Illinois Chicago,Chicago, IL 60612, USA.5. Division of Gynecologic Oncology, Department of Obstetrics and Gynecology,University of Illinois Chicago, Chicago, IL 60612, USA.Purpose:Metaplastic breast carcinoma (MpBC) is a rare and aggressive subtype of breast cancer, oftencharacterized by triple-negative (TN) receptor status and a limited response to standardchemotherapy. The optimal treatment strategy remains undefined. This study evaluates overallsurvival (OS) in patients with TN-MpBC treated with neoadjuvant chemotherapy (NAC) orneoadjuvant chemo-immunotherapy (NACIO) compared to upfront surgery using the NationalCancer Database (NCDB).Methods:A retrospective cohort analysis was conducted using the NCDB to identify patients diagnosedwith stage I-III TN-MpBC between 2010 and 2022 treated with NAC, NACIO, or upfront surgery. Primary endpoints included overall survival (OS), pathologic complete response (pCR),and breast conservation rates. Breast conservation and pathologic complete response wereanalyzed using logistic regression, and overall survival was analyzed using Cox proportionalhazard model.Results:Of 4,953 patients, 3429 (69.2%) underwent upfront surgery, 1232 (24.9%) received NAC, and292 (5.8%) received NACIO. No significant difference in OS was observed between NACIOand surgery-first approaches (HR = 0.80, 95% CI: 0.51-1.27; p = 0.3), but NAC was associatedwith a 37% increased risk of mortality compared to upfront surgery (HR = 1.37, 95% CI: 1.21-1.56; p < 0.001 NACIO was associated with a 62% higher likelihood of achieving pCRcompared to NAC (OR = 1.62, 95% CI: 1.11-2.38; p = 0.013). The rate of breast conservationwas not significantly different between NACIO and upfront surgery (OR = 0.8, 95% CI: 0.61-1.05; p = 0.11), but patients receiving NAC were 27% less likely to undergo breast-conservingsurgery compared to those undergoing surgery first (OR – 0.73, 95% CI: 0.63-0.84; p < 0.001).Conclusion:In patients with TN-MpBC, NACIO demonstrated comparable survival outcomes to upfrontsurgery and improved pCR rates compared to NAC. These findings suggest that integratingimmunotherapy into neoadjuvant treatment may offer clinical benefit, warranting furtherprospective investigation.

S. Lee, S. Park, S. Lim; General Surgery, Inha University Hospital, Incheon, KOREA, REPUBLIC OF.

BackgroundOlder adults with breast cancer are under-represented in clinical trials despite the increasing aging population and extended life expectancy. Concerns about comorbidities and treatment-related toxicity lead to undertreatment. It remains unclear whether reduced treatment intensity leads to inferior survival outcomes, or whether intensive treatment in frail individuals contributes to harm. This study aimed to investigate real-world treatment patterns and their association with survival outcomes in older breast cancer patients. MethodsWe retrospectively reviewed patients aged ≥65 years who underwent curative surgery for breast cancer at Inha University Hospital between January 2007 and December 2018. Clinical characteristics, treatment modalities (chemotherapy, radiotherapy, endocrine therapy, anti-HER2 therapy), and treatment completion rates were recorded. Disease-free survival (DFS) and overall survival (OS) were compared based on age and treatment receipt and completion using Kaplan-Meier analysis and multivariate Cox regression. ResultsA total of 278 patients were included (median age 70.0 years). Total mastectomy was performed in 51.1%, and axillary lymph node dissection in 31.2%. For adjuvant therapies, 75.5% received endocrine therapy, 44.2% radiotherapy, 38.1% chemotherapy, and 8.4% anti-HER2 therapy. Treatment completion rates varied, with dropout rates of 31.8% for anti-HER2 therapy, 27.8% for endocrine therapy, and 15.9% for chemotherapy. OS significantly declined with increasing age groups (65-69 vs. 70-74 vs. ≥75), with 7-year OS rates of 96.4%, 94.0%, and 81.1%, respectively (p = 0.011), whereas DFS and breast cancer specific survival did not differ significantly by age. In univariate Cox models, OS was associated with age and treatment factors including chemotherapy and endocrine therapy completion, while DFS was more closely linked to pathologic features including lymphovascular invasion and Ki-67 proliferation index. In multivariate analysis adjusting for stage and endocrine therapy completion, older age (≥75 years) remained independently associated with worse overall survival (OR 1.79, 95% CI 1.01-3.18, p = 0.047). ConclusionsWhile older age was independently associated with worse OS, DFS did not differ by age, indicating that mortality in older patients is more attributable to non-cancer causes, and that appropriately treated older adults can achieve comparable recurrence outcomes. These findings highlight the need for individualized treatment decisions based on functional status rather than chronological age, particularly to avoid undertreatment in fit older adults.

R. R. Miranda, L. d. Graziano, G. C. Trofa, W. A. De Lima, L. Testa; Clinical Oncology, Instituto do Câncer do Estado de São Paulo, Sao Paulo, BRAZIL.

Background: Symptomatic medullary infiltration (SMI) in metastatic breast cancer is rare and associated with significant hematologic compromise. No standard treatment exists, and data-guided management are limited. Retrospective studies suggest similar overall survival (OS)with chemotherapy (CT) and endocrine therapy combining aromatase inhibitors (AI) andCDK4/6 inhibitors. However, direct comparisons between CT and AI alone are scarce. This study evaluated OS in patients with SMI treated with CT or AI-based endocrine therapy in the first- or second-line setting. Methods: We retrospectively reviewed records of patients with metastatic breast cancer who underwent bone marrow biopsy at a single academic center from 2015 to 2023. Inclusion criteria were histologically confirmed SMI, symptomatic cytopenias, and receipt of either CT or hormone therapy (HT; AI or tamoxifen ± ovarian suppression, excluding CDK4/6 inhibitors) in the first or second line. Clinical, pathological, and survival data were analyzed. OS was estimated using Kaplan-Meier methods; independent prognostic factors were assessed via multivariable Cox regression. Results: Of 306 patients screened, 24 met inclusion criteria. Median age was 53 years; all tumors were hormone receptor-positive, and 5 were HER2-positive. Common manifestations included anemia (96%), thrombocytopenia (62%), dacrocytosis (58%), and leukopenia (33%). Most patients (n=23) had ≥3 metastatic sites; ECOG performance status was 0 (n=1), 1 (n=10), 2 (n=10), and 3 (n=3). In the first-line setting, median OS was 5.0 months with CT versus 2.0 months with HT (HR 2.4; 95% CI 0.9-6.4; p = 0.07). On multivariable analysis, CT was associated with improved OS (HR 0.06; p = 0.01), while HER2-positivity (HR 50; p = 0.01) and ≥3 metastatic sites (HR 4.3; p = 0.004) were associated with worse outcomes. Latin ethnicity emerged as a protective factor (HR 0.01; p = 0.01). In the second-line setting, CT conferred longer OS (5.0 vs.1.4 months; HR 0.2; p = 0.02), although not confirmed in the multivariable model. Age (HR 1.2;p = 0.02), ECOG 3 (HR 369; p = 0.04), and non-Latin race (HR 0.01; p = 0.03) were significant predictors of poorer survival. Conclusions: In this real-world cohort of patients with SMI from metastatic breast cancer, chemotherapy was associated with improved OS in the first-line setting compared to hormone therapy. No survival benefit was observed in second-line. HER2-positivity, advanced age, poor performance status, and extensive metastatic disease were associated with worse outcomes. Latin ethnicity was consistently protective across treatment lines.

A. Reddy¹, N. Schoof², M. Sophie³, C. Proenca⁴, C. Caetano⁵, C. Seitz⁶, A. Frenz⁷, K. Genga⁸, J. Milosavljevic⁹, S. Hagenaars¹⁰, C. Flach¹¹, J. Nguyen¹²; ¹Mercy Clinic Oncology, Mercy, Fort Smith, AR, ²Global Medical & Evidence Women’s Healthcare, Bayer AG, Berlin, GERMANY, ³Global Medical & Evidence Study Operations, Bayer Healthcare SAS, Bordeaux, FRANCE, ⁴HEOR, Bayer Consumer Health AG, Basel, SWITZERLAND, ⁵Global Medical & Evidence Women’s Healthcare, Bayer Consumer Health AG, Basel, SWITZERLAND, ⁶Clinical Development, Bayer AG, Berlin, GERMANY, ⁷Medical Affairs Statistics, Bayer AG, Berlin, GERMANY, ⁸Global Safety, Bayer SA, Sao Paulo, BRAZIL, ⁹Global regulatory, Bayer AG, Berlin, GERMANY, ¹⁰Epidemiology, IQVIA Solutions, Amsterdam, NETHERLANDS, ¹¹Real-World Methods & Evidence Generation, IQVIA Ltd, London, UNITED KINGDOM, ¹²Global Medical & Evidence RWE Centre of Excellence, Bayer HealthCare Pharmaceuticals Inc, Whippany, NJ.

Background: Patients with breast cancer who are non-adherent to adjuvant endocrine therapy have worse clinical outcomes than those who are adherent.¹ Side effects of treatment, including induced vasomotor symptoms (iVMS), are a common cause of non-adherence.² There is a knowledge gap on how iVMS and non-adherence in this population are related to healthcare resource use (HCRU). Methods: In a retrospective cohort study using the Guardian Research Network electronic health record (EHR) US database, we identified women aged 18-70 years treated with adjuvant endocrine therapy following an initial diagnosis of stage 0-III hormone receptor-positive breast cancer from Jan 2016-Jun 2023. Women were stratified into 4 subgroups by adherence to adjuvant endocrine therapy (adherence; ≥80% days covered) and presence of iVMS at the start of follow-up (date of therapy initiation)/distinct follow-up periods. All-cause and breast cancer-related HCRU were identified from EHRs and manual curation of clinical notes. HCRU rates were calculated as events/patient-month. Quasi-Poisson regression models were used to calculate incident rate ratios (IRRs) with 95% CIs for all-cause and breast cancer-related HCRU between iVMS (vs. non-iVMS) and adherent (vs. non-adherent) subgroups, adjusted for confounders. Results: 4459 women were included; mean age at index date was 57 years. Most had ≥1 HCRU event during follow-up (99% for all-cause events, 94% for breast cancer-related events); the most common, respectively, were outpatient visits (98% & 93%), laboratory services (88% & 76%), and primary care visits (66% & 62%). As shown in the Table, non-adherent women with iVMS had the highest all-cause and breast cancer-related HCRU rates from 1 to <3 months’ follow-up (7.24 & 3.04 events/patient-month, respectively). Adherent women with iVMS had the highest HCRU rates during follow-up periods thereafter (3 to <12 months, 12 to <36 months, and 36 to 60 months; see the Table). In the regression models, patients with iVMS had higher rates of all-cause and breast cancer-related HCRU vs. those without iVMS over all follow-up periods (IRRs ranged from 1.16-1.30 and from 1.19-1.35, respectively). Irrespective of iVMS, adherent patients had a lower rate of all-cause and breast cancer-related HCRU vs. non-adherent patients in the first 3 months’ follow-up (IRR 0.84, 95% CI: 0.81-0.87 and IRR 0.77, 95% CI: 0.74-0.80, respectively) and higher rates in later follow-up periods (p<0.001). Conclusion: Our results suggest that women who experience iVMS after adjuvant endocrine therapy for hormone receptor-positive breast cancer have higher rates of HCRU than those who do not experience iVMS. Effective management of iVMS could translate into lower HCRU rates. Refs 1. Eliassen et al. BMC Cancer. 2023;23(1):625. 2. Franzoi et al. Lancet Oncol 2021; 22: e303-13

E. Mayer¹, K. A. Betts², R. Ramasubramanian², X. Nie², T. Pham³, C. Chen³; ¹-, Dana-Farber Cancer Institute, Boston, MA, ²-, Analysis Group, Los Angeles, CA, ³Oncology Outcomes Research, AstraZeneca, Gaithersburg, MD.

Background Endocrine therapy (ET) + cyclin-dependent kinase 4/6 inhibitor (CDK4/6i) is the standard-of-care first-line (1L) treatment for hormone receptor-positive (HR+)/HER2-negative (HER2−) metastatic breast cancer (mBC). Given that outcomes tend to worsen following progression to next-line therapy, understanding the relationship between the duration of 1L treatment and subsequent outcomes may be an important factor for clinical decision-making. This real-world, retrospective, observational cohort study investigated the relationship between time to discontinuation (TTD) of 1L therapy and overall survival (OS) in patients with HR+/HER2− mBC. Methods Adults with HR+/HER2− mBC were identified from electronic health records in the US Flatiron Health Database. Included patients had started 1L ET + CDK4/6i between March 1, 2018, and March 31, 2024, and had ≥2 clinical activities on different days after 1L initiation. Patients were followed until September 30, 2024. Descriptive statistics were used to summarize demographics, baseline characteristics, and treatment patterns. 1L TTD was defined as time from 1L initiation to final administration of 1L therapy (whichever component was administered last) or death. TTD and OS were assessed using Kaplan-Meier methodology. The relationship between 1L TTD and OS was assessed using rank correlation and a multivariate, covariate-adjusted, time-dependent Cox regression model. Results A total of 2910 patients were included, with a mean age of 63.2 years. Most were White (66.2%) and postmenopausal (71.4%), with Eastern Cooperative Oncology Group performance status (ECOG PS) ≤1 (63.2%), and estrogen receptor (ER) expression >70% (82.0%); 49% had recurrent disease (4.7% unknown), and few had liver metastases (16.1%). With a median (interquartile range) follow-up of 24.8 (14.0-41.0) months, median 1L TTD was 20.6 (95% CI: 19.4-22.0) months, and median OS was not reached. OS rate was 92.1% at 12 months and 83.8% at 24 months. There was a strong positive correlation between TTD and OS (r = 0.74 [95% CI: 0.70-0.78]). For each additional month on 1L treatment, the adjusted hazard ratio for OS was 0.95 (95% CI: 0.94-0.96; p<0.001). In real-world terms, this means that an additional 2, 4, 6, 8, and 10 months on 1L treatment would result in cumulative hazard ratios (calculated as 0.95^number of months) of 0.90, 0.81, 0.74, 0.66, and 0.60, respectively, and a 10%, 19%, 26%, 34%, and 40% lower risk of death, respectively. Lower ECOG PS, de novo disease, and ER expression >70% were also associated with better survival outcomes. Age, region, menopausal status, and practice type were not associated with survival outcomes. Conclusions In this real-world dataset, a longer duration of 1L treatment prior to clinical progression was highly positively correlated with longer OS, suggesting a clinical benefit to extending 1L treatment in HR+/HER2− mBC. It is therefore critical to identify ways to increase the duration of 1L therapy to improve patient outcomes.

K. Zhang, X. Zhu, X. Ying, Z. Wang; Breast Surgery, Fudan University Shanghai Cancer Center, Shanghai, CHINA.

BACKGROUND Trastuzumab deruxtecan (T-DXd) is a novel antibody-drug conjugate (ADC) that has demonstrated improved survival outcomes in patients with metastatic human epidermal growth factor receptor 2 (HER2)-low breast cancer, and is approved by Food and Drug Administration (FDA) for these patients. However, real-world evidence regarding the efficacy of T-DXd remains limited.METHODS We retrospectively collected clinical and demographic data of HER2-low mBC patients treated with T-DXd between November 2021 and December 2024 at Fudan University Shanghai Cancer Center. Real-world progression-free survival (rwPFS) was estimated using the Kaplan-Meier method. Treatment response was assessed according to RECIST 1.1 criteria. A T-DXd-prognostic score was established, according to regression coefficients found in the multivariate Cox regression analysis. RESULTS A total of 126 Chinese female patients with HER2-low mBC treated with T-DXd was enrolled. The median age was 56 years (IQR: 48 to 64), and 40 patients was TNM-IV stage. In this cohort, 72 (57.14%) had HER2-1+ mBC and 54 (42.86%) had HER2-2+ mBC. Hormone receptor (HR) status was positive in 82 (65.08%) patients and negative in 44 (34.92%). The median number of prior lines of advanced therapy was 3 (IQR: 2 to 5). Last follow-up was conducted on December 30, 2024, the median rwPFS was 9.10 months, which was significantly longer than the median rwPFS of 3.50 months observed with the last prior treatment chosen by physician. In patients with HR positive, those with low PR expression (≤ 10%) have significantly higher rwPFS than other patients (17.77 vs. 6.13 months; p < 0.01). Among 111 patients with measurable disease, the objective response rate (ORR) was 30.63%, and the disease control rate (DCR) was 72.07%. We developed a prognostic score using the regression coefficients from the multivariate Cox regression model, which included age, HER2 expression, and HR status as covariates. And then, patients were stratified into low- and high-risk groups by the prognostic score. According to risk stratification, the median rwPFS was 5.13 months in the high-risk group and 12.40 months in the low-risk group (hazard ratio [HR] 2.25, 95% confidence interval [CI] 1.31 – 3.88, p < 0.01). CONCLUSION In this real-world cohort of Chinese patients with HER2-low mBC, T-DXd demonstrated meaningful clinical benefit, with notably longer rwPFS than last prior treatment. Furthermore, we established a risk stratification model that effectively predict patient prognosis.

A. Haiderali¹, Y. Sun², L. Ai³, F. Beca³; ¹Value & Implementation, Merck, North Wales, PA, ²Biostatistics and Research Decision Sciences (BARDS), Merck, Rahway, NJ, ³MRL, Merck, Rahway, NJ.

Background: Pembrolizumab (pembro) was approved by the Food and Drug Administration in July 2021 to treat high-risk, early-stage triple-negative breast cancer (TNBC) based on the KEYNOTE-522 trial. To support post-launch assessments, this real-world study aimed to outline patient characteristics and treatment patterns in patients with Stage II-III TNBC in the US community setting. Methods: This retrospective study used electronic medical records accessed via the Syapse data platform to examine previously untreated adults diagnosed with Stage II-III TNBC from August 2021 to July 2023. We analyzed patient characteristics, surgery rates and types, treatment patterns and duration, and reasons for treatment discontinuation in the neoadjuvant and adjuvant settings. Results: 322 patients were identified with Stage II (61.3%) or Stage III (38.7%) TNBC and who had undergone definitive surgery. Mean age was 58 years (standard deviation [SD]: 15). 47% had an ECOG performance status of 0, 14% had an ECOG of 1, while 37% had unknown status. In the neoadjuvant setting, most patients (75%) received pembro + chemotherapy, 12% received chemotherapy alone and 12% received no neoadjuvant therapy. The most common therapy in patients receiving neoadjuvant pembro + chemotherapy was pembro + carboplatin + taxanes + anthracyclines (A) + cyclosphosphamide (C) (83%) while the most common therapy in patients receiving chemotherapy alone was taxanes + AC (50%). Patients receiving pembro + chemotherapy were more likely to undergo mastectomy (56% vs 38%) and less likely to undergo lumpectomy (44% vs. 63%). Among patients receiving adjuvant therapy in the cohort previously treated with neoadjuvant pembro + chemotherapy, the most frequently administered adjuvant regimens were pembro monotherapy (70%) and pembro + capecitabine (10%). On the other hand, capecitabine was the most commonly administered treatment (75%) among patients receiving adjuvant therapy in the cohort that received neoadjuvant chemotherapy without pembro. The median (95% CI) time on pembro in the neoadjuvant and adjuvant settings was 5.3 (5.1, 5.6) and 5.6 (5.6, 5.7) months, respectively. Comparatively, median time on chemotherapy was 4.2 (3.4, 4.9) and 5.2 (4.4, 5.7) months, respectively. The primary reasons for discontinuation among patients who had received neoadjuvant chemotherapy + pembro (n=236) were completion of planned therapy (72%) and intolerance/toxicity (24%). In the adjuvant pembro group (n=97), primary reasons for discontinuation were completion of therapy (78%) and intolerance/toxicity (8.2%). Conclusion: Findings show a high utilization of pembro in neoadjuvant and adjuvant early-stage TNBC, highlighting its role as standard of care. Treatment duration for pembro was consistent with that reported in clinical trials and previous real-world studies, supporting use in routine clinical practice. High treatment completion rates suggest that pembro is generally well tolerated, supporting its use as a viable treatment option across perioperative TNBC setting.

A. Haiderali¹, L. Okoth², S. Annavarapu², J. K. Paulus², W. Pan³, P. Conkling², M. Danso⁴; ¹Value & Implementation, Merck, North Wales, PA, ²Real World Research, Ontada, Boston, MA, ³MRL, Merck, Rahway, NJ, ⁴Virginia Oncology Associates, US Oncology, Norfolk, VA.

Background: Pembrolizumab, approved by the FDA in July 2021, is a standard of care (SOC) for neoadjuvant treatment of high-risk esTNBC, based on effectiveness established in the KEYNOTE-522 trial. Understanding factors affecting clinical integration are now critical to optimize patient outcomes. This study explored physician perspectives on pembrolizumab use in neoadjuvant and adjuvant settings and treatment decision-making process for high-risk esTNBC. Methods: In January 2025, physicians from The US Oncology Network completed a brief online survey and a virtual focus group discussion. Physicians were chosen for their TNBC management experience and geographical diversity. Survey data were analyzed quantitatively, while the discussion was transcribed and key themes identified qualitatively. Results: Six medical oncologists and two breast surgeons completed the survey and focus group discussion. SOC adoption The discussion revealed that the implementation of pembrolizumab is primarily driven by its status as the SOC, potential to enhance patient survival, and manageable side effect profile. On the survey, physicians estimated they use neoadjuvant pembrolizumab plus chemotherapy in 90% -100% of their esTNBC patients. Rare exceptions for non-use Focus group physicians reported rare exceptions to pembrolizumab as SOC. These include patients with immunotherapy contraindications, like severe autoimmune diseases or kidney transplants. Patients usually adhere to medical advice but occasionally, some patients decline neoadjuvant or adjuvant therapy due to side effect concerns or fear of progression and prefer immediate surgery. Additionally, focus group physicians reported that occasionally patients are referred post-surgery by general surgeons without having received neoadjuvant therapy. In other instances, focus group physicians indicated that patients with low disease burden, inoperable tumors, or urgent surgical needs may also not receive pembrolizumab. Treatment of ER-Low Breast Cancer All focus group physicians reported treating breast cancer patients with ER-low (1% – 9%) status similarly to TNBC patients. Extensive adjuvant use Seven surveyed physicians described that they use adjuvant pembrolizumab in >75% of their esTNBC patients who achieve pCR. However, patient-specific contraindications and clinician concerns for toxicity remain barriers to its recommendation as reported by five and four surveyed physicians, respectively. Conclusions: This qualitative study of breast cancer physicians reveals broad adoption of pembrolizumab as SOC for high-risk esTNBC in The US Oncology Network, due to survival benefits and tolerable side effects. Usage is limited by comorbidities, patient preferences, and post-surgery referrals. Future efforts are essential to guide improvements in patient communication, enhance surgeon awareness on current neoadjuvant guidelines, shared decision-making, and multidisciplinary care coordination, ultimately optimizing patient outcomes.

H. Soliman¹, S. Dent², A. Liepa³, V. Stefaniak³, M. Huang³, T. Sugihara⁴, K. Moreira³, K. Hudson⁵, M. Goetz⁶; ¹Medical Oncology, Moffitt Cancer Center and Research Institute, Tampa, FL, ²Medicine, University of Rochester Medical Center, Rochester, NY, ³Oncology, Eli Lilly and Company, Indianapolis, IN, ⁴Research, Syneos Health, Morrisville, NC, ⁵Oncology, Texas Oncology, Austin, TX, ⁶Department of Oncology, Mayo Clinic, Rochester, MN.

Background: Two years of adjuvant abemaciclib plus endocrine therapy is approved and guideline-recommended in patients (pts) with HR+, HER2-, node-positive, early breast cancer (EBC) at high risk of recurrence. In initial real-world studies, the high rate (>85%) of treatment (tx) persistence beyond 3 months suggests that adjuvant abemaciclib is well-tolerated in routine clinical practice.^1,2 Dose reductions were associated with higher persistence in prior studies and clinical trial data have shown that efficacy of abemaciclib was maintained with dose reductions. This study describes 6-month tx persistence and dosing patterns in pts with HR+, HER2-, node-positive EBC initiating abemaciclib 150 mg twice daily (BID). Methods: Retrospective data were accessed from the US de-identified Flatiron Health Research Database. Adults with HR+, HER2-, node-positive, EBC, who initiated abemaciclib 150 mg BID from Jan 2022-Jun 2024 were eligible and further characterized by ≥1 vs no dose reduction. Data cut-off was Dec 2024. Persistence rate was the proportion of pts on abemaciclib >6 months, allowing for ≤60-day medication gap within this period. Time to dose modifications and reasons for discontinuation (DC) were summarized. Subgroup analyses were conducted in pts confirmed as meeting the monarchE high-risk criteria (N2, N3, or N1 plus Grade 3 and/or tumor >5 cm). All analyses were descriptive. Results: Of 1063 eligible pts, median age was 56 years (IQR 47, 65). Most had N1 (48%) or N2 (34%) disease. Median follow-up was 17.5 months (IQR 11, 25). Tx persistence at 6 months was 75%. DC was mostly due to adverse events (AEs; 19%) and <1% due to recurrence. Approximately 50% of pts had ≥1 dose reduction. Persistence was 85% in pts with ≥1 dose reduction and 64% in pts with no dose reductions. 70% of pts who DC’d by 6 months did not have a dose reduction. Median time from start of abemaciclib to first dose change and/or hold was 49 days (IQR 23, 111). During the first 30 days of tx and Days 31-90, DCs due to AEs were lower in pts with dose reductions vs pts with no dose reductions (Table). Persistence and use of dose reductions were similar in pts confirmed as meeting the monarchE high-risk criteria. Conclusion: In US clinical practice, a majority (75%) who initiated adjuvant abemaciclib continued abemaciclib beyond 6 months. Tx persistence was higher among pts with dose reductions relative to those with no dose reductions, and rates of early DCs due to AEs were low in pts with dose reductions. Given that dose reductions in monarchE were not associated with reduced efficacy, these additional real-world data support the use of early dose modifications to improve tolerability and tx persistence for adjuvant abemaciclib in pts with high risk of recurrence.

¹Hudson K, et al. Clin Cancer Res (2025) 31 (12_Supplement): P1-11-29.²Gorantla V, et al. Clin Cancer Res (2025) 31 (12_Supplement): P1-11-21.

J. C. Dickerson¹, J. Epps², A. Gyden², A. Cleveland³, K. Sabelko², A. W. Kurian¹, J. Jourquin², M. Bondy⁴; ¹Medicine (Oncology), Stanford University School of Medicine, Stanford, CA, ²Data Science & Scientific Programs, Susan G Komen Foundation, Dallas, TX, ³School of Medicine, Howard University College of Medicine, Washington DC, DC, ⁴Department of Epidemiology and Population Health, Stanford University School of Medicine, Stanford, CA.

Background: ShareForCures is Komen’s crowd-sourced breast cancer research registry that collects and integrates data from and on behalf of its participants. Participants living in the U.S. with a history of breast cancer consent to share their medical records and complete surveys. In the U.S. primary care literature, patients and their medical records are concordant at rates ranging from 65% to 93%. However, there are limited data on how patients with breast cancer self-report details of their diagnoses. Here, we leveraged a cohort of ShareForCures participants to assess whether the recollection of their diagnosis information matches the information in their medical records. Not all researchers can access medical records to extract diagnosis information, and a high concordance could allow researchers to rely more heavily on patient-reported clinical details. Methods: We compared data for participants in ShareForCures who had completed the enrollment survey and had abstracted medical records (requested from the oncology and primary care practices) available by April 30, 2025. We had asked participants for the following variables in the intake survey: 1) stage at diagnosis, 2) estrogen-receptor (ER) and HER2 status (e.g., positive or negative), 3) receptor combination (e.g., triple-negative or triple positive), and 4) histology (e.g., ductal or lobular). These same variables are abstracted from the medical record. For staging, we only examined stages 1 – 4 and did not assess the accuracy of sub-stages (e.g., IB). We used the AJCC anatomic/clinical staging system in effect at the time of diagnosis. A board-certified medical oncologist specializing in breast cancer (JCD) adjudicated any unclear cases. We used descriptive statistics to summarize the data. We define concordance as the fraction of participant-reported details that match the abstracted medical records.Results: Data were obtained from 151 participants enrolled between 2022 and 2024. The majority (78%) had a diagnosis between 2010 – 2024. On median, 292 (IQR, 129 – 579) pages of records were available for abstraction per participant. The median age at diagnosis was 45 (IQR, 39 -52). The cohort was predominantly white (80%), and 82% of the participants had at least a college degree. The median time from diagnosis to enrollment in ShareForCures was 6 years (IQR, 2 – 11). 14% of the cohort reported as living with metastatic disease at enrollment. The diagnostic stage was concordant in 79% of the cases. ER status and HER2 status were concordant in 84% and 83% of the cases, respectively. When receptor statuses were combined (e.g., triple-negative, triple-positive), concordance was 75%. Histology was concordant in 73% of cases. We observed concordance for all these variables in 50% of the cases. Conclusions: Despite the inherent challenges of abstracting information from medical records and the complexities of breast cancer diagnoses, half of the responses from ShareForCures participants were concordant with all the diagnostic details abstracted from their medical records, with concordance rates ranging from 73% to 84% for individual variables. Although we may have anticipated higher concordance rates in a highly educated, young population, further research is needed to explore factors influencing concordance, such as the completeness of medical records and the time elapsed since diagnosis. This preliminary analysis highlights the importance of integrating both participant-reported and medical record-derived information to ensure the accurate reporting of breast cancer diagnosis information for research purposes.

G. Sousa¹, A. M. Ferreira², I. Pereira³, A. Catarina⁴, D. Simão⁵, F. Machado⁶, G. Fernandes⁷, L. A. Ribeiro⁸, J. Fougo⁹, M. C. Nogueira¹⁰, P. H. Meireles¹¹, J. Abreu Sousa¹², P. Cortes¹³; ¹Serviço de Oncologia, IPO Coimbra, Coimbra, PORTUGAL, ²Departamento de Oncologia, IPO Porto, Porto, PORTUGAL, ³Serviço de Oncologia, Hospital da Senhora da Oliveira, ULS Alto Ave, Guimarães, PORTUGAL, ⁴Serviço de Oncologia, Hospital de Santa Maria, ULS Santa Maria, Lisboa, PORTUGAL, ⁵Serviço de Oncologia, Hospital dos Capuchos, ULS São José, Lisboa, PORTUGAL, ⁶Direcção, Centro Académico Clínico Egas Moniz Health Alliance (EMHA), Aveiro, PORTUGAL, ⁷Serviço de Oncologia, Hospital da Luz Lisboa, Lisboa, PORTUGAL, ⁸Serviço de Oncologia, Hospital CUF Tejo, Lisboa, PORTUGAL, ⁹Unidade de Mama, Hospital de São João, ULS São João, Porto, PORTUGAL, ¹⁰Medical Departement, MSD Portugal, Lisboa, PORTUGAL, ¹¹Serviço de Radioterapia, Hospital de São João, ULS São João, Porto, PORTUGAL, ¹²Departamento de Cirurgia, IPO Porto, Lisboa, PORTUGAL, ¹³Departamento de Oncologia, Hospital Lusíadas Lisboa, Lisboa, PORTUGAL.

Background: Breast cancer (BC) is the most common cancer and the leading cause of cancer-related death in women. Triple-negative BC (TNBC) and high-risk ER+ HER2- BC are aggressive BC subtypes with high recurrence rates. In Portugal, data on treatment of TNBC and high-risk ER+HER2- BC is limited. To address this, the PRISMA study collected quantitative data on treatment patterns and pathological complete response (pCR) from multiple Portuguese centers. Methods: Retrospective aggregated data from patients diagnosed between Jan-2019 and Jun-2023 were collected. The study included adult patients diagnosed with stage II – III TNBC or high-risk ER+ HER2- BC eligible for neoadjuvant (NAT) chemotherapy. Results: The study included 1585 patients, 642 (40%) with TNBC and 943 (60 %) with high-risk ER+HER2- BC. Most patients were ≥65 years with 1% being male. In both cohorts, most were diagnosed with stage II and were postmenopausal (62% and 73% in TNBC; 42% and 53% in ER+HER2-, respectively). Carcinoma of no special type was the predominant histology (88% TNBC and 83% ER+HER2- BC). In TNBC patients, the mean time between therapeutic decision and treatment initiation was five weeks (1 to 29 weeks), and from NAT completion to surgery was six weeks (3 to 8 weeks). Most TNBC patients underwent NAT chemotherapy (93%), primarily with carboplatin/paclitaxel and cyclophosphamide/doxorubicin or epirubicin (48%), resulting in a pCR rate of 47%. Surgery was performed in 99% of patients, with 59% undergoing conservative surgery. Adjuvant (AT) chemotherapy was given to 31% of patients, mostly with capecitabine (77%). Radiotherapy (RT) was performed in 72% of patients, primarily (66%) after conservative surgery, using conventional fractionation (50Gy/25fr, 48%). Among high-risk ER+HER2- BC patients, 81% cancers had Ki-67 ≥20%, and multi-gene assays were performed in 6%. 82% of high-risk ER+/HER2- patients underwent NAT and achieved a pCR of 9%. Dose dense AC or EC plus weekly paclitaxel was the most commonly used regimen (51%). The mean interval between NAT completion and surgery was 8 weeks (3 to 23 weeks). 59% of 939 patients undergoing surgery underwent breast conserving surgery. AT chemotherapy was administered to 18%, mostly with dose dense AC or EC and paclitaxel weekly (28%). RT was performed in 90% of patients, and 55% receiving it after conservative surgery. Regarding endocrine therapy (ET), 85% underwent adjuvant ET, with 68% using aromatase inhibitors. Ovarian suppression was performed in 26% of patients, frequently using gonadotropin-releasing hormone inhibitors (87%). Conclusions: The data provides a real-world characterization of TNBC and high-risk ER+HER2- BC treatment, demonstrating a high adherence to NAT chemotherapy and adjuvant ET, per guidelines, in this period. Observed delays in surgery suggest inter-hospital care variations that may inform healthcare policy, ultimately improving patient outcomes.

D. Bu, J. Torres, A. Sahu; Department of Medical Oncology, Goulburn Valley Health, Shepparton, AUSTRALIA.

Background Neoadjuvant therapy is increasingly utilised in early and locally advanced breast cancer to improve operability and provide an early in vivo assessment of treatment response. Achieving pathological complete response (pCR) is associated with improved long-term outcomes, particularly in HER2-positive and triple-negative breast cancer (TNBC). While major trials have reported neoadjuvant therapy outcomes by tumour subtype, real-world data from regional centres remain limited. This study evaluates pCR rates, treatment completion, and treatment-related toxicities in a regional Australian cohort receiving neoadjuvant therapy for breast cancer. Methods A retrospective audit was conducted of all female patients with early or locally advanced breast cancer who received neoadjuvant systemic therapy followed by surgery at Goulburn Valley Health, Victoria, between January 2020 and May 2025. Data collected included demographics, tumour subtype, treatment details, hospitalisations during therapy, and rate of pathological complete response. Results 70 patients underwent neoadjuvant therapy at Goulburn Valley Health. Subtypes included HER2-positive (n=28), triple-negative breast cancer (TNBC; n=26), and hormone receptor-positive/HER2-negative (HR+/HER2−; n=16). 47 patients (67.1%) completed their planned neoadjuvant therapy. 21 patients (30%) required hospital admission during their neoadjuvant therapy. Surgical procedures after therapy included breast-conserving surgery in 36 patients, single mastectomy in 25, and bilateral mastectomy in 8 patients. 1 TNBC patient did not proceed to surgery due to disease progression. Pathologic complete response (pCR) rates were 42.9% (12/28) in HER2-positive, 38.5% (10/26) in TNBC, and 6.3% (1/16) in HR+/HER2− patients. Notable differences in pCR rates were observed between patients who completed neoadjuvant therapy and those who did not. In the HER2-positive group, 57.1% (12/21) of patients who completed therapy achieved pCR, compared to 0% (0/7) among non-completers. In the TNBC group, pCR was achieved in 50% (8/16) of patients who completed therapy versus 20% (2/10) of patients who did not. Conclusion This regional Australian cohort demonstrates pCR rates comparable to published literature, with a higher pCR rate seen in HER2+ and TNBC subtypes versus HR+/HER2−. Completion of the planned neoadjuvant therapy regimen was associated with increased pCR rates in both TNBC and HER2-positive subgroups. These findings highlight the importance of supportive care to minimise treatment interruptions, aiding in neoadjuvant therapy completion.

C. A. Chigbo¹, K. Udeogu², F. Sheima³, N. Chukwuma³, A. Khan³, S. Redana³, S. Mcgrath³, A. Ring³, S. Johnston³, N. Battisti³; ¹Radiation and clinical oncology, University of Nigeria teaching Hospital Ituku Ozalla Enugu and The Royal Marsden Foundation Trust, Enugu and Sutton Surrey, UNITED KINGDOM, ²Radiation and clinical oncology, University of Nigeria teaching Hospital Ituku Ozalla Enugu, Enugu, NIGERIA, ³medical oncology, The Royal Marsden NHS foundation trust sutton, Sutton,Surrey, UNITED KINGDOM.

Background: Triple-negative breast cancer (TNBC) is associated with high rates of early recurrence and poor prognosis. Chemotherapy remains the mainstay of treatment for early-stage TNBC in the preoperative setting. The KEYNOTE-522 recently demonstrated that adding pembrolizumab to chemotherapy significantly increases pathological complete response (pCR) rates in TNBC. However, real-world efficacy data remains limited. This study aims to evaluate the pCR rates among TNBC patients treated with neoadjuvant pembrolizumab at our Institution. Methods: We retrospectively retrieved data on patients diagnosed with stage I-III TNBC receiving neoadjuvant pembrolizumab at The Royal Marsden between June 2021 and June 2024. We collected data on patient demographics, tumour characteristics, treatment, and surgical pathology. We used simple statistics to evaluate the rate of pCR (ypT0/is, ypN0) after neoadjuvant systemic therapy. Results: Seventy-eight patients were included in the analysis. The median age at diagnosis was 49 years (interquartile range: 40-58). Most patients had clinical stage IIA at presentation (n=32, 41.0%) and invasive ductal carcinoma (n=74, 94.9%). Most tumours were grade 2 (n=65, 83.3%). Fifty-eight patients (74.3%) were able to complete the full regimen of chemotherapy. Among 20 patients discontinuing the treatment earlier, toxicity was the main reason for treatment discontinuation in 10 (50.0%). Forty-eight patients (61.5%) completed 8 cycles of pembrolizumab before surgery. Pembrolizumab was discontinued in 20 (25.2%), most commonly due to severe immune-related adverse effects in 15 patients (75.0%). Surgery involved breast-conservation in 43 patients (55.1%) and mastectomy in 35 patients (44.9 %). Nodal surgeries performed included sentinel lymph node biopsy in 43 patients (55.1%), axillary nodal clearance in 17 patients (21.8%), and targeted axillary dissection in 16 patients (20.5%). Overall, 41 patients achieved a pathologic complete response (pCR) rate (52.6%). pCR was more frequent in earlier-stage tumours: ( 100.0% [n=2] in stage I, 58.5% [n=31] in stage II, and 34.8% [n=8] in stage III) and in higher-grade tumours (36.4% [n=4] of grade 1 tumours, 55.4% [n=36] in grade 2 tumours, and 50% [n=1] in grade 3 tumours). pCR was achieved by 40 patients with ductal tumours (97.6%) versus 1 (2.4%) patient with other histology types pCR was seen in 29 patients who completed the planned course of chemotherapy (50%) versus 12 patients who did not (60%), and in 26 patients who completed the planned 8 cycles of pembrolizumab (54.2%) versus 15 of those who did not (50%). However, no statistically significant association was found between pCR and clinical stage, tumour grade /histology, number of chemotherapy or number of pembrolizumab cycles received (p = 0.05). Conclusion: In our analysis, the addition of pembrolizumab to chemotherapy resulted in similar pCR rates compared with published evidence. These findings reinforce the role of immunotherapy in early TNBC.. Further analyses with longer follow-up are warranted to evaluate the impact of pCR on survival in the real world.

T. Sahin¹, F. Kemik², H. Muglu³, S. Biter⁴, S. Tunbekici⁵, A. Oruc⁶, A. Guren⁷, K. Kaban⁸, M. Aykan⁹, B. Koylu², O. Ekinci¹⁰, I. Deliktas Onur¹¹, A. Kalem¹², O. Altunok¹³, M. Seyyar¹⁴, B. Guney¹⁵, O. Akdogan¹⁶, M. Yazici¹⁷, N. Majidova¹⁸, E. Esin¹⁹, D. Cabuk¹⁷, O. Yazici¹⁶, R. Gursu¹⁵, M. Yilmaz¹³, H. Yesil Cinkir¹², O. Ates¹¹, E. Celik¹⁰, N. Karadurmus⁹, N. Mandel⁸, I. Bayoglu⁷, M. Araz⁶, E. Goker⁵, E. Bayram⁴, D. Erdem²⁰, F. Selcukbiricik², G. Basaran²¹, A. Sezer²², A. Bilici³, S. Gunduz², D. Guven¹, S. Aksoy¹; ¹Department of Medical Oncology, Hacettepe University, Ankara, TURKEY, ²Department of Medical Oncology, Koç University School of Medicine, Istanbul, TURKEY, ³Department of Medical Oncology, Istanbul Medipol University, Istanbul, TURKEY, ⁴Department of Medical Oncology, Cukurova University, Adana, TURKEY, ⁵Department of Medical Oncology, Ege University, Izmir, TURKEY, ⁶Department of Medical Oncology, Necmettin Erbakan University, Konya, TURKEY, ⁷Department of Medical Oncology, Marmara University, Istanbul, TURKEY, ⁸Department of Medical Oncology, American Hospital, Istanbul, TURKEY, ⁹Department of Medical Oncology, Health Science University, Gulhane School of Medicine, Ankara, TURKEY, ¹⁰Department of Medical Oncology, Prof. Dr. Cemil Taşcıoğlu City Hospital, University of Health Sciences, Istanbul, TURKEY, ¹¹Department of Medical Oncology, Dr. Abdurrahman Yurtaslan Ankara Oncology Training and Research, Ankara, TURKEY, ¹²Department of Medical Oncology, Gaziantep University, Gaziantep, TURKEY, ¹³Department of Medical Oncology, Bakirkoy Dr. Sadi Konuk Training and Research Hospital, Istanbul, TURKEY, ¹⁴Department of Medical Oncology, Gaziantep City Hospital, Gaziantep, TURKEY, ¹⁵Department of Medical Oncology, Istanbul Training and Research Hospital, Istanbul, TURKEY, ¹⁶Department of Medical Oncology, Gazi University, Ankara, TURKEY, ¹⁷Department of Medical Oncology, Kocaeli University, Kocaeli, TURKEY, ¹⁸Department of Medical Oncology, VM Medical Park Maltepe Hospital, Istanbul, TURKEY, ¹⁹Department of Medical Oncology, Bayındır Hospital, Ankara, TURKEY, ²⁰Department of Medical Oncology, Samsun Medical Park Hospital, Samsun, TURKEY, ²¹Department of Medical Oncology, Acıbadem University, Istanbul, TURKEY, ²²Department of Medical Oncology, Başkent University, Adana, TURKEY.

Background: Trastuzumab deruxtecan (T-DXd) has transformed the treatment landscape of HER2+ metastatic breast cancer (mBC), with significant improvements in survival reported in clinical trials. However, limited data exist regarding its performance in real-world settings, particularly in lower-middle-income countries (LMICs). We aimed to evaluate the real-world effectiveness and safety of T-DXd in patients with HER2+ mBC in Türkiye. Methods: This multicenter, retrospective cohort study, conducted by the Turkish Oncology Group, evaluated the real-world outcomes and tolerability of T-DXd in patients with HER2+ mBC across 22 oncology centers in Türkiye. The primary endpoints were real-world progression-free survival (rwPFS) and overall survival (OS). Secondary endpoints included objective response rate (ORR) and safety outcomes. Results: A total of 206 patients were included. The median age was 49 years (IQR: 42-59), and the median follow-up was 11.5 months. Among all patients, 72.3% had HER2 IHC 3+ disease, and 61.7% were HR-positive. T-DXd was administered in second line in 54 patients (26.2%), as third-line therapy in 63 patients (30.6%), and in the fourth line or beyond in 90 patients (43.7%). Patients had received a median of two lines of prior therapy (range: 0-8).The median rwPFS was 16.8 months (95%CI: 12.7-20.9), and the median OS was 29.2 months (95%CI: 22.1-36.3). Among the 192 patients evaluable for response, the ORR was 77.6% and the disease control rate (DCR) was 91.7%. Second line use of T-DXd in was associated with significantly longer rwPFS compared to later lines (p = 0.004). Treatment-related adverse events (AEs) of any grade occurred in 59% of patients. Interstitial lung disease (ILD) was reported in 20 patients (9.7%), with 4 cases being grade 3 or higher. Among the 12 patients with grade 1 ILD eligible for rechallenge, 83.3% (10/12 patients) were rechallenged. Conclusion: In this large real-world cohort from an LMIC, T-DXd demonstrated robust antitumor activity and a manageable safety profile in patients with HER2+ mBC. These findings are consistent with prior clinical trial data and support the applicability of T-DXd in broader clinical settings.

J. Wagner, I. Vasconcelos, J. Blohmer; Breast Center, Charité – Universitätsmedizin, Berlin, GERMANY.

Background Keynote-522 administers four cycles of Carboplatin + Paclitaxel (Carbo/P) together with pembrolizumab (Pembro), followed by Doxorubicin/Epirubicin + Cyclophosphamide (EC). In routine care, some centres invert the order, initiating therapy with EC. Whether sequencing influences delivery of the complete regimen or the likelihood of achieving a pathologic complete response (pCR) is uncertain.MethodsElectronic drug-administration logs from all patients with stage I-III TNBC treated with Pembro-EC-Carbo/P between January 2022 and July 2024 were analysed. Each EC or Carboplatin infusion was counted as a macro-cycle (maximum four each), and every Paclitaxel dose was grouped into twelve weekly micro-cycles, yielding a theoretical maximum of twenty cycles. Carboplatin administrations were classified as high-dose (area under the curve, AUC ≈ 5) or low-dose (AUC ≈ 1.5). pCR was defined as ypT0 or documented “pCR”. Pathogenic germline variants (pV) and clinical stage at diagnosis were retrieved from the hospital registry. Group comparisons used the Mann-Whitney U and Fisher’s exact tests (α = 0.05).ResultsSixty-five patients met inclusion criteria (median age 50 years; stage I 10%, II 46%, III 44%). Forty-four began with EC (EC-first) and twenty-one with Carbo/P (Carboplatin-first). EC-first patients completed a median of 18 cycles compared with 15 cycles in Carbo-first (p = 0.004); 73% versus 38% finished phase-2 Carboplatin, and 46% versus 24% received at least 18 cycles. High-AUC Carboplatin exposure (median four infusions) and cumulative Paclitaxel dose (2,300 mg versus 2,250 mg) were similar. The pCR rate was 48% (21/44) for EC-first and 38% (8/21) for Carboplatin-first (p = 0.46). Documented BRCA1/2 (pV) or other pVs were present in 8% of patients; their pCR rate was 57% compared to 43% in patients without a pV. Therapy discontinuation occurred in 14% of both cohorts, most commonly due to hematologic toxicity or disease progression.ConclusionsCommencing pembrolizumab-based neoadjuvant therapy with EC was associated with superior regimen completion and a numerically higher, though not statistically significant, pCR rate compared with starting with Carbo/P, without an increase in early termination. Of note, there were considerably more stage III patients than in the trial population—potentially harder to sterilise—which may account for the lower pCR rates seen. These real-world findings support prospective evaluation of an EC-first sequence and emphasise the importance of maintaining dose intensity in everyday practice.

J. Roth¹, J. Albers¹, M. Gerken², O. Ortmann¹, S. Seitz¹; ¹Gynecology and Obstetrics, University of Regensburg, Regensburg, GERMANY, ²Tumor Center Regensburg, University of Regensburg, Regensburg, GERMANY.

The KEYNOTE-522 trial demonstrated significantly higher rates of pathological complete response (pCR) with the addition of pembrolizumab to neoadjuvant chemotherapy in patients with non-metastatic triple-negative breast cancer (TNBC). In this analysis, we aimed to evaluate whether real-world data support the benefit of adding immunotherapy to neoadjuvant chemotherapy for patients with early-stage TNBC. Additionally, we analyzed several subgroups to identify whether specific patient populations derive greater benefit from immunotherapy.Data were collected at the Tumor Center Regensburg. We included 160 patients diagnosed with non-metastatic TNBC between January 2020 and May 2025 at the Comprehensive Cancer Center Regensburg. Of these, 88 patients received neoadjuvant chemotherapy plus pembrolizumab, while 72 patients received chemotherapy alone. We observed pCR rates of 61.4% in the chemotherapy plus pembrolizumab group compared to 51.4% in the chemotherapy-only group, demonstrating an absolute increase of 10% favoring the addition of pembrolizumab.Subgroup analyses revealed that patients with a high Ki-67 score, particularly above 35%, achieved significantly higher pCR rates. Patients with BRCA mutations also showed markedly higher pCR rates in the pembrolizumab arm. Interestingly, younger patients demonstrated significantly higher pCR rates in both treatment arms compared to older patients. Detailed subgroup analyses will be presented.This real-world study demonstrates that the addition of pembrolizumab in routine clinical practice is associated with improved pCR rates, showing an absolute difference of 10%. Moreover, it suggests that specific subgroups may particularly benefit from immunotherapy. However, larger real-world studies are needed to enable more robust subgroup analyses.

Y. Chen, G. Song, H. Li; Department of Breast Oncology, Peking University Cancer Hospital, Beijing, CHINA.

Real-world effectiveness of Trastuzumab Deruxtecan in HER2-low Metastatic breast cancer: a single-center retrospective study Yifei Chen, Guohong Song, Huiping Li Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Breast Oncology, Peking University Cancer Hospital &Institute, Beijing 100142, China Background: Clinical trials of trastuzumab deruxtecan (T-Dxd) have expanded options for HER2-low breast cancer, yet real-world patients often present with poorer prognostic features such as active brain metastases or heavy pretreatment. Robust effectiveness data in routine practice are therefore needed. Methods: This is a retrospective real-world monocentric study conducted by 81 patients with HER2-low advanced breast cancer, who were treated with T-Dxd. Database from the Department of Breast Oncology at Peking University Cancer Hospital was reviewed, spanning March 2023 to January 2025. All patients underwent at least one radiologic response assessment. Results: The median progression-free survival (PFS) was 6.0 months (95%CI, 3.8-8.1). There were 68 HR+(83.95%) and 13 HR- (16.05%) patients included. HR+ disease showed a median PFS of 6.7 months (95%CI, 5.2-8.2) versus 3.4 months (95%CI, 2.1-4.7) in triple-negative breast cancer (TNBC), no statistical significance between these two groups (P=0.062). TNBC patients had a significantly shorter median overall survival (OS) (8.7 months, (95%CI, 2.2-15.2) , P=0.002), while mOS was not reached in HR+ group.Presence of visceral, liver, lung, or CNS lesions did not materially alter PFS (6.0 vs 5.9 months, P=0.906). Among 13 patients (16.05%) with active brain metastases, disease-control rate was 84.62% and 5/6 evaluable patients achieved CNS partial response.Baseline IHC score (HER2 1+ vs 2+) did not affect PFS (5.9 vs 6.0 months, P=0.707). But patients whose metastatic sites showed up-regulated HER2 expression achieved longer PFS (7.0 vs 3.4 months, P=0.015).The cohort had received a median of 4 prior lines of systemic therapy, including a median of 2 chemotherapy regimens. Administering T-Dxd after more than 3 prior chemotherapy lines or after exposure to topoisomerase I/II inhibitors significantly shortened PFS (4.5 vs 7.0 months, P=0.018 and 3.2 vs 6.7 months, P=0.002, respectively).Of the 48 patients who underwent germline BRCA testing, 13 carried BRCA1/2 mutations and 35 were wild type. Although mPFS was numerically longer in the mutant subgroup (7.5 months) than in the wild-type subgroup (4.8 months), the difference was not statistically significant (P = 0.607). Among the 13 BRCA-mutated patients, 10 had previously received PARP inhibitors; their mPFS did not differ from that of PARP-naïve patients (7.5 vs 4.5 months, P = 0.989).PAM-pathway alterations (PIK3CA/AKT/PTEN) were evaluated in 41 patients, with 11 found to be mutant. Median PFS was similar between the PAM-mutated and wild-type groups (6.0 vs 4.2 months, P = 0.065). Conclusions: In routine clinical practice, T-Dxd delivers meaningful disease control for heavily pre-treated HER2-low metastatic breast cancer, including patients with active brain metastases—but its effectiveness is more modest than that seen in randomized trials. Greatest benefit is observed when: (i) metastatic lesions up-regulate HER2 expression, and (ii) T-Dxd is introduced earlier in the chemotherapy sequence. Outcomes are less favorable in triple-negative disease and after prior topoisomerase-targeted therapy, suggesting that biomarker- and timing-guided patient selection could optimize real-world use.

K. O. West¹, J. Epps¹, E. G. Marks¹, A. L. Gyden¹, K. A. Sabelko¹, M. L. Bondy², J. Jourquin¹; ¹Data Science, Susan G. Komen, Dallas, TX, ²Epidemiology and Population Health, Stanford University School of Medicine, Stanford, CA.

Background: To optimize care and improve outcomes for all breast cancer patients, multi-modal data need to be integrated with the experiences of patients. However, access to these datasets that reflect the diversity of patients is often limited and siloed within single institutions. To address these challenges, Susan G. Komen® (Komen) launched ShareForCures® (SFC), a direct-to-consumer, online, IRB-approved breast cancer research registry, designed to integrate real-world, longitudinal data from adults who have been diagnosed with breast cancer and live in the United States and to provide this data for research. Methods: We analyzed data from participants who enrolled in SFC within the first two years and developed the SFC Research Hub, which facilitates data exploration, cohort creation and data access application. A taskforce of research experts (clinical oncologists, translational scientists, and research advocates) provided guidance and feedback throughout the development of the SFC Research Hub by completing surveys, meeting with Komen staff, and participating in user testing. Results: From July 2023 to June 2025, 1,214 participants enrolled in SFC (median age = 55 years [range: 27-93], 99% women, 75% non-Hispanic White). Only four participants withdrew after enrollment, resulting in a retention rate of 99.7%. Participants were geographically dispersed across the United States, including Puerto Rico. Most participants received oncology care outside of NCI-designated comprehensive cancer centers and were diagnosed within the past five years. The majority of participants reported their first breast cancer diagnosis as invasive ductal carcinoma (57%), with 39% reporting ER+/HER2- disease. Notably, 18% of participants reported living with metastatic breast cancer (18%) and 14% experienced a recurrence (14%). All participants reported demographic and diagnostic information, and 53% of participants completed additional questionnaires and/or shared saliva samples for germline whole genome sequencing. Medical records were requested for 52% of participants, 30% were retrieved and curated, and 13% have access to a summary of their records in the platform. The SFC Research Hub was designed and developed with end users in mind, offering secure access to integrated, deidentified data shared by SFC participants. To access SFC data, researchers must agree to a code of conduct, acknowledge their institution’s data use agreement with Komen, and receive approval of their data access application describing their research project from Komen. In return, researchers will share their findings with SFC participants. Conclusions: Through SFC, Komen is creating a real-world database that connects researchers with data contributed by participants with diverse experiences. The SFC Research Hub is expected to launch in 2026, enabling researchers to leverage SFC data to enhance our understanding of real-world breast cancer patient experiences, ultimately accelerating discoveries and improving outcomes for all breast cancer patients.

V. Gorantla¹, R. Choksi¹, F. Kudrik², S. Reddy³, S. Reganti³, S. Rosenfeld⁴, G. Cioffi⁵, D. Parris⁵, A. Rui⁵, M. Gart⁵, C. Wall⁵, B. Wang⁵, P. Varughese⁵, J. Donegan⁵, L. Morere⁵, R. Geller⁵, J. Scott⁵, D. Patt⁶; ¹Medical Oncology, University of Pittsburgh Medical Center (UPMC), Pittsburgh, PA, ²Medical Oncology, South Carolina Oncology Associates, Columbia, SC, ³Medical Oncology, Cancer Care Specialists, Reno, NV, ⁴Medical Oncology, Highlands Oncology Group (HOG), Fayetteville, AR, ⁵PrecisionQ, IntegraConnect, West Palm Beach, FL, ⁶Medical Oncology, Texas Oncology, Austin, TX.

Background: In the DESTINY-Breast12 trial, individuals with HER2-positive (HER2+) metastatic breast cancer (mBC) who received trastuzumab deruxtecan (T-DXd) had similar progression-free survival (PFS) regardless of the presence of brain metastases (BrM). We sought to evaluate time to treatment discontinuation or death (TTD), time to next treatment (TTNT; a surrogate for PFS), and overall survival (OS) using real-world data to assess patients (pts) outside of a clinical trial setting for both HER2+and HER2-low mBC.  Methods: We used the Integra Connect PrecisionQ real-world de-identified electronic health record database of >3 million cancer pts across >500 sites of care to identify 374 HER2+ mBC pts and 512 HER2-low mBC pts for the analysis. Eligible pts were adults with HER2+ or HER2-low mBC with ≥2 documented visits who initiated T-DXd between 1-1-2020 and 5-31-2024, with observation through 11-30-2024. The index date was the initiation of T-DXd. Documentation of BrM was determined at or prior to index date. Patient data included structured data supplemented with data obtained via chart abstraction. TTD, TTNT, and OS by documentation of BrM were analyzed using Kaplan-Meier analysis. Unadjusted hazard ratios (HR) were estimated using Cox proportional hazard models.  Results: A total of 374 HER2+ pts were identified, including 94 with documented BrM and 280 without. The median age at index was 62.5 (interquartile range [IQR] 54, 71) years. A total of 512 HER2-low pts were identified, 80 of whom had documented BrM and 432 of whom did not. The median age at index was 65 (IQR 56, 71) years. Pts with HER2+ mBC did not have statistically significant differences in median TTD, TTNT, or OS regardless of the presence of BrM. However, pts with HER2-low mBC without BrM had significantly longer median TTD (5.5 months vs. 3 months, logrank p=0.002), TTNT (7.2 months vs. 5.8 months, logrank p=0.002), and OS (15.8 months vs. 10.2 months, logrank p<0.001) compared to those with BrM.    Conclusions: This real-world comparison of T-DXd treatment reaffirmed findings from DESTINY-Breast12 in which PFS did not differ among HER2+ mBC pts based on the presence of BrM. While this study showed significantly longer median TTD, TTNT, and OS in HER2-low mBC pts without BrM compared to those with BrM, further research and larger samples sizes are needed to understand how the line of therapy for T-DXd impacts these findings.

S. M. Tolaney¹, S. Valliant², S. Hunter³, O. Tymejczyk⁴, A. Yu⁵, J. Earla⁶, E. Pang⁷; ¹Breast Oncology, Dana-Farber Cancer Institute, Boston, MA, ²Global Oncology HEOR, V&E, Daiichi Sankyo, Inc., Basking Ridge, NJ, ³RWE, Daiichi Sankyo, Inc., Basking Ridge, NJ, ⁴Global Oncology RWE Generation, Daiichi Sankyo, Inc., Basking Ridge, NJ, ⁵Global Scientific & Medical Affairs Oncology, Merck & Co., Inc., Rahway, NJ, ⁶Outcomes Research Value & Implementation (V&I), Merck & Co., Inc., Rahway, NJ, ⁷Global Oncology Medical Affairs, Daiichi Sankyo, Inc., Basking Ridge, NJ.

Background: Human epidermal growth factor receptor 2-positive breast cancer (HER2+ BC) accounts for 15% to 20% of approximately 300,000 new BC cases diagnosed annually in the US. The treatment landscape for HER2+ metastatic BC (mBC) has evolved significantly, and trastuzumab deruxtecan (T-DXd [a HER2 antibody-drug conjugate]) is now the preferred standard of care in the second-line (2L) setting. Optimal post-T-DXd treatment pathways are unclear due to the lack of data for regimens in the 3L or 4L setting for patients with HER2+ mBC. This study aimed to better characterize real-world (rw) treatment patterns and clinical outcomes in patients with HER2+ mBC who were previously treated with T-DXd in the rw practice setting. Methods: This was a noninterventional, retrospective, observational cohort study of patients diagnosed with HER2+ mBC who initiated a subsequent treatment after receiving T-DXd in the metastatic setting, using the US-based Flatiron Health Enhanced Datamart. The study observation period was from January 1, 2011, to March 31, 2024. Patients with HER2+ mBC treated with ≥1 T-DXd-containing line of therapy (LOT) and a subsequent LOT, with an index date ≥90 days prior to the end of the observation period, were included. Index date was defined as the start of the LOT that followed the first T‑DXd-containing LOT. Patient demographics, clinical characteristics, and treatment utilization were assessed descriptively. The primary (rw progression-free survival [rwPFS]) and secondary (rw overall survival [rwOS], rw time to discontinuation or death [rwTTD/D], and rw time to next treatment or death (rwTTNT/D)] endpoints were assessed using Kaplan-Meier methods. Results: The study included 228 patients (mean age, 60.3 years; 99.6% were female and 66.7% were White). Most patients initiated their index treatment in the 4L setting (median of 3 LOTs prior to index date; line of index treatment: 2L [4.4%], 3L [22.4%], 4L [31.1%], 5L [22.8%], 6L [11.0%], 7L+ [8.3%]). 64.5% of patients had ≥3 metastatic sites at the index date; 31.6% had CNS metastases. With a median follow-up of 10.4 months (range, 0.5-42.4 months), the median rwPFS was 4.3 months (95% CI, 3.5-5.0 months) and the median rwOS was 15.7 months (95% CI, 12.1-20.0 months). The median rwTTD/D and rwTTNT/D were 6.2 and 6.9 months, respectively. The most common regimens received as the index LOT were trastuzumab + tucatinib + chemotherapy (TTC; 34.2%), other anti-HER2 (18.9%), trastuzumab + chemotherapy (12.7%), other (12.7%), margetuximab + chemotherapy (8.8%), trastuzumab emtansine (T-DM1; 6.6%), and anti-HER2 TKI + chemotherapy (6.1%). Treatment sequencing varied by index line number. T-DM1-based regimens were more common when the index LOT was 3L (15.7%) vs 4L (5.6%) or 5L (3.8%), and 21% to 22% of patients with index 3L or 4L treatment received other anti-HER2 therapies immediately post T-DXd vs 13.5% with index 5L treatment. Conclusions: Treatment sequencing data suggest that TTC and other anti-HER2 therapies are being used in the post-T-DXd rw setting, though potential differences by line exist. This study demonstrates an ongoing and substantial unmet need for more effective treatments among patients with HER2+ mBC previously treated with T-DXd, as shown by the short rwPFS/OS and short times on subsequent treatments following T-DXd.

G. Kutomi¹, K. Kida², Y. Kajiura², K. Narui³, K. Kataoka⁴, M. Taguri⁵, K. Harada⁵, H. Shima⁶, R. Nakamura⁷, T. Ohnishi⁸, T. Nakayama⁹, M. Nagahashi¹⁰, T. Sankai¹¹, K. Orimoto¹², Y. Horimoto¹², T. Ishikawa¹²; ¹Department of Breast Oncology, Juntendo University School of Medicine, Tokyo, JAPAN, ²Department of Breast Surgical Oncology, St. Luke’s International Hospital, Tokyo, JAPAN, ³Department of Breast and Thyroid Surgery, Yokohama City University Medical Center, Kanagawa, JAPAN, ⁴Advanced Medical Research Center, The Institute of Medical Science, The University of Tokyo, Tokyo, JAPAN, ⁵Department of Medical Data Science, Tokyo Medical Univesity, Tokyo, JAPAN, ⁶Department of Surgery, Division of Breast Surgery, Sapporo Medical University School of Medicine, Hokkaido, JAPAN, ⁷Department of Breast Surgery, Chiba Cancer Center Hospital, Chiba, JAPAN, ⁸Department of Breast Surgery, National Cancer Center Hospital East, Chiba, JAPAN, ⁹Department of Breast and Endocrine Surgery, Osaka International Cancer Institute, Osaka, JAPAN, ¹⁰Department of Surgery, Division of Breast and Endocrine Surgery, Hyogo Medical University School of Medicine, Hyogo, JAPAN, ¹¹Department of Breast and Thyroid Surgery, Kitasato University School of Medicine, Kanagawa, JAPAN, ¹²Department of Breast Oncology and Surgery, Tokyo Medical Univesity, Tokyo, JAPAN.

Background: With recent advances in breast cancer treatment, changes in local recurrence and survival following breast-conserving surgery (BCS) are also anticipated over time. Techniques for BCS vary across countries, and anatomical differences among ethnic groups may influence patterns of local recurrence risk. Objective of this study:  To investigate the recent rates of local recurrence and prognosis following BCS in Japan using multi-institutional real-world data, with a particular focus on identifying trends and risk factors for local recurrence through comparison with historical data. Methods: This multicenter retrospective cohort study included 8,897 breast cancer patients who underwent BCS between January 2014 and December 2018 at 25 participating institutions across Japan. Data on patient demographics, surgical details, pathological factors including margin status, adjuvant therapy, and outcomes were collected. The primary endpoint was local recurrence rate. Secondary endpoints included distant recurrence rate, overall mortality, and breast cancer-specific mortality. Local recurrence rate (LRR), disease-free survival (DFS) and overall survival (OS) were estimated by Kaplan-Meier analysis; Results: Median follow-up was 6.6 years. In the overall population (N=8,897), Clinical stages at diagnosis were Stage 0 (n=918:10.3%), Stage I (n=4,539:51.0%), Stage II (n=2,566: 28.8%), and Stage III (n=360:4.0%). 5 year LRR, DFS and OS were 2.0%(1.7-2.3: 95%Cl), 94.1%(93.6-94.6: 95%Cl) and 97.8%(97.4-98.1: 95%Cl), respectively. 10 year LRR, DFS and OS were 4.6%(3.6-5.5: 95%Cl), 86.2%(84.1-88.3: 95%Cl) and 94.1%(93.1-95.1: 95%Cl), respectively. Potential risk factors for local recurrence are younger age of onset, tumor size, high Ki-67 , LV invasion, lack of adjuvant therapy (Table 1). Adjuvant systemic treatment was suggested to contribute to a reduced risk of local recurrence in all subtypes. Conclusions: Our recent data suggest that outcomes of BCS in Japan have improved compared to the past. As a growing number of new systemic therapies continue to be introduced each year, it is crucial to incorporate contemporary data—rather than relying solely on historical studies—when considering optimal surgical strategies.

K. H. Natsuhara¹, L. Park², S. Udayachalerm³, R. Mireia⁴, B. Murphy⁵, B. Nordstrom³, L. A. Huppert¹; ¹Oncology, University of California, San Francisco/Helen Diller Family Comprehensive Cancer Center, San Francisco, CA, ²Oncology outcomes research, Astrazeneca, Gaithersburg, MD, ³RWE, PPD Evidera Real World Data & Scientific Solutions, Thermo Fisher Scientific, Wilmington, NC, ⁴RWE, PPD Evidera Real World Data & Scientific Solutions, Thermo Fisher Scientific, Sundbyberg, SWEDEN, ⁵RWE, PPD Evidera Real World Data & Scientific Solutions, Thermo Fisher Scientific, Wilmington, NC, USA, Wilmington, NC.

BACKGROUND: In patients with hormone receptor-positive/human epidermal growth factor receptor 2-negative metastatic breast cancer (MBC) with ≥ 1 PIK3CA, AKT1, or PTEN tumor alterations, capivasertib plus fulvestrant is approved in the US for use after progression on at least one endocrine-based treatment. This study assessed real-world treatment patterns of capivasertib in the US. METHODS: This retrospective cohort study used Flatiron Health electronic health record-derived database. Eligible patients were ≥18 years, diagnosed with MBC, initiated capivasertib between November 16, 2023 and July 31, 2024, and had at least 6 months (mos) of potential follow-up time from capivasertib initiation (index date). Real-world time to treatment discontinuation (rwTTD) and time to next line of treatment (rwTTNT) were assessed from the index date. Summary statistics were used to describe patient characteristics at baseline and treatment patterns. rwTTD and rwTTNT were estimated using Kaplan-Meier methods. The line of therapy (LOT) was defined using an algorithm that incorporated prior treatment use. RESULTS: This study identified 412 patients with MBC who received capivasertib. The median age was 67 years (IQR 60, 75). The majority were female (98.8%), white (71.6%), and from community practice settings (83.0%). Prior to capivasertib initiation, sites of disease included: bone (91.0%), liver (44.2%), lung (28.2%), and brain (7.0%). PIK3CA, AKT1, or PTEN alterations were documented in 90.3% of patients: PIK3CA (75.0%), PTEN (14.3%), and AKT1 (10.0%) alterations. Co-mutations with ESR1 mutations were observed in 25.5% of patients. Prior therapies for MBC included: CDK4/6 inhibitors (87.1%), fulvestrant (66.0%), chemotherapy (31.8%), alpelisib (20.6%), and antibody-drug conjugates (14.1%) in any prior LOT. Most patients received capivasertib with fulvestrant (n=387, 93.9%); in 25 patients (6.1%), use with another endocrine therapy/combination or alone was recorded in the chart, but could not be verified due to data limitations. Among patients recorded as having received capivasertib with fulvestrant (n=387/412, 93.9%), more than half of patients received capivasertib in second-line (2L) (n=115, 29.7%) or 3L (n=102, 26.4%), though many were treated in 4L+ (n=146, 37.7%). 2L and 3L median rwTTNT was 7.1 mos (IQR 5.8, NE) and 6.9 mos (IQR 6.1, 7.8), respectively. 2L and 3L median rwTTD was 6.9 mos (IQR 5.3, NE) and 6.6 mos (IQR 5.2, 7.1), respectively (Table 1). CONCLUSIONS: Findings from this large database analysis of US patients demonstrate the effectiveness of capivasertib + fulvestrant in real-world practice. Clinical outcomes in 2L and 3L closely match those observed in the CAPItello-291 Phase 3 randomized controlled trial, which supported FDA approval of the capivasertib + fulvestrant regimen. Numerically improved outcomes were observed in patients who used capivasertib in earlier vs later line settings.

R. Rodgerson¹, M. Youssef²; ¹Norwich Medical School, University of East Anglia, Norwich, UNITED KINGDOM, ²Breast Surgery/General Surgery, Norfolk and Norwich University Hospital, Norwich, UNITED KINGDOM.

¹Sparano JA et al. TAILORx trial: endocrine vs chemoendocrine therapy in HR+/HER2− breast cancer Background: The TAILORx¹ trial established the 21-gene Recurrence Score as a key tool for guiding chemotherapy decisions in node negative, hormone receptor-positive, HER2-negative breast cancer. While its prognostic utility is well supported in clinical trials, its real-world validation remains limited. This study evaluates the 21-gene Recurrence Score’s performance in a real-world cohort and compares outcomes with TAILORx¹-defined risk groups. Methods: We conducted a retrospective cohort study using prospectively collected data of 388 node-negative patients who underwent 21-gene Recurrence Score testing between 2015 and 2024 in a tertiary referral cancer centre. Patients were stratified into five groups based on TAILORx¹ criteria: Group A (Age > 50, RS 11-25), Group B (Age ≤ 50, RS 11-15), Group C (Age ≤ 50, RS 16-25), Group D (RS 0-10 all ages), Group E (≥ 26 all ages). Treatment data (Endocrine Therapy [ET] vs. Chemotherapy + ET [CET]) and survival outcomes were analysed using Kaplan-Meier, log-rank tests and cox regression. Results: Group A (n=151) showed slightly more events than expected (10 observed vs. 8.2 expected), but outcomes remained consistent with TAILORx¹, which found no chemotherapy benefit in this group. Group B (n=22) had significantly worse outcomes than expected (HR 6.51, p=0.021), contrasting with TAILORx¹, where this group had excellent survival with ET alone. Group C (n=42) had no events, suggesting better-than-expected outcomes. Group D (RS 0-10) also showed fewer events than predicted. Group E (RS ≥26) outcomes aligned with TAILORx¹, supporting chemotherapy use. Multivariable analysis identified CET (HR 4.25, p=0.034) and intermediate risk (HR 9.31, p=0.036) as significant predictors of poorer outcomes, likely reflecting treatment selection bias. Conclusions: Our real-world data largely align with TAILORx¹, confirming the prognostic value of the 21-gene Recurrence Score in node-negative patients. However, worse-than-expected outcomes in group B suggest biological heterogeneity or treatment adherence issues. These findings support continued use of the 21-gene Recurrence Score for risk stratification and highlight the need for careful clinical judgement in younger patients. Larger studies are warranted to validate these trends.

R. Rodgerson¹, M. Youssef²; ¹Norwich Medical School, University of East Anglia, Norwich, UNITED KINGDOM, ²Norfolk and Norwich University Hospital, University of East Anglia, Norwich, UNITED KINGDOM.

¹Kalinsky K et al. RxPONDER (SWOG S1007), RS ≤25, HR+/HER2−, node+ BC. Cancer Res. 2023;83(5 Suppl):GS1-01 Background: The 21-gene Recurrence Score is a validated prognostic and predictive tool for breast cancer, with evidence supporting its utility over a 9-year follow-up. The RxPONDER¹ trial further confirmed its clinical relevance in a controlled setting. However, its performance in real-world clinical practice remains underexplored. This study evaluates the application of the 21-gene Recurrence Score in routine care using RxPONDER¹ criteria and determines whether its prognostic value remains in real-world data. Methods: We conducted a retrospective cohort study using prospectively collected data from Node-positive patients at the Norfolk and Norwich University, a tertiary referral cancer centre treating 650 breast cancer patients per year (2015-2024). Eligible patients were hormone receptor-positive, HER2-negative breast cancer patients with 1-3 positive lymph nodes and available 21-gene Recurrence Scores. Treatment and survival data were extracted from hospital records. Patients were stratified by menopausal status and recurrence score. Kaplan-Meier curves and Cox regression analyses assessed outcomes and compared with RxPONDER¹ findings. Results: 282 patients were included. Chemotherapy was administered to all high-risk premenopausal patients (24.1%) and selectively to intermediate-risk patients based on additional clinical factors. In post-menopausal patients (75.9%), chemotherapy was primarily reserved for high-risk cases. High 21-gene Recurrence Scores (>25) were significantly associated with poorer outcomes (HR 6.59, 95% CI 1.39-31.15, p = 0.017), intermediate scores (11-25) showed a non-significant trend (HR 2.38, p = 0.265). Endocrine therapy adherence was the strongest independent predictor of survival (HR 0.012, p = 0.004). Chemotherapy plus endocrine therapy (CET) showed no statistically significant benefit after adjustment (HR 1.82, p = 0.5) These findings align with RxPONDER¹: chemotherapy showed no significant benefit in postmenopausal patients, but some benefit in premenopausal patients. Conclusions: The 21-gene Recurrence Score remains prognostic in node-positive patients and real-world outcomes mirror RxPONDER¹ findings. Our study highlights the importance of endocrine therapy adherence and supports continued use of the 21-gene Recurrence Score for guiding chemotherapy decisions in clinical practice. Larger cohort real-world studies are needed to further validate these findings.

B. Zigler, V. Wang, V. Smith; Real World Data, Q-Centrix, Chicago, IL.

Objective: This study aims to evaluate age-related patterns pertaining to the anatomical sites of second primary cancers occurring within five years of an initial breast cancer diagnosis. Methods: Our analysis focuses on patients (n=68,109) whose first recorded cancer diagnosis was early-stage breast cancer, diagnosed between 2008 and 2019. Age, diagnosis dates, and all anatomical cancer sites of these 68,109 patients were extracted from the Q-Centrix Clinical Data Warehouse. The Q-Centrix Clinical Data Warehouse is a proprietary database of de-identified clinical data produced through expert-driven human abstraction. The subset sourced from the Clinical Data Warehouse includes information from 78 hospitals, health systems, and cancer centers across the country. Patients were split into 6 age groups: 40 years of age compared to those < 40 years of age. A p-value cutoff of <0.05 was considered significant. A second analysis was conducted on the subset of patients who developed a second non-simultaneous cancer within five years of the initial breast cancer diagnosis. Of the 68,109 patients who had breast cancer logged as their first cancer in our data warehouse, 4680 (~7%) fit these criteria. The site of the second cancer was categorized as breast or non-breast. 29 patients in this group did not have a second cancer site stored in the data warehouse. 2 additional patients did not have their age stored in the data warehouse. These patients were dropped from the final set, bringing the total to 4,649. A logistic regression model was then run to determine the odds of the second primary site being located outside the breast versus inside the breast in patient age-groups >40 years of age compared to those <40 years of age. A p-value cutoff of <0.05 was considered significant. The age distribution of this group included 119 patients <40 years of age, 40-49 (n=561), 50-59 (n=1070), 60-69 (n=1426), 70-79 (n=1038), and 80+ (n=435). Results: The odds of developing a second non-simultaneous cancer within 5 years of an initial early-stage breast cancer diagnosis relative to the <40 age group was .68 in the 50-59 age group, .60 in the 60-69 age group, .55 in the 70-79 age group and .59 in the 80+ age group (p-value <0.05). The odds of the 40-49-year age group relative to the <40-year age group was not statistically significant. In the group that did develop a second cancer diagnosis within 5 years, the odds of the tumor location being outside the breast versus inside the breast were 2.05 times greater for patients aged 50-59 years. A 60-69-year-old patient was 3.49 times likelier, a 70-79-year-old patient was 4.76 times likelier, and a patient 80 years or older was 5.05 times likelier to have a second cancer site outside of the breast relative to a patient who was <40 years of age (p-value<.05). The odds of the 40-49-year age group developing a cancer located outside the breast versus inside the breast relative to the <40-year age group was not statistically significant. Conclusions: The odds ratios in the second analysis suggest that the odds of developing a second cancer outside the breast, relative to within the breast, within five years of an initial early-stage breast cancer diagnosis, increase progressively with patient age. Further analyses are required to determine how this relationship differs with respect to the original breast cancer diagnosis receptor type, stage, and anti-neoplastic treatment modality.

S. Mehta¹, H. Neuhalfen², A. Peevyhouse², D. Adhikari², C. Williams², M. Garretson³, S. Blau², M. Walker², D. Peevyhouse⁴; ¹HEOR, Daiichi-Sankyo, Basking Ridge, NJ, ²RWD, ONCare Alliance, Tacoma, WA, ³HEOR, Aaron Peevyhouse, Basking Ridge, TN, ⁴RWE, ONCare Alliance, Tacoma, WA.

Background: Trastuzumab deruxtecan (T-DXd) was initially (12/2019) approved by the FDA for treatment of patients (pts) with HER2+ unresectable or metastatic breast cancer (mBC) with two or more prior anti-HER2 regimens. T-DXd was later (5/2022) approved for use by pts with one prior anti-HER2 regimen. This study examined clinical outcomes in pts with HER2+ mBC treated with T-DXd 2L and 3L+ settings. Methods: This retrospective cohort study used deeply-curated electronic medical record data from practices affiliated with ONCare Alliance. Adult pts with mBC diagnosis, confirmed HER2+ status, who received T-DXd in the 2L or later setting 1/2020 to 8/2024 were included. Pt characteristics, treatment utilization and medical events of interests were assessed descriptively by 2L and 3L+ cohorts. Clinical outcomes (duration of therapy [DoT], real-world time to treatment failure [rwTTF], overall survival [OS] and real-world progression-free survival [rwPFS]) were assessed by 2L and 3L+ cohorts using Kaplan-Meier methods. Clinical outcomes of 1L and 2L rwTTF were examined in an exploratory subgroup of pts with 1L taxane+trastuzumab+pertuzumab based regimen (THP) followed by 2L T-DXd vs. 2L trastuzumab emtansine (T-DM1). Results: A total of 300 pts (70 2L and 230 3L+ pts [61.3% in 3L/4L]) treated with T-DXd were included (overall mean age = 59.3 yrs; 82.3% White). At mBC diagnosis, a greater proportion of pts in the 2L T-DXd cohort vs. 3L+ cohort had distant bone / visceral metastasis (45.7% vs. 38.3%) and visceral only metastasis (47.1% vs. 42.2%), where a significantly lower proportion had bone only metastasis (7.1% vs. 19.6%; p = 0.0493). Fewer 2L pts had brain metastasis at initiation of T-DXd (14.3% vs. 37.0% in 3L+, p = 0.0031), but a higher rate of baseline comorbidities was seen in 2L pts (50.0% vs. 30.4%, p = 0.0027). Prior to the initiation of 2L T-DXd, 64.3% (n=45) pts received a trastuzumab+pertuzumab based regimen and 22.8% (n=16) received T-DM1 in 1L; prior to 3L+ T-DXd use, 38.7% (n=89) received T-DM1 in 2L. Within a median follow-up of 17.0 months (mo), pts receiving T-DXd in 2L had longer median DoT than 3L+ pts (20.5 mo vs. 12.5 mo, p = 0.0390), longer rwPFS (15.3 mo in 2L vs. 12.4 mo in 3L+, p = 0.0179), longer OS (median NR in 2L vs. 29.0 mo in 3L+, p = 0.0050), and numerically longer rwTTF (13.6 mo in 2L vs. 10.4 mo in 3L+, p = 0.0565). Of pts with a response assessment (66 2L, 205 3L+ pts), an overall objective response was observed in 80.3% 2L vs. 71.7% 3L+ pts (p = 0.1672). The overall rates of any grade medical event of interest were consistent across 2L and 3L+ cohorts (fatigue [72.9% vs. 73.0%], nausea/vomiting [78.6% vs. 72.2%], diarrhea [55.7% vs. 43.9%], and interstitial lung disease (ILD)/pneumonitis [8.6% vs. 10.4%], except respiratory infection, which was higher in 2L T-DXd [38.6% vs. 18.7%, p = 0.0006]). Of the pts who had discontinued T-DXd at any point (45 2L and 180 3L+), the most common reason for discontinuation was disease progression (51.1% vs. 55.0%), followed by toxicity other than nausea/vomiting/ILD (17.8% vs. 11.7%), pt choice (8.9% vs. 6.1%) and toxicity related to ILD (6.7% vs. 6.7%). Among exploratory subgroups, median rwTTF was 1L THP 11.6 mo à 2L T-DXd 14.2 mo (n=38) vs. 1L THP 11.6 mo à 2L T-DM1 8.4 mo (n=60) (2L p = 0.0367). Conclusion: The study findings affirm the real-world clinical effectiveness and safety of T-DXd in pts with HER2+ mBC as observed in the DESTINY clinical trials. Despite higher disease and comorbidity burden in this small sample of pts with 2L T-DXd use, longer delays in time to progression and discontinuation were observed compared to later line use of T-DXd; and longer rwTTF compared to 2L T-DM1 use, reinforcing the importance of utilizing T-DXd as early as possible in the treatment pathway to improve long-term pt outcomes.

B. Ghimire¹, L. Rogers², M. Girgis¹; ¹Hematology-Oncology, Henry Ford Health, Detroit, MI, ²Neurosurgery, Henry Ford Health, Detroit, MI.

Background: The incidence of central nervous system (CNS) metastases in breast cancer is increasing. While local treatments such as surgery and radiation remain standard, systemic therapies have shown promise in HER2-positive disease. However, data on the efficacy of systemic therapy in HER2-low breast cancer with CNS involvement remain limited. This study describes outcomes of upfront systemic therapy in HER2-low breast cancer patients with CNS metastases treated at a single institution.Methods: We retrospectively reviewed breast cancer patients with CNS metastases treated at Henry Ford Health between Jan 2014 and July 2024. HER2-low status was defined as: HER2 immunohistochemistry 1+, or 2+ with negative fluorescent in situ hybridization (FISH). Eligible patients received no concurrent local CNS therapy; prior local treatment was permitted if unrelated to the studied lesions. CNS responses were to be assessed using the Response Assessment in Neuro-Oncology for brain metastases (RANO-BM) or the modified RANO-LM (leptomeningeal metastases) criteria. Results: Sixteen HER2-low patients were included. The median age was 56 years (range, 38-93); 63% (n = 10) were African American. Most (75%) had hormone receptor-positive disease, and 53% presented with de novo metastatic disease. Thirteen patients (81%) had HER2 IHC 1+, and only three had HER2 IHC 2+/FISH-negative disease. The majority (88%) had parenchymal CNS metastases; one patient had leptomeningeal disease, and one had both. Eight patients (50%) had prior CNS metastases, and 38% received local therapy before study inclusion. Notably, a significant proportion of patients (88%) had non-measurable disease by RANO-BM criteria (lesions <10 mm), with 69% having lesions smaller than 5 mm. Systemic therapies for the CNS disease included cytotoxic chemotherapy in seven patients (44%), trastuzumab deruxtecan (T-DXd) in four (25%), abemaciclib in two (13%), other CDK4/6 inhibitors in two (13%), and sacituzumab govitecan in one (6%). Commonly utilized chemotherapy included taxanes (paclitaxel or nab-paclitaxel) in 4 of 7 patients. In the 16 patients, the overall response rate (ORR) was 31.3%, the disease control rate (DCR) was 56.3%, the median duration of response (DOR) was 7 months, and the median progression-free survival (PFS) was 2 months. In a comparison cohort of HER2-positive patients (n=17), ORR was 53%, DCR was significantly higher at 94% (p=0.017), with similar DOR (5 months), and numerically longer PFS (3 months, p=0.351). Outcomes among the African American patients (n=10) mirrored the overall HER2-low group, with ORR 30%, DCR 50%, DOR 5 months, and PFS 1 month. Notably, the patients with HER2 IHC 2+ tumors (n=3; all HR+) experienced higher benefit (ORR 67%, DCR 100%) with no disease progression at last follow-up. HER2-low patients treated with T-DXd (n=4) demonstrated a DCR of 75%, with only one progression. Chemotherapy yielded a poor ORR of 29%, though two patients achieved complete CNS responses with taxane-based regimens. Conclusion: This “real-world” experience highlights modest intracranial activity of systemic therapy in HER2-low breast cancer with CNS metastases. Although response rates were lower than in HER2-positive counterparts, HER2 2+ tumors and patients treated with T-DXd showed encouraging outcomes. These findings support the need for prospective studies focusing on HER2-low CNS disease and suggest T-DXd as a promising therapeutic option, even in the absence of concurrent local treatment. Additionally, our study underscores a unique challenge in the management of breast cancer and brain metastases: CNS lesions are often smaller than the >10 mm threshold typically required for clinical trial eligibility, necessitating special attention and adapted approaches for response assessment.

D. L. Miranda, D. Dias e Silva, B. Viesser Miyamura, U. Donizeti Rocioli Junior, P. Serrano Uson Junior, J. Rodrigues Beal, P. Taranto, J. Pontes Batista Cassoli, F. Moura; Department of Oncology, Einstein Hospital Israelita, São Paulo, BRAZIL.

Introduction: Breast cancer is the leading cause of cancer-related death among women in Brazil and worldwide. However, its impact is not evenly distributed, with significant variations in incidence, mortality, and survival across different countries and regions. The incidence of breast cancer among young adults under the age of 50 has been increasing globally. This rise carries important implications both at the individual and societal levels, including a greater disease burden, reduced economic productivity, and an increased risk of long-term adverse clinical outcomes. There is a scarcity of data in the literature regarding this trend in Brazilian and Latin American populations. Objectives: We aimed to investigate the distribution profile of breast cancer diagnoses in adults under 50 years of age at two tertiary cancer centers in Brazil, as well as to compare it with the profile of patients aged 50 years and older, with a focus on clinical presentation and outcomes. Methods: We used real-world data from Einstein Hospital Israelita and Hospital Municipal Vila Santa Catarina between 2018 and 2023, including patients diagnosed with malignant breast neoplasms, according to the International Classification of Diseases – 10th Revision (ICD-10). Early-onset breast cancer was defined as a diagnosis in adults aged 18 to 49 years. Data extraction was automated using electronic medical record (EMR) systems and big data sources to obtain information related to ICD codes, demographic data, and medical history. For the calculation of years of life lost (YLLs), projected life expectancy was estimated for each individual based on their adjusted year of birth, sex, and place of residence, allowing for more precise and personalized estimates. Results: A total of 3,102 patients were analyzed, of whom 1,752 (56%) were aged 50 years or older and 1,350 (44%) were between 18 and 49 years old. Among the latter group, 28% reported their ethnicity, with the majority identifying as white (20%). Women accounted for 99.7% of the cases. Male sex was more frequent in the group aged 50 and older (1% vs. 0.3%; p=0.023). In the 18 to 49-year-old group, 61% of patients presented with localized or locally advanced disease (clinical stages I to III), while 39% had metastatic disease (clinical stage IV). Similarly, among patients aged 50 years or older, 59% were diagnosed at stages I to III, and 41% at stage IV. The median body mass index was lower in the younger group (24.6 kg/m² vs. 26.1 kg/m²; p<0.001). Over the study period, there was an observed increase in breast cancer diagnoses among individuals aged 18 to 49, with a 10% rise in rates, from 4.47/10,000 in 2018 to 4.92/10,000 in 2023. In contrast, a 7.1% decrease was observed in the group aged 50 and older, from 11.97/10,000 in 2018 to 11.11/10,000 in 2023. Additionally, there was a higher proportion of germline testing among patients aged 18 to 49 (21% vs. 11%; p<0.001). When assessing years of life lost (YLLs), patients under 50 years of age exhibited a significantly higher burden, with a median of 42 years lost (IQR 37.5-46.0), in contrast to a median of 21 years (IQR 13.0-26.0) among those aged 50 and older. Conclusions: In line with global trends, the apparent increase in breast cancer cases among individuals under 50 years of age in Brazil raises hypotheses regarding both the rise in incidence and the possibility of distinct characteristics compared to those aged 50 and older. This pattern highlights the need for further investigations to better understand risk factors and to improve screening and management strategies for this age group.

L. Moscetti¹, I. Sperduti², S. Zaniboni¹, L. Belluzzi¹, E. Zattarin¹, L. Cortesi³, P. Vici⁴, F. Piacentini¹, C. Omarini¹, E. Barbieri¹, F. Canino¹, M. Barbolini¹, F. Caggia¹, M. Dominici¹, A. Toss¹; ¹Oncology, Azienda Ospedaliero-Universitaria di Modena Policlinico di Modena, Modena, ITALY, ²Biostatistical Unit—Clinical Trials Center,, IRCCS Regina Elena National Cancer Institute, Roma, ITALY, ³Oncology, Azienda USL-IRCCS Reggio Emilia, Reggio Emilia, ITALY, ⁴Oncology, IRCCS Regina Elena National Cancer Institute, Roma, ITALY.

Background: First-line treatment for HR+/HER2- advanced breast cancer (ABC) is based on CDK4/6 inhibitors (CDK4/6i) and endocrine therapy (ET). The three available CDK4/6i – palbociclib (P), abemaciclib (A), and ribociclib (R) – demonstrated comparable efficacy in pivotal Phase III trials in terms of progression-free survival (PFS). However, only R achieved a significant overall survival (OS) benefit. Most previous analyses comparing these CDK4/6i focused on efficacy, safety, and tolerability, generally showing no significant differences. Limited real-world (RW) data exist regarding inter-drug comparisons in the RW setting.Methods: We conducted a meta-analysis of the RW studies in the first-line HR+/HER2- ABC setting (with P, A, and R) to assess potential outcome differences between the three drugs. A systematic literature search was performed using PubMed with the terms: “breast cancer,” “real world,” “palbociclib,” “abemaciclib,” “ribociclib” “dalpiciclib”. Treatment comparisons utilized as effect size the percentage (%) of 2-years real-world PFS (rwPFS) and 95% confidence intervals (CI). The % of 2-year rwPFS (%2yPFS) was estimated from the median rwPFS for this analysis Heterogeneity was assessed using the χ2 Q test (p50% considered significant). The pooled effect size estimate was calculated with a random-effect model using the 2-year PFS as endpoint.Results: 67 studies were identified 56 reported the median rwPFS as the primary outcome, one reported time to next treatment (TTNT), 8 reported time to chemotherapy or time to treatment discontinuation, 2 did not reported any outcome. Considering 56 studies involving four CDK4/6 inhibitors reporting rwPFS, no significant differences were observed when comparing all three drugs (%2yPFS 49, 95% IC 46-51, p=0.39). High heterogeneity was observed across the included studies (I2=81%, p<0.00001). Four out of 56 trials were excluded from the final analysis. The sensitivity analysis conducted in the 52 studies involving four trials with A (%2yPFS 49, CI 95% 40-59), thirty-nine trials with P (%2yPFS 48, CI 95% 45-50) and nine with R (%2yPFS 54, CI 95% 48-60) confirmed the effect size observed. In the analysis comparing the three CDK 4/6 inhibitors, no differences were observed when comparing A and P (p=0.751) or A and R (p=0.376), but a possible difference was observed when comparing R and P (p=0.045). Conclusion: This analysis did not reveal significant differences in 2-year rwPFS, the primary outcome in most real-world studies, among the CDK4/6 inhibitors. Any observed differences between R and P should be interpreted with consideration for the patient characteristics within the studies analysed. Further adjustment of the analysis using multiple variables is planned to assess inter-trial differences and mitigate bias inherent in real-world settings.

A. Niyazov¹, R. Sharma², S. Bilthare², S. Iyer²; ¹Value&Evidence, Pfizer, New York, NY, ²Evidence, HEOR&RWE, Putnam, Inizio Advisory, New York, NY.

Background Over the last 15 years, several therapies have been approved for the treatment of metastatic breast cancer (mBC) in the United States (U.S.). Given the evolving treatment landscape, it is important to assess and understand overall survival (OS) and related predictors in the real-world setting. Methods Data were obtained from the Surveillance, Epidemiology, and End Results (SEER), which covers approximately 48% of the U.S. population. Patients diagnosed with mBC (ICD-10: C50.0 to C50.9) between 2010 and 2021 were included. Follow-up continued until death or December 2021. Overall survival (OS) and cancer-specific survival (CSS) were estimated using Kaplan-Meier methods. Median survival and 5-year survival rates were reported. Predictors of survival were assessed using multivariate Cox proportional hazards modeling. Results The cohort included 37,017 patients with mBC. The majority (58%) were aged <65 years, with a mean age of 61 years. 54% of the patients had liver or lung metastases. Prior surgery was reported for 25% of the patients. Among patients with subtypes reported (n=31,656), the proportion of patients with HR+/HER2-, HER2+ (HR+/HER2+, HR-/HER2+), and triple negative breast cancer (TNBC) subtypes were 60%, 26%, and 14% respectively. In the overall mBC cohort, median OS was 28 months, with a 5-year OS rate of 28% and median CSS was 32 months, with a 5-year CSS rate of 32% (Table 1). Among patients aged ≥65 years in the overall mBC cohort, median OS and CSS were 18 and 23 months, respectively, with 5-year survival rates of 20% and 26%. In the HR+/HER2- mBC subgroup, median OS and CSS were 35 and 39 months, with a 5-year OS rate of 30% and 34% respectively. In the HER2+ mBC subgroup, median OS and CSS were 44 and 49 months, with a 5-year OS rate of 41% and 44% respectively. In the triple negative mBC subgroup, median OS and CSS was 12 and 13 months, with a 5-year OS rate of 12% and 14% respectively. Significant predictors of OS and CSS included age, race, histology, breast cancer subtype and prior surgery status (p < 0.05). Overall survival prognosis was significantly (p<0.001) worse for TNBC compared to HR+/HER2- mBC patients (HR;95% CI:2.38;2.29,2.48). Conclusion Overall survival in patients diagnosed with mBC between 2010 to 2021 varied by breast cancer subtype with prognoses relatively worse in TNBC patients compared to HR+/HER2- patients. Continued development of novel therapies for TNBC patients will be key to achieving further improvements in survival outcomes.

C. Brezden-Masley¹, S. Shokar², A. Nam², R. A. Qadeer², Z. Senhaji Mouhri³, B. Salvo⁴, N. Bonar⁴, B. Suero⁴; ¹Medicine, Mount Sinai Hospital, Toronto, ON, CANADA, ²Scientific Affairs, AstraZeneca Canada, Mississauga, ON, CANADA, ³Oncology Medical Affairs, AstraZeneca Canada, Mississauga, ON, CANADA, ⁴Value and Evidence, EVERSANA, Burlington, ON, CANADA.

Background: Trastuzumab deruxtecan (T-DXd) is a HER2-targeted antibody drug conjugate approved for the treatment of HER2-positive (HER2+) and HER2-low metastatic breast cancer (mBC). Currently, there is limited evidence assessing how T-DXd is used in a Canadian real-world (RW) setting. The aim of this observational study was to describe RW treatment-related outcomes using data collected from patients with HER2+ mBC who enrolled in AstraZeneca Canada’s patient support program (PSP) for treatment with T-DXd, following regulatory approval based on the DESTINY-Breast03 (DB-03) trial. Methods: This interim analysis included all patients enrolled in the PSP from June 2022 to August 2023 and initiated T-DXd therapy. The index date was the date of treatment initiation with follow-up until treatment discontinuation or close of the PSP. Primary objectives included rates of treatment discontinuation and dose modifications (dose reduction or discontinuation or dose interruptions >1 cycle length). Secondary objectives included time to treatment discontinuation (TTD), reasons for discontinuation (reported by physicians), and duration of treatment (excluding cumulative length of dose interruptions). Time-to-event outcomes were analyzed using the Kaplan-Meier method; other outcomes were summarized descriptively. Results: A total of 347 patients were included with a mean age of 60 years (SD, 13.2); 6% (n=19) had no prior lines of therapy in the metastatic setting, 64% (n=222) had 1, 9% (n=30) had 2, and 4% (n=14) had 3+, with 18% (n=62) missing data; 30% (n=103) had stable brain metastases at enrollment. Median follow-up was 5.6 months (range 0.2-29.7). Among patients that started at a dose of 5.4 mg/kg (84.4%, n=293) or a lower dose of 4.4 or 3.2 mg/kg (n=20, 5.8%), 32% (n=101) had a dose reduction, 28% (n=87) had a discontinuation, 51% (n=161) had either a dose reduction or discontinuation, and 51% (n=161) had a dose interruption. Some patients (n=34, 9.8%) received a dose not specified in the label (neither 5.4, 4.4, or 3.2 mg/kg). Cumulative probabilities of treatment discontinuation at 3, 6 and 9 months were 10.2% (95% CI, 6.8-13.4), 18.2% (95% CI, 13.6-22.6), and 29.7% (95% CI, 23.3-35.6), respectively. Overall median TTD was 14.3 months (95% CI, 12.4-18.4); median TTD among patients with stable brain metastases was 15.2 months (95% CI, 15.2-not reached). Median duration of treatment (excluding dose interruptions) was 12.7 months (95% CI, 10.3-18.4). Of the total observed discontinuations (28%, n=98) progression was the most common reason (44%, n=43) followed by prescriber decision (23%, n=22), death (16%, n=15), patient decision (12%, n=12), or other/unknown/missing data (6%, n=6). Conclusion: RW use of T-DXd in the Canadian PSP, designed for patients eligible under the regulatory authorization based on DB-03, reflected a largely second-line setting, with a median TTD consistent across the overall population and patients with stable brain metastases. Due to the short duration of follow-up, TTD may be underestimated. During the PSP enrollment period, T-DXd use was still in its early stage of experience in Canada and as such, understanding of optimal therapy management may have still been evolving.

V. Singh¹, A. Al-Alwan¹, S. Kabraji², E. Levine², V. Gupta²; ¹Department of Medicine, Roswell Park Comprehensive Cancer Center, Buffalo, NY, ²Breast Oncology, Deparment of Medicine, Roswell Park Comprehensive Cancer Center, Buffalo, NY.

Introduction: Capivasertib in combination with Fulvestrant is approved for a second or later line treatment option for metastatic ER/PR positive HER2 negative breast cancer, for patients harboring one or more PIK3CA, AKT1, and PTEN alterations, especially after use of CDK4/6 inhibitors. These mutations are seen in ~55% patients with HR+ mBC. There is limited real-world data on the use of the combination. The purpose of this analysis is to assess the real-world efficacy and safety of this regimen in patients with HR positive metastatic breast cancer. Methods: We conducted a single-center, IRB-approved retrospective chart review of patients diagnosed with metastatic breast cancer (mBC) who received capivasertib in combination with Fulvestrant, with the last follow-up date as of June 30, 2025. Patient-specific demographic, clinical, pathological, and treatment data were collected. Data was summarized using descriptive statistics. Time to treatment failure (discontinuation either because of progression or adverse effects) and PFS were calculated by the Kaplan-Meier method. Results: We identified 28 patients who received Capivasertib; median age – 57 years (IQR 49-66.5). 21 (75%) had PICK3CA, 5 (17.9%) PTEN, and 4 (14.3%) AKT1 mutation with 2 patients had both PICK3CA and PTEN mutation. All the patients had received prior CDK4/6 inhibitors and 11 had exposure to prior chemotherapy. The median follow-up was 7.6 months (IQR, 4.1-12.3) compared to 13 months (IQR 9·1-16·7) in CAPItello-291, with a median time to treatment failure of 5 +/- 0.5 months (5.8 months in CAPItello-291). Median PFS was 6 +/- 0.5 months (7.2 months in CAPItello-291). Treatment was discontinued in 19 (67.9%) patients due to disease progression and in 3 (10.7%) patients because of adverse effects. The reason for discontinuation was hyperglycemia, liver injury, and skin rashes. Medications were either discontinued or reduced for 10/28 (34%). Skin rash was the most common reason for dose reduction. 7/28 (25%) patients died by the last follow-up date, with 4/7 (57.1%) having prior exposure to chemotherapy. 4/7 (57.1%) Patients had either visceral or treated brain metastases before starting capivasertib. 1/4 (25%) of patients with treated brain metastasis and 3/15 (20%) with one or more visceral metastases died during the study period. Conclusion: In this single-center experience, the findings of CAPItello-291 was validated, that a combination of capivasertib and fulvestrant is an effective treatment in second or later-line therapy for metastatic HR+ HER2- breast cancer patients harboring AKT pathway alterations, with a similar discontinuation rate.

S. Preston¹, S. Ryan², D. Speakman³; ¹Clinical Research, BCAL Diagnostics, Sydney, AUSTRALIA, ²Management, BCAL Diagnostics, Sydney, AUSTRALIA, ³Surgery, Peter MacCallum Cancer Centre, Melbourne, AUSTRALIA.

Background: BREASTEST Plus is a novel blood-based diagnostic assay used alongside imaging to support breast cancer screening decision-making. While prior validation studies have demonstrated the analytical and clinical performance of the assay, real-world evidence (RWE) on its clinical utility and long-term impact on patient outcomes remains essential. To address this, BCAL Diagnostics has initiated a prospective, observational registry study aimed at evaluating how BREASTEST Plus influences physician decision-making and patient outcomes in routine clinical practice. Methods: This multi-centre, prospective registry will enroll a minimum of 2,000 women across Australia who undergo BREASTEST Plus testing as part of their clinical assessment. Inclusion criteria are broad, reflecting routine clinical use, and will include both symptomatic and asymptomatic women aged ≥30 years. Treating clinicians will complete a structured decision-impact survey following receipt of results to assess how the assay influenced diagnostic or management decisions. Patients will be followed for up to five years, with key endpoints including one and two year sensitivity and specificity. Results: Primary endpoints are: (1) proportion of cases in which BREASTEST Plus results changed clinical management, and (2) concordance of assay results with cancer diagnoses over time. Secondary endpoints include reduction in unnecessary procedures, and patient-reported metrics. Interim analyses will be performed at 12-month intervals to inform clinical and regulatory stakeholders. Conclusion: This RWE registry is the first of its kind for a lipid-based breast cancer diagnostic and will provide critical insights into the utility, impact, and long-term value of BREASTEST Plus in everyday practice. Results will inform guidelines, reimbursement decisions, and broader adoption strategies across healthcare systems.

O. Tredan¹, Y. Delpech², S. Bara³, M. Lotz⁴, M. Moreau⁵, D. Stamenic⁵, M. Le Foll-Elfounini⁵, L. Mansi⁶; ¹Gynecology, Breast Oncology, Medical Oncology, CENTRE LEON BERARD, LYON, FRANCE, ²Breast, Oncogynecologic and Reconstructive Surgery, Centre Antoine LACASSAGNE, NICE, FRANCE, ³Registre des Cancers de la Manche, Centre Hospitalier du Cotentin, Cherbourg-en-Cotentin, FRANCE, ⁴Medical Affairs, ROCHE, Boulogne-Billancourt, FRANCE, ⁵Medical Evidence & Data Science, ROCHE, Boulogne-Billancourt, FRANCE, ⁶Medical Oncology, CHRU Jean Minjoz, Besançon, FRANCE.

Objectives Assess the Overall survival (OS) rates at 5,10 and 12 years in French women with breast cancer (BC) by BC subtype Material and methods Data were extracted from a 2% representative sample of the French National Claims Database which covers around 98% of the total French population. All French women aged ≥18 years diagnosed with BC between 2010 and 2023 were identified using markers of BC management. HER2+ and HR+ status were determined based on the reimbursement of HER2-targeted therapy and endocrine therapy, respectively. The BC subtype of patients without HER2-targeted nor endocrine therapy could not be determined because of the lack of tracking drugs. These patients constituted the “undefined” group with regard to their BC subtype and were composed of 2 main subgroups: ÏPatients treated with systemic treatment(s) (potentially composed among others of TNBC or patients with visceral crisis)ÏPatient with BC in situ diagnosis without systemic treatment A one year historical period has been used. OS was defined as the time from the BC diagnosis date, or otherwise from the date of the first evidence of BC specific treatment until death from any cause. Results A total of 12 219 incident BC cases were identified between 2010 and 2023, of which 7 878 (64,5%) were HR+/HER2- and, 1 414 (11.6%) HER2+ including 895 (7,3%) HER2+/HR+ and 519 (4,3%) HER2+/HR-. The “undefined” group (N=2 927, 24.0% of total incident BC cases) was composed of 1 188 (9.7%) patients treated with systemic treatment(s), 768 (6.3%) patients with BC in situ diagnosis without systemic treatment and 971 patients with invasive cancer diagnosis without systemic treatment (8.0 %) In the HER2+ BC subtype, the 5-years, 10-years and 12-years OS rates were 87.7% (95% CI: 85.6%, 89.4%), 80.4% (95% CI: 77.6%, 82.8%) and 74.4% (95% CI: 70.5%, 77.8%). Among HER2+, the corresponding OS rates were 90.4% (95% CI: 88.1%, 92.4%), 81.0% (95% CI: 77.3%, 84.2%) and 73.7% (95% CI: 68.3%, 78.3%) in HER2+/HR+ and 82.7% (95% CI: 78.8%, 86.0%), 79.2% (95% CI: 74.7%, 82.9%) and 75,4 (95% CI: 69.6%, 80.3%) in HER2+/HR-, showing a better survival in HER2+/HR+ at 5 years but quite similar OS rates at 12 years. In the HR+/HER2- BC subtype, the 5-years, 10-years and 12-years OS rates were 88.8% (95% CI: 88.0%, 89.5%), 77.6% (95% CI: 76.3%, 78.8%) and 73.7% (95% CI: 72.1%, 75.1%). Among the undefined group, the 5-years, 10-years and 12-years OS rates were 73.0% (95% CI: 70.1%, 75.6%), 66.7% (95% CI: 63,4.%, 69.8%) and 65.1% (95% CI: 61,5.%, 68.5%) in patients treated with systemic treatment(s), in patients treated with systemic treatment(s), which fits with the bad prognosis of TNBC and patients with visceral crisis. OS rates were 98.0% (95% CI: 96.6%, 98.8%), 93.1% (95% CI: 90.2%, 95.1%) and 91.4% (95% CI: 87.9%, 94.0%) in patients with an in situ BC diagnosis without systemic treatment, demonstrating as expected higher survival rates than other groups. ConclusionAs of today, 12-year OS rates tend to be similar in HER2+ (regardless of the HR status) and HR+/HER2- groups, demonstrating an efficient BC management evolution, especially in the HER2+ group. These results also highlight a significantly higher 5-year survival for HR+ compared to HER2+. However, this difference tends to equalize at 12 years, in line with the long-term recurrence risk of HR+.

A. Haiderali¹, J. R. Earla², P. Kondaparthi³, J. Nathani⁴, S. Sharma⁵; ¹Value & Implementation, Merck, North Wales, PA, ²Value & Implementation, Merck, Rahway, NJ, ³HEOR, Parexel International, Hyderabad, INDIA, ⁴HEOR, Parexel International, Bengaluru, INDIA, ⁵HEOR, Parexel International, Chandigarh, INDIA.

Background: Triple-negative breast cancer (TNBC) is associated with a poorer prognosis compared to other subtypes. Neoadjuvant chemotherapy with anthracyclines and taxanes aims to improve pathological complete response (pCR) rates. Patients without pCR face higher relapse risks and worse outcomes, necessitating escalation strategies for residual disease. Objective: This review aimed to summarize real-world treatment patterns for patients with early-stage TNBC focusing on adjuvant therapy for those with residual disease after neoadjuvant chemotherapy. Methods: A systematic literature search was conducted using Embase and MEDLINE databases (2014-2024) and relevant conference proceedings (2021-2024). Real-world studies on treatment utilization rates, discontinuation rates, efficacy, and safety were included. Results: Six studies from the USA, Brazil, Italy, Turkey, and Middle East Africa region were identified. Capecitabine alone or in combination with radiotherapy emerged as the primary adjuvant pharmacological therapy for residual TNBC after neoadjuvant chemotherapy. This was reported in three studies, with utilization rates ranging from 31.7% to 42.1%. Additionally, adjuvant radiotherapy was reported in two studies, with higher usage rates ranging from 71.1% to 94.7%. Most patients received sequential rather than concurrent radiotherapy and capecitabine treatment. The rates of discontinuation varied by cause, with toxicity accounting for 6.0% to 17.0% of discontinuations and disease progression leading to 12.6% to 17.0% of discontinuations. Two-year disease-free survival (DFS) rates after adjuvant capecitabine ranged from 62.0% to 88.9%. The three-year overall survival (OS) rate for patients with residual disease treated with adjuvant capecitabine, either alone or in combination with radiotherapy, was 76.2%. The proportion of patients experiencing disease progression (PD) after adjuvant therapy ranged from 28.9% to 64.2%. Conclusion: This review highlights significant unmet needs in early TNBC patients with residual disease after neoadjuvant therapy. While guidelines recommend capecitabine for this patient population, they also recommend exploring newer therapies like pembrolizumab and olaparib for specific patient sub-populations. There are treatment strategies available for the peri-operative setting, but the associated evidence was not captured in this review. The high rates of residual disease, treatment discontinuation, and disease progression underscore the need for more effective and tolerable adjuvant therapies. Currently, multiple novel therapies are being evaluated for this patient population including antibody drug conjugates (ADCs) and other targeted immunotherapies to improve outcomes and mitigate the unmet need.

M. Li¹, C. T. Van Geelen², L. E. Lara Gonzalez², K. Clarke², S. Lingaratnam³, P. A. Francis¹, S. Loi¹; ¹Department of Medical Oncology, Peter MacCallum Cancer Centre, Melbourne, AUSTRALIA, ²Sir Peter MacCallum Department of Oncology, University of Melbourne, Melbourne, AUSTRALIA, ³Department of Pharmacy, Peter MacCallum Cancer Centre, Melbourne, AUSTRALIA.