Rapid Fire 2

J. Holtschmidt¹, A. Schneeweiss², N. Frickel³, N. Filmann⁴, M. Untch⁵, A. Hartkopf⁶, V. Müller⁷, C. Solbach⁸, M. van Mackelenbergh⁹, J. Blohmer¹⁰, K. Lübbe¹¹, T. Karn¹², F. Holms¹³, P. A. Fasching¹⁴, P. Jank³, M. Darsow¹⁵, F. Marmé¹⁶, M. Braun¹⁷, E. Stickeler¹⁸, R. Weide¹⁹, T. Fehm²⁰, C. Schem²¹, A. Eidmann³, B. Felder⁴, S. Loibl²², C. Denkert²³; ¹Medicine and Research Departement, GBG c/o GBG Forschungs GmbH, Neu Isenburg, GERMANY, ²Division of Gynaecological Oncology, National Center for Tumor Diseases (NCT), University Hospital and German Cancer Research Center, Heidelberg, GERMANY, ³Institute of Pathology, Philipps-University Marburg, Marburg, GERMANY, ⁴Medicine and Research Departement, GBG c/o GBG Forschungs GmbH, Neu-Isenburg, GERMANY, ⁵Department of Obstetrics and Gynecology, Interdisciplinary Breast Cancer Center, Medical School Berlin, Helios Kliniken Berlin-Buch, Berlin, GERMANY, ⁶Department of Women’s Health, University Hospital Tübingen, Tübingen, GERMANY, ⁷Department of Gynecology, University Medical Center Hamburg-Eppendorf, Hamburg, GERMANY, ⁸Breast Unit, University Medical Center, Goethe-University Frankfurt, Frankfurt am Main, GERMANY, ⁹Department of Gynecology and Obstetrics, University Hospital of Schleswig-Holstein, Campus Kiel, Kiel, GERMANY, ¹⁰Department of Gynecology with Breast Center, Charité – Universitätsmedizin Berlin, Berlin, GERMANY, ¹¹Breast center, Diakovere Henriettenstift, Hannover, GERMANY, ¹²Department of Gynecology and Obstetrics, University of Frankfurt, UCT Frankfurt-Marburg, Frankfurt am Main, GERMANY, ¹³Department of Obstetrics and Gynecology, St. Barbara-Klinik Hamm-Heessen GmbH, Hamm, GERMANY, ¹⁴Department of Obstetrics and Gynecology, University Hospital Erlangen, Comprehensive Cancer Center Erlangen-EMN, Erlangen, GERMANY, ¹⁵Competence Centre for Breast Surgery and Breast Health, Luisenkrankenhaus Düsseldorf, Düsseldorf, GERMANY, ¹⁶University Medical Center Mannheim, University of Heidelberg, Mannheim, GERMANY, ¹⁷Breast Cancer Center, Department of Gynecology, Red Cross Hospital, Munich, GERMANY, ¹⁸Breast Center, Department of Gynecology and Obstetrics, RWTH University Hospital Aachen, Achen, GERMANY, ¹⁹Department of Hematology and Oncology, Praxis für Haematologie und Onkologie, Koblenz, GERMANY, ²⁰Department of Gynecology and Obstetrics, University Hospital Düsseldorf, Centrum für Integrierte Onkologie (CIO) ABCD, Düsseldorf, GERMANY, ²¹Mammazentrum Hamburg, am Krankenhaus Jerusalem, Hamburg, GERMANY, ²²Medicine and Research Departement, GBG c/o GBG Forschungs GmbH, Neu-Isenberg, Goethe University Frankfurt, Frankfurt am Main, GERMANY, ²³Institute of Pathology, Philipps-University Marburg and University Hospital Marburg (UKGM), Marburg, GERMANY.

Background: Residual invasive disease after NACT for TNBC is associated with high recurrence rates and poor overall survival (OS). The assessment of pathologic complete response (pCR) vs. non-pCR in early breast cancer is not consistently linked to OS. For instance, it does not address partial responses or favourable changes in tumor biology during NACT. Therefore, we investigated proliferation (Ki67) and tumor-infiltrating lymphocytes (TILs) in invasive residual tumor (RT) for improved prediction of outcome. Study Design: Pts with TNBC treated with anthracycline/taxane-containing NACT in nine GBG/AGO-B trials (GeparTrio, GeparQuattro, GeparQuinto, GeparSixto, GeparSepto, GeparOcto, GeparNuevo, GeparOla, and GeparX) were included. Of 3017 pts with TNBC enrolled, 1505 had ypT>0/is and 640 had prospectively collected RT-samples for evaluation of TILs and Ki67. Endpoints were distant disease-free survival (DDFS; primary endpoint) and OS (both as land-mark analysis). Results: Of the 640 pts included, most had cT2 (57.6%), 36.9% had cN+ with 61.6% having stage II disease. At baseline (BL), 93.4% of tumors had Ki67>15% (median 51%), the median for TILs at BL was 20%. After treatment, 54% of RTs had Ki67>15% (median 18%) with a median absolute change in Ki67 of -27.5% compared to BL. Median TILs in RT were 20% with a median change of +5% compared to BL. In pts with ypT1, ypN0 at surgery Ki67 was lower and TILs were higher in RT compared to pts with >ypT1y, pN0 at surgery with no correlation with ypN status. Ki67 >15% vs ≤15% in RT was associated with worse DDFS (HR 1.71; 95% CI 1.33-2.21; p<0.0001) and OS (HR 2.02; 95% CI 1.51-2.71; p15% and TILs ≤10% had the worst DDFS (HR 3.62 95% CI 2.00-6.52; p<0.0001) and OS (HR 7.57 95% CI 3.19-17.94; p<0.0001). 5y survival rates in the 4 groups Ki67≤15% and TILs ≥50%; Ki67≤15% and TILs 15% and TILs >10%; Ki67>15% and TILs <10% were: DDFS 83.7% (74.5-94.1); 66.3% (60.1-73.1); 55.8% (49.9-62.4); 42.4% (32.2-55.8) and OS 92.1% (84.9-99.9); 75% (69.3-81.2); 61.5% (55.6-67.9); 48% (37.4-61.7). The combination of Ki67 and TILs remained significant in different multivariate models for DDFS and OS with clinical and pathological tumor stage. Pts with limited residual disease (ypT1, ypN0) had meaningfully improved DDFS (HR 0.33; 95% CI 0.24-0.45; p<0.0001) and OS (HR 0.25; 95% CI 0.17-0.37; pypT1ypN0. Amongst pts with ypT1, ypN0, those with Ki67>15% in RT trended towards worse DDFS (HR 1.48; 95% CI 0.88-2.48; p=0.14) and OS (HR 1.93; 95% CI 0.99-3.76; p=0.055) compared to Ki67 ≤15%. In the bivariate model including limited residual disease (ypT1, ypN0), Ki67 ≤15% remained an independent predictor of DDFS and OS. Amongst pts with ypT1ypN0 those with Ki67≤15% and TILS≥50% in RT had numerically better survival compared to pts with ypT1, ypN0 not meeting these criteria (5y DDFS rates: 87.5% (76.7-99.9) vs 76.1% (70.3-82.4); 5y OS rates: 96.8% (90.8-100) vs 82.7% (77.3-88.4). Conclusion: Our results suggest that the combined assessment of Ki67 and TILs in residual disease after NACT for TNBC could contribute to prediction of prognosis as well as to improved personalized selection of post-neoadjuvant therapy strategies. Low Ki67 in RT was prognostic for superior DDFS and OS especially when combined with moderate-strong TILs in RT. Amongst pts with ypT1, ypN0, those with low Ki67 and strong TILs in RT had the highest 5yr survival rates.

B. M. Felsheim¹, V. Nekljudova², L. A. Carey¹, J. Huober³, A. Schneeweiss⁴, S. M. Tolaney⁵, M. Untch⁶, C. S. Kuzma⁷, A. Fernandez-Martinez⁸, S. Rachakonda², R. Suresh⁹, D. G. Stover¹⁰, P. Rastogi¹¹, M. Darsow¹², D. E. Lake¹³, H. S. Rugo¹⁴, J. O’Shaughnessy¹⁵, M. Golshan¹⁶, A. D. Pfefferle¹, W. M. Sikov¹⁷, O. Metzger⁵, C. Denkert¹⁸, C. E. Geyer Jr.¹¹, C. M. Perou¹, S. Loibl²; ¹Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, ²Medicine and Research Department, GBG c/o GBG Forschungs GmbH, Neu-Isenburg, GERMANY, ³Cantonal Hospital St. Gallen, Breast Centre St. Gallen, St. Gallen, SWITZERLAND, ⁴National Center for Tumor Diseases, University Hospital and German Cancer Research Center, Heidelberg, GERMANY, ⁵Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, ⁶Gynecologic Oncology and Breast Cancer Center, Department of Gynecology and Obstetrics, Helios Hospital Berlin-Buch, Berlin, GERMANY, ⁷FirstHealth of the Carolinas-Moore Regional Hospital, Southeast Clinical Oncology Research Consortium, Pinehurst, NC, ⁸Drug Development Department (DITEP), Gustave Roussy Cancer Campus, Villejuif, FRANCE, ⁹Department of Internal Medicine, Washington University, St. Louis, MO, ¹⁰Department of Internal Medicine, The Ohio State University, Columbus, OH, ¹¹Department of Medicine, University of Pittsburgh, Pittsburgh, PA, ¹²Breast Center, Luisenhospital Dusseldorf, Dusseldorf, GERMANY, ¹³Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, ¹⁴Department of Medical Oncology, City of Hope Comprehensive Cancer Center, Duarte, CA, ¹⁵Baylor University Medical Center, Texas Oncology, US Oncology, Dallas, TX, ¹⁶Department of Surgery, Yale School of Medicine, New Haven, CT, ¹⁷Women and Infants Hospital of Rhode Island, Warren Alpert Medical School of Brown University, Providence, RI, ¹⁸Institute of Pathology, University of Marburg, Marburg, GERMANY.

Background: Triple-negative breast cancer (TNBC) is a heterogeneous disease with the lowest survival rate of all clinical subtypes of breast cancer, but patients who achieve a pathologic complete response (pCR) to neoadjuvant chemotherapy (NACT) have a good prognosis. Results from the phase III KEYNOTE-522 trial established a new standard of care (SOC) for stage II-III TNBC, leading to US Food and Drug Administration approval in 2022 for the addition of carboplatin and pembrolizumab to NACT. Although the addition of carboplatin had previously been shown to increase pCR rates to NACT, it was not widely adopted as part of SOC NACT until its incorporation into both arms of KEYNOTE-522. Given the toxicities associated with carboplatin, there remains a need to better define its therapeutic benefit and to identify prognostic and predictive biomarkers of patient response and survival. Methods: We performed a pooled analysis of three randomized early-stage TNBC clinical trials that investigated the addition of carboplatin to NACT: BrighTNess (NCT02032277, n = 471), CALGB 40603 (NCT00861705, n = 351), and GeparSixto (NCT01426880, n = 262). We evaluated its impact on pCR, event-free survival (EFS), and overall survival (OS), and we explored germline BRCA1 and BRCA2 (gBRCA) mutation status as a potential biomarker. Additionally, we examined the prognostic and predictive value of eight published gene expression signatures (IgG, CD4, CD8, B-cell T-cell cooperativity, CD274, Immune1, Hypoxia core, VEGF). To analyze associations with pCR, we fit logistic mixed-effects regression models with study as a random effect. Associations with EFS and OS were evaluated using Cox proportional hazards models stratified by study. Multivariate models included age, tumor size, nodal status, gBRCA mutation status, and tumor grade as covariates. Results: For the pooled dataset (n = 1084), in multivariate models, the addition of neoadjuvant carboplatin was significantly associated with increased pCR rate (odds ratio [OR] = 1.89, 95% confidence interval [CI] = 1.41-2.55, p < 0.001) and EFS (hazard ratio [HR] = 0.71, 95% CI = 0.54-0.93, p = 0.01), but not OS (HR = 0.93, 95% CI = 0.65-1.31, p = 0.66). When considering only gBRCA mutant samples (n = 137), we found that the addition of carboplatin conveys a significant EFS benefit (HR = 0.50, 95% CI = 0.25-1.00, p = 0.05) but had no significant impact on pCR rate or OS. Among the eight gene expression signatures tested, all six immune signatures were associated with a higher pCR rate in multivariate models, with Benjamini-Hochberg (B-H) adjusted p < 0.05. Four signatures (IgG, CD8, CD274, and Immune1) were associated with improved EFS and OS (B-H adjusted p < 0.05). However, no interaction between carboplatin and any tested signature was significantly predictive of pCR, EFS, or OS. Whole transcriptome analyses are ongoing to identify gene expression features that may predict response to neoadjuvant carboplatin. Conclusions: Within a pooled analysis of the BrighTNess, CALGB 40603, and GeparSixto clinical trials, we found that neoadjuvant carboplatin was associated with a significant improvement in pCR rate and EFS, but not OS. The addition of carboplatin significantly improved EFS in patients with gBRCA mutations despite not significantly improving pCR rate or OS. While many immune-related gene expression signatures were prognostic, none were predictive for benefit from neoadjuvant carboplatin. These findings support the inclusion of neoadjuvant carboplatin in SOC treatment of stage II-III TNBC and further emphasize the prognostic importance of the TNBC immune microenvironment. Support: P50-CA058223; https://acknowledgments.alliancefound.org. BrighTNess was funded by AbbVie and GeparSixto was funded by GSK.

X. Chen¹, J. Huang¹, H. Shi¹, J. Zhu², W. Wu³, G. Ye⁴, Q. He⁵, Y. Shi⁶, A. Zhang⁷, X. Xie⁸, X. Wang⁹, X. Chen¹⁰, W. Wu¹¹, J. Wu¹², Z. Li¹³, Z. Li¹⁴, Y. Dai¹⁵, W. Ren¹⁶, Q. Shao¹⁷, Y. Chen¹⁸, Y. Zeng¹⁹, M. Pegram²⁰, K. Shen¹; ¹Department of General Surgery, Comprehensive Breast Health Center, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, CHINA, ²Department of Breast Diseases, Maternity and Child Health Care Hospital, Jiaxing University School of Medicine, Zhejiang, CHINA, ³Department of Breast and Thyroid Surgery, Ningbo Medical Center Lihuili Eastern Hospital, Zhejiang, CHINA, ⁴Department of Breast Surgery, The First People’s Hospital of Foshan, Guangdong, CHINA, ⁵Department of Breast, International Peace Maternity and Child Health Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, CHINA, ⁶Department of Thyroid and Breast Surgery, Lishui People’s Hospital, Zhejiang, CHINA, ⁷Breast Disease Center, Guangdong Women and Children’s Hospital, Guangzhou, Guangdong, CHINA, ⁸Department of Breast Surgery, The First Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou, Zhejiang, CHINA, ⁹Department of Breast Surgery, First People’s Hospital of Wujiang District, Jiangsu, CHINA, ¹⁰Department of Breast Surgery, First Affiliated Hospital of Fujian Medical University, Fujian, CHINA, ¹¹Department of Breast Surgery, Ruian People’s Hospital, Zhejiang, CHINA, ¹²Department of Breast Surgery, Cancer Hospital of Shantou University Medical College, Shantou, Guangdong, CHINA, ¹³Department of Oncological Surgery, Shaoxing Second Hospital, Zhejiang, CHINA, ¹⁴Department of Breast Surgery, Ningbo Women and Children’s Hospital, Zhejiang, CHINA, ¹⁵Department of Surgical Oncology, Taizhou Central Hospital, Zhejiang, CHINA, ¹⁶Department of Breast Surgery, Shaoxing Shangyu People’s Hospital, Zhejiang, CHINA, ¹⁷Breast Department, Jiangyin People’s Hospital, Jiangsu, CHINA, ¹⁸Department of Breast Surgery, Fuding Hospital, Fujian, CHINA, ¹⁹Department of Breast Surgery, Wenzhou People’s Hospital, Zhejiang, CHINA, ²⁰Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA.

Background: RJBC 1501 (NCT02455141) is a prospective phase III study to compare the efficacy and safety of adjuvant epirubicin plus cyclophosphamide (EC) followed by taxanes (T) versus same regimen plus carboplatin (EC-TCb) in early-stage triple negative breast cancer (TNBC).Methods: Patients with node positive or node negative (with tumor size ≥1.0cm) TNBC who received definitive surgery were randomized 1:1 to receive EC-T or EC-TCb. Taxanes consisted of either weekly paclitaxel for 12 doses or docetaxel every 3 weeks for 4 cycles. Carboplatin was given weekly (AUC 2) for 12 doses or every 3 weeks (AUC 5-6) for 4 cycles, concurrent with taxanes. The primary endpoint was disease-free survival (DFS) in the intention-to-treat (ITT) population. Secondary endpoint includes distant DFS (DDFS), overall survival (OS), and safety.Results: Between March 2016 and March 2023, 786 patients were randomized (EC-T: n = 391; EC-TCb: n = 395). Baseline characteristics were balanced: median age ≤50 years (49.6%), T1 stage (46.6%), node-negative (72.3%). A majority of patients (76.5%) received 3-weekly docetaxel. After a median follow up of 4.52 (IQR 2.83 to 6.06) years, 103 events were reported: 62 in the EC-T group and 41 in the EC-TCb group. Addition of carboplatin significantly improved DFS (hazard ratio [HR], 0.66; 95% CI, 0.44 to 0.97, P = 0.034), with 3-year DFS of 89.8% (95%CI 86.8 to 92.9%) for EC-T and 93.1% (95%CI 90.5 to 95.7%) for EC-TCb. EC-TCb regimen was also associated with a superior DDFS (HR, 0.61; 95% CI, 0.38 to 0.98, P = 0.040) and OS (HR, 0.39; 95% CI 0.16 to 0.94, P = 0.029) compared to EC-T treatment. Grade 3-4 adverse events were more frequent among EC-TCb arm (49.9%) than EC-T arm (38.7%), primarily driven by higher rates of neutropenia (47.0% vs 37.8%) and thrombocytopenia (4.5% vs 0%). Other grade 3-4 toxicities were comparable between groups.Conclusion: Adding carboplatin to adjuvant EC-T chemotherapy significantly improves DFS, DDFS, and OS in patients with early-stage TNBC. While additional carboplatin treatment was associated with increased hematologic toxicity, no new safety signals emerged.

Y. Liu, Y. Gong, X. Zhu, G. Liu, K. Yu, F. Yang, L. Chen, M. He, Z. Hu, C. Chen, A. Cao, J. Li, Y. Hou, G. Di, J. Wu, Y. Jiang, L. Fan, Z. Wang, Z. Shao; breast surgery, Fudan University Shanghai Cancer Center, Shanghai, CHINA.

Background: The benefit of incorporating carboplatin into adjuvant anthracycline/taxane-based chemotherapy in triple-negative breast cancer (TNBC) remains controversial. This study aimed to evaluate the efficacy and safety of epirubicin and cyclophosphamide followed by weekly paclitaxel with or without carboplatin as adjuvant therapy for patients with high-risk early-stage TNBC.Methods: This open-label, randomized, phase 3 trial was conducted in China. Female patients with operable high-risk TNBC (defined as either regional node-positive or node-negative with a Ki-67 labeling index of ≥50%) after definitive surgery were randomized in a 1:1 ratio into either the carboplatin group (two-week epirubicin and cyclophosphamide followed by weekly paclitaxel combined with carboplatin) or the control group (three-week or two-week epirubicin and cyclophosphamide followed by weekly paclitaxel). The primary endpoint was disease-free survival (DFS) in the intention-to-treat population. Second endpoints included recurrence-free survival (RFS), distant disease-free survival (D-DFS), overall survival (OS) and safety. Results: Of the 808 enrolled patients, 807 received study treatment. At a median follow-up of 44.7 months, the three-year DFS rate was 92.3% in the carboplatin group and 85.8% in the control (hazard ratio [HR] 0.64, 95% confidence interval [CI] 0.43 to 0.95; P=0.026; Figure 1A). For secondary endpoints, the carboplatin group was associated with superior outcomes in three-year RFS (93.8% vs. 88.3%; HR, 0.59; 95% CI 0.37 to 0.93; P = 0.021; Figure 1B), three-year D-DFS (94.8% vs 89.8%; HR, 0.61; 95% CI 0.37 to 0.98; P = 0.039; Figure 1C), and three-year OS (98.0% vs 94.0%; HR, 0.41; 95% CI 0.20 to 0.83; P = 0.011; Figure 1D). Exploratory forest plot analyses for DFS in the ITT population showed HRs that consistently favored the carboplatin group (Figure 2). The incidence of grade 3-4 treatment related adverse events were 66.7% (269/403) for the carboplatin group and 55% (222/404) for the control group. No treatment related deaths occurred.Conclusions: The addition of carboplatin to adjuvant anthracycline/taxane-based chemotherapy significantly improves survival outcomes with manageable toxicity in patients with high-risk early-stage TNBC.Trial registration number: ClinicalTrials.gov (NCT04296175). Figure 1 Clinical outcomes. Kaplan-Meier plots show disease-free survival (A), recurrence-free survival (B), distant disease-free survival (C) and overall survival (D) for patients. Figure 2 Exploratory subgroup analyses for disease-free survival. HR, Hazard Ratio; CI, confidence interval.

M. Reinisch¹, A. Schneeweiss², V. Schaser³, C. Solbach⁴, C. Denkert⁵, P. Rastogi⁶, F. Moreno⁷, T. Freeman⁶, T. Link⁸, J. Mouta⁹, S. Seiler¹⁰, R. Mey¹¹, Á. Rodríguez Lescure¹², V. Bjelic-Radisic¹³, P. A. Fasching¹⁴, M. Balic⁶, M. Untch¹⁵, K. Rhiem¹⁶, K. Lüdtke-Heckenkamp¹⁷, J. Huober¹⁸, S. Morales¹⁹, I. Blancas²⁰, J. Holtschmidt³, V. Nekljudova³, N. Wolmark⁶, C. E. Geyer⁶, S. Loibl²¹; ¹Interdisciplinary Breast Unit, University Medical Center Mannheim, University of Heidelberg, Mannheim, GERMANY, ²Division of Gynaecological Oncology, National Center for Tumor Diseases (NCT), University Hospital and German Cancer Research Center, Heidelberg, GERMANY, ³Medicine and Research Departement, GBG c/o GBG Forschungs GmbH, Neu-Isenburg, GERMANY, ⁴Breast Unit, University Medical Center, Goethe-University Frankfurt, Frankfurt am Main, GERMANY, ⁵Institute of Pathology, Philipps-University Marburg and University Hospital Marburg (UKGM), Marburg, GERMANY, ⁶NSABP Foundation, Inc., University of Pittsburgh School of Medicine, and UPMC Hillman Cancer Center, Pittsburgh, PA, ⁷Medical Oncology Department, Hospital Universitario Clínico San Carlos, GEICAM Spanish Breast Cancer Group, Madrid, SPAIN, ⁸Department of Gynecology and Obstetrics, Medical Faculty and University Hospital Carl Gustav Carus, National Center for Tumor Diseases, Technische Universität Dresden, Dresden, GERMANY, ⁹Product Development Medical Affairs Oncology, Roche Farmacêutica Química Lda, Amadora, PORTUGAL, ¹⁰Department of Obstetrics and Gynecology, Sana Klinikum Offenbach, Offenbach am Main, GERMANY, ¹¹Department of Internal Medicine, Hematology and Oncology, Hämato-Onkologie Praxis im Medicum, Bremen, GERMANY, ¹²Medical Oncology Department, Hospital General Universitario de Elche, GEICAM Spanish Breast Cancer Group, Elche, SPAIN, ¹³Department of Obstetrics and Gynecology, Helios University Clinic Wuppertal, University Witten/Herdecke, Wuppertal, GERMANY, ¹⁴Department of Gynecology and Obstetrics, University Hospital Erlangen, Comprehensive Cancer Center Erlangen-EMN, Erlangen, GERMANY, ¹⁵Department of Obstetrics and Gynecology, Interdisciplinary Breast Cancer Center, Medical School Berlin, Helios Kliniken Berlin-Buch, Berlin, GERMANY, ¹⁶Center for Hereditary Breast and Ovarian Cancer, University Hospital Cologne, Cologne, GERMANY, ¹⁷Department of Internal Medicine, Hematology and Oncology, Niels-Stensen-clinics GmbH, Georgsmarienhütte, GERMANY, ¹⁸Breast center, HOCH Health Ostschweiz, Cantonal Hospital, St. Gallen, SWITZERLAND, ¹⁹Oncology Department, Hospital Arnau de Vilanova, GEICAM Spanish Breast Cancer Group, Lleida, SPAIN, ²⁰Medicine Department, Granada University, Hospital Universitario Clínico San Cecilio, Instituto de Investigación Biosanitaria de Granada (ibs.Granada), GEICAM Spanish Breast Cancer Group, Granada, SPAIN, ²¹Medicine and Research Departement, GBG c/o GBG Forschungs GmbH, Neu-Isenburg, Goethe University Frankfurt, Frankfurt am Main, GERMANY.

Introduction NACT is associated with a high risk of ovarian failure in premenopausal women with breast cancer. The impact of CPI added to NACT on chemotherapy-induced ovarian failure (CIOF) remains underexplored. This study analyses the effects of combined NACT and CPI on ovarian function, assessed through different hormonal parameters in patients (pts) with TNBC. Methods This prospective, substudy included women aged≤45 years (yrs) without history of hysterectomy and/or ovarectomy enrolled within this trial (SABCS2024). Pts received anthracycline, cyclophosphamide, taxane and carboplatin containing NACT with atezolizumab (CTA) or without (CT). The main objective was to assess the rate of CIOF, defined as postmenopausal levels of follicle-stimulating hormone (FSH>25.8 IU/l) and Estradiol (E2<5 pg/ml), further objectives were the assessment of Anti-Mullerian Hormone (AMH), and amenorrhea rate. Blood samples were prospectively collected at baseline (BL), at end of therapy (EOT), and at 6, 12, 18 and 24 months (mo) after EOT. E2 (pg/ml), FSH (IU/l), and AMH (ng/ml) were centrally assessed. Pts had to have at least a BL sample and one additional sample collected at one of the other time points to be evaluable. Results A total of 173 pts were included in the ovarian substudy across 85 centres in Germany and Spain. 133 pts (CT n=63; CTA n=70) had blood samples taken on at least two time points. The median age at BL was 37 yrs (range 33-41 yrs, 35%≥40 yrs), the median BMI was 24 kg/m², 12%≥30 kg/m². The E2 levels (Table) decreased during therapy but increased after EOT. In both arms E2 levels recovered 24 mo after EOT with median E2 levels of 53.3 in CTA vs 81.6 in CT (p=0.348). In both arms E2 did not reach baseline values. Increase in median FSH levels after EOT was observed over time and remained postmenopausal in the CPI group after 24 mo. 34.2% pts experienced CIOF at EOT (CTA: 40.6%, CT: 26.8%; p=0.13), and overall, 10% had persistent CIOF 24 mo after EOT; which was higher when CPI was added (CTA 7.5%; CT 2.5%; p=0.06, Table). At BL, AMH<0.22, suggestive of impaired fertility, was observed in only a minority of pts (8.6% CTA, 12.7% CT) but in all pts at EOT. After 24 months, recovered AMH≥0.22 was measured in 27.5% (CTA) and 25% (CT) of pts (Table). Conclusion This first prospective study investigating the influence of CPI on ovarian failure. Two years after treatment 10% had permanent CIOF after receiving NACT for TNBC. Pts with CPI tended to have higher rates of CIOF at all timepoints and fewer pts had an ovarian function recovery supporting the biological theory that CPI on top of chemotherapy influence fertility. Our results contribute to understanding CPI’s impact on fertility in young pts receiving carboplatin containing NACT with CPI for early TNBC and provide valuable insights for fertility counselling.

W. P. Weber¹, C. Tausch², S. Hayoz³, Z. Matrai⁴, G. Xepapadakis⁵, C. Simonson⁶, V. Bjelic-Radisic⁷, G. T. Lam⁸, G. Montagna⁹, M. Gnant¹⁰, L. H. Rosenberger¹¹, E. de Bree¹², R. Satler¹³, M. Fehr¹⁴, C. Leo¹⁵, L. Lelievre¹⁶, S. Bucher¹⁷, S. Schmid¹⁸, R. Exner¹⁹, K. Reisenberger²⁰, U. Beckmann²¹, S. Muenst²², G. Henke²³, D. R. Zwahlen²⁴, T. Ruhstaller²⁵, K. Ribi²⁶, C. Urban²⁷, A. Crown²⁸, J. E. Lee²⁹, J. Boileau³⁰, A. D. Williams³¹, Y. Jonghan²⁹, M. L. DiNome¹¹, A. Poultsidi³², E. Gonzales³³, S. M. Wong³⁰, A. Schulz³⁴, M. Nealeigh³⁵, S. G. Ahn³⁶, A. M. Botty van den Bruele¹¹, B. J. Chae²⁹, A. Mueller¹³, D. Hagen¹³, J. M. Ryu²⁹, A. Savolt³⁷, C. Kurzeder³⁸, J. Heil³⁹, D. Egle⁴⁰, M. Heidinger¹, M. Knauer²⁵; ¹University of Basel, Basel, Switzerland & Breast Clinic, University Hospital Basel, Basel, SWITZERLAND, ²Breast Center, Zurich, SWITZERLAND, ³Swiss Cancer Institute, Bern, SWITZERLAND, ⁴Department of Breast and Sarcoma Surgery, National Institute of Oncology, Pudapest, HUNGARY, ⁵IASO Hospital, Breast Clinic, Department of Breast Surgery, Maroussi, Athens, GREECE, ⁶Centre Hospitalier du Valais Romand, Department of Gynecology, Sion, SWITZERLAND, ⁷Helios University Hospital Wuppertal – Breast Center / Senology, University of Witten/Herdecke, Wuppertal, GERMANY, ⁸Department of Gynecology and Obstretrics, Geneva University Hospitals, Geneva, SWITZERLAND, ⁹Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, ¹⁰Comprehensive Cancer Center, Medical University of Vienna, Vienna, AUSTRIA, ¹¹Department of Surgery, Duke Cancer Institute, Durham, NC, ¹²Department of Surgical Oncology, University Hospital of Heraklion, Heraklion, GREECE, ¹³Breast Center, Cantonal Hospital Winterthur, Winterthur, SWITZERLAND, ¹⁴Department of Gynecology, Cantonal Hospital Frauenfeld / Breast Unit Thurgau, Thurgau, SWITZERLAND, ¹⁵Cantonal Hospital Baden, Baden, SWITZERLAND, ¹⁶Department of Gynecology, Lausanne University Hospital CHUV, Lausanne, SWITZERLAND, ¹⁷Breast Center, Cantonal Hospital Lucerne, Lucerne, SWITZERLAND, ¹⁸Breast Cancer Center St. Gallen, HOCH Health Ostschweiz Hospital Grabs, St. Gallen, SWITZERLAND, ¹⁹Department of Surgery, Medical University of Vienna, Vienna, AUSTRIA, ²⁰Department of Gynecology and Obstetrics, Klinikum Wels-Grieskirchen, Wels, AUSTRIA, ²¹Brustzentrum der Niels-Stensen-Kliniken, Franziskus-Hospital Harderberg, Georgsmarienhütte, GERMANY, ²²Institute of Pathology, University Hospital Basel, University of Basel, Basel, SWITZERLAND, ²³Radiation Oncology Department, Team Radiology Plus, Münsterlingen, SWITZERLAND, ²⁴Department of Radiation Oncology, Cantonal Hospital Winterthur, Winterthur, SWITZERLAND, ²⁵Tumor and Breast Center Eastern Switzerland, St. Gallen, SWITZERLAND, ²⁶Quality of Life Office, International Breast Cancer Study Group, A Division of ETOP IBCSG Partners Foundation Bern, Switzerland, Careum School of Health, part of the Kalaidos University of Applied Sciences, Bern, SWITZERLAND, ²⁷Nossa Senhora das Graças Hospital, Curitiba, BRAZIL, ²⁸Swedish Cancer Institute, Seattle, WA, ²⁹Department of Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, KOREA, REPUBLIC OF, ³⁰Jewish General Hospital Segal Cancer Centre, Departments of Surgery and Gerald Bronfman Oncology McGill University, Montreal, QC, CANADA, ³¹Department of Surgical Oncology, Fox Chase Cancer Center, Philadelphia, PA, ³²Department of Surgery, University Hospital of Larissa, University of Thessaly, Larissa, GREECE, ³³Oncoplastic Surgery Department, Instituto de Oncología Ángel H. Roffo, Universidad de Buenos Aires, Buenos Aires, ARGENTINA, ³⁴University of Basel, Basel, Switzerland & Department of Clinical Research, University Hospital Basel, Basel, SWITZERLAND, ³⁵Breast Care and Research Center, Walter Reed National Military Medical Center, Bethesda, MD, ³⁶Department of Surgery, Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul, KOREA, REPUBLIC OF, ³⁷Department of Breast and Sarcoma Surgery, National Institute of Oncology, Budapest, HUNGARY, ³⁸Breast Clinic, University Hospital Basel, Basel, Switzerland & University of Basel, Basel, SWITZERLAND, ³⁹Department of Obstetrics and Gynecology, Heidelberg University Hospital, Germany & Breast Center Heidelberg, Heidelberg, GERMANY, ⁴⁰Breast Cancer Center Tirol, Department of Gynecology, Medical University Innsbruck, Innsbruck, AUSTRIA.

Introduction The safety of omitting axillary dissection (ALND) in patients with clinically node-positive breast cancer (cN+ BC) may depend on the nodal disease burden left behind in the axilla. This study aimed to evaluate nodal disease volume, quantify nodal understaging without ALND, and identify factors associated with additional nodal disease at ALND in these patients. Methods The international phase-III TAXIS trial (NCT03513614) randomized patients with cN+ stage II-III BC to ALND or axillary radiotherapy (ART) following tailored axillary surgery (TAS). Nodal disease was detected by imaging or palpation at initial diagnosis. TAS removed sentinel, biopsied, and palpably suspicious nodes. Patients had upfront surgery or residual nodal disease after neoadjuvant chemotherapy (NACT). 1500 patients were randomized from 08/2018 to 08/2025. Results Of 1418 patients with available data, 712 (50.2%) underwent ALND. Nodal disease was detected by imaging in 735 patients (51.8%), and by palpation in 683 (48.2%). Clinical nodal stage was cN1 in 1232 (86.9%) and cN2/3 in 186 (13.1%). Tumors were HR-positive and HER2-negative in 1140 patients (80.4%), HER2-positive in 160 (11.3%), and triple negative in 96 (6.8%). 552 patients (38.9%) underwent NACT.TAS removed a median of 5 nodes (interquartile range [IQR] 3-7), 2 (IQR 1-4) of which were positive. After TAS, ALND removed a median of 11 additional nodes (IQR 8-16), one (IQR 0-4) of which was positive. Among 712 patients undergoing ALND, additional positive nodes after TAS were removed in 430 (60.4%), AJCC pN upstaging occurred in 226 (31.7%), and 336 (47.2%) had (y)pN2/3 stage. Nodal burden by use of NACT is shown in the table.On multivariable logistic regression the number of positive nodes on TAS was associated with higher odds of having additional positive nodes on ALND in the NACT (odds ratio [OR] 1.57, 95% confidence interval [CI] 1.21-2.03, p<0.001) and upfront surgery group (OR 1.39, 95%CI 1.23-1.57, p<0.001). Furthermore, the odds of having additional positive nodes on ALND were higher in macrometastatic vs. isolated tumor cells/micrometastatic nodal disease on TAS after NACT (OR 2.24, 95%CI 1.10-4.55, p=0.026), and in palpable vs. imaging-detected nodal disease at upfront surgery (OR 1.66, 95%CI 1.05-2.63, p=0.032). Conclusion Nodal disease burden is high in patients included in the TAXIS trial. Among patients who underwent ALND, almost half had (y)pN2/3 disease, and 60.4% had additional positive nodes removed that were missed by TAS. Nodal disease volume on TAS was associated with higher odds of having additional positive nodes on ALND. Interim analysis raised no safety concerns in the TAXIS study, and long-term follow-up will determine if ART is oncologically non-inferior to ALND.