Poster Spotlight 13: Focus on CNS

L. Huppert¹, C. Yau², D. Idossa³, A. Kahn⁴, F. M. Howard⁵, E. Shagisultanova⁶, A. Zimmer⁷, E. Stringor-Reasor⁸, J. Perlmutter⁹, D. Yee¹⁰, R. Nanda¹¹, N. Hylton¹², W. F. Symmans¹³, R. Shatsky¹⁴, C. Isaacs¹⁵, L. Van’t Veer¹⁶, H. S. Rugo¹⁷, P. R. Pohlmann¹⁸, A. DeMichele¹⁹, L. Pusztai⁴, L. Esserman²; ¹Department of Medicine, Division of Hematology/Oncology, University of California, San Francisco, San Francisco, CA, ²Department of Surgery, University of California, San Francisco, San Francisco, CA, ³Medical Oncology, University of California, San Francisco, Rochester, MN, ⁴Medical Oncology and Hematology, Yale School of Medicine, New Haven, CT, ⁵Medicine, University of Chicago, Chicago, IL, ⁶Hematology/Oncology, University of Colorado, Aurora, CO, ⁷Department of Medicine, Division of Hematology/Oncology, Oregon Health Sciences University Knight Cancer Institute, Portland, OR, ⁸Hematology/Oncology, University of Alabama, Birmingham, AL, ⁹ISPY Patient Advocate, ISPY Patient Advocate, San Francisco, CA, ¹⁰Medicine and Pharmacology, University of Minnesota, Minneapolis, MN, ¹¹Medicine, University of Chicago, Chiacgo, IL, ¹²Department of Radiology and Biomedical Imaging, University of California, San Francisco, San Francisco, CA, ¹³Pathology, MD Anderson, Houston, TX, ¹⁴Department of Medicine, Division of Hematology/Oncology, University of California, San Diego, San Diego, CA, ¹⁵Medicine and Oncology, Georgetown Lombardi Comprehensive Cancer Center, Washington DC, DC, ¹⁶Laboratory Medicine, University of California, San Francisco, San Francisco, CA, ¹⁷Department of Medical Oncology & Therapeutics Research, Division of Breast Medical Oncology, City of Hope, Duarte, CA, ¹⁸Department of Breast Medical Oncology, Division of Cancer Medicine, MD Anderson, Houston, TX, ¹⁹Department of Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA.

Background: The incidence of central nervous system (CNS) metastases varies with BC subtype, but there is limited data about clinical and molecular predictors of CNS vs non-CNS recurrence risk after neoadjuvant chemotherapy (NACT). Here we present patterns of distant recurrence among patients (pts) in the I-SPY2 trial. Methods: This analysis included 2023 pts with molecularly high-risk stage II and III BC who enrolled in the I-SPY2 trial from 2010-2022 with event-free survival (EFS) data (as of 6/22/25). We analyzed type of recurrence (local vs distant) and site(s) of initial distant recurrence (CNS-only, both CNS- and non-CNS, or non-CNS only). We used a competing risk (Fine-Gray) model to estimate cumulative incidence of site-specific relapse at five years and assessed associations with clinical/molecular subtype, clinical staging (cT, cN), and response to NACT by Residual Cancer Burden (RCB) class. Results: Among 2023 evaluable pts, at a median follow up of 4.7 yrs there were 361 EFS events, most of which were distant recurrences (n=259, 72%). Of the pts with distant recurrences, most had initial non-CNS events (180/259, 69%), 36 pts had initial simultaneous CNS- and non-CNS events (36/259, 14%), and 43 pts had initial CNS-only events (43/259, 17%). Table 1 summarizes the cumulative incidence of initial CNS- and/or non-CNS recurrences at 5 years by clinical/molecular features. Rates of CNS-only recurrence were low and similar across clinical and response predictive subtypes (p=0.47 and =0.19 respectively). Risk of distant recurrence increased in pts with larger tumors and node positive disease at both CNS- and non-CNS sites (see Table 1). Rates of initial non-CNS recurrence increased with the amount of residual disease at surgery, with lowest rates in pts with RCB-0 and highest rates in pts with RCB-III (p<0.01). In contrast, the rate of CNS-only recurrence was low but remained similar across the four RCB classes (p=0.67). Because of this, 39% (18/46) of pts with RCB-0/I disease had initial CNS-only recurrence, whereas only 12% (24/204) of pts with RCB-II/III disease had initial CNS-only recurrence. Most CNS recurrences, isolated or not (64/79, 81%), occurred within the first three years after surgery. Conclusions: In pts with molecularly high-risk stage II and III BC who underwent NACT, the incidence of initial CNS-only metastases was low, but the rate was consistent across the four RCB classes, supporting that the CNS is a sanctuary site. Initial CNS-only recurrence accounted for 39% of EFS events for pts with RCB-0/I vs 12% for pts with RCB-II/III. CNS recurrence risk was similar across high-risk BC subtypes, but higher in pts with larger tumors and node positive disease. These results support future research to identify biomarkers that predict CNS recurrence risk and to incorporate CNS-penetrant therapies into early-stage treatment for CNS high-risk pts.

W. Dong, S. Wang, A. Puri, M. Vasquez, J. Chang, H. ZHAO, S. Wong; Cancer Center, Houston Methodist Research Institute, Houston, TX.

Background: Brain metastases (BM) are a major cause of mortality in metastatic breast cancer, often arising in advanced disease and carrying a dismal prognosis. While current research emphasizes tumor-intrinsic drivers, the role of latent viral infections has been largely overlooked. Notably, cytomegalovirus (CMV) reactivation has been detected in 90% of BM lesions from breast cancer patients, implicating it as a potential but underexplored contributor to metastasis.Methods: We developed a CMV-infected breast cancer BM mouse model and evaluated the therapeutic efficacy of the anti-CMV drug foscarnet—alone and in combination with capecitabine—in survival studies. Mechanistically, we performed single-cell spatial transcriptomics and multiome (ATAC + RNA) profiling on brain tissues from three groups: non-infected controls, CMV-infected vehicle-treated, and CMV-infected foscarnet-treated mice. Clinical relevance was further assessed through survival analysis and immune profiling of brain metastases from 20 breast cancer patients, stratified by CMV reactivation status.Results: CMV infection significantly reduced survival in vehicle-treated mice compared to non-infected controls (P = 0.0063). Foscarnet monotherapy significantly prolonged survival (P = 0.026), and the combination of foscarnet and capecitabine yielded an even greater survival benefit (P < 0.0001). CMV-infected, vehicle-treated mice exhibited a significant peritumoral enrichment of CXCR3⁺C1q⁺ microglia, a population reduced in both non-infected and foscarnet-treated groups. Transcriptomic and in vitro analysis revealed that CMV infection reprograms microglial into an M2-like, immunosuppressive phenotype, characterized by upregulation of TGF-β, ARG1, IL-10, PPARG, and CHIL3. Additionally, CMV-infected 4T1 tumor cells expressed high levels of CXCL9 (P=4×10⁻¹⁰), a ligand for CXCR3, and CCL2 (P=6 ×10⁻⁶), a key inducer and recruiter of M2-microglial polarization. Breast cancer BM patients with high CMV-reactivation showed remarkably shorter survival in comparing to those patients without or low CMV-reactivation (P=0.005)Conclusion: Our findings reveal that CMV reactivation promotes brain metastasis by reprogramming microglia into an M2-like, immunosuppressive state. Infected tumor cells further amplify this effect by recruiting and sustaining immunosuppressive microglial populations, fostering a pro-metastatic brain microenvironment. Although anti-CMV therapy is not currently part of the standard-of-care for breast cancer brain metastases, our data—supported by emerging clinical evidence—identify CMV as a key, underrecognized driver of disease progression and therapeutic resistance. To translate these findings into clinical impact, we have initiated a Phase II trial at our cancer center to assess the benefit of adding anti-CMV therapy to standard treatment in CMV-reactivated BM patients. Targeting this viral-immunologic axis may represent a paradigm shift in the management of brain metastases.

I. Fernandes¹, J. W. Zhu¹, I. Konjundzic², W. Tran¹, V. Moravan³, K. J. Jerzak¹; ¹Odette Cancer Centre, Sunnybrook Health Sciences Centre, Toronto, ON, CANADA, ²NA, Sunnybrook Research Institute, Toronto, ON, CANADA, ³NA, VM Stats, Toronto, ON, CANADA.

Background: Risk factors and timing of BrM development among patients receiving NAC for BC are not well defined. Methods: A retrospective study of two cohorts of patients at the Sunnybrook Odette Cancer Centre was conducted. Cohort 1 included 469 patients treated with NAC for BC from 2008 – 2019. Cohort 2 included 801 patients treated for BC BrM with radiation and/or surgery from 1995 – 2023, among whom 117 received NAC. After unduplicating records, 586 patients were included in the final analysis. Descriptive statistics were used to summarize patient and treatment characteristics. Cox proportional hazards regression was used to estimate hazard ratios (HR) and identify predictors of BrM. Univariable analyses (UVA) were performed for all covariates. Bayesian Information Criteria determined best models from subsets of covariates for multivariable analyses (MVA). The proportional-hazards assumption was appraised by visually inspecting graphs of Schoenfeld residuals and testing their independence over time. Statistical significance was defined as p<.05. Results: In the combined cohort of 586 patients who received NAC for BC, the median age at BC diagnosis was 49.0 (42 – 58) years. The most common BC subtype was HER2+ (n=225, 38.4%), followed by hormone receptor (HR)+/HER2- (n=213, 36.3%) and triple negative BC (n=132, 22.5%). In total, 77 patients (13.1%) had inflammatory disease. Following NAC, 134 patients (22.9%) achieved a pathologic complete response (pCR) and 409 (69.8%) had residual disease; 276 (47.1%) had residual nodal involvement. In total, 152 (25.9%) patients developed BrM with a median follow-up of 38.0 months (IQR 19.1 – 70.9). The median time from BC diagnosis to development of BrM was 29.6 (16 – 50.5) months in the overall cohort; it was shortest for patients with triple negative BC [18.0 (15.0 – 31.0) months] and longest for those with HR+/HER2- disease [49.1 (19.8 – 76.3) months]. In a Cox proportional hazard regression, factors associated with a shorter time to BrM development included lack of pCR [HR 4.17 (95% CI 2.04 – 8.33), p<0.0001], inflammatory BC [HR 3.81 (95% CI 2.63 – 5.52), p<0.0001], residual nodal involvement [HR 2.76, (95% CI 1.79 – 4.27), p<0.0001)], presence of lymphovascular invasion [HR 2.38 (95% CI 1.51 – 3.75, p=0.0002] and HER2+ or triple negative BC [HR 1.75 (95% CI 1.21 – 2.51, p= 0.002]. In a MVA, residual nodal involvement, inflammatory BC, as well as HER2+ or triple negative subtype were independently associated with a shorter time to BrM development (Table). Conclusions: The median time to BrM development was <24 months among patients with triple negative or HER2+ BC. Given that patients with residual nodal involvement and those with inflammatory BC have a particularly high risk of developing BrM, the possible utility of BrM screening in select populations of patients receiving NAC for BC warrants further study.

A. Brenner¹, M. Youssef², P. Kumthekar³, M. Schulder⁴, J. Floyd⁵, A. Bao⁶, W. Phillips⁷, P. Vroman⁷, J. Michalek⁸, M. Moore⁹, M. Rosol¹⁰, M. Hedrick¹⁰; ¹Medicine, Neurology, and Neurosurgery, University of Texas Health Science Center at San Antonio, San Antonio, TX, ²Neurology, Hematology and Oncology, University of Texas Southwestern Medical Center, Dallas, TX, ³Neurology, Medicine, Northwestern Medicine, Chicago, IL, ⁴Neurosurgery, Northshore University (Northwell Health), Lake Success, NY, ⁵Neurosurgery, University of Texas Health Science Center at San Antonio, San Antonio, TX, ⁶Radiation Oncology, Case Western Reserve University, Cleveland, OH, ⁷Radiology, University of Texas Health Science Center at San Antonio, San Antonio, TX, ⁸Population Health Sciences, University of Texas Health Science Center at San Antonio, San Antonio, TX, ⁹Clinical Research, Plus Therapeutics, Houston, TX, ¹⁰Clinical Development, Plus Therapeutics, Houston, TX.

Background: Leptomeningeal metastases (LM) is a devastating systemic cancer complication most often seen with breast, lung, and melanoma, with limited treatment options and poor survival. Rhenium (¹⁸⁶Re) Obisbemeda (Reyobiq^TM) provides the combination of effective therapeutic beta radiation, simultaneous gamma decay for imaging, and ~90-hour physical half-life for optimal radiation delivery. A summary of the completed Phase 1 dose escalation study, with an emphasis on those patients with breast cancer primaries, will be presented. Methods: ReSPECT-LM was a Phase 1 dose escalation study for patients with LM from any primary cancer. Adult patients were given a single dose of ¹⁸⁶RNL via intraventricular catheter (Ommaya reservoir) in an outpatient setting to determine the maximum tolerated/feasible dose (MTD/MFD), safety, tolerability, and response. Seven administered dose cohorts in a 3+3 design, from 6.6 mCi to 109.96 mCi, were planned. Results: A total of 29 subjects received 6.6, 13.2, 26.4, 44.10, 66.14, or 75 mCi of Reyobiq (cohorts 1-6, respectively). Thirteen of the 29 treated subjects had breast cancer as their primary cancer (45%). Twenty-one subjects were evaluable per protocol (completed Day 28 safety follow up). Ten of the evaluable patients (48%) had primary breast cancer. Five were triple negative (ER negative/PR negative/HER2 negative); three were ER positive/HER2 negative; and two were HER2 positive. Including all evaluable patients, no dose limiting toxicity (DLT) was observed in cohorts 1-4, with 1 DLT of grade 4 cytopenia in each of cohorts 5 and 6. Following the cohort 6 safety review, enrollment was concluded, and the recommended phase 2 dose was determined to be 44.10 mCi. The majority of adverse events across the trial were Grade 1 and 2. There were no serious adverse events reported in the 44.10 mCi dose cohort 4 (n=6). A dose-dependent increase in the absorbed dose to the cranial and spinal subarachnoid space was observed, reaching a mean of 272 Gy in cohort 6. Radiographic response data was available for nine breast cancer patients, with two (22%) showing response based on investigator assessment. An additional four patients showed stable disease through day 112 for a Clinical Benefit Rate (CR+PR+SD) of 67%. Additionally, a clinical response with evident decrease in disease symptoms was noted in three of ten evaluable patients (30%), with three patients (30%) showing stable symptoms through day 112. Radiographic response data available for 17 patients (all primary cancers included) showed five partial responses and eight stable disease through day 112 (76% benefit rate). Additionally, a clinical response with decrease in disease symptoms was noted in two of 15 evaluable patients (13%), and 11 showing stable symptoms through day 112 (clinical benefit rate of 87%). CSF tumor cell enumeration (TCE) assays (CNSide test) were performed with a maximum reduction over baseline of 100% seen at Day 28. Seven of eight breast cancer patients (87.5%) with CTC studies showed partial response, with one of eight stable (12.5%). Five of seven total patients (any primary cancer) with a TCE response >80% survived ≥ 1 year following treatment with Reyobiq. Across cohorts 1-4 (20 patients) median overall survival was nine months, comparing favorably with literature reported survival of ~4 months. Conclusion: Reyobiq shows excellent safety and promising activity for LM. A single dose for patients with LM was well-tolerated up to the RP2D of 44.10 mCi, with high absorbed doses to the treatment area, acceptable organ doses, and encouraging response and reductions in tumor cell count. Within the breast cancer patients, response rate and survival were also promising. Based on these data, a multiple dose administration dose optimization study has been initiated and is currently enrolling.

I. Kojundzic¹, J. Fritz¹, B. Id Said², H. Soliman², S. Vuong³, M. Ennis⁴, E. Warner³, K. J. Jerzak³; ¹Sunnybrook Research Institute, University of Toronto, Toronto, ON, CANADA, ²Department of Radiation Oncology, Sunnybrook Odette Cancer Centre, University of Toronto, Toronto, ON, CANADA, ³Division of Medical Oncology, Sunnybrook Odette Cancer Centre, University of Toronto, Toronto, ON, CANADA, ⁴Applied statistician, Sunnybrook Research Institute, University of Toronto, Toronto, ON, CANADA.

Background:Breast cancer (BC) is the most frequent cancer among women and the second leading cause of central nervous system (CNS) metastases. Given limited data regarding the impact of young age on outcomes of women with metastatic breast cancer (MBC) and CNS metastases, we compared the clinical-pathological features, treatment patterns and outcomes of women ≤40 and those ≥40 years-of-age with CNS metastases in an established single-centre retrospective cohort. Methods: Patients with MBC and CNS metastases who were treated with surgery, whole-brain radiotherapy (WBRT), or stereotactic radiosurgery (SRS) at the Sunnybrook Odette Cancer Centre, Toronto, Canada between 2008 and 2018 were included. Clinical data was abstracted from electronic medical records. Patient characteristics were described with medians and interquartile ranges for continuous variables and percentages for categorical variables. Categorical variables were compared between young (<40 years of age) and older patients (≥40 years of age) using Chi-square tests and continuous variables using Wilcoxon rank-sum tests. Univariable and multivariable Cox proportional hazards models for brain-specific progression-free survival (bs-PFS) and overall survival (OS) were also generated with pre-specified variables of interest. Results: In total, 683 patients were included, of whom 7.5% (n=51) were <40 years of age and 92.5% (n=632) were ≥40 years of age at the time of CNS metastases. Similar characteristics were observed among young and older women with CNS metastases, with no statistically significant difference in BC subtype, tumour histology, and/or median time from MBC diagnosis to development of CNS metastases. Most patients in each age group had neurological symptoms at the time of initial presentation with CNS metastases (<40 years: 67.9% vs. ≥ 40 years: 77.8%, p = 0.24). However, we found that young women were significantly more likely to develop LMD than older women (39.6% vs. 22.3%, p= 0.004). In addition, young women were significantly more likely to be re-treated for CNS metastases (43.4% vs 24.5%, p=0.003). There was no significant difference in median bs-PFS (log-rank p = 0.35) or OS (log-rank p value = 0.52) between young and older women with MBC and CNS metastases (Table). Conclusions:In our study of women with MBC and CNS metastases who were <40 years of age were more likely to develop LMD than women ≥40 years of age. Although young women were also more likely to be re-treated for progression of CNS metastases, their bs-PFS and OS were not inferior that of patients ≥ 40 years-of-age.

P. Forsyth¹, V. Law¹, K. Ahmed², C. Piteo¹, B. Evernden¹, Y. Pina¹, S. Inna³, N. Tran¹, P. Kalinski⁴, B. Czerniecki⁵; ¹Neuro-Oncology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL, ²Radiation Oncology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL, ³Metabolism & Physiology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL, ⁴Swanson School of Engineering, University of Pittsburgh School of Medicine, Pittsburgh, PA, ⁵Breast Oncology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL.

Background: Leptomeningeal disease (LMD) is a devastating complication of breast cancer (BC) and occurs in ˜5% of patients and has a poor prognosis. The CSF of patients with LMD have an innate, but not adaptive, immuno cellular profile. We found in murine LMD models IT cDC1s were safe, induced a Th1 response, cured most HER2+ LMD, and prevented LMD recurrence. This provoked a Th1 response, was CD4+ > CD8+ T cell and B cell dependent. We hypothesized in BC LMD patients that a RP2D would be identified, and the CSF would be remodeled to have a Th1 adaptive immunological profile identified by transcriptomic analysis. Methods: This is a phase I dose escalation study (NCT05809752) that establishes 1) safety and 2) associations between clinical outcomes & translational CSF studies. Eligibility includes TNBC or HER+ LMD pts, prior pCSpRT/WBRT, ECOG PS ≤2, normal marrow and organ function and ommaya reservoir. IT cDC1 IT were administered weekly x 12 (1 x 10⁶ – 5 x 10⁷) until PD, DLT or withdrawal. Endpoints were 1) the safety/MTD, and 2) association between clinical and immune profiles in the CSF. DLTs were defined as ≥ gr. 3 not due to LMD. Final pre & post cDC1 treatment cyto-, chemokine profiles and cellular/tumor profiles (scRNA-seq) were determined. Results: As of 6/24/25, the first 6 patients in whom transcriptomics was possible, received 1 x 10⁶ – 2 x 10⁷ DCs weekly without DLTs. Headaches were common and grade 3 in two (33%) patients. Performance status remained stable or improved in five (83%) patients. Two (33%) had PD of LMD. At follow-up, one patient died from RT leukoencephalopathy. The median OS was 15 mos and five (83%) are alive. A focused clinical cytokine panel showed marked elevation of CSF Th1 cytokines: IFN-g (2. 5 – 5.2 x ULN), IL-6 (16.9 – 220 x ULN), IL-12 (3 -9.7 X ULN), TNF-a (14 – 34 X ULN); the Th2-related IL-4 was not elevated. Transcriptomic analyses of CSF showed a remodeled environment with marked increase in CD4+ T, CD8+ T and B cells with a reduction of tumor cells. Antibodies to HER2 or HER3 developed in four of five (80%) patients. Conclusion: Our results show IT cDC1s activates a CD4+ Th1 adaptive immune response which is otherwise lacking in LMD. Mechanistic studies are in progress. This treatment resulted in an average survival of 15 months, which is significantly longer than other clinical trials in LMD. A phase 2 combination study of IT cDC1s will open I January 2026 (NCT pending).

K. Ahmed¹, P. Kumthekar², Y. Pina³, Y. Kim⁴, M. DeJesus¹, G. Rico¹, S. Mannarino¹, B. Evernden³, L. Sharp², D. Primdahl², R. Lukas², D. Oliver¹, P. Grogan³, A. Armaghani⁵, R. Costa⁵, A. Soyano⁵, J. Arrington⁶, H. Soliman⁵, H. Yu¹, H. Han⁵, P. Forsyth³; ¹Radiation Oncology, Moffitt Cancer Center, Tampa, FL, ²Neuro Oncology, Northwestern University, Chicago, IL, ³Neuro Oncology, Moffitt Cancer Center, Tampa, FL, ⁴Biostatistics and Bioinformatics, Moffitt Cancer Center, Tampa, FL, ⁵Breast Oncology, Moffitt Cancer Center, Tampa, FL, ⁶Radiology, Moffitt Cancer Center, Tampa, FL.

Background: Treatment options for HER2⁺ leptomeningeal disease (LMD) remain limited with a high unmet clinical need. The use of IT trastuzumab has been studied in the management of HER2⁺ breast LMD. We previously reported 80 mg as the recommended phase II dose of IT pertuzumab alongside 80 mg IT trastuzumab and now report results from the pre-specified interim analysis. Methods: The study is a multi-institutional, phase II trial of radiation therapy followed by IT trastuzumab/pertuzumab in the management of HER2⁺ breast LMD. HER2⁺ LMD patients identified by magnetic resonance imaging (MRI) and/or cerebrospinal fluid cytology with a life expectancy > 8 weeks, and KPS ≥ 60 were eligible. There was no limit on prior IT or systemic therapies. The primary objective was to evaluate overall survival (OS) following study treatment. Clinical trial information: NCT04588545. Results: A total of 20 patients were enrolled to the phase II study between November 2022 and February 2025. Median age was 48 (range: 33-63) and 8 patients (40%) had a baseline KPS ≤ 70. Eleven patients (55%) were hormone receptor (HR)^–/HER2⁺ and 9 (45%) were HR⁺/HER2⁺. Median follow-up is 20.7 months. Median survival has not been reached (95% CI: 19.4 – Not reached (NR)) with a 12-month OS of 86%. Median LMD progression free survival (LMD-PFS) has not been reached (95% CI: 7.2 – NR) with a 12-month LMD-PFS of 65%. The best LMD response has been a complete response in 4 (20%), partial response in 5 (25%), and stable disease in 11 (55%) of patients. The most common grade ≥ 2 adverse events attributed to IT trastuzumab/pertuzumab included fatigue (n=3; 15%), headache (n=2; 10%), and nausea/vomiting (n=2; 10%). Currently, twelve patients (60%) continue study therapy with 28.1 months as the longest treatment duration. Conclusions: The study met its predetermined endpoint for OS to warrant continuing enrollment in the second stage of the phase II trial. Initial trial results are encouraging with study therapy that is well tolerated.

X. Liang¹, S. Guohong¹, P. Yong², L. Zhijun³, L. Huiping¹; ¹Department of Breast Oncology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing),Peking University Cancer Hospital & Institute, Beijing, CHINA, ²Breast Tumor Center, Beijing Arion Cancer Center, Beijing, CHINA, ³Tumor Center, Beijing Luhe Hospital Affiliated to Capital Medical University, Beijing, CHINA.

Background: Sacituzumab govitecan (SG), the first Trop-2-targeting antibody-drug conjugate (ADC), has shown improved PFS and OS in pre-treated mTNBC and HR+/HER2− metastatic breast cancer (MBC) patients in trials like ASCENT and TROPiCS-02. Despite its approval in China, real-world data on SG efficacy and safety in Chinese HER2− MBC patients remain limited. This multicenter study evaluated SG in this population. Methods: Retrospective data were collected from three hospitals on HER2− MBC patients who received SG treatment between June 2023 and December 2024, and completed at least one imaging assessment. Outcomes included real-world progression-free survival (rwPFS), objective response rate (ORR), disease control rate (DCR), real-world overall survival (rwOS), and safety. Results: A total of 58 HER2− metastatic breast cancer patients treated with SG were included, with a median age of 52.5 years. The median number of prior lines of therapy in the metastatic setting was 3 (range: 1-10). SG was administered in the second line for 31% of patients and in the third or later lines for 69%. The cohort included 43 TNBC patients (74.1%) and 15 HR+/HER2− patients (25.9%), with metastatic sites involving the liver (55.2%), bone (53.3%), lung (41.4%), and brain (20.6%).At a median follow-up of 11.0 months, the overall population showed an ORR of 34.5%, a DCR of 81.0%, a median rwOS of 16.32 months, a 6-month rwOS rate of 77.6%, and a median rwPFS of 4.41 months. In mTNBC patients, the ORR was 34.8%, DCR was 79.1%, median rwPFS was 4.97 months, and median rwOS was 16.32 months. In HR+/HER2− patients who received a median of 2 lines of prior endocrine therapy and 2 lines of chemotherapy, the ORR was 33.33%, DCR was 86.6%, median rwPFS was 4.41 months, and median rwOS was not reached. Among 12 patients with baseline brain metastases (11 TNBC, 1 HR+/HER2−BC), including 3 with stable brain metastases without prior radiotherapy, 5 with stable brain metastases post-radiotherapy, and 4 with newly diagnosed active brain metastases without radiotherapy, the ORR was 25%, DCR was 91.6%, median rwPFS was 5.43 months, and median rwOS was 17.50 months. The intracranial objective response rate (icORR) was 41.6%, and the median intracranial PFS (icPFS) was 14.9 months. Two patients received concurrent chemoradiotherapy, with one achieving intracranial complete response (CR) and one intracranial partial response (PR), both remaining free of intracranial progression with icPFS >14.9 months. Safety analysis showed that neutropenia (51.7%) and diarrhea (22.4%) were the most common adverse events (AEs), with grade 3+ incidences of 15.5% and 6.9%, respectively. Febrile neutropenia occurred in 1.7% of patients. Prophylactic granulocyte colony-stimulating factor (G-CSF) was used in 36.2% of patients. Nine patients (15.5%) received long-acting G-CSF as primary prophylaxis, and none of these patients experienced grade 3+ neutropenia. Conclusions: This RWS expands real-world evidence of SG in Chinese advanced TNBC and HR+/HER2− breast cancer, confirming its efficacy and manageable safety. SG showed robust disease control in both subgroups, notably in patients with brain metastases, who showed better outcomes than the overall population, suggesting potential blood-brain barrier permeability of SG. This provides a new therapeutic option for patients with brain metastases lacking effective treatments. Compared with global trials, lower incidences of neutropenia and diarrhea were observed, possibly reflecting improved supportive care, especially that prophylactic G-CSF use clinically reduced the incidence and severity of SG-related neutropenia. Future studies should explore SG plus local therapies for brain metastases and standardized G-CSF prophylaxis to optimize outcomes.

R. Bartsch¹, A. Llombart-Cussac², M. Gión³, J. Garde-Noguera⁴, R. Greil⁵, M. Ruiz-Borrego⁶, M. Valero⁷, J. García-Mosquera⁸, M. Arumi⁹, J. Cortés¹⁰, M. Campolier¹¹, J. Guerrero¹², J. Rodríguez-Morató¹³, P. González-Alonso¹³, I. Mas-Rincón¹⁴, M. Vaz-Batista¹⁵, M. Marhold¹, F. Oberndorfer¹⁶, J. Furtner¹⁷, T. Fuereder¹⁸, A. Berghoff¹⁸, M. Preusser¹⁸; ¹Medicine, Medical University of Vienna, Vienna, AUSTRIA, ²Medicine, Hospital Arnau de Vilanova; Translational Oncology Group, Facultad de Ciencias de la Salud, Universidad Cardenal Herrera-CEU; Medica Scientia Innovation Research (MedSIR), Valencia, SPAIN, ³Oncology, Hospital Ramón y Cajal, Madrid, SPAIN, ⁴Oncology, Hospital Arnau de Vilanova, Valencia, SPAIN, ⁵Medicine, Paracelsus Medical University Salzburg; Salzburg Cancer Research Institute-Center for Clinical Cancer and Immunology Trials (SCRI-CCCIT); Cancer Cluster Salzburg, Salzburg, AUSTRIA, ⁶Medicine, Hospital Universitario Virgen del Rocío, Sevilla, SPAIN, ⁷Oncology, Hospital Quirónsalud Sagrado Corazón, Sevilla, SPAIN, ⁸Oncology, Dr. Rosell Oncology Institute (IOR), Dexeus University Hospital, Pangaea Oncology, Quironsalud Group, Barcelona, SPAIN, ⁹Oncology, Vall d’Hebron Instituto de Oncología, Barcelona, SPAIN, ¹⁰Oncology, International Breast Cancer Center (IBCC), Pangaea Oncology,  Quiron  Group; IOB Madrid; Hospital Beata María Ana; Universidad Europea de Madrid; Hospital Universitario Torrejón, Ribera Group; Medica Scientia Innovation Research (MedSIR), Madrid, SPAIN, ¹¹Trial, Medica Scientia Innovation Research (MEDSIR), Barcelona, SPAIN, ¹²Data Analytics, Medica Scientia Innovation Research (MEDSIR), Barcelona, SPAIN, ¹³Scientific Impact, Medica Scientia Innovation Research (MEDSIR), Barcelona, SPAIN, ¹⁴Scientific, Medica Scientia Innovation Research (MEDSIR), Barcelona, SPAIN, ¹⁵Oncology, Hospital Professor Doutor Fernando Fonseca EPE, Lisbon, PORTUGAL, ¹⁶Pathology, Medical University of Vienna, Vienna, AUSTRIA, ¹⁷Medicine, Research Center for Medical Image Analysis and Artificial Intelligence (MIAAI), Faculty of Medicine and Dentistry, Danube Private University, Krems, AUSTRIA, ¹⁸Oncology, Medical University of Vienna, Vienna, AUSTRIA.

Background : TUXEDO-3 (NCT05865990) is an international, multicenter, multicohort, single-arm, phase II trial that enrolled patients with metastatic breast cancer (mBC) and newly diagnosed brain metastases (BMs) or BMs progressing after local therapy (active BMs) (cohort 1), advanced non-small cell lung cancer and active BMs (cohort 2), and leptomeningeal disease (LMD) from any solid tumors (cohort 3) to evaluate the efficacy and safety of the antibody-drug conjugate (ADC) patritumab deruxtecan (HER3-DXd). The treatment showed central nervous system (CNS) activity in all three cohorts. In cohort 1, HER3-DXd activity was observed irrespective of the BC subtype in a heavily pretreated population, showing that HER3-DXd may be a promising novel therapeutic option for patients with breast cancer and CNS involvement. The number of available ADCs across stages and lines of therapy in breast cancer is growing, but evidence on their optimal sequencing remains limited, highlighting an important unmet need, especially in the context of CNS involvement. Here, we performed an unplanned post-hoc, descriptive, pooled efficacy analysis of all patients with HER2-positive mBC and CNS involvement from the TUXEDO-3 trial who had received prior therapy with T-DXd.Methods: The study design and results of the TUXEDO-3 trial have been recently reported (Preusser et al., Nat Med, 2025) and presented at ASCO 2025. Patients with HER2-positive mBC with active BMs and CNS involvement that received prior ADC were included in this post hoc analysis. We evaluated progression-free survival (PFS) for intracranial disease as per RANO-BM criteria, PFS for extracranial and bicompartmental (intracranial and extracranial) disease as per RECIST v.1.1, and overall survival (OS). PFS and OS were estimated using the Kaplan-Meier method, reporting the median with 95% confidence intervals (CI) based on the log-log method.Results: Between 12 December 2023 and 2 July 2024, 35 patients with mBC and CNS involvement [active BMs (n=21) and LMD (n=14)] were enrolled across cohorts 1 and 3. Of them, 10 (28.6%) had HER2-positive mBC, including 9 (90.0%) with active BMs and 1 (10%) with LMD, who also had parenchymal BMs. Median age was 54.5 (range: 35.0-75.0) years. The number of previous treatment lines for advanced disease in the HER2-positive mBC population was 4.0 (range: 2.0-7.0); all patients had received prior T-DXd, three (30.0%) had additional T-DM1, and six (60%) tucatinib as well. Three patients (30%) received T-DXd as last treatment line prior to enrollment. At data cutoff (28 February 2025), one patient remained on treatment and six continued in follow-up. Median follow-up was 4.7 (range: 2.0-10.3) months, and median treatment duration was 3.2 (range: 0.0-9.7) months. Median intracranial and bicompartmental PFS were 6.3 months (95%CI: 1.4-Not reached), whereas median extracranial PFS and OS were not reached. Conclusions: In this post hoc analysis of the prospective TUXEDO-3 trial, HER3-DXd showed promising PFS and OS in patients with HER2-positive mBC and active BMs or LMD, previously treated with T-DXd. Despite the small sample size, these findings suggest a potential strategy for sequential ADC treatment in a patient population with no established standard of care. With a median PFS exceeding 6 months, further investigation of HER3-DXd in patients progressing on T-DXd is warranted.

N. Niikura¹, T. Yamanaka², Y. Aoyama³, A. Kataoka⁴, T. Toyama⁵, S. Sakai⁶, M. Endo⁷, K. Kaneko⁶, H. Iwata⁸, T. Yamashita², J. Tsurutani⁹, R. Horii¹⁰, Y. Kikawa¹¹, Y. Hirakawa¹², S. Yamazaki¹², W. Hashimoto¹³, E. Tokuda¹⁴, S. Saji¹⁴; ¹Department of Breast Oncology, Tokai University School of Medicine, Tokyo, JAPAN, ²Department of Breast Surgery and Oncology, Kanagawa Cancer Center, Kanagawa, JAPAN, ³Breast Oncology Center, The Cancer Institute Hospital of Japanese Foundation for Cancer Research, Tokyo, JAPAN, ⁴Department of Breast Oncology, Aichi Cancer Center Hospital, Aichi, JAPAN, ⁵Department of Breast Surgery, Nagoya City University Graduate School of Medical Sciences, Aichi, JAPAN, ⁶Department of Radiology, Fukuoka University Hospital, Fukuoka, JAPAN, ⁷Division of Diagnostic Radiology, Shizuoka Cancer Center, Shizuoka, JAPAN, ⁸Department of Advanced Clinical Research and Development, Nagoya City University Graduate School of Medical Sciences, Aichi, JAPAN, ⁹The Innovative Center of Translational Research and Clinical Science for Cancer Therapy, Showa Medical University Hospital, Tokyo, JAPAN, ¹⁰Department of Pathology, Yokohama City University Medical Center, Kanagawa, JAPAN, ¹¹Department of Breast Surgery, Kansai Medical University Hospital, Osaka, JAPAN, ¹²Oncology Medical Science Department I, Daiichi Sankyo Co., Ltd., Tokyo, JAPAN, ¹³Data Intelligence Department, Daiichi Sankyo Co., Ltd., Tokyo, JAPAN, ¹⁴Department of Medical Oncology, Fukushima Medical University School of Medicine, Fukushima, JAPAN.

Background: The DESTINY-Breast04 (DB-04) trial established trastuzumab deruxtecan (T-DXd) as the standard of care for patients (pts) with the metastatic breast cancer (mBC) newly classified as HER2-low status (HER2 IHC 1+, or 2+/ISH−). However, in the DB-04 trial, the number of pts with hormone receptor-negative (HR−)/HER2-low mBC was limited, and pts with stable brain metastases (BMs) were included, while those with active BMs were excluded. The HALLOW study (UMIN000051259) is a large-scale ongoing prospective observational study conducted in Japan with the aim of providing effectiveness and safety data for T-DXd in these clinically important populations, which were underrepresented in the DB-04 trial. Here, we report the interim analysis results for pts with BMs. Methods: The HALLOW study enrolled, from June 2023, approximately 600 pts diagnosed with HER2-low mBC (HR+/−, with/without BMs, including active BMs) who had previously received chemotherapy and were scheduled to receive T-DXd treatment. This interim analysis included pts diagnosed with BMs (current or past) by local investigators. For the effectiveness analysis, only those with BMs confirmed by Brain-independent central review (ICR) based on brain MRI and/or CT images were included. Active BMs were defined as cases where no local treatment was performed on the brain lesion or where there was regrowth or symptom worsening after local treatment. Effectiveness outcomes included intracranial progression-free survival (IC-PFS) and intracranial objective response rate (IC-ORR) assessed by Brain-ICR according to RECIST version 1.1, while progression-free survival (PFS) and overall survival (OS) were assessed by investigators. For the safety analysis, pts who had received T-DXd at least once were included. Safety outcomes include incidence of treatment-emergent adverse events (TEAEs) graded by CTCAE, including ≥ grade (Gr) 3 TEAEs, ≥ Gr1 interstitial lung disease (ILD), and ≥ Gr1 TEAEs that led to discontinuation of T-DXd treatment. Follow-up plan will continue until July 2026. Results: At the data cutoff date of August 31, 2024, 42 pts had physician-diagnosed BMs, of whom 33 were Brain-ICR confirmed and met the criteria for active BMs. In this set, the median age was 55 (range: 42-79) years; the median prior line of chemotherapy in the metastatic setting was 2 (range: 0-7); HER2 status at each local site was IHC 2+/ISH− in 7 pts (21%) and IHC 1+ in 26 pts (79%); 25 pts (76%) were HR+, 8 pts (24%) were HR−. 5 pts (15%) had Brain-ICR-confirmed leptomeningeal disease. At a median follow-up period of 4.1 months (mo) (range: 1.4-12.6), the median IC-PFS was 8.0 mo (95% confidence interval [CI]: 3.9-not estimated), and the 6-mo IC-PFS rate was 57.6% (95% CI: 30.7-77.4) until the data cutoff date. A total of 22 pts was eligible for proper tumor evaluation during the follow-up period by Brain-ICR. Among the 22 pts who could be properly evaluated, the IC-ORR was 9.1% (complete response n=0, partial response n=2; 95% CI: 1.1-29.2). The median PFS was 6.7 mo (95% CI: 4.0-11.1), with a 6-mo PFS rate of 59.0% (95% CI: 34.9-76.7). The median OS was not reached, and the 6-mo survival rate was 77.1% (95% CI: 51.5-90.3). In the safety analysis set (n=42; median follow-up period: 4.1 mo [range: 0.4-12.6]), ≥ Gr3 TEAEs and ≥ Gr3 TEAEs related to T-DXd treatment occurred in 18 (43%) and 11 (26%) pts, respectively. ≥ Gr1 ILD occurred in 2 pts (5%), 1 (2%) of whom experienced Gr 5 ILD, and ≥ Gr1 TEAEs that led to T-DXd discontinuation occurred in 3 pts (7%), with two of these being ILD and the other seizure. Conclusions: While longer follow-up and additional data are needed to confirm these findings, the current data provide tentative support for the effectiveness and safety of T-DXd in this BMs population including active BMs, which was not included in the DB-04 trial.