Despite evidence that antibody drug conjugates (ADCs) are active in brain metastases, their role in primary central nervous system (CNS) tumors remains unclear. We report two adults with molecularly defined ependymoma - a MYCN-amplified spinal tumor with intracranial dissemination and a supratentorial ZFTA-RELA-fused tumor with multiple recurrences - who demonstrated radiographic response and/or durable clinical and metabolic stability with trastuzumab deruxtecan (T-DXd). HER2 expression was identified by immunohistochemistry in both tumors, consistent with prior systematic profiling of ADC targets in CNS tumors. Multiplexed imaging showed broad but heterogeneous HER2 expression across tumor states in both cases; in the MYCN-amplified tumor, this occurred alongside EGFR/MAPK-enriched proliferative niches, whereas the ZFTA-RELA tumor showed more diffuse organization without strong coupling of EGFR and proliferation. These findings provide early clinical evidence supporting HER2-directed ADCs in ependymoma and highlight the value of integrated molecular and spatial profiling in interpreting therapeutic response in rare CNS tumors.

1055 Background: Brain metastases (BMs) are a common site of progression in HER2+ mBC due to limited BBB penetration of systemic therapies. ZN-A-1041 is an oral, selective HER2 TKI designed for high intact BBB permeability. We report ZN-A-1041-101-US (NCT05593094) Phase Ic expansion results of ZN-A-1041 + T-DXd in patients (pts) with HER2+ mBC refractory to prior treatments (txs), or + PH as maintenance therapy after first-line taxane + H ± P induction. Phase Ia and Ib (dose-escalation as single agent or in combination therapies) results have been reported (Anders ASCO 2023). Methods: The study enrolled pts with HER2+ mBC, with or without BMs (including leptomeningeal disease). Pts in Phase Ic received ZN-A-1041 800 mg twice daily (BID) + PH (Arm C), or were randomized to ZN-A-1041 800 mg or 600 mg BID, + T-DXd 5.4 mg/kg every 3 weeks (Arms A and B, respectively). Primary objectives: safety and tolerability. Secondary objectives included systemic objective response rate (ORR) and disease control rate (DCR) per Response Evaluation Criteria in Solid Tumours version 1.1. Results: As of July 31, 2025 (last pt in), enrollment in Arms A, B, and C was 24, 23, and 20 pts, respectively; median age was 57, 54, and 46 years; 50, 36, and 70% had de novo stage IV disease. Baseline central nervous system (CNS) metastases were present in 58, 59, and 16% of pts. Median prior lines of therapy for metastatic disease was 1, 1, and 0. Median ZN-A-1041 tx duration was 23.0, 24.6, and 42.9 weeks. The most frequent all-grade tx-emergent adverse events (TEAEs) across Arms A, B, and C, respectively, were nausea (83, 96, and 47%), diarrhea (62, 77, and 68%), and vomiting (46, 64, and 47%); diarrhea (17, 9, and 5%) was the most frequent Grade ≥3 TEAE. Preliminary systemic efficacy is summarized in the Table. Intracranial lesion shrinkage was observed in pts with BMs across all tx arms. Conclusions: ZN-A-1041 showed manageable safety profiles and promising clinical activity when combined with standard anti-HER2 therapies in pts with HER2+ mBC, both with or without CNS metastases. High disease control in pts pretreated with T-DXd and notable continued responses in the PH maintenance setting support further clinical evaluation of these combinations. Clinical trial information: NCT05593094 . Arm n ORR, % (95% CI) Complete response, % of pts DCR, % (95% CI) A: ZN-A-1041 800mg + T-DXd 20 65.0 (40.8, 84.6) 10.0 95.0 (75.1, 99.9) B: ZN-A-1041 600mg + T-DXd 21 76.2 (52.8, 91.8) 9.5 90.5 (69.6, 98.8) C: ZN-A-1041 800mg + PH 13* 30.8 (9.1, 61.4) 5.6 100 (75.3, 100.0) *Efficacy reported for 13 pts with measurable disease receiving maintenance therapy with ZN-A-1041 + PH after taxane + H ± P induction. CI, confidence interval.

De novo oligometastatic breast cancer (OMBC) is often defined as up to five metastases in two or fewer organs at presentation. Studies have suggested favorable outcomes for patients with OMBC; however, management remains controversial. We analyzed outcomes of patients with de novo OMBC treated with physician-expressed curative intent at a single institution. We identified patients by performing a keyword search for terms of interest within institutional electronic medical records. We defined OMBC as four or fewer metastases in one organ. Primary surgery was required for inclusion in the analytic cohort. Recurrence-free survival (RFS) and overall survival (OS) were evaluated using Kaplan–Meier methods. Thirty-nine patients were identified: 12 hormone receptor-positive (HR+)/HER2+ , 2 HR-negative (HR-)/HER2-, 21 HR+ /HER2-, and 4 HR-/HER2+ . Thirty-three patients (84.6

Abstract Background: Endocrine therapy (ET) is standard of care for ER+ MBC, but virtually all patients (pts) develop ET resistance over their disease course. Biomarkers predictive of loss of ER dependence to guide therapy (tx) are lacking. Methods: We identified 122 pts with ER+/HER2- MBC enrolled in the EMBRACE study at Dana Farber Cancer Institute who received 1-2 lines (L) of ET and had a blood drawn within +/- 30 days of switch from 1L to 2L (n=77) or from 2L to 3L (n=53). Using 1mL plasma, we profiled genome-wide enhancers, promoters and DNA hypermethylation to infer pathway activation and gene expression levels. Samples that did not meet quality thresholds (n=16) or had tumor fraction <0.5% (n=48) were excluded. We applied the Precede ER dependence index (PERDI) that quantifies relative activities of ER-driven vs estrogen-starvation-induced enhancers and classified samples as PERDI-high or -low using a predefined threshold. We investigated the association between PERDI and time-to-next-treatment (TTNT). A conditional landmark approach defined TTNT beginning from 30 days after the start of tx of interest (ET or non-ET) until the start of the next tx line, considering only tx switch for tumor progression as events. Time-dependent ROC curves were used in the prespecified primary analysis investigating the association between PERDI and early progression on ET. Kaplan Meier methods and Cox proportional hazard models were used in additional analyses. Results: A total of 71 pts (79 samples) were included: 57 pts had draws collected before ET (40 switch from 1L to 2L ET, 17 from 2L to 3L ET); 22 pts had samples collected from 2L ET to 3L non-ET. Most common next-line ET regimens were SERD (n=17), SERD + CDK4/6 inhibitors (i) (n=14), aromatase inhibitors (AI) + mTORi (n=9), SERD + other targeted therapy (n=6). Among 57 pts starting next-line ET, PERDI was associated with landmark TTNT (median TTNT 2.4 months (mo) with low vs 4.1 mo with high PERDI, HR 2.65, 95% confidence interval [CI] 1.24-5.66, p=0.012). However, PERDI did not reliably identify early progressors to next-line ET (time-dependent AUC at 2 mo c = 0.51). Among 22 pts who switched from ET to non-ET (primarily chemotherapy), PERDI was not associated with TTNT (HR 0.66, 95% CI 0.23-1.85, p=0.426), suggesting a potential predictive role specifically for ET. Among pts with high PERDI but poor response to next-line ET, preliminary analyses identified 6 outliers for activity of known resistance pathways (e.g. FGFR1, ERBB2). Conclusions: We observed a significant association between PERDI and benefit from ET. Our exploratory analysis integrating resistance pathways beyond ER further identified pts with high PERDI but ET resistance. Upon further clinical validation, this blood based comprehensive epigenomic assay could become a valuable tool to guide tx for pts with ER+/HER2- MBC. Citation Format: Stefania Morganti, Jonathan Beagan, Ningxuan (Shirley) Zhou, Khoi Nguyen, Kalie Smith, Ashka Patel, Catherine Stever, Katheryn Santos, Molly Skeffington, Olivia D'Amico, Travis Clark, Justin Finkle, Anthony D'Ippolito, Mike Zhong, Jamey Guess, Kristian Cibulskis, Aparna Gorthi, Tyrone Tamakloe, Charlene O'Brien, Baovy Tran, Mary McGillicuddy, Nabihah Tayob, Sara M. Tolaney, Nancy U. Lin, Hillary Heiling, Corrie A. Painter, Matthew L. Eaton, J. Carl Barrett, Heather A. Parsons. Characterization of functional estrogen receptor (ER) dependence via comprehensive epigenomic liquid biopsy stratifies endocrine therapy (ET) responders with metastatic breast cancer (MBC) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 1020.

Immunosuppression and metastasis are critical hallmarks of breast cancer, often linked to poor patient outcomes. The secreted cytokine chitinase-3-like 1 (CHI3L1) is frequently overexpressed in breast cancer samples and promotes an immunosuppressed tumor microenvironment. Notably, CHI3L1 expression is elevated in metastatic patient samples when compared with the matched primary breast tumor. To investigate its role in breast cancer metastasis, we generated an inducible genetically engineered mouse model that overexpresses CHI3L1 in the mammary epithelium. Ectopic expression of CHI3L1 in the polyomavirus middle T (PyMT) mouse model of breast cancer suppressed antitumor immune responses, accelerated mammary tumor onset, and enhanced lung metastasis. Mechanistically, elevated CHI3L1 expression in the mammary epithelium enhanced neutrophil recruitment, which subsequently degraded the extracellular matrix and increased the number of circulating tumor cells. These findings reveal a key mechanism driving metastatic dissemination and argue that therapeutically targeting Chi3l1 could enhance antitumor immunity and suppress metastasis.

Abstract Introduction: While women diagnosed with breast cancer at young ages remain at risk of locoregional recurrence in long-term survivorship, predictors of risk remain unclear. Methods: Women ≤40 years of age diagnosed with breast cancer for which they underwent surgery between January 2016 and April 2023 (N=1,088) were identified from a prospectively maintained database with detailed clinicopathologic and treatment information collected. The primary outcome was locoregional recurrence (≥6 months after primary BC diagnosis) without concurrent distant metastasis. Univariable associations between patient characteristics, primary tumor and treatment variables, and outcome were assessed via Fine and Gray subdistribution models, considering distant metastasis and death as competing risks. Backward selection of variables by AIC was performed using crr step in R to build a multivariable model predicting risk of locoregional recurrence. A sensitivity analysis was completed among individuals who did not have a mastectomy. Results: A total of 1,053 women ≤40 years of age who did not experience a competing risk within the first 6 months were included. Mean age at first BC diagnosis was 35.3 (SD=4.2) years. Most patients were diagnosed with Stage 1 or 2 disease (77%) and had (HR)+/HER2- tumors (51%) [HR+/HER2+ (18%), HR-/HER2- (16%), HR-/HER2+ (10%), unknown HER2 (5%)]. Over a median of 3.6 (IQR=3.3-3.8) years of follow up, 34 women had a local or regional recurrence without concurrent metastasis. In univariable models, higher hazard of locoregional recurrence was associated with in situ disease (vs. invasive, p=0.05), smaller tumor size (p=0.005), lumpectomy (vs. mastectomy, p<0.001), non-receipt of endocrine therapy (ET) if HR+ (vs. HR+ w/ ET, p=0.009), and non-receipt of adjuvant chemotherapy (p=0.004). The multivariable model was tested among individuals with non-missing grade and stage (N=1037, events=34). Variables selected included stage (stage 3 vs. stage 1: aSHR=3.41, p=0.04), HR and ET combined (HR+ w/o ET vs. HR+ w/ET: aSHR=3.60, p=0.007), and surgery and RT combined (mastectomy only vs. lumpectomy+RT: aSHR=0.22, p=0.003; mastectomy+RT vs. lumpectomy+RT: aSHR=0.08, p<0.001). Other variables (age, race, BMI, known germline mutations, tumor grade, HER2 status, and adjuvant chemotherapy) were not selected. When restricted to individuals without mastectomy (N=405, events=26), receipt of ET emerged as the key predictor of locoregional recurrence (HR+ w/o ET vs. HR+ w/ET: aSHR=3.09, p=0.02). Conclusion: In a modern cohort of young BC patients, receipt of ET for HR+ disease emerged as the most important factor in predicting hazard of early locoregional recurrences. This highlights the importance of recommending ET for young BC patients with HR+ disease, while finding ways to increase tolerability of ET for young BC patients to encourage adherence. Citation Format: Kristen D. Brantley, Tonia Parker, Julie Vincuilla, Alyssa R. Martin, Elizabeth A. Mittendorf, Catherine Stever, Craig Snow, Rebecca A. Ottesen, Sara M. Tolaney, Tari A. King, Nancy U. Lin, Ann H. Partridge. Risk factors for early locoregional recurrence among young-onset breast cancer patients: Findings from a single institutional prospective dataset [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 5223.

601 Background: NCIT improves survival in high-risk eTNBC; however, trial-based data show that most relapses after NCIT are early. Real-world data are lacking. Methods: This retrospective study included pts from the DFCI Multicenter TNBC registry with eTNBC or estrogen receptor (ER)-low (≤10%), HER2-negative breast cancer (BC) treated with NCIT who underwent surgery before 7/1/2025. Aims were to evaluate (1) patterns of relapse; (2) BC–specific event–free survival (BC-EFS) from the first NCIT dose to relapse, contralateral BC, or death; (3) first-line (1L) metastatic systemic treatment patterns, and (4) time to progression (TTP). Results: 220 pts were identified, with median age of 50.1 yrs (IQR: 40.5-60.8). Median follow-up (FU) was 32.7 months (mo) (IQR, 30.4–34.4). At last FU, 29 pts (13.2%) had relapsed (locoregional, n=2; distant, n=27). Among these, 86.2% had not experienced pathologic complete response. Among relapsed pts with PD-L1 assessment (n=16), 43.8% (n=7) had a Combined Positive Score (CPS) <10; 56.2% (n=9) had a CPS ≥10. BC-EFS is shown in the Table. 1L therapy consisted of antibody-drug conjugate (ADC) in 51.7% (n=15), Poly ADP-ribose Polymerase inhibitor (PARPi) in 13.8% (n=4), chemotherapy in 13.8% (n=4), ADC+PARPi in 3.4% (n=1), CIT in 3.4% (n=1), and HER2-directed in 3.4% (n=1); 10.3% (n=3) died before 1L therapy. Median (m)TTP in 1L (n=26) was 7.7 mo (95% CI, 6.0–13.0) and detailed in the Table. Among pts with disease-free interval (DFI) ≤6 mo (n=8), mTTP was 5.1 mos (2.7–NR), with TTP rates of 50.0% (25.0–100.0) at 6 mo and 16.7% (2.9–95.3) at 12 mo. In those with DFI 6–12 mo (n=9), mTTP was 9.7 mo (7.4–NR); TTP rates were 88.9% (70.6–100.0) at 6 mo and 25.4% (7.7–83.8) at 12 mo. For DFI >12 mo (n=9), mTTP was 8.6 mo (5.6–NR), with TTP rates of 71.4% (44.7–100.0) at 6 mo and 28.6% (8.9–92.2) at 12 mo. Among pts treated with 1L ADC (n=16), mTTP was 8.6 mo (7.4–NR); TTP rates were 77.9% (58.4–100.0) at 6 mo and 26.0% (9.9–68.3) at 12 mo. In non-ADC-treated pts (n=10), mTTP was 6.2 mo (3.78–NR), with TTP rates of 60.0% (36.2–99.5) at 6 mo and 20.0% (5.8–69.1) at 12 mo. Median overall survival (from diagnosis) among pts with relapse was 26.3 mo (95% CI, 25.0–NR). Conclusions: Relapse after NCIT was predominantly early with poor metastatic outcomes, underscoring an urgent need for new strategies in this population largely excluded from clinical trials. Any NCIT(n = 216) KEYNOTE-522(n = 176) 1L for metastatic TNBC(n = 26) Time from NCIT start (mo) BC-EFS % (95% CI) Event N BC-EFS % (95% CI) Event N Time from 1L start (mo) TTP survival % (95% CI) Event N 6 100.0(100.0, 100.0) 0 100.0(100.0, 100.0) 0 6 70.8(54.6, 91.7) 7 12 95.4(92.5, 98.4) 9 95.0(91.7, 98.4) 8 12 23.6(11.0, 50.5) 17 18 89.4(84.9, 94.0) 19 89.7(84.9, 94.8) 15 18 14.2(5.0, 40.3) 19 24 86.4(81.3, 91.8) 23 86.0(80.3, 92.2) 19 24 9.4(2.5, 35.2) 20 36 79.9(72.2, 88.3) 27 82.2(74.8, 90.3) 21

INTRODUCTION:Recent advances in HER2-directed therapies have improved outcomes for patients with HER2+ advanced/metastatic breast cancer (a/mBC), but disease progression ultimately occurs in most cases. Dual targeting of HER2 with tyrosine kinase inhibitors and antibody-drug conjugates has the potential for non-cross-resistant treatments that improve disease control. METHODS:HER2CLIMB-04, a single-arm, open-label, phase 2 study, evaluated tucatinib plus trastuzumab deruxtecan (T-DXd) in patients with HER2+ a/mBC who experienced disease progression on or were intolerant of previous HER2-directed therapy and a taxane. Patients with stable or progressing brain metastases (BMs) were permitted. The primary endpoint was confirmed objective response rate (cORR) by the investigator. Secondary endpoints included duration of response (DOR), progression-free survival (PFS), overall survival (OS), and safety. RESULTS:A total of 70 patients (median age 57 years, median 2 prior lines for a/mBC) received tucatinib 300 mg orally BID and T-DXd on day 1 of each 21-day cycle. The cORR was 51.4% with a median DOR of 11.9 months (95% CI, 6.0-not estimable); median PFS was 11.5 months, and OS was 28.4 months. The most common treatment-emergent adverse events were diarrhea (80.0%), nausea (77.1%), and fatigue (72.9%). Antidiarrheal prophylaxis, introduced for 44 patients, was associated with reduced any grade diarrhea. Survival outcomes in patients with or without BMs are described. CONCLUSION:Although the addition of tucatinib to T-DXd did not demonstrate a clear benefit compared with previously demonstrated T-DXd monotherapy efficacy, when given with antidiarrheal prophylaxis, the combination was tolerable and showed clinical activity in patients with HER2+ a/mBC. CLINICAL TRIAL NUMBER:NCT04539938.

Background:A subset of breast cancer patients will eventually develop leptomeningeal disease (LMD). There is a lack of large, in-depth analyses of the pattern of care and outcomes, with a particular focus on radiation therapy (RT). We report our experience in interdisciplinary LMD management, specifically addressing the role of RT. Materials and methods:This multicenter study analyzed female breast cancer patients with LMD treated at three academic centers between 2005 and 2020. Results:A total of 232 LMD patients were included. The median age at LMD diagnosis and Karnofsky performance status (KPS) were 54.5 years and 80%, respectively. Most patients presented with LMD localized in the brain (53.8%), underwent RT (66.4%), and received systemic therapy (61.6%). One hundred fifty-four patients received 205 RT courses, with whole-brain RT used most often (120 treatments, 58.5%). With a median follow-up of 4.5 months (range 0.1-72.0 months), 220 deaths were observed. The median overall survival (OS) was 4.7 months (95% confidence interval: 3.9-5.5). RT was not associated with improved OS and showed heterogeneous interactions across clinical contexts. Systemic therapy was associated with improved OS, especially in patients with a poor KPS. Discussion:This study highlights the dismal prognosis of LMD. RT was not associated with improved OS. Our findings, along with the reviewed literature, demonstrate that determining the potential benefit of RT on OS is challenging due to interactions between treatments and their timing, underscoring the need to clarify the optimal use and timing of RT in randomized clinical trials.

1083 Background: Pts with HR+ MBC exhibit variable responses to 1L ET + CDKi therapy. We analyzed clinicopathologic features and genomic landscapes of biopsies obtained at the time of the diagnosis of MBC to identify determinants of sensitivity/resistance to 1L CDKi, with a focus on distinguishing endocrine-sensitive from endocrine-resistant (ETR) disease. Methods: A single center cohort included pts with biopsies obtained within 3 months of diagnosis of HR+, HER2-negative MBC (distant recurrent and de-novo [DNIV]), diagnosed between 2013 - 2020. Tumors underwent targeted DNA sequencing (OncoPanel). Clinical data were obtained from the EMBRACE database. Results: The entire cohort included 666 pts, of them 321 (48%) treated with 1L ET + CDKi. Among pts who received adjuvant ET (n = 347), 54 (15.6%) had primary ETR, 140 (40.3%) secondary ETR, and 153 (44.1%) were endocrine-sensitive. Of these pts, 56% (n = 191) received 1L CDKi therapy. The median time to next treatment (TTNT) in pts treated with 1L CDKi differed significantly by disease presentation, with a median of 1.3 years (95% CI, 0.9–1.5) for recurrent MBC and 2.3 years (95% CI, 1.7–3.6) for DNIV (log-rank p = 0.0005). TTNT also varied significantly according to endocrine sensitivity, with median TTNT of 0.6, 0.9, and 1.8 years for primary ETR, secondary ETR, and endocrine-sensitive disease, respectively (p = 0.0005). In the entire cohort, SNVs/indels were most frequent in PIK3CA , TP53 , and CDH1. CCND1 , FGFR1 , and MYC amplifications were most frequent amplifications. TP53 and ESR1 mutations were enriched in ETR tumors, compared with ET sensitive cancers (q < 0.2). ESR1 mutations were detected in 15% of ETR tumors, versus 8% in endocrine-sensitive cancers and 3% in DNIV. Prior adjuvant aromatase inhibitor exposure occurred in 39%, 61%, and 44% of patients with primary ETR, secondary ETR, and ET-sensitive tumors, respectively. When comparing poor and exceptional responders to 1L CDKi, TTNT <6 months versus >36 months, mutations in TP53 and N F1 were significantly enriched in the poor responders (q < 0.2). We also evaluated the association between specific genomic alterations and TTNT on 1L CDKi; mutations in TP53 , NF1 , and ERBB2 , as well as amplifications of RAD21 , FGFR1 and deletions of RB1 , CDKN2A were associated with shorter TTNT on 1L ET plus CDKi (q < 0.2). Conclusions: In our cohort, distinct genomic alterations were associated with ETR and shorter TTNT on 1L CDKi. These findings underscore the biology of ETR and support the clinical relevance of early genomic profiling to refine risk stratification and guide therapeutic decision-making. Notably, the high prevalence of ESR1 alterations in ETR tumors carries important implications for adjuvant and 1L treatment strategies, particularly the potential role of oral selective estrogen receptor degraders in this setting.

Abstract Background Leptomeningeal disease (LMD) in metastatic breast cancer (MBC) patients (pts) remains a therapeutic challenge and is associated with a poor prognosis. Data on the efficacy of novel CNS-active agents, such as trastuzumab deruxtecan (T-DXd), in this setting are limited. Methods We are conducting a prospective observational registry that accrues MBC pts with LMD after giving informed consent. We collect clinical data as well as blood and cerebrospinal fluid (CSF) samples. Descriptive analyses were conducted on the cohort enrolled to date. We report time-on-treatment with T-DXd calculated with Kaplan–Meier estimation using SPSS. Results To date, 28 women with MBC (14 [50%] HR+/HER2-, 2 [7.1%] HR+/HER2+, 5 [17.9%] HER2+/HR-, 7 [25%] triple-negative) diagnosed with LMD (median age at LMD diagnosis 53 years [range 32-70]) have been accrued. The median time from MBC to LMD diagnosis was 22 months (range 0-90). As first-line treatment approach for LMD, 13 (46.4%) pts received radiation, followed by systemic therapy in 10 (35.7%) pts, while 15 (53.6%) pts received systemic therapy only. Fourteen (50%) pts were treated with T-DXd after LMD diagnosis, of which 9 pts were classified as HER2-low (HER2 IHC 1+ or 2+ FISH negative). Eight pts discontinued T-DXd for disease progression and two for toxicity, while four pts remain on T-DXd. The median time-on-treatment with T-DXd was 6.0 months (95% CI 2.3-9.7). Seven of 14 (50%) pts treated with T-DXd were deceased. CSF was collected in 13/28 (46%) pts of which 7 had successful NGS testing of CSF. Targetable genomic alterations were detected in 6/7 pts. Conclusions In this prospective registry, T-DXd demonstrated encouraging activity in MBC pts with LMD, including the HER2-low subset. We show the feasibility of CSF-based molecular profiling to identify actionable alterations in LMD.

Unique disease characteristics of younger patients warrants investigation of tumor genomics in young-onset metastatic breast cancer (MBC). Targeted DNA sequencing was completed for tumors of MBC patients diagnosed between 2009-2020. Multivariable logistic regression tested associations between single nucleotide variants (SNVs) and copy number variants and age at MBC diagnosis. Multivariable Cox regression estimated hazard ratios for overall survival (OS) by somatic alterations. Among 2,357 MBC patients, tumors of those ≤40 years at diagnosis (vs. >55) were more likely to harbor amplifications in ERBB2 and MYC (p < 0.01) and mutations in TP53 (odds ratio [OR] = 1.83, p < 0.001), and less likely to harbor mutations in CDH1 and PIK3CA (p < 0.001). OS was shorter among younger recurrent MBC patients [median: 2.8 (≤ 40) vs. 3.6 years ( > 55), p = 0.04], with SNVs in TP53 and PTEN associated with shorter OS. Distinct tumor genomics of young-onset MBC patients suggest differences in tumor biology that should guide investigation of targetable pathways.

The intestinal microbiome shapes immune responses and is associated with patient outcomes in cancer following immunotherapy. We evaluated differences between the intestinal microbiome profiles of patients with early-stage invasive breast cancer (BC) and ductal carcinoma in situ (DCIS) by subtype using whole genome metagenomic sequencing. There were no significant differences in microbiome composition between DCIS and invasive BC as measured by alpha diversity (p = 0.20, ANOVA) or beta diversity (p = 0.52, PERMANOVA). Within invasive BC, patients with hormone receptor-positive (HR + )/HER2 + BC differed significantly in beta diversity relative to other subtypes (p < 0.05), with differences in six species (q < 0.25). Bacteroides ovatus was significantly more abundant in patients with stage III BC vs. stage I (p = 0.0003). Functional pathway analysis using HUMAnN3 revealed stage-specific enrichment of amino acid biosynthesis and nucleotide-related pathways. Altogether, these findings highlight potential microbial signatures associated with BC subtype and stage.

BACKGROUND:Whether outcomes of germline BRCA1/2 (gBRCA1/2)-associated breast cancer differ compared with sporadic tumors is controversial. We explored the impact of gBRCA1/2 pathogenic variant (PV) status beyond established prognostic features. METHODS:We conducted 2 retrospective, matched cohort studies comparing gBRCA1/2 PV carriers and noncarriers with HER2-negative, stage I-III breast cancer (Clinical Outcomes Quality Database [COQD] cohort: 185 carriers, 555 noncarriers; Young Women's Breast Cancer Study [YWS] cohort: 113 carriers, 226 noncarriers). Matching factors were age, stage, hormone receptor status, and year of diagnosis. Clinicopathological features, treatments, and survival outcomes were compared between carriers and noncarriers. RESULTS:Most patients in COQD had stage I-II disease (87.2%), and more carriers than noncarriers had genetic testing before diagnosis (33% vs 5.6%, P < .001). In YWS, 22.7% of patients had stage III tumors, and few were tested before diagnosis (14.8% of carriers vs 1.7% of noncarriers; P < .001). Carriers in COQD received chemotherapy more often than noncarriers (81.1 vs 67.0%, P < .001), including platinum (P = .010); the proportion was similar for carriers and noncarriers in YWS. After adjusting for chemotherapy, relapse-free survival was longer in carriers than noncarriers in COQD (adjusted hazard ratio = 0.48 [95% CI = 0.26 to 0.87], P = .016), and a favorable trend was observed for other survival outcomes in both cohorts. Triple-negative tumors appeared to drive the differences. CONCLUSIONS:We observed a trend toward improved outcomes in gBRCA1/2 PV carriers compared with noncarriers. These findings suggest that carriers should not receive more aggressive treatment solely based on their germline mutation status. Prospective clinical trials in this population are warranted.

Abstract Brain metastases (BM) represent a significant unmet need in ER+/HER2– mBC. Although endocrine therapy (ET) plus CDK4/6i is the 1L systemic treatment, most agents have limited BBB penetration, and tumors eventually develop resistance to ET, leading to disease progression. Elacestrant is the only single-agent oral SERD to significantly improve PFS versus standard-of-care ET in the EMERALD trial in both the overall population (HR = 0.70; 95% CI:0.55-0.88; P = 0.0018) and in patients with ESR1-mutant tumors (HR = 0.55; 95% CI:0.39-0.77; P = 0.0005), with a manageable safety profile (Bidard, 2022). Preclinical data demonstrate both elacestrant and abemaciclib cross the BBB (Conlan, 2020; Tolaney, 2020), providing a rationale for evaluating this combination in patients with BM. ELECTRA (NCT05386108) is an open-label, multicenter, phase 1b/2 study evaluating elacestrant plus abemaciclib in patients with BM from ER+/HER2– breast cancer. Eligibility includes locally advanced/mBC with ≥1 active, measurable BM (RECISTv1.1), prior therapy in the metastatic setting including ≥1 ET, ≤2 chemotherapy regimens, and 0-2 prior CDK4/6i (excluding abemaciclib). Phase 1b established the RP2D. Phase 2 primary endpoint is ORR (RECISTv1.1). Secondary endpoints include iORR, DoR, CBR, PFS, OS, PK, and QoL. Exploratory endpoints include CSF PK of elacestrant plus abemaciclib. This analysis reports phase 2 CSF PK results. In evaluable patients (n = 7), elacestrant achieved clinically meaningful CSF concentrations, with levels exceeding the target engagement threshold in 50% of patients. Abemaciclib attained CSF levels sufficient for CDK4/6 inhibition. These findings confirm that the combination achieves pharmacologically relevant drug exposure in the CNS. Updated safety, and clinical efficacy data, including intracranial-response assessments, will be presented (n = 33). Both elacestrant and abemaciclib successfully penetrated the BBB, achieving clinically meaningful CSF concentrations in most patients. These PK data support the continued evaluation of this all-oral BBB-penetrant combination for patients with ER+/HER2– mBC and BM. The phase 2 portion of ELECTRA is actively enrolling worldwide.

TPS1147 Background: Due to dramatic improvements in neoadjuvant and adjuvant HER2-directed therapy (tx), most patients (pts) with early HER2+ breast cancer are cured. As a result, over half of pts newly diagnosed with HER2+ metastatic breast cancer (MBC) now present with de novo stage IV disease. Anti-HER2 tx has also significantly extended survival for pts with HER2+ MBC, with a subgroup of exceptional responders alive many years (yrs) after diagnosis. However, the paradigm for HER2+ MBC remains non-curative, and pts receive tx indefinitely with significant toxicities and costs. The SAPPHO study is investigating whether an intensification approach of sequential, non-cross resistant anti-HER2 tx followed by tx discontinuation is associated with long-term disease control in pts with HER2+ MBC. Methods: SAPPHO is an open-label, phase II, single-arm trial testing a sequential regimen of non-cross resistant, HER2-targeted tx with curative intent in pts with de novo HER2+ MBC. Eligible pts must have biopsy-proven, de novo MBC with high HER2 expression (3+ by immunohistochemistry). Pts with brain metastases are eligible upon receipt of local tx. Treatment consists of an induction regimen (trastuzumab-pertuzumab-taxane [THP] x 4 cycles, followed by trastuzumab deruxtecan [TDXd] x 6 cycles, followed by trastuzumab emtansine [TDM1]-tucatinib x 4 cycles), followed by a maintenance regimen (HP-tucatinib for 1 yr). Given results from DESTINY-Breast09, the sequence of TDXd-P x 6 cycles followed by THP x 4 followed by TDM1-tucatinib x 4 can be chosen as alternative induction tx per investigator and patient choice. Pts who remain progression-free after completing maintenance will stop all anti-HER2 tx. Endocrine tx will be continued for pts with hormone receptor+/HER2+ tumors. Tumor specimens from breast and a metastatic site are collected at baseline and the end of induction. Serial plasma samples for ctDNA analysis are collected at baseline, during treatment, and during follow-up. The primary endpoint is the probability of being progression-free and off anti-HER2 tx 4 yrs from the start of induction. With a sample size of 72 pts, the study is designed to have 91% power to reject the null hypothesis that the probability of being off anti-HER2 tx and progression-free is less than 24%, with an alternative hypothesis of 40%. Key secondary endpoints are overall survival, overall response rate by modified RECIST 1.1 after induction, and safety. Correlative endpoints include the relationship between ctDNA dynamics and outcomes. Patient-reported outcomes will be analyzed, including quality of life, illness intrusiveness, financial toxicity, anxiety, distress about cancer progression, perception of benefit and risk of progression. SAPPHO began enrollment in Q3 2024, and the study is open at 4 US sites within the Translational Breast Cancer Research Consortium (NCT05721248). Clinical trial information: NCT05721248 .

Abstract Background Invasive lobular carcinoma (ILC) exhibits distinct biological and metastatic behavior compared with invasive breast carcinoma of no special type (BC-NST), yet patterns of central nervous system (CNS) dissemination remain incompletely defined. We examined determinants of CNS metastases and LMD to assess whether histology confers independent CNS risk. Methods Retrospective analysis using data from EMBRACE, a prospectively maintained cohort of patients with metastatic BC (mBC). Patients with BC-NST or ILC were included. CNS mets was defined as parenchymal brain mets and/or leptomeningeal disease (LMD). Associations between histology and CNS mets or LMD were evaluated using logistic regression. Multivariable models were adjusted for age, tumor grade, hormone receptor status, HER2 status, and de novo versus recurrent presentation. Results 3835 patients with mBC (3247 BC-NST; 588 ILC) were included (median follow-up, 16.4 years). Overall, 78.2% had recurrent disease; subtype distribution was HR+/HER2 − (61.2%), HER2 + (19.7%), and TNBC (19.1%). CNS mets occurred in 26.4% of BC-NST and 17.5% of ILC cases. ILC was associated with lower odds of CNS mets in unadjusted analyses (OR 0.59; 95% CI, 0.47–0.74) but not after adjustment (OR 1.08; 0.83–1.41). No histology-based difference was observed in HER2+ disease. Among HER2− tumors, CNS mets were less frequent in ILC than BC-NST (OR 0.63; 0.49–0.81), driven by TNBC (OR 0.25; 0.06–0.74), with no difference in HR+/HER2−. In multivariable models, CNS mets were associated with younger age, higher grade, ER/PR-negative status, HER2+ disease, and recurrent presentation. LMD occurred in 5.7% of BC-NST and 11.1% of ILC cases and was more frequent in ILC in adjusted analyses (OR 3.52; 2.44–5.05). Conclusion Histology differentially influences CNS dissemination in mBC. Although the lower CNS metastasis risk in ILC can be explained by tumor and clinical factors, ILC remains independently associated with a markedly higher risk of LMD.

Patients with triple-negative breast cancer (TNBC) are encouraged to consider clinical trials given limited treatment options, yet little is known regarding barriers to trial participation in this population. We examined whether patient-level factors, including disease knowledge, were associated with TNBC patients’ participation in trials. From a prospective multicenter registry of patients with newly-diagnosed TNBC, we identified those with stage I-III tumors who completed at least one survey assessing TNBC knowledge, risk perceptions, treatment rationales, and participation in trials. Accuracy of tumor characteristics reported by patients was verified with medical records. Logistic regression was used to identify factors associated with self-reported trial participation. TNBC knowledge varied among patients, with many reporting their tumor characteristics incorrectly and/or underestimating their recurrence risk. Among 116 patients with trial participation responses, 55 (47

Social determinants of health (SDOH) and health-related social needs (HRSN) impact cancer outcomes, yet few programs systematically address these needs. We examined the feasibility of routine assessment of SDOH/HRSN within a clinical metastatic breast cancer (MBC) program and subsequent linkage to support services. We approached patients with MBC seen at an NCI-designated center from January-October 2023 who were ≤ 6 months from MBC consultation or diagnosis. Enrolled participants were administered a baseline survey of SDOH/HRSN, referred to appropriate services, and surveyed again at 3–6 months. Outcomes included feasibility of SDOH/HRSN documentation (defined as ≥ 80