Mayer, Erica L.

12010 Background: BWEL (Alliance A011401; NCT02750826) is a Phase III trial that randomizes patients (pts) with stage II-III breast cancer and body mass index (BMI) ≥27 kg/m 2 1:1 to a 24-month (mo) lifestyle-based WLI + health education (HE) or HE alone. Here we report prespecified secondary outcomes of the impact of the WLI on patient-reported QOL and symptoms. Methods: The first 540 BWEL pts (randomized between 9/2016 and 7/2017) were included in this substudy that collected PROMIS 29 Profile 2.0 and Global Health scores at enrollment, 6 and 24 mos. Adjusting for baseline scores, mean physical function (predefined substudy primary outcome), global physical and mental health, fatigue and other scores were compared at 6 and 24 mos using analysis of covariance (ANCOVA). P-values <0.05 were considered significant. Positive differences in positive attributes (e.g., physical function) and negative differences in negative attributes (e.g., anxiety) represented better outcomes in the WLI arm. Results: At baseline, median BMI was 32.9 kg/m 2 (26.5 – 69.1), median age was 53 (25 - 78) years; 83.9% of pts were non-Hispanic White, 10.7% were Black and 5.9% were Hispanic. At 6 mos, the WLI (vs HE) arm had significantly better physical function (ANCOVA-based mean difference between arms 1.9 [95% CI 0.8, 3.0]; p<0.001), global physical health (2.0 [95% CI 0.9, 3.0]; p<0.001), global mental health (1.30 [95% CI 0.2, 2.4], p=0.03), social roles and activities (2.3 [95% CI 1.1, 3.6]; p<0.001), and fatigue (-1.7 [95% CI -3.1, -0.4], p=0.01) (Table). Improvements were generally maintained at 24 mos. Similar findings were seen in analyses using longitudinal mixed modeling. Conclusions: The BWEL WLI demonstrated QOL benefits for patients with breast cancer, resulting in significantly better physical function, global physical and mental health, and symptoms. Future analyses will evaluate which populations experienced the most benefit, as well as the relationships among QOL, symptoms, and weight loss. Support: U10CA180821, U10CA180882, UG1CA189823; U10CA180820; U10CA180868; U10CA180863, CCS 707213; U10CA180888; UG1CA189858; https://acknowledgments.alliancefound.org. Clinical trial information: NCT02750826 . Analysis of covariance-adjusted least squares means values at 6-mos adjusted for baseline scores. QOL/Symptom Attributes HE WLI Between arm difference (95% CI)* P value Physical Function 47.1 49.0 1.9 (0.8, 3.0) <0.001 Global Physical Health 46.2 48.1 2.0 (0.9, 3.0) <0.001 Global Mental Health 48.6 49.9 1.3 (0.2, 2.4) 0.03 Social Roles and Activities 52.7 55.0 2.3 (1.1, 3.6) <0.001 Anxiety 50.2 50.0 -0.2 (-1.6, 1.2) 0.77 Depression 47.5 47.5 -0.0 (11.2, 1.2) 0.96 Fatigue 50.6 48.9 -1.7 (-3.1, -0.4) 0.01 Sleep Disturbance 51.0 51.1 0.1 (-0.6, 0.8) 0.80 Pain Interference 51.3 50.3 -1.0 (-2.4, 0.4) 0.15 *Positive differences in positive attributes and negative differences in negative attributes favor WLI arm.

1024 Background: Invasive lobular carcinoma (ILC) is a distinct breast cancer (BC) subtype with dissemination patterns differing from invasive breast carcinoma of no special type (IBC-NST). While genomic differences between ILC and IBC-NST have been described, the extent to which molecular and immune profiles vary by metastatic organ and histology is poorly characterized. Methods: We conducted a retrospective analysis to evaluate organ- and histology-specific molecular features of metastatic BC (mBC). Patients with metastatic IBC-NST or pure ILC underwent NGS (592, NextSeq; WES/WTS, NovaSeq; Caris Life Sciences). Tumor mutational burden (high ≥10 mut/Mb), PD-L1 expression (22C3), and immune cell fractions (RNAseq deconvolution, quanTIseq) were assessed. Analyses were restricted to sites with ≥10 biopsies per histology. Comparisons used chi-square or Mann–Whitney U tests with multiple testing correction (q < 0.05). Results: A total of 2645 mBC biopsies (605 ILC; 2040 IBC-NST) were analyzed (Table). In ILC, ERBB2 mut frequency differed by metastatic site (q<0.01), with higher prevalence in liver (32.7%) and lower in gastrointestinal (GI) lesions (3.7%). In IBC-NST, ESR1 and GATA3 mut and FGFR1 amplification were enriched in liver metastases, whereas PD-L1 expression was highest in skin (20.7%) and lowest in liver (5.0%). No organ-specific differences were observed for PIK3CA, AKT, PTEN, BRCA1/2 or RB1 . Across metastatic sites, both ILC and IBC-NST showed differences in B cells, macrophages (M1/M2), neutrophils, NK cells, dendritic cells, CD8+ T cells, and Tregs (all q < 0.05); CD4+ T-cell differences were observed only in IBC-NST (q = 0.002). In organ-specific ILC vs IBC-NST comparisons, CDH1 mut were more frequent in ILC across sites, along with higher PIK3CA mut in skin (ILC 51.3% vs IBC-NST 34.4%) and higher ERBB2 mut in liver (32.7% vs 3.3%), whereas a higher TP53 mut frequency was observed in IBC-NST in skin (28.5% vs 52.3%) and lymph nodes (LND) (23.5% vs 55.5%) (all q < 0.01). Conclusions: mBC exhibits marked organ-specific molecular and immune heterogeneity that differs by histology. These findings support histology- and site-aware interpretation of metastatic biopsies and may inform biomarker assessment and treatment decisions in advanced disease. BC-NST ILC Skin LND Bone Breast Liver Perit. CNS q-value Skin LND Bone Breast GI Liver GYN Perit. CNS q-value N (specimens) 785 401 109 361 220 15 44 - 172 84 62 56 56 54 43 37 11 - ERBB2 mut (%) 3.2 3.1 3.2 2.3 3.3 7.1 2.5 1.0 7.1 7.4 16.4 15.4 3.7 32.7 2.4 5.7 11.1 <0.01 ESR1 mut (%) 9.4 5.2 8.3 16.0 28.2 7.1 2.4 0.0 7.8 7.2 8.9 9.8 16.7 26.0 4.9 20.0 0.0 0.9 FGFR1 amp (%) 10.1 6.6 5.6 12.8 16.5 0.0 9.7 0.02 4.4 3.4 6.7 6.1 2.4 5.6 7.7 18.5 0.0 1.0 IHC-PD-L1 (%) 20.7 - 5.3 16.0 5.0 11.1 10.3 0.02 8.9 - 5.0 5.7 6.1 0.0 0.0 0.0 14.3 1.0 TMB-High (%) 10.7 10.1 8.8 8.8 8.5 14.3 21.4 0.8 27.6 11.0 19.6 28.0 11.3 19.6 9.8 32.4 22.2 0.8 Perit: peritoneum; CNS: central nervous system; GYN: genital tract.

Abstract Background Breast cancer (BC) diagnosed during pregnancy or postpartum often presents with aggressive features, potentially influenced by hormonal, immunological, and tissue remodeling changes. Studies have suggested that postpartum BC may be associated with worse outcomes, though most evidence is retrospective and constrained by methodological limitations. This study evaluated associations between pregnancy history, recency of childbirth, and long-term outcomes in a prospective cohort of young patients with early-stage BC. Patients and Methods Patients aged ≤40 years with stage I–III BC enrolled in the Young Women’s Breast Cancer Study were categorized at diagnosis as nulligravid, nulliparous, pregnant, or parous (≤5 vs 5 to 10 years postpartum). Analyses were stratified by BC subtype (estrogen receptor-positive [ER+]/HER2−, HER2+, and triple-negative [TNBC]), with distant recurrence-free survival (DRFS) as the primary endpoint. Results Among 859 patients, 257 (29.9%) were nulligravid, 50 (5.8%) nulliparous, 37 (4.3%) pregnant, and 515 (60.0%) parous. Pregnant patients had proportionally more TNBC, nodal involvement, T3/T4, and grade 3 tumors. After 11.1 years median follow-up, pregnancy or postpartum status was not independently associated with DRFS in multivariable models adjusted for age, tumor characteristics, and treatment, with consistent findings across ER+/HER2−, HER2+, and TNBC subtypes. Sensitivity analyses, including further categorization of postpartum diagnoses (&lt;2 vs 2 to 5 years), yielded consistent results. Conclusions Pregnancy history and recency of childbirth were not independently associated with long-term DRFS. Despite more aggressive features at diagnosis, patients diagnosed during or after pregnancy had comparable outcomes after adjustment, suggesting no adverse prognostic impact. Clinical trial registration NCT01468246 (https://clinicaltrials.gov/study/NCT01468246? term=NCT01468246&rank=1).

Abstract The INFORM trial (NCT01670500) was a randomized, two-arm Phase II neoadjuvant study comparing the efficacy of a platinum-based regimen (cisplatin) versus an anthracycline (AC)-based regimen in participants with germline BRCA1/2 mutations and early-stage, HER2-negative breast cancer. MicroRNAs (miRNAs) are emerging as promising non-invasive biomarkers for disease detection and treatment monitoring. The initial aim of this study was to evaluate whether pretreatment plasma miRNA profiles were associated with treatment outcomes in the INFORM trial cohort. Pretreatment plasma samples from 97 INFORM participants (n=53 cisplatin and n=44 AC) were screened for 352 miRNAs commonly implicated in cancer using the qPCR-based ID3EALTM Cancer Panel. Twenty out of 53 participants achieved residual cancer burden (RCB) score of 0 or 1 with cisplatin and 20/44 with AC. Higher plasma miR-362-3p expression was associated with a favorable response to cisplatin (1.7-fold; p&lt;0.01), but not to AC. MiR-362-3p expression in paired pretreatment tumor biopsies (n=79) did not significantly correlate with plasma expression and was not associated with RCB 0/1 (p&gt;0.05). In TCGA, miR-362-3p expression was higher in breast tumors than in adjacent normal tissue, and higher in triple negative breast cancers (TNBCs) compared with hormone receptor-positive tumors (both FDR&lt;0.001), independent of BRCA mutation or Single Base Substitution Signature 3 (SBS3) status. The miR-362-3p findings in INFORM did not replicate in a sister trial, TBCRC 030 (NCT01982448; 11 out of 46 cisplatin-treated patients achieved RCB 0/1, p=0.46). These results suggest that while miR-362-3p is unsuitable as a circulating biomarker for cisplatin response, it may play an important biological role in mediating cisplatin sensitivity in TNBCs, independent of BRCA1/2 mutations. Functional studies demonstrated that miR-362-3p is expressed and secreted by TNBC cell lines, operates as a tumor suppressor, and generally correlates with cisplatin sensitivity. Overexpression of miR-362-3p rendered MDA-MB-231 and CAL-51 cells cisplatin sensitive, while knockdown induced resistance in MDA-MB-436 cells. Ongoing studies are testing whether these effects translate in xenograft models. In silico and functional assays identified BCLAF1, a DNA damage response (DDR) regulator, as a direct target of miR-362-3p. Overexpression of miR-362-3p suppresses BCLAF1 mRNA and protein levels. Our findings demonstrate that miR-362-3p enhances cisplatin responsiveness by targeting BCLAF1. A miR-362-3p-based therapeutic may be useful as a co-agent to enhance tumor responses to platinum-based chemotherapy. Citation Format: Zhaoji Liu, Shizhong Ke, Xiaohui Li, Catherine Wu, Madison M. Uyemura, Brian R. Sardella, Erica S. Massicott, Lin Wang, Emily K. Aronson, Dimitra Karagkouni, Nikolas Kalavros, Ioannis S. Vlachos, Felipe Batalini, Cristina S. Bogsan, Jit Kong Cheong, Lihan Zhou, He Cheng, Phillip Munson, Erica L. Mayer, Judy E. Garber, Stuart J. Schnitt, Nadine M. Tung, Andrea L. Kasinski, Frank J. Slack, Gerburg M. Wulf, Yujing J. Heng. MiR-362-3p enhances platinum response in breast cancer [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 7903.

Abstract Platinum-based chemotherapy remains a cornerstone of treatment for triple-negative breast cancer (TNBC), yet the molecular determinants governing platinum response remain poorly defined. By leveraging the randomized Phase II INFORM trial, which compared neoadjuvant cisplatin to anthracycline-based therapy in BRCA1/2 -mutant breast cancer—we identified miR-362-3p as a specific regulator of cisplatin sensitivity. Higher plasma miR-362-3p expression was exclusively associated with favorable clinical outcome in the cisplatin arm, with no association observed in the AC arm, decoupling platinum-specific vulnerability from general chemotherapy response. We used gain- and loss-of-function TNBC models to establish that miR-362-3p functions as a potent sensitizer to cisplatin in vitro and in vivo . Integrated TCGA analysis and experimental validation identified BCLAF1, a key regulator of DNA damage response, as a direct repression target of miR-362-3p. We uncovered a novel role for the miR-362-3p/ BCLAF1 axis in overcoming platinum resistance in TNBC.

Importance Obesity is associated with a higher risk of recurrence, mortality, comorbidities, treatment-related adverse effects, and poor quality of life in patients with breast cancer. Scalable interventions are needed to promote weight loss in this population. Objective To evaluate the impact of a remotely delivered weight loss intervention (WLI) on weight change at 1 year in patients with breast cancer and obesity and to explore factors associated with weight change. Design, Setting, and Participants The Breast Cancer Weight Loss trial is a phase 3, randomized clinical trial evaluating the impact of a telephone-based WLI on invasive disease–free survival and other outcomes in women with obesity and early breast cancer at 637 sites across the US and Canada. Participants were enrolled to the study between August 2016 and February 2021. Participants included women with stage II to III, ERBB2 -negative breast cancer and a body mass index (BMI) of 27 or higher. Interventions Participants were randomized to a 2-year, telephone-based WLI plus health education or health education alone control group. Main Outcome and Measures The primary end point for this prespecified secondary analysis was weight change at 1 year. Weight was measured at baseline and 1 year, and changes in weight were compared between groups. Weight change was evaluated with a linear mixed-effects model including treatment group, weight over time, a time-by-group interaction, menopausal status, race and ethnicity, and hormone receptor status. Results A total of 3180 women with breast cancer and BMI of 27 and higher were included in the study; 1591 were randomized to the WLI and 1589 to the control group. At baseline, the mean (SD) age of participants was 53.4 (10.6), and the mean (SD) BMI was 34.4 (5.6). The racial and ethnic breakdown included 406 (12.8%) Black, 231 (7.3%) Hispanic or Latino, 2906 (91.4%) non-Hispanic, and 2555 (80.3%) White participants. WLI participants lost a mean of 4.3 kg (95% CI 3.9-4.6 kg), or 4.7% (95% CI, 4.3%-5.0%) of baseline body weight at 1 year vs control participants, who gained 0.9 kg (95% CI, 0.5-1.3 kg), or 1.0% (95% CI 0.1%-1.4%) of baseline body weight ( P &amp;lt; .001). Participants randomized to WLI experienced significant weight loss (vs control group participants) across demographic and tumor factors. WLI effect differed significantly by menopausal status, with postmenopausal participants having greater weight loss than premenopausal participants, and by race and ethnicity, with Black and Hispanic participants having less weight loss compared to other races and ethnicities. Conclusions and Relevance In this secondary analysis of a randomized clinical trial, a telephone-based WLI induced significant weight loss in patients with breast cancer with overweight and obesity across demographic and treatment factors. Further follow-up of the Breast Cancer Weight Loss trial will evaluate whether the WLI improves disease outcomes. Trial Registration ClinicalTrials.gov Identifier: NCT02750826

TPS1125 Background: Despite the many available treatments for patients (pts) with HR+, HER2– recurrent/metastatic breast cancer (MBC), optimal treatment after progression on CDK4/6 inhibitors (CDK4/6i) is unclear. One possible CDK4/6i resistance mechanism is increased expression of Aurora kinase A (AURKA), a key mitosis regulator associated with poor prognosis. Further implicated in CDK 4/6i resistance, high c-Myc or RB1 loss of function (LOF) are associated with transcriptional co-regulation or synthetic lethality, respectively, with AURKA. Alisertib is a highly selective, reversible, ATP-competitive, orally administered, small-molecule AURKA inhibitor with antiproliferative activity in HR+ BC-derived cell lines and BC xenograft models. Models with elevated AURKA or c-Myc expression, or RB1 LOF show greater alisertib sensitivity. Alisertib had activity in phase 1 and 2 trials, including objective response rates (ORRs) of 19.6–20% and median progression-free survival (PFS) of 5.4–5.6 months alone or with fulvestrant in pts with HR+/HER2–, endocrine-resistant MBC. The most common treatment-related grade ≥3 adverse events (AEs) were neutropenia, anemia, and leukopenia. Methods: ALISCA-Breast1 (NCT06369285) is a randomized phase 2 study. Primary objective: to determine the optimal alisertib dose administered with endocrine therapy (ET) based on AEs and serious AEs per CTCAE v5.0 and efficacy (ORR, duration of response, disease-control rate, PFS, overall survival). Secondary objectives: to identify biomarkers of efficacy and alisertib pharmacokinetics (PK). Key inclusion criteria: ≥18 years; ECOG performance status 0 or 1; confirmed HR+, HER2–, recurrent/metastatic breast adenocarcinoma not amenable to curative therapy; available tumor tissue for biomarker analyses; progression on or after ≥2 prior ET lines in recurrent/metastatic setting; prior CDK4/6i with ET in recurrent/metastatic setting. Key exclusion criteria: prior chemotherapy in recurrent/metastatic setting; prior AURKA-specific or pan-Aurora-targeted agents; unstable brain metastases. Eligible pts will be randomized 1:1:1 to alisertib 30 mg, 40 mg, or 50 mg orally twice daily on days 1−3, 8–10, and 15–17 every 28 days, plus physician’s choice of anastrozole, letrozole, exemestane, fulvestrant, or tamoxifen not previously used in recurrent/metastatic setting or progressed upon in adjuvant setting; ≤50 pts will be enrolled per arm in the USA and Europe. All pts will undergo sparse PK sampling. Tumor tissue will be centrally assessed for biomarkers, including RB1, MYC, TP53, ESR1, PI3K/AKT pathway, HER2 and AURKA genomic alterations/expression levels. The study will determine the optimal alisertib dose to combine with ET and may identify biomarker(s) defining pts with the greatest benefit from alisertib-based therapy. Clinical trial information: NCT06369285 .

1586 Background: Black and Hispanic breast cancer (BC) survivors have a higher prevalence of obesity and experience less success with weight loss interventions (WLI) than White BC survivors. The BWEL trial (Alliance A011401; NCT02750826) is a phase III randomized trial evaluating the impact of a 2-year telephone-based WLI on invasive disease-free survival in participants (pts) with stage II-III HER2-negative BC and a BMI ≥ 27 kg/m 2 . At 12-months, the WLI induced significant weight loss across demographic factors, including race and ethnicity. However, Black and Hispanic pts lost less weight and completed fewer calls than White pts. Here, we evaluate intervention adherence, engagement and tool utilization in BWEL pts by race and ethnicity. Methods: BWEL randomized pts to a WLI plus health education (HE) or HE alone. WLI pts received semi-structured telephone-based health coaching, delivered in English or Spanish, and received an activity monitor and wireless scale. Pts self-reported race and ethnicity. Mean values for call duration, call density (time to complete the initial 12-week intensive intervention phase), intervention attrition, and frequency of Fitbit use and weight tracking over 12-months were compared by race and ethnicity, comparing least squares means with Tukey-Kramer adjustment for multiple comparisons with adjusted p-values. Results: Of 3181 pts randomized to the study between 08/2016 and 02/2021, 1591 pts were allocated to the WLI arm. 80.5% of pts were White, 12.8% Black, and 7.1% Hispanic. Average BMI was 34.5 (±5.7) kg/m2. Compared to White pts, Black pts had fewer days of Fitbit usage (113.6 vs. 159.8, p<0.0001) and weight tracking (77.9 vs. 135.6 days, p< 0.0001). Hispanic pts had fewer days of Fitbit usage (108.8 vs. 154.9, p= 0.001) and weight tracking (87 vs. 129.5 days, p=0.0002) compared to non-Hispanic pts. There were no differences in attrition rate, average call duration, or call density by race or ethnicity. Conclusions: In a phase III WLI trial, engagement with tools designed to support weight loss was significantly lower in Black and Hispanic pts. Future work is needed to explore ways to enhance engagement and improve weight loss outcomes for racial and ethnic minority pts. Support: U10CA180821, U10CA180882, UG1CA189823; https://acknowledgments.alliancefound.org . Clinical trial information: NCT02750826 . Measure of engagement Race Ethnicity WhiteN=1281 BlackN=204 p-value Non-HispanicN=1459 HispanicN=113 p-value Withdrew from intervention n (%) 58 (4.5%) 13 (6.4%) 0.56 70 (4.8%) 6 (5.3%) 0.51 Call Duration (min)Mean (SD) 34.5 (7.6) 34.6 (9.1) 0.99 34.6 (7.8) 33.3 (7.9) 0.25 Call density(weeks)Mean (SD) 14.2 (7.2) 14.2 (8.8) 0.99 14.2 (7.3) 14.2 (9.7) 0.99 Days of Fitbit UseMean (SD) 159.8 (132.2) 113.6 (124.7) < 0.0001 154.9 (131.8) 108.8 (125.7) 0.001 Days of weight trackingMean (SD) 135.6 (109.5) 77.9 (87.5) < 0.0001 129.5 (108.8) 87 (96.5) 0.0002

526 Background: The PALLAS trial (NCT02513394) investigated the efficacy of the addition of palbociclib (palbo) to standard adjuvant endocrine therapy (ET) to reduce breast cancer recurrence. Previous analyses of this trial have not shown significant benefit of combination palbo+ET over ET alone. Given prior data showing that extent of neutropenia is associated with response to palbo and other cell cycle-specific therapies, we evaluated whether extent of neutropenia could identify responders to palbo in the adjuvant setting. Methods: PALLAS is a global, open-label, phase III trial that randomized patients (pts) with stage II-III hormone-receptor positive, HER2-negative breast cancer to receive ET for ≥5 years with or without standard-dose palbo for 2 years in 28-day cycles. The primary endpoint is invasive disease-free survival (iDFS). For this exploratory analysis, the palbo population was classified into pts with treatment-emergent high-grade neutropenia (HGN) with maximum grade ≥3 (absolute neutrophil count <1000), or low-grade/no neutropenia (LGN) with maximum grade <2; these groups were compared to each other and to the ET alone group for 5-year iDFS outcomes. Logistic regression examined individual baseline characteristics associated with HGN during the first 3 cycles within the palbo group. Impact of HGN during the first 3, 6, and 12 cycles on iDFS was tested using univariate and multivariable landmark Cox regression. Results: The safety population included 5736 pts, 2840 allocated to palbo+ET, 2896 to ET alone. Prior publications reported no new safety signals, low rates of serious infection, and no grade 5 treatment-related events. The palbo+ET group consisted of 1006 (35.4%) LGN and 1834 (64.6%) HGN. 5-year iDFS results are shown in the table. Pts who received palbo+ET and developed HGN by the end of cycle 6 had significantly improved 5-year iDFS compared to those who received ET alone (p=0.04), which remained statistically significant when adjusting for body mass index (BMI), prior chemotherapy, and race. Multivariable logistic regression showed lower BMI, prior chemotherapy, Asian race, and prior mastectomy were significantly associated with HGN (all p<0.05). Conclusions: In this exploratory analysis of the phase III PALLAS adjuvant trial, addition of palbo to ET appeared to be superior to ET alone in pts who developed HGN in the first 6 cycles of treatment but not in those who had LGN. These findings are consistent with observations in the metastatic setting suggesting that neutropenia could be a useful biomarker for palbo concentration and efficacy. Clinical trial information: NCT02513394 . Maximum grade neutropenia measured at end of cycle: 5-year iDFS Palbo+ET HGN (%) Palbo+ET LGN (%) ET alone (%) Hazard Ratio p-value 3 84.9 84.4 1.06 0.54 84.9 82.9 1.17 0.06 6 85.6 84.9 1.08 0.44 85.6 83.4 1.19 0.04 12 86.3 85.9 1.06 0.57 86.3 85.0 1.12 0.20

561 Background: Obesity and other lifestyle factors are associated with breast cancer (BC) risk and outcomes. These relationships appear to vary in pre- vs postmenopausal women. Here we explore associations between pathological features, diet quality and physical activity (PA) in patients (pts) with BC enrolled in the BWEL (Alliance for Clinical Trials in Oncology A011401) trial, stratifying for menopausal status. Methods: BWEL is a phase III trial evaluating the impact of a weight loss intervention on disease outcomes in 3180 pts with stage II-III HER2– BC and body mass index ≥27 kg/m 2 . The first 542 BWEL pts underwent assessment of PA (7-Day PA Recall) and diet (24-hour Diet Recall) at enrollment. Healthy Eating Index 2020 (HEI) score (0-100, higher value = healthier diet) and minutes/week (min/wk) of moderate/vigorous PA (MVPA) were calculated. Estrogen receptor (ER) and progesterone receptor (PR) expression level (%) were abstracted from pathology reports. Analyses of links between HEI score, MVPA min/wk, % ER/PR, stratified by menopausal status, were conducted using t-tests; differential associations by menopausal status used linear regression models with interaction term. Results: In 523 pts with available pathology data, 76.5% had ER/PR+ BC, 56.2% were postmenopausal. Median HEI score was 50.1 (range 18.1-96.4), median MVPA min/wk was 0 (range 0-630), median time from diagnosis to enrollment was 10.0 months (range 2.4-13.1). In postmenopausal pts, higher diet quality was linked to increased % ER and PR (HEI above vs below median, mean % ER 78.0 vs 66.1, p=0.012; mean % PR 57.7 vs 43.1, p=0.004). The relationship between HEI score and % ER/PR differed significantly by menopausal status (interaction term of menopausal status and % ER: p=0.006; and % PR: p=0.012); there were no significant associations between HEI scores and % ER/PR in premenopausal pts. There were no significant associations between PA and % ER/PR. Conclusions: Healthier diet was associated with higher % ER and PR in postmenopausal pts with BC, but no relationship was seen in premenopausal pts. These data suggest that lifestyle factors may influence BC pathologic features related to outcomes in older women. Support: U10CA180821, U10CA180882, UG1CA189823, U24CA196171, https://acknowledgments.alliancefound.org . Clinical trial information: NCT02750826 . % ER mean (SD) p value % PR mean (SD) p value Post-Menopausal HEI* score≤50.1 [n=134]>50.1 [n=156] 66.1 (43.3)78.0 (36.8) 0.012 43.1 (41.8)57.7 (41.0) 0.004 MVPA † min/wk0 [n=147]≥1 [n=147] 74.5 (39.3)70.3 (41.2) 0.37 50.0 (41.8)53.0 (42.0) 0.41 Pre-Menopausal HEI* score≤50.1 [n=124]>50.1 [n=103] 70.5 (38.5)65.5 (43.0) 0.15 53.5 (41.1)49.1 (43.0) 0.43 MVPA † min/wk0 [n=112]≥1 [n=113] 66.3 (41.0)66.3 (41.2) 0.99 49.5 (41.4)52.6 (42.7) 0.59 *Healthy Eating Index. † Moderate/Vigorous Physical Activity.