Background Chemotherapy resistance is the main obstacle to breast cancer recurrence, metastasis, and mortality. Drug-tolerant persister (DTP) cells are a novel type of target cell associated with tumor resistance, and autophagy is a key factor in maintaining the survival of tumor DTP cells. However, it is unclear whether the activation of autophagy in breast cancer DTP cells is related to their overexpression of the transcriptional regulatory factor CDCA7. Methods We analyzed CDCA7 expression using public datasets and clinical samples and established breast cancer cell lines with CDCA7 overexpression and knockdown to assess the role of CDCA7 in breast cancer. Autophagy was assessed via electron microscopy, mRFP-GFP-LC3 imaging, and immunoblotting. Mechanistic studies employed ChIP-seq, dual-luciferase assays, and site-directed mutagenesis. Functional assays measured chemosensitivity (CCK-8), migration/invasion (scratch/Transwell), and in vivo tumorigenicity (mouse xenograft). Results CDCA7 was significantly upregulated in breast cancer DTP cells. Overexpression of CDCA7 in breast cancer cells significantly enhanced autophagy-related biological processes and molecular functions. Through ChIP-seq and targeted knockout experiments, we identified the binding sites of CDCA7 on the autophagy-related protein genes ULK1 , ATG2A , and ATG3 . Using transmission electron microscopy and mRFP/mCherry-GFP-LC3B tandem fluorescent tagging, we observed that CDCA7 knockdown significantly reduced the number of autolysosomes in breast cancer DTP cells and markedly inhibited autophagic flux. Moreover, CDCA7 knockdown not only decreased drug resistance in breast cancer cells but also reduced metastasis, invasion, and tumorigenic ability in vivo , ultimately prolonging the survival of tumor-bearing mice. Conclusion CDCA7 drives breast cancer chemoresistance by transcriptionally activating a pro-survival autophagy program in DTP cells, nominating it as a promising therapeutic target.

Study on the role of TIGAR in regulating mitochondrial function and inhibiting pyroptosis of breast cancer cells.

Differential prognostic impact of clinicopathologic factors for late recurrence in ER-positive breast cancer according to menopausal status.

Deep learning on histopathological images to predict breast cancer recurrence risk and chemotherapy benefit: a multicentre, model development and validation study

Previous studies reported low [18F] fluorodeoxyglucose ([18F]FDG) PET uptake in estrogen receptor-positive breast tumours, potentially missing detection of distant metastases. This study assessed the proportion of estrogen receptor-positive hypometabolic tumours, clinical factors influencing [18F]FDG uptake, and the prognostic impact. Baseline [18F]FDG PET/computed tomography (CT) and [18F]FDG PET/MRI exams of female patients diagnosed with estrogen receptor-positive locally advanced (cT3-4N0 or cT1-4N+), metastatic, or recurrent breast cancer between 2013-2022 were retrospectively collected. Different thresholds of maximum standardised uptake value (SUVmax) and tumour-to-background ratio (TBR; SUVmax tumour/SUVmax background) were applied to determine the proportion of hypometabolic [18F]FDG PET exams. Logistic regression and survival analysis were performed. 119 patients underwent [18F]FDG PET/CT and 31 [18F]FDG PET/MRI. The proportion of hypometabolic tumours for SUVmax thresholds 2.0, 2.5, 3.0, TBR of contralateral breast less than or equal to 1, and TBR of liver less than or equal to 1 was 8.4, 15.1, 21.8, 5.1, and 28.6%, respectively for [18F]FDG PET/CT and 16.1, 19.4, 29.0, 6.9, and 35.5% for [18F]FDG PET/MRI. Clinically tumour status (cT-status), histology type, and tumour grade were associated with the presence of a hypometabolic tumour. No PET-derived variables were associated with recurrence-free survival. A considerable proportion of estrogen receptor-positive breast tumours showed low SUVmax, indicating potential suboptimal staging on [18F]FDG PET. In patients with lower cT-status, lobular histology and low-grade estrogen receptor-positive tumour, [18F]FDG PET may be less reliable as staging procedure. Further research is necessary to determine the optimal metabolic threshold for defining a hypometabolic tumour.

To evaluate the clinical benefit of extended endocrine therapy (eET) after 5 years of adjuvant treatment with luteinizing hormone-releasing hormone agonists (LHRHa) in premenopausal women with node-positive, hormone receptor-positive early breast cancer (eBC). We conducted a cohort study analysis on two prospectively collected data sets (the Young Women's Breast Cancer Study and IEO Breast Cancer Cohort). Eligible patients were diagnosed with eBC at age ≤40 years (between 2005 and 2016), had node-positive, hormone receptor-positive disease, and remained premenopausal after 5 years of adjuvant LHRHa with no evidence of recurrence. The primary end point was invasive breast cancer-free survival (IBCFS), calculated from the sixth year after the initiation of adjuvant endocrine therapy (ET; study baseline), and adjusted through the propensity score (PS) weighting analysis. A total of 501 patients were included in the analysis: 287 received eET for a median duration of 3.7 years (IQR, 2.3-5.0), including 48% tamoxifen monotherapy and 52% LHRHa plus tamoxifen or aromatase inhibitor. After a median follow-up of 7.3 years from the study baseline, the PS weighted IBCFS rates at 5 years were 85% in the eET group and 78% in the non-eET group (hazard ratio [HR], 0.63 [95% CI, 0.44 to 0.89]; P = .0135). The PS weighted distant recurrence-free survival rates at 5 years were 91% and 83% in the eET and non-eET group, respectively (cause-specific HR, 0.49 [95% CI, 0.31 to 0.79]). In both groups, bone fractures and major cardiovascular events were reported in 1% of patients. In this cohort study analysis, extending ET in premenopausal patients with node-positive eBC after 5 years of LHRHa treatment was associated with a clinically meaningful reduction in both invasive and distant breast cancer recurrences.

Background Early-stage breast cancer (BC) shows heterogeneous recurrence risk. Circulating tumor DNA (ctDNA) is promising non-invasive biomarker for minimal residual disease and recurrence prediction, though prognostic performance varies by assay and context. Methods Eligible studies on ctDNA-based recurrence and survival were identified through comprehensive searches, quality assessed, and analyzed using random-effects meta-analysis to estimate pooled hazard ratios for clinical outcomes. Heterogeneity (I2, τ2, Cochran’s Q), subgroup (detection method or assay type), and sensitivity analyses were performed to examine the consistency and robustness of results. Results For recurrence-free survival endpoints, the pooled HR was 3.28 [95% CI: 1.81; 5.93], indicating a high risk of recurrence-related events among ctDNA-positive patients, though substantial heterogeneity was observed (I2 = 93.3%). Pooled effect sized for overall survival (8.92 HR [0.45; 177.87], I2 = 74.7%) and recurrence/relapse (5.21 [0.98; 27.69], I2 = 84.4%) indicating substantial heterogeneity. Subgroup analysis showed lower heterogeneity with digital PCR and personalized ctDNA assays, and sensitivity testing confirmed result stability (2.47 [1.89; 3.23], I2 = 0%). Conclusion CtDNA positivity, detected through mutation-based assays strongly associated with increased risk for early recurrence in early-stage BC. Digital PCR and personalized assays demonstrated superior consistency; however, prospective trials are needed to establish its clinical utility.

Abstract Background: Breast cancer (BC) recurrence risk is highest within the first 5-years following initial diagnosis, making survivorship care a critical window for intervention. As survivorship rates increase, identifying modifiable lifestyle factors that may reduce recurrence risk becomes increasingly important. While the protective factors of recreational physical activity (rPA) before BC diagnosis are well-documented, the role of post-diagnosis rPA, particularly its impact on recurrence remains less explored. Objectives: This study aimed to determine 1) if high levels of post-diagnosis rPA reduce BC recurrence risk in female survivors compared to minimal rPA and 2) if adhering to the Physical Activity Guidelines for Americans (i.e., 150 minutes of moderate-intensity physical activity weekly) reduces recurrence risk. Methods: We included observational cohort studies evaluating the association between post-diagnosis rPA and recurrence risk among adult female BC survivors published up to January 2025, in any language or geographic location. Excluded studies were interventional studies, hospital/clinical studies, male BC survivors, and those under 18 years. Databases (Medline, CINAHL, Web of Science) were searched in February 2025. Two reviewers independently screened studies at all stages. Data synthesis and analysis used pooled risk estimates (RR/HRs) and 95% confidence intervals. A meta-analysis was conducted on Stata using a random-effects model to examine the effects of post-diagnosis of rPA on BC recurrence, separately for minimal vs high rPA and meeting vs not meeting recommended guidelines. Subgroup analyses explored BC subtypes, study characteristics, menopausal status, and follow-up period as potential sources of heterogeneity. Heterogeneity was assessed using Cochran’s Q test and I2 statistics. Results: Out of 2,635 studies screened, 22 passed the initial screening for full-text review, and 9 were included in the meta-analysis (9 high versus low; 5 meeting vs not meeting guidelines). The analysis included 37,787 BC survivors and 4,524 recurrences were reported. Meta-analysis showed that female BC survivors who engaged in high levels of rPA after diagnosis had a 13% lower risk of BC recurrence compared to those with minimal activity (RR=0.87, CI=0.77-0.96, I2=0.00%, n=9). However, meeting the minimum recommendations of rPA alone was not associated with a reduced risk of recurrence (RR=0.93, 95% CI=0.85-1.02, I2=0.00%, n=5). Subgroup analysis showed stronger associations in studies conducted in the Netherlands and Germany, as well as in those with rPA assessment periods greater than 5 years after diagnosis. Using the Newcastle Ottawa Scale, study quality was classified as good (n=7) or fair (n=2). Conclusion: These findings suggest that high levels of rPA postdiagnosis reduces recurrence risk by 13%. Because the current minimum recommendations may not be sufficient to reduce recurrence risk, further research is needed to determine optimal rPA recommendations and guidelines for BC survivors. Additionally, these findings emphasize the value of healthcare professionals promoting higher levels of rPA within survivorship care plans for BC survivors. Citation Format: J. Weathington, I. Lynch, B. Sukhu, T. Glatz, E. Lee. The Relationship between Post-Diagnosis Recreational Physical Activity and Breast Cancer Recurrence: A Systematic Review and Meta-Analysis [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2025; 2025 Dec 9-12; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(4 Suppl):Abstract nr PS1-05-25.

Abstract Background: Breast cancer (BC) is the most frequent cancer in women from western countries. 30% of BC patients are likely to develop recurrence and risk remains indefinitely. Monitoring recurrence and evaluating response to therapy are important aspects of clinical decision making in the treatment of BC. According to clinical guidelines, BC follow-up is based on clinical examination and bilateral mammogram only. Serum tumor markers such as cancer antigen 15-3 (CA15-3) and other imaging techniques are used by many physicians, but without clear recommendations from clinical societies. We used an in-house developed modular proteomic array platform, the Matrix Protein Array to identify a protein biomarker (BF-09 antigen) that was differentially expressed in BC tissues versus normal counterparts, present in early and late stages and measurable in serum. The development of an ELISA assay to establish its diagnostic performance in discriminating BC patients from healthy individuals and benign cases was previously described 1-2. The present study is designed to assess the utility of our assay for monitoring BC recurrence and therapy response. Methods: The concentration of BF-09 antigen was measured by ELISA assay in 379 retrospective serial serum samples from 85 BC patients and changes in biomarker concentration were correlated to change in disease status as determined by standard of care. BC patient samples were obtained from a biobank at the IRCCS San Raffaele Pisana Research Center (Italy). Patients were followed for up to 10 years (median 23.1 months, range 2.9-203 months) and were examined periodically with imaging to document the remission or progression of the disease. 67% of patients were diagnosed with early-stage BC (I-III) while 33% had metastatic breast cancer (stage IV). Treatments received by patients were neoadjuvant therapy (NAT, 16.5%), adjuvant therapy (AT, 18.8%), metastatic breast cancer therapy (MBCT, 35.3%), or multiple therapies (AT± NAT and/or MBCT, 29.4%). A significant increase or decrease in BF-09 concentration was defined as a change equal or superior to 2.5 times the %CV of the assay as compared to a previous point and interpreted as progression or no progression, respectively. Sensitivity (SE), specificity (SP), negative (NPV) and positive predictive values (PPV) as well as overall concordance of the assay with disease status were calculated. Results: Total concordance of BF-09 serum level with disease status was not affected by BC subtypes (luminal A/B, HER2 positive or triple negative) or stage (Chi-square, p≥0.05). Overall performance of the assay in detecting progressive disease was 81.8% sensitivity at 92.6% specificity with 68.7% PPV and 96.2% NPV. The BF-09 assay could identify BC recurrence both in early BC patients following curative surgery/treatment and in metastatic BC patients during therapy follow up, in some cases years before patients started suffering from clinical symptoms. We were also able to show the utility of BF-09 antigen assay in monitoring therapy response in the neoadjuvant setting prior to surgery. Conclusion: Our findings show that the BF-09 biomarker assay quantitatively reflects therapy response both in the (neo)adjuvant therapy and metastatic therapy settings and detects cancer relapses in a timely manner. This appears to be the first time a protein biomarker has shown high accuracy and applicability for these clinical indications and this could offers new opportunities for BC patient management. Further testing is needed to confirm these results in a prospective trial population. 1 Chavany et al. New breast cancer marker BF-09 is overexpressed in tumor extracts and secreted in serum, Biochemistry and Biophysics Reports, Volume 43, 2025,102097. 2 Chavany et.al. A Serum Biomarker for the Early Detection of Breast cancer. Cancer Res (2024) 84 (9_Supplement): PO5-07-08. Citation Format: J. Dea, C. Chavany, R. P. Valle, R. Hernandez-Gonzalez, M. Jendoubi. A novel serum protein-based assay for monitoring response to therapy and recurrence of breast cancer. [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2025; 2025 Dec 9-12; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(4 Suppl):Abstract nr PS4-02-07.

Abstract Background: Surgical management has greatly evolved from a radical mastectomy to the most recent advancement of a more conservative oncoplastic breast surgery (OBS). It has not only proven to be safe, but also has shown superior cosmetic outcomes compared to standard breast conservation surgery as it is able to address larger and even multi-focal tumors. Nevertheless, this is a relatively novel concept in our developing country with a limited number of professionals trained in the field. Furthermore, there is a financial aspect and stigma to take into consideration. Patients have to pay out of pocket for treatment which deters them from risking the possibility of a second surgery - incase of incomplete resection margins. It also adds the burden on the surgeon to deliver optimal cosmetic outcomes with no intervention to the contralateral breast. The purpose of this study is to determine the long-term oncological and cosmetic outcomes of patients with early-stage breast cancer who underwent OBS at our institution. Methodology: A single-center retrospective study was conducted on adult female patients with biopsy proven Stage I to III breast cancer who underwent OBS from January 2017 to June, 2022. Patients who underwent bilateral breast surgery were excluded. A total of 194 women were eligible for the study and data was extracted from patient records to determine the long term oncologic outcomes— breast cancer recurrence, disease-free survival (DFS), and overall survival (OS). Cosmetic outcomes were evaluated via patient-reported satisfaction using the Harvard breast cosmesis scale, through telephonic interview after obtaining informed verbal consent. The study was approved by the institutional Ethical Review Committee (ERC 2025-11482-34955). Results: The mean age of women at diagnosis was 48.3 ± 13.2 years with 81% having invasive ductal carcinoma. Sixty-seven percent of the women had hormone receptor positive breast cancer, while 20% had triple negative disease. Among all the patients who were included in the study, half of the patients received neoadjuvant chemotherapy before OBS, followed by adjuvant radiation therapy. Of note, only 6 (3.1%) out of 194 women had a positive margin for which they underwent a second procedure. Level 1 OBS was performed among 77% of the patients. Among those who underwent Level 2 OBS a variety of local perforator flaps were performed. We had a 68% response rate among the patients who were approached via telephone to determine the self-reported cosmetic outcomes, with 91% of the participants reporting ‘Good’ (51%) or ‘Excellent’ (40%) cosmetic outcomes when compared to the contralateral breast. Eight (4.1%) out of 16 patients had an ipsilateral recurrence, while the remaining developed distant metastases. The Kaplan Meier analysis showed that the mean OS of the study participants was 96 months (95% CI=92.2-99.7) since diagnosis, with death as the outcome event. The mean DFS was 93 months (95% CI=89.5 - 97.6) since diagnosis until recurrence as the outcome event. There were significant differences in survival times for patients by recurrence (log rank test, p=0.000) and hormone receptor status (log rank test, p=0.015). There was no significant difference in survival times for patients by type of OBS (log rank test, p=0.860). Conclusion: Oncoplastic breast surgery is a safe and effective option for early-stage breast cancer, with low margin positivity and favorable long-term outcomes. Our study demonstrates excellent survival and high patient-reported cosmetic satisfaction, especially with Level 1 OBS. These findings support its broader use—even in resource-limited settings—as a balanced approach to oncologic safety and aesthetic outcomes. Citation Format: S. N. Virji, L. Vohra, S. Khan, I. Khan. Re-defining Breast Cancer care in an LMIC- a single center study on long term oncological and cosmetic outcomes of Oncoplastic Breast Surgery [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2025; 2025 Dec 9-12; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(4 Suppl):Abstract nr PS2-03-04.

Abstract Background: There is growing evidence supporting the benefits of the Mediterranean diet in breast cancer (BC) prevention, but their contribution to prognosis remains unclear. Our objective is to investigate whether adherence to the Mediterranean dietary patterns before diagnosis is associated with the risk of BC recurrence and tumor proliferation in an exploratory cohort of the multicenter case-control EpiGEICAM study. Methods: Transcriptome-wide gene expression was assessed using the nCounter Breast Cancer 360 panel (NanoString). Formalin-fixed paraffin-embedded tumor tissues from an exploratory cohort of 89 pre- or perimenopausal BC patients from the EpiGEICAM study were used. The PAM50 gene expression signature was employed to classify tumors into the gold-standard BC intrinsic molecular subtypes, and to compute both the PAM50 risk of recurrence (ROR) and PAM50 proliferation scores. Dietary patterns over the five years prior to diagnosis were identified in the control population of the EpiGEICAM study, applying principal components analysis without rotation of the variance-covariance matrix over 26 inter-correlated food groups. The association between adherence to Mediterranean dietary patterns and both ROR and proliferation scores was analyzed using linear regression models with continuous outcomes. All models were adjusted for age and adherence to a Western dietary pattern, with additional adjustment for PAM50 molecular subtype in the proliferation score analysis. Results: The mean age was 44 years and 28% had a family history of BC. Regarding molecular subtypes, 49.4% corresponded to Luminal A, 22.5% to Luminal B, 13.5% to HER2-enriched and 14.6% to Basal-like subtype. High adherence to the Mediterranean dietary pattern was observed in 56% of participants, with higher prevalence among women with Luminal A and Luminal B subtypes. The mean ROR score was 51 (95%CI=46-57) in women with low adherence to the Mediterranean diet, and 46 (95%CI=40-51) in those with high adherence. Mean proliferation scores were 4.8 (95%CI=4.6-5.1) and 4.5 (95%CI=4.3-4.8), respectively. Although no statistically significant associations were observed, women with high adherence to the Mediterranean dietary pattern showed lower mean ROR score (β=-5.8; 95%CI=-14.0-2.5) and a reduced proliferation score (β=-0.14; 95%CI=-0.40-0.12) compared to those with low adherence. Conclusion: The present EpiGEICAM exploratory analysis showed that adherence to a Mediterranean dietary pattern prior to diagnosis may be associated with lower breast cancer PAM50 proliferation and risk of recurrence scores. Studies with larger sample sizes are needed to confirm these results and to clarify the effect of the Mediterranean diet on the biology and prognosis of this tumor. Citation Format: V. Lope, P. Fernández, Á. Guerrero-Zotano, P. Sánchez-Rovira, A. Antón-Torres, M. Benavent-Viñuales, J. Baena-Cañada, S. Antolín, M. Muñoz, L. Paris, J. Chacón, C. Olier, S. González, J. García-Sáenz, Á. Jimenez-Arranz, A. Oltra, J. Brunet, M. Marin-Alcala, A. De Juan, B. Pérez-Gómez, R. Rincón, R. Caballero, B. Bermejo, M. Martín, M. Pollan. Association between adherence to the mediterranean dietary pattern and PAM50-derived breast cancer proliferation and recurrence risk scores. Exploratory analysis from the Epigeicam study [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2025; 2025 Dec 9-12; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(4 Suppl):Abstract nr PS3-01-27.

Abstract Background: The standard first-line therapy for most previously untreated locally recurrent unresectable or metastatic triple-negative breast cancer (TNBC) with PD-L1 combined positive score (CPS) <10 is chemotherapy alone. New therapeutic options with superior efficacy are needed. Sacituzumab tirumotecan (sac-TMT; MK-2870/SKB264) is a novel antibody-drug conjugate (ADC) composed of an anti-trophoblast cell surface antigen 2 (TROP2) monoclonal antibody coupled to a cytotoxic belotecan derivative, topoisomerase I inhibitor payload via a novel linker. Sac-TMT monotherapy has shown promising efficacy with a manageable safety profile in metastatic TNBC. There is strong biologic rationale supporting combination of an ADC with pembrolizumab regardless of PD-L1 expression. The TroFuse-011 study (NCT06841354) evaluates sac-TMT ± pembrolizumab vs treatment of physician’s choice (TPC) in participants with previously untreated locally recurrent unresectable or metastatic TNBC with PD-L1 CPS <10. Trial design: Eligible participants (≥18 y) with centrally confirmed locally recurrent unresectable or metastatic TNBC, measurable disease per RECIST v1.1, ECOG PS 0 or 1, and a tumor tissue sample evaluable for central PD-L1 and TROP2 testing are randomized 2:1:2 to receive sac-TMT (Arm A), sac-TMT + pembrolizumab (Arm B), or TPC (Arm C; Table). Primary endpoints are PFS per RECIST 1.1 as assessed by BICR (Arm A vs C and Arm B vs C) and OS (Arm A vs C). Secondary endpoints are PFS (Arm B vs A), OS (Arm B vs C and Arm B vs A), ORR (Arm A vs C and Arm B vs C) and DOR, patient-reported outcomes, and safety. Tumor imaging occurs at baseline, Q8W after randomization until week 48, and Q12W thereafter. Enrollment is ongoing. Citation Format: A. Bardia, X. Peng, K. L. Smith, J. A. Mejia, H. S. Rugo. Trofuse-011: a phase 3, randomized, open-label study of sacituzumab tirumotecan with or without pembrolizumab vs treatment of physician’s choice for previously untreated locally recurrent unresectable or metastatic triple-negative breast cancer [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2025; 2025 Dec 9-12; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(4 Suppl):Abstract nr PS5-08-18.

Abstract Background: Despite its widespread adoption, there is a lack of data as to whether breast MRI for local staging and surgical planning of newly diagnosed breast cancer patients improves oncologic outcomes. The Alliance A011104 phase III trial was designed to test the hypothesis that MRI detection of mammographically occult disease helps to tailor surgical intervention thereby reducing local recurrence and improving local regional control. Here we report on the primary outcome of 5-year local regional recurrence. Methods: Patients with newly diagnosed clinical stage I-II, ER/PR- and HER2- negative (triple- negative) or ER/PR-negative and HER2-positive breast cancer, deemed eligible for breast- conserving surgery (BCS) based on clinical exam, mammography +/- ultrasound were randomized to undergo staging breast MRI or no further local staging. Patients with multifocal tumors that could be encompassed in a single operative resection were eligible. Patients who were carriers of gBRCA 1/2, or who had bilateral breast cancer, or a prior history of breast cancer were excluded. Initial eligibility was limited to patients not scheduled to receive neoadjuvant chemotherapy; however, a subsequent amendment allowed for enrollment after completion of neoadjuvant chemotherapy. Categorical variables were compared between arms with a chi-square or Fisher’s exact test. LRR, distant recurrence and overall survival (OS) were estimated with Kaplan-Meier point estimates and 95% confidence intervals (CIs). Hazard ratios (HRs) and 95% CIs were obtained from Cox proportional hazards models. Results: Of 319 patients enrolled from 2/2014-12/2019,161 were randomized to undergo breast MRI and 158 to no breast MRI evaluation. The mean age at enrollment was 58.9 years (range 29-85). Most patients (72.1%) had T1 tumors, 93.4% were cN0 and 19.7% were HER2 positive. Systemic chemotherapy was utilized in 85% with 17.6% receiving treatment neoadjuvantly; receipt of systemic therapy was unknown for 15 patients (4.7%). Two hundred and ninety-eight patients (93.4%) underwent surgical intervention; 91.9% underwent BCS as initial surgical procedure with no significant differences noted between groups (92.7% in the no MRI group and 91.9% in the MRI group [p=0.62]). Of patients who underwent breast surgery, 293 underwent axillary evaluation with the majority (270 patients, 92%) undergoing sentinel lymph node biopsy as the only axillary intervention. Among patients who received neoadjuvant chemotherapy, the overall pathologic complete response rate was 39.3%, 29.0%in the MRI arm vs. 52.0% no MRI arm (p=0.10). Receipt of adjuvant radiation was comparable between arms, 85.4% and 85.0% receiving radiation in the no MRI and MRI arms, respectively. Among 298 patients evaluable for the primary endpoint, with median follow-up of 61.1 months (0.2, 68.1), there were no differences in rates of LRR; 5-year local regional control was 93.2% (89.0-97.6%) in the MRI group and 95.7% (92.3-99.1%) in the no MRI group (HR: 1.1, 95% CI: 0.3, 3.9). For the entire cohort, 5-year distant recurrence-free rate and OS were 94.3% (91.7, 97.1) and 92.2% (89.1, 95.4), respectively, with no differences between groups. Conclusions: With multimodality therapy, rates of 5-year LRR in patients with early stage triple- negative and HER2-positive breast cancer are very low. Breast MRI for local staging and surgical planning in this setting does not result in improved local regional control. Support: U10CA180821, U10CA180882; UG1CA189823; U10CA180868 (NRG Oncology); ClinicalTrials.gov Identifier: NCT01805076; https://acknowledgments.alliancefound.org Citation Format: I. Bedrosian, K. Ballman, L. M. McCall, C. E. Comstock, G. W. Unzeitig, T. Yen, A. Weiss, B. G. Haffty, J. M. Bensenhaver, S. M. DeSnyder, J. J. Liu, A. H. Partridge, L. A. Carey, K. K. Hunt.Effect of Preoperative Breast MRI Staging on Local Regional Recurrence (LRR) in Early Stage Breast cancer: Alliance A011104/ACRIN 6694 [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2025; 2025 Dec 9-12; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(4 Suppl):Abstract nr GS2-07.

Abstract Background: TNBC patients exhibit an aggressive disease course with at least 25% developing recurrence or metastasis within 3-5 years, despite standard-of-care therapies. Clinicopathologic factors (CP; age, growth pattern, tumor size, margin status and grade) have limited value in identifying high risk TNBC patients. Early and accurate prediction of recurrence in TNBC patients from clinical mammograms would facilitate therapy optimization. However, new strategies to identify high-risk patients are needed. In this study, we used radiomics features at the tumor boundary to predict recurrence in TNBC patients and LLM/GPT to explain the prediction in natural language. Materials and methods: Mammograms from node negative TNBC patients (n=77; aged 30-90 years, lesion size of 2-45 mm, grades 2 and 3) who underwent adjuvant chemotherapy and had 5-yr follow-up were analyzed. Lesions were manually segmented and tumor boundary (1 mm containing both intra-tumoral and peritumoral regions) was automatically determined. Over 2,000 radiomics features from the tumor boundary and the central regions of the tumor were extracted to quantify heterogeneity, texture, shape, and size of the tumor. Recursive feature elimination using non-linear random forest classifier was used to reduce feature dimensionality and prevent over-fitting. A random forest classifier was employed to build an AI/machine learning model for risk of recurrence using the reduced feature dimension. Top ranking features along with clinicopathological variables were further used in a Bayesian network (BN) to create an interpretable machine learning model. To generate a patient-specific report, a sentence transformer model was further used for BN graph embedding, which aided in querying the graph in natural language inheriting the node/feature specific dependencies of the BN in LLM/GPT (BN LLM). Results: Recurrence prediction was significantly improved by analysis of radiomics features at the tumor boundary (using continuous gradient magnitude and texture features) and shape features, as compared to the same features extracted from the entire tumor. In a 3-fold validation framework, gradient and texture features at tumor boundary, along with tumor shape, better predicted recurrence (mean AUC of 0.78 (std 0.15)) as compared to the same features from the entire tumor (mean AUC of 0.35 (std 0.11)). The addition of clinical variables did not improve the AUC. Using clinical variables alone, AUC of 0.6 (std 0.09) was obtained. Using BN LLM an example patient specific report in natural language is summarized below: Patient A clinical profile : Tumor size – large; age – younger (<50 y); KI67 – high; lymph node invasion – yes; peritumoral probability – high; grade – high. Probability of recurrence based on tumor boundary radiomics: High Top ranking clinical parameter: Younger age (<50 y) has high probability of recurrence. Prediction: Patient A is at high risk for recurrence. Conclusions: Heterogeneity features at the tumor boundary quantified by continuous gradient magnitude and texture features in routine clinical mammograms could predict TNBC recurrence. To the best of our knowledge, this is the first time that BN LLM has been used to generate patient specific clinically explainable report of risk for TNBC patients. This model will be validated in a larger cohort with a holdout validation set in future studies. Citation Format: S. Ghose, S. Cho, C. Davis, S. Gandhi, L. Lan, A. Mansuri, H. Trivedi, Y. Polar, F. Ginty, S. Badve. Tumor Boundary and Shape Features are Predictive of Recurrence in Triple Negative Breast Cancer (TNBC) Patients [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2025; 2025 Dec 9-12; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(4 Suppl):Abstract nr PD6-04.

Abstract Background: The addition of a checkpoint inhibitor to platinum containing neoadjuvant therapy (NACT) has significantly improved pathological complete response (pCR), progression-free (PFS) and overall survival (OS) in early triple negative breast cancer (eTNBC). However, clinical management of this breast cancer (BC) subtype remains challenging, as only between 40-50% of patients achieve a pCR and the rest witness rapid disease recurrence. Biomarkers to accurately predict pCR and recurrence, therefore, constitute unmet clinical needs. We herein deploy DNA-methylation patterns in tumor tissue as well as cell-free DNA (cfDNA) methylation before and after NACT for the identification of response and relapse biomarker in eTNBC. Patients and Methods: Blood and tumor tissue of 49 patients presenting with first diagnosis of eTNBC between Jan 2013 and Apr 2018 were evaluated for tumor DNA (n=27) and cfDNA methylation before (n=32) and after NACT (n=19). Paired plasma samples were available in 14 cases, paired tumor-plasma samples in 15 cases, respectively. Bead-based concentration and column isolation of cfDNA was achieved with the QiaAmp Mini Elute cfDNA Mini kit (Qiagen). Following fluorometric-based quantification, cfDNA methylation sequencing libraries were prepared with the Enzymatic Methylseq kit (New England Biolabs) followed by hybrid capture with an in-house panel. Libraries were sequenced on a Nextseq 2000 P4 flow cell and data analyzed with the Bismark suite. Missing values were imputed by K-Nearest Neighbors imputation (KNN). Differential methylation analyses was performed with the RnBeads suit and a penalized least absolute shrinkage and selection operator (LASSO) regression was used for biomarker identification. Maximal log-rank statistic was used for the determination of biomarker cut-off for all continuous variables. Results: Of all differentially methylated sites between pre- and post-therapy plasma samples, about 60% of sites showed a significant decrease in methylation levels. In paired analyses, tumor and plasma DNA methylation profiles mirrored each other for a substantial number of the selected markers. We identified sixteen differentially methylated sites associated with a pCR, most of which were located on chromosome 5. Single response marker analyses revealed markers with sensitivity and specificity higher than 0.8. Combination of at least two markers resulted in sensitivity and specificity over 0.9. The negative and positive predictive values were above 0.8 and 0.9 for single and combined markers, respectively. A prognostic index score combining all 16 response markers was significantly prognostic for OS (HR: 0.16, p value 1.25e-05). Furthermore, a 17 disease recurrence signature could be established with single markers attaining sensitivity and specificity of above 0.7 and 0.9, respectively, while combination of at least two markers reached 100% sensitivity and specificity. A recurrence risk signature combining all 17 recurrence markers was strongly prognostic for OS (HR: 0.16, p value 2.26e-05). Conclusion: Collectively, we have established cfDNA prognostic indicator signatures for pCR and recurrence in eTNBC. The validation of these signatures is ongoing in one of our independent validation cohorts and large multicentric cohorts could further foster clinical translation. Citation Format: S. Kasimir-Bauer, C. H. Zuendorf, A. Bittner, O. Hoffmann, R. Kimmig, J. Siveke, S. Lueong. A cell-free DNA prognostic indicator for pathological response and recurrence in early triple negative breast cancer [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2025; 2025 Dec 9-12; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(4 Suppl):Abstract nr PS4-10-09.

Abstract Breast cancer remains a leading cause of cancer-related deaths among women worldwide, largely due to the high risk of recurrence and metastasis in HER2-negative and hormone receptor-negative triple-negative breast cancer (TNBC) patients. While bone metastasis is common, the molecular mechanisms driving its initiation remain poorly understood. We recently identified a subpopulation of cancer stem cells (CSCs) with ancestral features, marked by the FXYD domain-containing ion transport regulator 3 (FXYD3), a Na+/K+ pump component. These “ancestor-like CSCs” persist in breast tissues during neoadjuvant chemotherapy (NAC), linking them to drug-tolerant persisters (DTPs) and positioning them as critical therapeutic targets for preventing local recurrence (Li M, Gotoh N et al., J Clin Invest, 2023). Despite this, the mechanisms underlying DTP dormancy in the bone marrow and their transformation into bone metastasis-initiating cells remain unclear. Given the stromal richness of TNBC tissues, we explored interactions between cancer-associated fibroblasts (CAFs) and breast cancer cells using a co-culture system. RNA-sequence analysis revealed a strong upregulation of granulocyte colony-stimulating factor (GCSF) in co-cultured CAFs. Notably, we identified FXYD3+ and GCSF receptor-positive cancer cells as a distinct subpopulation of CSCs with bone metastasis initiation potential. To investigate the temporal-spatial dynamics of bone metastasis initiation, we performed single-cell RNA sequencing (10x Genomics) and immunofluorescent imaging using metastatic bone marrow from the patient-derived xenograft (PDX) models. These analyses revealed how bone metastasis-initiating CSCs exploit the plasticity of bone marrow cells to establish a CSC niche at the single-cell level. Our findings provide critical insights into the mechanisms of recurrence and metastasis in breast cancer, offering novel therapeutic opportunities to target ancestor-like CSCs and prevent disease progression. Citation Format: N. Gotoh. Heterogeneous dormant breast cancer cells leverage bone marrow cell plasticity at the single-cell level to drive metastasis initiation [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2025; 2025 Dec 9-12; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(4 Suppl):Abstract nr PS3-13-04.

Abstract Background: Obesity is a known risk factor for breast cancer (BC) incidence and recurrence. Glucagon-like peptide-1 (GLP-1) medications have emerged as effective treatments for weight management, with potential implications for oncology supportive care. However, their real-world use and impact among patients with BC remain poorly characterized. We extracted information from the electronic health record (EHR) using large language models (LLMs) to assess (1) documentation of GLP-1 use among patients with BC; (2) clinical, sociodemographic, and social determinants of health (SDOH) factors associated with GLP-1 use; and (3) the association between GLP-1 use and ctDNA testing and test results among a US-based cohort of patients with BC. Methods: We leveraged the US-based Flatiron Health Research Database, focusing on patients diagnosed with BC from January 2011 to February 2025. We used an LLM to extract GLP-1 medication details from unstructured EHR documents. We tested several prompt engineering strategies to optimize LLM extraction performance, including chain-of-thought and text curation techniques. We estimated a series of multivariable logistic regression models assessing associations between patient characteristics and GLP-1 use (i.e., documentation of GLP-1 use in EHR), sequentially adjusting for clinical factors (e.g., age, stage, year of diagnosis), sociodemographics (e.g., race/ethnicity), and SDOH (e.g., telemedicine use, practice setting, urban/rural). In exploratory analyses, we also estimated the unadjusted association between GLP-1 use and ctDNA testing (yes vs. no) and result (positive vs. negative) at any time. Results: Among our cohort of 967,968 patients diagnosed with BC, 64,400 (6.65%) patients had documented evidence of GLP-1 use and 16,689 (1.72%) patients underwent ctDNA testing. The LLM extracted GLP-1 use with high performance (F1 score = 0.94). Adjusted analyses revealed a higher likelihood of GLP-1 use among the following patient groups relative to their counterparts: patients with obesity (BMI≥30 vs. BMI<30; Odds Ratio [OR]=2.38; 95%CI:2.31-2.45), HR+/HER2- patients (vs. HR-/HER2-; OR=1.05; 95%CI:1.01-1.10), non-Latinx (NL) Black patients (vs. NL-White; OR=1.37; 95%CI:1.31-1.44), patients residing in rural areas (vs. urban; OR=1.13; 95%CI:1.08-1.18), and telemedicine users (vs. non-users; OR=1.39; 95%CI:1.35-1.43) were more likely to have evidence of GLP-1 use. Older patients (aged >75 vs aged 18-49; OR=0.54; 95%CI:0.46-0.64), advanced stage patients (stage IV vs. stage I OR=0.64; 95%CI:0.58-0.71), Latinx patients (vs. NL-White; OR=0.94; 95%CI:0.89-0.99), Asian patients (NL-White; OR=0.67; 95%CI:0.60-0.75), patients receiving care at community practices (vs. academic; OR=0.81; 95%CI:0.77-0.85), and those residing in neighborhoods with higher levels of limited English proficiency (high [LEP] vs. low LEP; OR=0.83; 95%CI:0.78-0.89) were less likely to have evidence of GLP-1 use. Compared with patients with no evidence of GLP-1 use, GLP-1 users had higher rates of ctDNA testing (OR=1.84; 95%CI:1.75-1.93) and a lower likelihood of ctDNA positivity (OR=0.76; 95%CI:0.67-0.85). Conclusions: Clinical, sociodemographic, and SDOH factors influence GLP-1 use among patients with BC. In exploratory analyses, we found that GLP-1 use was also associated with lower rates of ctDNA positivity, a biomarker linked to minimal residual disease and increased risk of recurrence. This study demonstrates the feasibility of using LLMs to extract GLP-1 medication details from the EHR, and helps lay the groundwork for future research evaluating the clinical impact of GLP-1 use on BC outcomes and recurrence risk, as well as equitable access to these therapies. Citation Format: C. A. Ryals, A. Blarre, B. Adamson, D. Bower, G. G. Ho, O. Mbah, S. Radlein, E. Fidyk, F. Cody Stanford, A. B. Cohen. Real-world glucagon-like peptide-1 use and association with clinical characteristics, social determinants, and circulating tumor DNA positivity in patients with breast cancer [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2025; 2025 Dec 9-12; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(4 Suppl):Abstract nr PD8-07.

Abstract Background In patients (pts) with HER2-negative, high-risk early breast cancer (BC), adjuvant (adj) olaparib (OLA) significantly improves invasive disease-free survival and overall survival in those carrying germline BRCA1 or BRCA2 (gBRCA) pathogenic variants (PVs) 1). To optimize clinical outcomes, timely gBRCA testing as a companion diagnostic is essential. However, the real-world uptake of gBRCA testing in this population remains unclear. Methods We enrolled newly diagnosed pts with invasive HER2-negative BC who underwent curative surgery from January 1, 2023 to December 31, 2023 in Japan. Patient selection was based on the inclusion criteria from the OlympiA trial1). Specifically, ER-positive pts required either ≥ 4 positive lymph nodes after surgery or non-pathological complete response (pCR) with a CPS+EG score ≥ 3 following neoadjuvant chemotherapy (NAC). ER-negative pts required an invasive tumor >2 cm or ≥ 1 nodal metastasis after surgery, or non-pCR after NAC. Furthermore, we collected both patient-level and institutional data. The primary outcome was the proportion of pts who underwent gBRCA testing. Secondary outcomes included: (1) factors linked to no testing; (2) proportion of PVs among those tested; (3) proportion of pts with gBRCA PVs who started OLA; and (4) other treatments used in pts with gBRCA PVs not receiving OLA. Based on a previous U.S. report in which 87% of young women with BC underwent gBRCA testing2), we hypothesized that at least 88% of eligible pts should be tested. Assuming an expected testing rate of 88%, a sample size of 688 pts was required to maintain a 95% confidence interval (CI) width of 0.05. The target sample size was set at 700 to account for potential exclusions. Results Of 824 pts recruited from 46 facilities during the primary enrollment, 700 were randomly selected for secondary registration. After excluding 9 ineligible pts, a total of 691 were analyzed. The median age was 62 [20-96] years, 99% were female, 52 had bilateral BC, 157 had a family history of BC, and 18 had dementia. ER status was positive in 51%. NAC was administered to 362 pts (52%), including 148 (21%) with ER-positive BC, while 199 (29%) ER-positive BC pts had upfront surgery. Regarding facility characteristics, the median number of breast cancer specialists per facility was 3 [1-17], and genetic counselors were available in 27 facilities (59%). gBRCA testing was performed in 437 of 691 pts (63.2%; 95% CI, 59.5-66.9). Of 254 untested patients, 168 (66%) were not informed, mainly due to physician oversight (57%) or perceived ineligibility related to age, comorbidities, or treatment refusal (40%). Among 69 pts who were informed but declined testing, the reasons for no testing were psychological distress (46%), cost of testing (35%), and concerns about genetic implications for family members (12%). Among 42 pts (9.6%) with gBRCA PVs (10 pts were ER-positive), 32 received OLA. Of the remaining 10, all but 3 had perioperative chemotherapy, and none received abemaciclib. Results of our multivariate analysis on missed testing will be presented at the conference. Conclusions Despite its clinical importance as a companion diagnostic for adj OLA, timely gBRCA testing was underutilized in the real world. Two-thirds of untested pts were not informed of the testing option, highlighting a potential gap between clinical trial evidence and practice. To ensure equitable access to adj OLA, greater efforts are needed to improve physician awareness and streamline institutional workflows supporting genetic testing. References 1) Geyer CE et al. Ann Oncol. 2022;33(12):1250-1268. 2) Rosenberg SM et al. JAMA Oncol. 2016;2(6):730-736. Citation Format: T. Taji, Y. Uemura, Y. Kimura, N. Maeda, A. Ito, H. Seki, D. Takabatake, M. Harao, S. Nakamoto, R. Matsunuma, C. Koganezawa, T. Iwamoto, H. Mukai, Y. Kikawa. Real-world uptake of gBRCA testing as a companion diagnostic for olaparib in patients with HER2-negative recurrent high-risk early breast cancer in Japan: a cross-sectional multicenter study (BRCAwareness) [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2025; 2025 Dec 9-12; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(4 Suppl):Abstract nr PS2-06-30.

Abstract Background: Oncologists currently rely on genomic assays such as Oncotype Dx, MammaPrint and EndoPredict to guide adjuvant chemotherapy decisions in early-stage breast cancer. While offering improved risk stratification, they are costly, time-consuming, and inaccessible in many settings. Whole-slide H&E images, already generated for every patient, embed complementary prognostic biology that remains under-exploited in daily practice. Advances in artificial intelligence (AI) have shown promise in predicting molecular biomarkers directly from H&E-stained histopathology slides. In this study, we validate TRINITY AI, a multimodal deep learning platform that integrates morphology, clinicopathologic variables, and AI-inferred transcriptomics from H&E slides to predict a recurrence risk score. Methods: TRINITY AI was trained on 1219 breast cancer cases from TCGA and CPTAC. A self-supervised transformer based foundation model was used to infer transcriptomic profiles from H&E whole slide image (WSI). These inferred profiles along with clinical variables (e.g. patient age, tumour size, grade, nodal status) and morphological features are embedded into a shared latent space to learn patient-level cross-modal relationships to yield a continuous risk score. External diagnostic validation employed three distinct cohorts (n = 166) with matched Oncotype Dx scores for qualified slides that underwent strict quality control and pathologist confirmation. Prognostic utility was interrogated in 1051 TCGA cases with ≥5-year distant-recurrence follow-up using multivariable Cox models (endpoint = distant recurrence-free interval [DRFI]). Results: Against the pooled external cohort, TRINITY AI classified low-risk disease with specificity 95%, negative predictive value 92%, and area-under-the-curve 0.88, outperforming clinicopathologic nomograms and approximating Oncotype Dx. In cohort-specific analysis, it achieved a negative predictive value (NPV) >87% and specificity >92%. High-risk predictions conferred a 3.80-fold increase in DRFI hazard (95 % CI 2.08-7.18) after adjustment for size, grade, nodal status, and subtype; C-index 0.698 (95% CI: 0.622-0.770). Conclusions: TRINITY AI transforms the ubiquitous H&E slide into a genomics-grade breast cancer recurrence assay that resides within the pathologist’s digital workflow. With its performance across independent cohorts, high rule-out capacity, rapid turnaround, and fractional cost make it a pragmatic solution for equitable precision oncology. Critically, it offers a new option in underdeveloped and developing countries, where patients are often forced to choose between the cost of chemotherapy and that of expensive genomic testing. Its survival performance further supports TRINITY AI as a robust, independent predictor of distant breast cancer recurrence. Citation Format: J. Shinde, A. Ulle, C. Cha Chinglemba, Y. Thoudam, T. Gupte, S. PM, G. Shafi, H. Kothavade, E. Gustafson, R. Jawale, A. Khan, R. Kolhe, K. Bloom, M. Uttarwar. Multimodal Deep Learning for Recurrence Stratification for Early-Stage Breast Cancer in Resource-Constrained Environments [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2025; 2025 Dec 9-12; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(4 Suppl):Abstract nr PD11-11.

Abstract Background: Hormone receptor positive (HR+)/Human Epidermal Growth Factor Receptor 2 negative (HER2–) breast cancer is the most common subtype of breast cancer and is primarily treated with endocrine therapy (ET), including tamoxifen (tam) alone or ovarian function suppression (OFS) with tam or aromatase inhibitors (AI). Body mass index (BMI) can influence the effectiveness of ET; however, the impact of BMI on outcomes in premenopausal women remains unclear. Previous studies in postmenopausal women have shown worse outcomes among obese women receiving ET. Given the rise in obesity and limited literature focused on premenopausal patients, it is essential to gain a better understanding of how BMI affects ET outcomes. Methods: We analyzed the medical records of premenopausal women (defined as age < 50) with Stage 1-3 HR+/HER2– breast cancer from January 2012 to December 2023. We collected demographic, clinicopathologic characteristics, and treatment information. Patients with non-invasive breast cancer, those who did not begin ET, and those who received an AI alone were excluded. We examined recurrence and survival outcomes by BMI and ET type, controlling for age, tumor grade, and stage. Results: 723 women with Stage 1-3 HR+/HER2- breast cancer treated with ET were identified. Of these, 345 were characterized as normal weight (BMI ≤ 24.9), 210 were overweight (BMI 25.0-29.9), and 168 were obese/severely obese (BMI ≥ 30.0). There was a significant difference in BMI among racial groups, with Black and Hispanic patients diagnosed with breast cancer being more likely to be obese/severely obese than White or Asian/Pacific Islander (API) women. Women with higher BMIs were also more likely to be diagnosed with larger tumors (≥ 3.0 cm), but there was no significant interaction between BMI and clinical stage, node positivity, or grade. Of the 723 total patients treated with ET, 185 (25.6%) received OFS with either Tam or an AI. 538 (74.4%) of patients were treated with Tam alone. Multivariable analysis controlling for age, grade, and stage did not show that increasing BMI was associated with Tam alone use (OR 0.99 (0.96-1.01), p=0.2997). At a median follow-up of 66 months, 64 patients were found to have a breast cancer recurrence: 32 recurrences occurred in women with normal weight, 17 recurrences occurred in those who were overweight, and 15 recurrences occurred in those who were obese/severely obese. 5-year survival rates were 94.6% in the obese/severely obese group; 95.1% in the overweight group and 98.1% in the normal weight group (p=0.7027). Conclusions In contrast to currently reported data in postmenopausal women, we did not find that premenopausal women with early-stage HR+/HER2– breast cancer and higher BMIs were at increased risk of recurrence or worse survival but longer term follow up is needed. Citation Format: P. Saha, O. Israel, C. Sanchez, L. Eldridge, K. Kuchta, K. A. Yao. Impact of Obesity in Premenopausal Women with Early-Stage HR+/HER2- Breast Cancer Treated With Adjuvant Endocrine Therapy [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2025; 2025 Dec 9-12; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(4 Suppl):Abstract nr PD8-03.