Citations

Abstract The addition of two years (yrs) of adjuvant abemaciclib to ET resulted in statistically significant and clinically meaningful improvement in overall survival (OS) over ET in patients (pts) with HR+, HER2-, node-positive, high-risk EBC. At 7 yrs, abemaciclib+ET demonstrated sustained IDFS and DRFS benefits ([HR=0.73, 95% CI: 0.66, 0.82), and (HR=0.75, 95% CI: 0.66, 0.84)]). Higher nodal involvement (N2 or N3) is an independent prognostic factor for worse outcomes in EBC. However, previous monarchE data highlight that pts with limited nodal disease (1-3 axillary lymph nodes (ALN)) are at high recurrence risk when additional clinical risk factors are present, such as high-grade (G) tumor and/or large tumor size. Here, we show subgroup analyses by ALN.monarchE is a phase 3, open-label, randomized trial in pts with HR+, HER2-, node-positive, high-risk EBC. Pts were randomized (1:1) to receive ET for at least 5 yrs +/- abemaciclib for 2 yrs (treatment (tx) period). High-risk EBC was defined as either 1-3 ALN (N1) with G3 disease and/or tumor ≥5 cm or, ≥4 ALN (N2: 4-9, N3: ≥10) (Cohort 1 (C1)). A smaller group of pts were enrolled with N1, G≤2, tumor size <5 cm, and central Ki-67 ≥20% (C2). IDFS, DRFS and OS were assessed in C1 by ALN (N1, N2, N3) using the Kaplan-Meier (KM) method, and unstratified Cox proportional hazard model including interaction effect between tx arm and ALN. Of 5120 randomized pts in C1, 1761 (34.4%) had N1, 2223 (43.4%) had N2, and 1123 (21.9%) had N3 disease. At this analysis (data cut off:15Jul2025), in the ET arm, a comparable number of patients with N1 and N2 disease had IDFS events at 6 yrs (21.6% and 25.4%), while event no. in the N3 subgroup was notably higher (38.1%). A similar trend was observed in DRFS and OS (Table). With a median follow-up time of 76.8 months in C1, the addition of abemaciclib to ET reduced the risk of developing an IDFS event by 24.8% (N1), 31.5% (N2) and 27.4% (N3) compared to ET. The absolute improvements in IDFS rates at 6 yrs were 4.6% (N1), 6.9% (N2), and 8.1% (N3). Reductions in the risk of developing DRFS events were 25.2% (N1), 31.2% (N2), and 25.7% (N3), with corresponding 6yr absolute benefit of 3.8% (N1), 6.4% (N2), and 6.8% (N3). Abemaciclib+ET consistently reduced the risk of death compared to ET across ALN subgroups by 12.3% (N1), 15.5% (N2), and 26.8% (N3), which resulted in absolute improvements in OS of 1.4% (N1), 1.6% (N2), and 2.7% (N3). Baseline disease characteristics, IDFS and DRFS KM curves by ALN will be presented. In the ET arm, pts with N1 + ≥1 additional risk factor had recurrence and death risks comparable to pts with N2, while pts with N3 had poorer prognosis. The addition of adjuvant abemaciclib to ET led to a clinically meaningful reduction in the risk of recurrence and death regardless of nodal burden, confirming the consistent and sustained benefit of 2 yrs of tx with abemaciclib and supporting its use in eligible pts with node-positive high-risk EBC. Citation Format: J. Cortes, S. R. D. Johnston, M. Martín, S. M. Tolaney, M. Goetz, H. Rugo, J. Sohn, O. Ozyilkan, M. Henriques Abreu, M. Zaiss, K. Maia Vianna, H. Melgaard Nielsen, A. Chan, H. Kalofonos, S. Morales, B. San Antonio, M. Munoz, B. R Grimes, S. Amdur, P. Neven. monarchE: subgroup analysis of adjuvant abemaciclib + endocrine therapy for HR+, HER2-, high-risk early breast cancer by nodal status [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 PS1-08-08.

Abstract Background: 18F-Fluoroestradiol (FES) positron emission tomography (PET) is approved for non-invasive detection of estrogen receptor (ER)-positive breast cancer (BC) and recent updates to the National Comprehensive Cancer Center Network clinical practice guidelines include FES-PET for staging recurrent/metastatic ILC. Given the wide range of FES-PET indications, we retrospectively reviewed the management of ER+ BC patients after FES-PET at Mayo Clinic. Methods: We identified ER+ BC patients who underwent FES-PET from April 2021 to June 2025 across the Mayo Clinic. BC context at the time of FES-PET requisition was categorized as early (EBC), locally recurrent (LRBC), or metastatic (MBC). Management changes were classified as either affecting BC or non-BC care (not mutually exclusive). For pts who underwent 18F-flurodeoxyglucose (FDG) PET-CT and had a discrepant result with FES-PET, we assessed the clinical impact of these discrepancies. Finally, we examined the change in clinical management when FES-PET was ordered to investigate rising tumor markers CA 15-3 or CA 27.29. Results: 166 pts underwent ≥1 FES-PET scan. At diagnosis, 57% had invasive lobular carcinoma (ILC), 33% invasive ductal carcinoma (IDC), and 5.4% mixed histology. ER expression ≥ 50% was observed in 81.4% and 1.2% were HER2+. Overall, FES-PET led to a change in management in 54.5% (n=90) of pts with 43.0% (n=71) experiencing a change in BC care and 16.4% (n=27) in non-BC care. Changes in BC care occurred in 36% of EBC, 68% of LRBC, and 43.7% of MBC. The most common BC management changes after FES-PET were change in treatment strategy in 23.6% (n=39), additional BC-related imaging including further FES-PET scans in 23.0% (n=38), upstaging in 10.3% (n=17), change in surgical planning in 10.3% (n=17), local therapy in 4.2% (n=7), and biopsy avoidance in 3% (n=5). Surgical planning changes were mostly deciding to proceed with curative intent surgery (n=11), though some surgeries were aborted upon FES-PET upstaging (n=6). Non-BC management changes included additional imaging to evaluate incidental findings in 11.5% (n=19) and procedures in 6.7% (n=11), including 5 biopsies, 2 bronchoscopies, 2 endoscopies, 1 hysterectomy, and 1 cholecystectomy. FDG/FES discordancy was observed in 22.3% of the overall population (n=37). The most common pattern was FDG-/FES+ (n=19), leading to upstaging of BC in 8 and the sole use of FES-PET for future restaging in 13 BC patients. The second most common pattern was FDG+/FES- (n=18), attributed to non-BC related FDG uptake in 11 (false-positive FDG) or post-treatment ER loss in 7. Three FDG+/FES- patients were found to have additional cancers: two non-small cell lung cancers and one lymphoma. Non-malignant causes of false positive FDG were inflammation (n=3), silicone implants (n=1), thymic hyperplasia (n=1), and unknown (n=5). Six patients initially upstaged with FDG-PET imaging proceeded to curative-intent surgery after negative FES-PET confirmatory scans (FDG+/FES-). When FES-PET was ordered to investigate rising CA 15-3 or CA 27.29 tumor markers, this led to upstaging/progression in 3 of 21 cases (1 EBC, 2 MBC). The mean tumor marker increase was 57.0% in patients with upstaging/progression versus 19.0% in those without (p=0.02, two-tailed Student’s t-test). Conclusions: FES-PET altered clinical management in approximately half of BC cases in this study. Changes in BC-specific management were most frequent in LRBC, followed by MBC and EBC. One in six patients had a non-BC clinical management change after FES-PET. FDG/FES discordance provided value in upstaging FDG non-avid cancers and downstaging FDG-avid lesions unrelated to BC, influencing curative treatment decisions. FES-PET ordered for rising tumor markers rarely changed management, though larger tumor marker increases were associated with upstaging or progression. Citation Format: N. Wiest, K. Bullock, T. Pai, M. Kornas, B. McKinley, E. Parent, P. Advani. FES-PET imaging in estrogen receptor-positive breast cancer: implications for clinical management [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 PS1-06-16.

Abstract Introduction: Endocrine therapy (ET) is central to treating hormone receptor-positive breast cancer (BC), but its side effects impact adherence and quality of life, especially in patients with metabolic dysfunction. Sodium-glucose cotransporter-2 (SGLT-2) inhibitors offer cardiometabolic benefits, potentially improving inflammation, glycemic control, and physical well-being. However, data on SGLT-2 use in BC patients is scarce. This study is the first to evaluate the real-world effects of SGLT-2 inhibitors on all-cause mortality and ET tolerability in BC patients. Methodology: We conducted a real-world analysis using the TrinetX database, which includes data from 184 million patients in 156 healthcare organizations, to identify BC patients on ET (letrozole, anastrozole, exemestane, tamoxifen) who received SGLT-2 inhibitors vs. those who did not. Patients were grouped by age (≤50 and ≥51 years as a surrogate for menopausal status. Primary outcome: all-cause mortality from the start of the index event, defined as the first day meeting BC diagnosis and ET use, with or without SGLT-2. Secondary endpoint: ET tolerability. Propensity score matching completed by TriNetX adjusted for confounders. Multivariate analysis yielded odds ratios and risk differences with 95% CI. Results: Among 1,136 BC patients ≤50 years, 568 were assigned to each group (SGLT-2 vs non-SGLT-2). For patients ≥51 years (n=28,600), each group included 14,300. Demographics across cohorts were comparable. No mortality benefit was seen in premenopausal patients. In postmenopausal women, SGLT-2 use reduced all-cause mortality—647/13,676 events (SGLT-2) vs 953/13,517 (non-SGLT-2) [OR: 0.655 (0.591-0.726)]. In premenopausal patients, SGLT-2 reduced endometrial cancer risk [RD: -0.018 (-0.029, -0.007)] but increased diarrhea risk [OR: 2.305 (1.078, 4.930)]. No significant differences were found in hot flashes, PE, DVT, depression, osteoporosis, joint pain, fatigue, nausea/vomiting, abdominal pain, or dizziness. Among postmenopausal patients, SGLT-2 reduced PE [OR: 0.757 (0.605-0.948)] and osteoporosis [OR: 0.877 (0.784-0.981)], but increased risks of depression [OR: 1.153 (1.007-1.319)], nausea/vomiting [OR: 1.120 (1.001-1.253)], diarrhea [OR: 1.193 (1.058-1.345)], and dizziness [OR: 1.234 (1.103-1.380)]. No significant differences were found for hot flashes, DVT, EC, joint pain, fatigue, or abdominal pain. Conclusion: This analysis reveals novel evidence supporting the cardiometabolic potential of SGLT-2 inhibitors in hormone receptor-positive BC, particularly postmenopausal populations. These agents were linked to lower all-cause mortality and improved tolerance of specific ET-related effects. However, certain adverse risks require caution. Future prospective studies are essential to validate their role and safety in oncologic care. Citation Format: C. Jones, J. Michalek, E. Obomanu, Y. Arya, A. Syal, S. Haddad, V. Kaklamani, S. Shaikh. Evaluating all-cause mortality and endocrine therapy tolerability with sodium glucose cotransporter-2 inhibitors in hormone receptor-positive breast cancer: A real-world 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 PS1-05-28.

Abstract BACKGROUND: Anthracycline chemotherapy-related cardiomyopathy (CCM) is a serious adverse event that can occur several years after completion of breast cancer (BC) therapy. Demographic and clinical risk factors have failed to predict which patients will experience CCM. Genetic variants can account for a significant proportion of inter-individual variation. Knowledge of genetic risk variants prior to chemotherapy will be informative for risk stratification and early intervention. The goal of our study is to identify genetic variants that predispose patients to CCM. Methods: We developed a cardiotoxicity registry at Mayo Clinic, Florida that enrolls patients who are to undergo standard of care chemotherapy in the early BC setting. Patients were (and continue to be) enrolled and consented for chart review and DNA sequencing. We sequenced whole exomes of the first 136 patients (anthracycline N=55, anti-HER2 (no anthracycline) N=71, other chemotherapy, N=10), primarily focusing on Titin (TTN) truncating variants, known to be present in ∼25% of patients with primary dilated cardiomyopathy, and previously reported in 7.5% of patients with CCM, followed by exploration of increased burden of rare non-synonymous variants in 60 established genes for primary cardiomyopathy. Filtering of rare non-synonymous variants included minor allele frequency <0.5% (in GnomAD database European, African and Asian ancestries) and CADDv1.7 PHRED score ≥20. Results: 18/55 (33%) patients treated with anthracycline experienced CCM. TTN truncating variants in were identified in 2/18 (11%) CCM patients and absent in 37 patients who did not experience CCM. Both patients with TTN variants had severe HF and required cardiac transplant. We identified a pathogenic variant in LMNA (p.Arg190Gln) in 1/18 (5.5%) patients and the same rare (p.Glu1127Gly) variant in RYR2 occurred in 2/18 (11%) of patients (Table 1). We noted enrichment of rare missense variants in anthracycline CCM patients compared to HER2 treated without anthracycline, CCM, p=0.0001. Conclusions: Pathogenic variants in TTN, LMNA, are enriched in BC patients (17%) who develop anthracycline-related cardiomyopathy. Early genetic screening may improve risk stratification and guide personalized cardiac monitoring to prevent CCM. Further research is needed to clarify the role of additional rare variants like RYR2 and to develop a CCM risk score based in idiopathic CM genes. Incorporating genetic risk assessments into treatment planning has the potential to enhance oncologic outcomes as well as long-term survivorship by preserving cardiac health. Citation Format: P. P. Advani, A. McPherson, J. Reddy, J. Schneider, S. Baheti, T. Nguyen, J. C. Ray, N. Norton. Genomic Insights into Anthracycline Cardiotoxicity: Enhancing Survivorship Care through Early Risk Identification [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 PS1-01-22.

Abstract Background: Combinations of antibody-drug conjugates and immunotherapy, such as trastuzumab deruxtecan (T-DXd) and rilvegostomig (rilve), respectively, offer promising efficacy but are associated with a heightened risk of drug-induced interstitial lung disease (ILD)/pneumonitis. Early detection and management are critical for optimizing patient safety, yet there are no standard protocols for real-time evaluation. We hypothesized that vigilant monitoring would enable early detection, prevent symptoms, and minimize the chance of treatment delays while testing novel therapeutic combinations that have a potential risk of ILD. Methods: We tested the combination of T-DXd and rilve administered every 3 weeks in the I-SPY2.2 phase 2 platform trial (NCT01042379), which enrolls patients with clinical stage II/III breast cancer commencing neoadjuvant systemic therapy. Given the potential risk of overlapping pulmonary toxicity of these two agents, we added rigorous monitoring with pulmonary function tests (PFTs), six-minute walk test (6MWT), and high-resolution chest CT (HRCT) scanning pretreatment and every 6 weeks thereafter. A real-time safety workflow was implemented, with pre-specified criteria for halting treatment and escalation to the next block of treatment. All abnormal findings reported on chest CT by site radiologist were centrally reviewed in real time by the study pulmonologist (T.K.) and cases of suspected ILD were adjudicated promptly by a safety committee consisting of the pulmonologist and several medical oncologists, enabling early study drug interruption and therapeutic interventions. Toxicity data were evaluated in the first 51 patients treated with T-DXd plus rilve, and a preplanned hold was initiated until safety was ascertained by the data and safety monitoring board. Results: Safety data were evaluated in the first 51 patients receiving T-DXd plus rilve. Eight ILD events were confirmed (15.68% incidence): 5 grade 1, 2 grade 2, and 1 grade 3. One patient had an early chest CT scan because of dyspnea. All cases were identified by HRCT scans; PFTs and 6MWT did not enhance early detection and were subsequently dropped from the monitoring protocol. No patient was symptomatic for more than 24 hours. Radiographic findings resolved within 14-55 days. Patients with grade 2 & 3 ILD were treated with corticosteroids. No cases of ILD required intensive care or escalated therapy beyond steroids. Early treatment escalation to the subsequent block of therapy occurred in 3 patients; all 3 patients were subsequently able to receive appropriate therapy. At the meeting, safety data from all 100 patients treated with this combination will be reported. Conclusion: Real-time, centralized monitoring and adjudication allowed for early detection and prompt management of ILD, which both mitigated severity and supported timely therapeutic management. Among the monitoring tools studied, HRCT scanning performed every 6 weeks proved most effective for early ILD identification; PFT and 6MWT did not enhance early detection. This approach offers a potential framework for future studies assessing pulmonary safety in regimens combining agents that have a known risk for inducing ILD. Citation Format: T. Kulkarni, R. Nanda, H. S. Rugo, C. C. OSullivan, K. M. Kalinsky, J. C. Boughey, P. R. Pohlmann, J. Perlmutter, D. Yee, A. Borowsky, F. Symmans, N. Hylton, L. Van ‘t Veer, C. Yau, L. Esserman. Real-time monitoring for drug-induced interstitial lung disease with Trastuzumab Deruxtecan and Rilvegostomig combination therapy prevents persistent, symptomatic disease: Safety insights from the I-SPY2.2 platform trial [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 PS1-01-09.

Abstract Background: Assessing invasive lobular carcinoma (ILC) with standard-of-care (SOC) imaging, such as 18F-fluorodeoxyglucose (FDG) PET-computed tomography (CT), is challenging. In May 2025, National Comprehensive Cancer Center Network guidelines added FES PET for recurrent/metastatic ILC staging. However, perceptions of the value added by FES PET to SOC imaging may vary, as only small ILC cohorts have been published. We evaluated FES PET’s clinical utility in the largest-studied cohort, to our knowledge, of ILC pts who have undergone FES PET. Methods: We identified all ILC pts who had an FES PET [PET-magnetic resonance (MR) or PET-CT)] between April 1, 2021, and May 1, 2025, at Mayo Clinic. Clinical and radiological data, including indications and management (mgmt) changes related to pts’ first FES PET, were obtained from clinical records. FES and SOC FDG PET were compared. Data were summarized with descriptive statistics. Results: 102 female pts were included: 88% White and 4.9% Black. Median age at initial breast cancer (BC) diagnosis was 57 (range, 36-79). At initial ILC diagnosis, most tumors were strongly estrogen receptor (ER) positive. Highest tumor grade was 1 in 25% of pts and 2 in 57%, with grade not documented in 19%; none had documented grade 3 ILC. Initial clinical prognostic stage was as follows: 26% stage 1, 21% stage 2, 10% stage 3, and 16% stage 4. At the time of FES PET, 37% had biopsy-confirmed metastatic ILC at the time of FES PET. The most common indications for FES PET were (re)staging ILC (49%), detecting suspected metastatic/recurrent BC (30%), and evaluating rising tumor markers like CA 15-3 or CA 27.29 (15%). 16% of pts were upstaged due to the FES PET result: 14 pts to stage 4 and 2 pts to stage 3. FES PET led to a mgmt change in 38 pts (37%), for whom the most common FES PET indications were (re)staging ILC (21 pts), detecting suspected recurrent/metastatic BC (11 pts), and detecting ER expression when biopsy was not feasible/nondiagnostic (7 pts). 19 scans (50%) led to a systemic therapy (tx) decision, 10 (26%) to a biopsy, 4 (11%) to additional imaging like MRI, 3 (8%) to locoregional tx, and 2 (5%) to a non-oncologic specialty referral to evaluate a suspected new metastasis. 11 pts had stage 4 BC pre-FES PET; their FES PET was ordered primarily for restaging (5 pts) or detecting ER expression (5 pts). Notably, of the 19 pts with a systemic tx-related change, 4 began a triple-negative BC regimen due to low FES uptake on the scan. Of the 15 pts who had FES PET to evaluate a rising tumor marker, a direct change in systemic tx occurred in 2 pts. 63/102 pts (62%) had FDG PET-CT prior to FES PET. Of these, 57% had discordant FDG and FES PET results. 39% had a higher number of avid metastatic lesions on FES PET as compared to FDG PET, primarily in the bone (8 pts) and lymph nodes (4 pts). 25% had bone, nodal, or soft tissue metastatic lesions that were FDG but not FES avid. 13 pts had FES PET-MRI; 9 of these had a prior FDG PET-CT. 2 PET-MRI pts had FES-avid metastatic lesions in unusual sites (brain, peritoneum) that were not FDG avid. Among the 38 pts with a mgmt change due to their FES PET result, 63% had prior FDG PET; 32% of the 38 pts had FES-avid metastatic lesions that were not seen on FDG PET, and 8% had FDG-avid but not FES-avid lesions. Conclusions: FES PET was useful for evaluating not only stage 4, but also early-stage ILC, with 1/3 of pts with an FES PET-driven mgmt change having early-stage BC. FES PET was most helpful for ILC (re)staging, detection of suspected recurrent/metastatic BC, and detection of ER expression when biopsy was not feasible/nondiagnostic. FES PET added clinically meaningful information beyond SOC imaging, with detection of FES-avid but not FDG-avid metastatic lesions in 1/3 of pts with an FES PET-driven mgmt change. Notably, FES PET-MRI demonstrated potential superiority over FDG PET in identifying atypical ILC metastases. Citation Format: T. Pai, C. Bullock, N. Wiest, E. Parent, P. Advani. Clinical utility of 18F-fluoroestradiol positron emission tomography (FES PET) in patients (pts) with lobular 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 PD9-09.

Abstract Background: Invasive lobular carcinoma (ILC) is the second most common breast cancer (BC) subtype, accounting for up to 15% of cases. Although several biologic differences between ILC and invasive carcinoma of no special type (NST) have been described, most data are derived from primary tumors. In contrast, the biology of metastatic ILC remains poorly defined. This study aimed to investigate the unique genomic, transcriptomic, and immune landscapes of metastatic ILC using a multi-omic approach. Methods: This real-world study included patients with confirmed NST or pure ILC who had a biopsy of a metastatic lesion or a breast lesion in the setting of known metastatic disease. Tumors underwent whole exome sequencing (NGS 592, NextSeq; WES, NovaSeq), whole transcriptome sequencing (WTS, NovaSeq) (Caris Life Sciences, Phoenix, AZ). Demographic and baseline molecular features were compared across histologic subtypes. Tumor mutational burden (TMB; high ≥10 mut/MB) was assessed by NGS. Immune cell populations were estimated by RNAseq deconvolution (quanTIseq). Pathway enrichment analysis was determined by GSEA. Overall survival (OS) was defined from the date of biopsy to death from any cause using Kaplan-Meier estimates. Statistical tests included chi-square and Mann-Whitney U with multiple testing correction (q<0.05). Results: Among 2,651 metastatic BC samples (ILC n = 608; NST n = 2,043), patients with ILC were older (median 67 vs 63 yrs) and more likely white (81.5% ILC vs 73.1% NST), all p<0.05. By IHC, ILC were more frequently HR+/HER2- (83.6% vs 55.9%), less commonly triple-negative (11.9% vs 29.8%) or HER2+ (4.6% vs 14.3%), all p<0.05. PAM50 subtypes differed between ILC and NST: luminal A (Lum A) (31.1% vs 13.7%) and luminal B (Lum B) (44.9% vs 43.8%) intrinsic subtypes were enriched in ILC, while NST was more frequently basal (1.2% vs 22.4%) and HER2-enriched (19.8% vs 22.2%), all p<0.05. Within luminal BC, Lum B was more common than Lum A in both histologies, but Lum A was proportionally more frequent in ILC (ILC: 40.3% Lum A vs 59.7% Lum B; NST: 23.4% Lum A vs 76.6% Lum B), p<0.0001. Comparative multi-omic analysis focused on the 922 HR+/HER2- tumors (ILC n = 275; NST n = 647). Compared to NST, ILC had higher frequency of CDH1 (87.3% vs 6.1%), PIK3CA (52.7% vs 38.5%), FOXA1 (9.0% vs 3.4%), ERBB2 (7.1% vs 2.0%), ARID1A, and NF1 (both q < 0.05) mutations and TMB high (17.7% vs 9.9%), but lower frequency of TP53 (15.7% vs 33.3%), ESR1 (10.9% vs 18.1%) and GATA3 (2.3% vs 14.9%) mutations along with FGFR1 amplifications (15.3% vs 6.7%), all q<0.05. ILC had higher expression of androgen receptor (91.2% vs 83.5%, q<0.05) and higher MAPK activation score (-0.81 vs -1.19, q<0.05), consistent with a luminal, hormone-driven phenotype. NST tumors demonstrated enrichment of pathways involved in the cell cycle and metabolic activity, including E2F targets, G2M checkpoint, MYC targets, mTORC1 signaling, glycolysis, and unfolded protein response (NES: 1.5-2.7, FDR<0.25). ILC tumors had higher infiltration of B cells, dendritic cells, neutrophils, NK cells and M2 macrophages, but lower M1 macrophages, all q<0.05. ILC had differential expression of immune checkpoint genes (upregulation: CD274 (PD-L1), PDCD1 (PD-1), TNFSF14, CEACAM1, CD160, fold change (FC): 1.2-1.5; down: HAVCR2 (TIM-3): FC: 1.2), all q<0.05. Median OS (mOS) was similar between luminal ILC and NST (33.8 vs 35.4 months (mo); HR 1.0, 95% CI 0.91-1.3). No mOS difference was seen between Lum A ILC and NST (47.4 vs 50.5 mo; HR 1.0, 0.84-1.43), while Lum B ILC had worse mOS than NST (27.4 vs 35.3 mo; HR 1.3, 1.1-1.6). Conclusions: This study represents the largest cohort to date with multi-omic characterization of metastatic ILC, revealing distinct genomic, transcriptomic, and immune features compared to NST. These findings highlight the unique biology of ILC and may inform future subtype-specific therapeutic strategies. Citation Format: G. Nader-Marta, S. Kumar Deshmukh, K. Fanucci, P. Tarantino, S. Schnitt, A. Lee, S. Oesterreich, S. Wu, J. Xiu, P. Advani, M. Lustberg, N. Lin, S. Tolaney, E. Mayer, O. Metzger, G. Sledge Jr., R. Jeselsohn. The Genomic, Transcriptomic, and Immune Hallmarks of Metastatic Lobular 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 PD9-07.

Abstract Introduction: Endocrine therapy (ET) improves survival in hormone receptor-positive breast cancer (BC) but has side effects that may affect compliance. GLP-1 receptor agonists (GLP-1 RA), used for diabetes and obesity, possess anti-inflammatory properties and may reduce cancer incidence. Their impact on all-cause mortality and ET tolerability remains underexplored. This real-world analysis is the first of its kind to examine the effects of GLP-1 RA on these outcomes. Methods: We used de-identified data across 130 million patients and 108 health systems from the TriNetX database to identify obese women (BMI ≥30) with BC receiving ET. Patients were grouped by GLP-1 RA exposure into age cohorts (≤50 and ≥51 years, as a surrogate for menopause). The primary endpoint was all-cause mortality; the secondary endpoint was ET tolerability. The index event was the first day meeting all criteria: BC and obesity diagnoses, and initiation of ET ± GLP-1 RA. Patients with outcomes before the study window were excluded. Propensity score matching performed by TriNetX adjusted for demographics, diabetes, comorbidities, cancer stage, and prior chemotherapy. Multivariate logistic regression assessed associations (risk ratios [RR], 95% CIs). Results: After matching, 2,574 patients were assigned to the age ≤50 group: Cohort A (GLP-1 RA exposure, n=1,287) and Cohort B (non-exposure, n=1,287). 13,012 patients were in the age ≥51 group: Cohort C (GLP-1 RA exposure, n=6,506) and Cohort D (non-exposure, n=6,506). In the ≤50 group, the mean age at index event was 42.3 ± 5.2, 99.5% female, 68.9% White, 16.9% Black, and a mean BMI of 37 in Cohort A, with similar demographics and BMI in Cohort B. In the ≥51 group, there was a mean age at index event of 61.8 ± 7.7, 99% female, 71.7% White, 17.4% Black, and a mean BMI of 37 in Cohort C with similar demographics and BMI in Cohort D. GLP-1 RA use significantly reduced all-cause mortality in all cohorts. In the age ≤50 group, there were 29/1,242 events in Cohort A and 71/1,258 in Cohort B [RR 0.414 (0.271-0.633)]. In the age ≥51 group, there were 240/6,287 events in Cohort C and 400/6,285 in Cohort D [RR 0.600 (0.513-0.701)]. GLP-1 RA use worsened ET side effects. In the age ≤50 group, GLP-1RA increased the risk of hot flashes [RR: 1.473 (1.235-1.756)], venous thromboembolism (VTE) [RR: 1.439 (1.090-1.902)], nausea/vomiting [RR: 1.460 (1.242-1.717)], abdominal pain [RR: 1.353 (1.184-1.545)], diarrhea [RR: 1.319 (1.096-1.589)], joint pain [RR: 1.382 (1.243-1.536)], and depression [RR:1.634 (1.382-1.932)]. No significant risk was found in endometrial cancer (EC) and osteoporosis. In the age ≥ 51 group, GLP-1 RA use increased hot flashes [RR: 0.1.239 (1.091-1.407)], [RR:0.591 (0.482-0.724)], nausea/vomiting [RR: 1.429 (1.324-1.542)], abdominal pain [RR: 1.310 (1.227—1.399)], diarrhea [RR: 1.446 (1.328-1.575)], joint pain [RR: 1.334 (1.270-1.400)], osteoporosis [RR: 1.110 (1.026-1.201)], and depression [RR: 1.536 (1.413-1.670)]. No significant differences were noted in VTE and EC risk. Conclusion: This real-world analysis demonstrates that GLP-1RA use is associated with a significant reduction in all-cause mortality among obese BC patients undergoing ET. However, GLP-1 RA exposure appears to exacerbate several ET-related adverse effects. Future prospective studies are needed to determine these associations as they may warrant clinical consideration. Citation Format: C. Jones, J. Michalek, E. Obomanu, Y. Arya, A. Syal, S. Haddad, V. Kaklamani, S. Shaikh. Real-world Analysis on the Impact of GLP-1 Receptor Agonists on All-cause Mortality and Endocrine Therapy-Tolerability in Obese Breast Cancer 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 PD8-06.

Abstract Background: Obesity is a poor prognostic factor in early breast cancer (BC). The BWEL trial (Alliance A011401; NCT02750826) is a phase 3 randomized trial testing the impact of a weight loss intervention (WLI) on invasive disease-free survival in women with stage II-III BC and a body mass index (BMI) ≥27 kg/m2. Here we report trajectories of weight change in BWEL WLI participants (pts). Methods: Eligible pts were within 16 months of diagnosis of stage II-III HER2-negative BC, had completed chemotherapy (chemo) and radiation (if given), and were randomized 1:1 to a telephone-based WLI, focused on caloric restriction and exercise, plus health education (HE) or to an HE-alone control group. WLI pts were assigned a trained coach at the BWEL call center and received 42 phone calls over the 2-year (yr) WLI period. Weight and height at baseline, 6 and 24 months were collected by study staff. All WLI pts were provided with a Fitbit wireless scale. Fitbit weight records (FWRs) were automatically imported to the BWEL portal for pts with wireless access and self-reported in the portal for pts without wireless access. FWRs were averaged (avg) by week (wk) from the WLI start date up to 104 wks. Baseline pt factors were self-reported; treatment history was abstracted from the medical record. Linear mixed-effect models were used to evaluate trajectories of weight change over the 104-wk WLI. Principal component analysis and multinomial models were used to examine distinct clusters of weight trajectories. Results: 3180 pts were enrolled from 637 sites between 8/2016 and 2/2021. FWRs were available from 1508 of 1591 WLI pts, with a total of 366,294 FWRs collected during the 2-yr WLI period. In pts with FWRs, mean baseline BMI was 34.4 ± 5.6 kg/m2, mean age was 53.2 ± 10.3 yrs, 10.8% self-identified as Non-Hispanic (NH) Black and 6.1% as Hispanic, 81.1% received chemo and 56.9% were postmenopausal. No statistically significant differences in baseline factors were observed between pts with and without FWRs. Intraclass correlation coefficient of baseline weights collected by study staff and by Fitbit scales was 0.99. In the WLI cohort, avg weekly weight (kg) decreased from 91.4 (95% CI: 90.6-92.3) at baseline to 85.6 (95% CI: 84.8-86.5) by wk 40, corresponding to a peak loss of 6.1% (95% CI: 5.7-6.4) of baseline weight. Weight remained stable until wk 52 and then gradually increased to 87.0 kg (95% CI: 86.2-87.9) at wk 104, corresponding to a 4.4% (95% CI: 4.0-4.8) loss at wk 104 vs. baseline. Principal component analysis identified 3 distinct weight trajectories: 67.6% of pts experienced peak weight loss of 6.6% (95% CI: 6.3-6.9) of baseline weight, 10.0% experienced peak loss of 17.5% (95% CI: 16.8-18.2) of baseline weight, and 22.4% did not achieve weight loss, gaining on avg 2.2% (95% CI: 1.7-2.6) of baseline weight. Pts with college (relative risk ratio [RRR]=1.41, 95% CI: 1.03-1.92) and post-graduate education (RRR= 1.58, 95% CI: 1.13-2.20) and those who were premenopausal (RRR=1.70, 95% CI: 1.28-2.26) were more likely to be in the cluster that did not lose weight. Pts who were NH White (RRR=3.60, 95% CI: 1.95-6.68), postmenopausal (RRR=1.94, 95% CI: 1.28-2.95), had no alcohol use (RRR=1.49, 95% CI: 1.03-2.16), had not received chemo (RRR=1.76, 95% CI: 1.15-2.72), and had <3 chronic conditions (RRR: 2.12, 95% CI: 1.23-3.66) were more likely to be in the cluster with the highest weight loss. Conclusion: Longitudinal weight data from BWEL demonstrate peak weight loss of 6.1% in the WLI cohort at 40 wks, with distinct trajectories indicating differential responses to the WLI. This work demonstrates the feasibility of using digital health tools to track outcomes in the setting of a large-scale weight loss intervention study and informs future precision behavioral interventions in oncology. Support: U10CA180821, U10CA180882, UG1CA189823; U10CA180863. https://acknowledgments.alliancefound.org. Citation Format: C. Cao, K. Ballman, L. McCall, C. Alfano, V. Bernstein, T. Crane, L. Delahanty, L. Frank, P. Goodwin, O. Hahn, D. Hershman, J. Hopkins, M. Irwin, E. Mayer, L. Minasian, L. Nebeling, M. Neuhouser, E. Paskett, P. Spears, V. Stearns, C. Thomson, T. Wadden, A. Weiss, J. White, C. Hudis, E. Winer, A. Partridge, L. Carey, J. Ligibel. Weight Trajectories in the Breast Cancer Weight Loss (BWEL) Trial (Alliance) [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 PD8-01.

Abstract Introduction: AC plus a taxane is standard neoadjuvant therapy for high-risk early breast cancer, but AC may be unnecessary for pathologic complete response (pCR) in many patients. I-SPY2 is a phase 2 trial evaluating the use of 12 weeks of paclitaxel +/- an investigational drug followed by AC. Serial measurements of Functional Tumor Volume (FTV) by MRI, inter-regimen biopsies and pathology from surgery were used to determine the contribution of AC to reduction in FTV or pCR. Methods: 1187 patients enrolled between 2010-2022 had serial measurements of FTV. 150 patients received an inter-regimen biopsy. The primary endpoint of I-SPY2 is pCR. To determine how much AC contributed to the reduction in FTV, we calculated the total FTV decrease between pre-treatment and pre-surgery, and then computed the percentage (%) of the total FTV decrease seen after 12 weeks of paclitaxel regimen. We attributed pCRs observed among patients for whom taxane contributed <90% FTV reduction to AC and estimated the % patients achieving pCR from AC. For the subset with inter-regimen biopsy, we estimated the percentage achieving pCR from those patients with invasive cancer present at inter-regimen biopsy. Results: We found that by week 12 (end of taxane), 64% (763/1187) of patients had achieved ≥90% of their total FTV reduction. In 424/1187 (36%) patients had with taxane <90% response, and subsequent AC contributed to more than 10% of the total decrease in FTV. 90 pCRs (21%) were observed among these 424 patients or, overall, approximately 8% of patients achieved pCR from AC after taxane. Of note, 54/1187 (4.5%) patients had no response to a taxane regimen and had decreased in FTV due to AC alone. Of the 54/1187 responding to AC only, there were 11 pCRs. These results varied by response predictive subtypes as shown. When the subpopulation with post-paclitaxel biopsy was examined, 63/150 (42%) patients had invasive cancer at this timepoint. 47 patients received AC and 4/47 (8.5%) achieved a pCR after AC. 13/47 (28%) achieved RCB 0/1. Conclusions: Serial measurements of FTV identifies patients who had a favorable response to a taxane regimen. For those with a suboptimal response, AC provided some contribution to further decrease in tumor volume. However, only a small fraction achieved a complete response. Immune positive and HER2+ (non-luminal) had the biggest benefit, with only 3-6% of other subtypes achieved pCR. Thus, AC can be reserved for those patients with suboptimal response to the initial taxane therapy. I-SPY2.2 utilizes these data to avoid AC by allowing patients to proceed to surgery after serial MRI and biopsy predict a pCR at an early timepoint. While AC remains the standard of care in many neoadjuvant regimens, the low response rates seen in I-SPY2 suggests that more active regimens need to be developed for patients with disease resistant to a taxane based therapy. Citation Format: D. Yee, C. Yau, P. Norwood, D. M. Wolf, P. R. Pohlmann, N. Onishi, L. van 't Veer, A. Borowsky, W. F. Symmans, J. Perlmutter, J. C. Boughey, E. Price, W. Li, I-SPY Investigators, N. Hylton, L. J. Esserman. Quantifying the Contribution of Doxorubicin and Cyclophosphamide (AC) to Pathologic Response Following Neoadjuvant Taxane Therapy: Analysis of the I-SPY2 TRIAL [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 PD6-09.