Abstract PS4-01-14: Evaluation of Metabolic Dysregulation, Endocrine Therapy Outcomes, and Tumor Biology in HER2-/HR+ Breast Cancer using a Multi-Omic, Real-World Analysis

Abstract Background: Metabolic dysregulation, including hyperglycemia (HG) and type 2 diabetes mellitus (T2DM), is increasingly prevalent among breast cancer (BC) patients (pts) and may influence treatment outcomes. In hormone receptor-positive (HR+) BC, metabolic comorbidities could affect tumor biology and response to endocrine therapy. This study integrates real-world clinical outcomes with multi-omic tumor profiling to evaluate the potential impact of HG/T2DM on endocrine therapy outcomes and tumor molecular signatures in pts with HER2-/HR+ BC. Methods: This retrospective analysis utilized BC samples profiled by Caris Life Sciences (Phoenix, AZ), including next-generation sequencing (592-gene panel or whole exome for DNA and whole transcriptome for RNA) and immunohistochemistry (IHC). Tumors were classified as HER2- (≤1+ intensity or ≤10% cells stained by IHC, or 2+/>10% and CISH-negative) and HR+ (ER or PR ≥1+/≥1%). Pts with no prior systemic therapy who initiated first-line aromatase inhibitor and/or fulvestrant (AI/Fulv) within 100 days post-biopsy were identified using linked claims data. ICD-10 codes were used to define HG and T2DM status, and medication exposure was assessed for insulin, metformin, and GLP-1 receptor agonists (Ins/Met/GLP-1RA). Clinical endpoints included overall survival (OS; time from first AI/Fulv to death or last contact) and time on treatment (ToT; from first to last AI/Fulv), as assessed via Cox proportional hazards models and log-rank tests. Among pts without reported exposure to Ins/Met/GLP1-RA, tumor molecular profiles were compared between pts with HG/T2DM and metabolically healthy controls (no HG/T2DM) using Mann-Whitney U and chi-square tests. Results: A total of 2,074 pts with HER2-/HR+ BC treated with first-line AI/Fulv were included in the analysis, comprising three cohorts: 1,119 pts without HG/T2DM and no exposure to Ins/Met/GLP-1RA; 398 pts with HG/T2DM and no exposure to these agents; and 557 pts with HG/T2DM who had received Ins/Met/GLP-1RAs. Median OS was 49, 48, and 52 months, respectively (p = 0.71), and median ToT was 17, 21, and 19 months, respectively (p = 0.37). Subgroup analyses stratified by CDK4/6 inhibitor exposure in first- or later-line therapy revealed consistent patterns, with no statistically significant differences in survival across metabolic strata. Molecular analyses identified notable distinctions in tumors from pts with HG/T2DM. Pathogenic mutations in PIK3CA (50.4% vs. 42.9%; p = 0.01), CASP8 (1.5% vs. 0.1%; p < 0.001), ACVR1B (2.1% vs. 0.2%; p = 0.02), and TSC2 (0.9% vs. 0.1%; p = 0.02) were more prevalent in the HG/T2DM group. Deletion events in CYLD (2.8% vs. 0.5%; p < 0.01), B2M (0.7% vs. 0.0%; p = 0.02), CDKN2C (1.1% vs. 0.1%; p = 0.02), RAD54L (1.1% vs. 0.1%; p = 0.02), and FANCA (2.8% vs. 0.9%; p = 0.03) were similarly enriched. Amplifications of HSP90AB1 and SS18 were detected only in HG/T2DM tumors (0.7% and 1.1%, respectively; p = 0.02 for both), while MDM2 amplification was more frequent in controls (3.1% vs. 0.7%; p = 0.03). Conclusion: Metabolic dysfunction was not associated with significant differences in clinical outcomes among pts receiving endocrine therapy. However, tumors from pts with HG/T2DM exhibited distinct molecular alterations, including higher frequencies of PIK3CA mutations, MDM2 and HSP90AB1 amplifications, and deletions in CYLD, B2M, and CDKN2C, suggesting enhanced proliferative signaling and reduced immune activation. These findings may contribute to endocrine resistance and underscore the need for biomarker-driven, metabolically informed treatment strategies. Prospective studies are warranted to validate these observations and inform future therapeutic approaches. Citation Format: J. Hundal, R. Plagens, A. Elliott, G. Sledge, C. Travaline, S. Graff, M. Lustberg, M. Vasekar, J. Leone. Evaluation of Metabolic Dysregulation, Endocrine Therapy Outcomes, and Tumor Biology in HER2-/HR+ Breast Cancer using a Multi-Omic, 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 PS4-01-14.