Abstract 2994: Integrative pathway analysis of I-SPY2 HER2+ breast cancers reveals drug-repurposing opportunities

Abstract Background: HER2-positive breast cancer (HER2+) accounts for approximately 20% of all breast cancers. Major advances in HER2-targeted therapy have improved outcomes; however, substantial room for response improvement remains. Molecular subtyping by BluePrint (BP) stratifies HER2+ disease into HER2 and Luminal types. While BP-HER2 tumors achieve up to 78% pathologic complete response (pCR) with standard therapy, BP-Luminal tumors exhibit persistently low pCR rates (15%). To address this unmet need, we profiled pretreatment molecular features distinguishing responders from non-responders across all HER2+ tumors and within BP subtypes to identify druggable pathways for rational combination or repurposing strategies. Methods: Baseline microarray profiles from 305 pretreatment HER2+ tumors (87 BP-Luminal, 218 BP-HER2) enrolled across five investigational agents or standard of care in the I-SPY2 trial were analyzed using Gene Set Variation Analysis (GSVA) across 2,265 canonical pathway gene sets. Differential pathway enrichment was assessed using linear models adjusting for treatment arm and false-discovery rate. Two comparisons were performed: (1) pCR vs. no pCR overall and within subtypes, and (2) BP-HER2 vs. BP-Luminal. Shared response- and subtype-specific pathways were grouped by functional similarity and cross-referenced with drug-target databases to identify FDA-approved or investigational compounds. Results: Across HER2+ tumors and within BP-HER2, we identified 42 pathways enriched in non-responders that were also elevated in BP-Luminal relative to BP-HER2, suggesting a luminal-linked resistance program even in non-luminal tumors. These pathways converged into eight metabolic and signaling themes. Growth-factor/RTK bypass (PI3K/AKT) and DNA repair Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 2994.