Abstract PS2-11-06: Quiescent-like phenotype characterizes treatment-resistant early-stage HER2-negative breast cancers and suggests novel therapeutic targets; analysis of over 2000 patients from the I-SPY2 trial

Abstract Introduction The I-SPY2 neoadjuvant platform trial (NCT01042379) evaluates new therapies in high molecular risk breast cancer patients. From 2010-2022, 24 therapies were tested in 2117 patients. One-third of these patients had HER2-negative tumors with low expression of immune genes and no DNA repair deficiency (DRD) (HER2-/Immune-/DRD- subtype). These patients had very low pathologic complete response (pCR) rates (∼10% on average) across all treatment and control arms, whereas those patients with Immune, DRD, or HER2 targetable tumors had higher pCR rates (with the most successful treatments achieving pCR rates between 60-100%), associated with long-term survival benefit. Here, we focus on characterizing the biology of HER2-/Immune-/DRD- tumors, with the aim of identifying novel targetable vulnerabilities to increase treatment sensitivity in these treatment-resistant tumors. Methods We analyzed pre-treatment transcriptomic data of HR+HER2- (n = 889) and triple-negative (TN) (n = 739) patients across 20 treatment arms in I-SPY2 for enrichment of canonical metabolic, signaling, and regulatory pathways from the Molecular Signatures Database (n = 2274) including Hallmark, BioCarta, Reactome, and Pathway Interaction Database (PID) gene sets. We compared 1) HR+HER2-/Immune-/DRD- (n = 617) vs. other (Immune+ and/or DRD+) HR+HER2- tumors (n = 272) and 2) TN/Immune-/DRD- (n = 177) vs. other (Immune+ and/or DRD+) TN tumors (n = 562). Comparisons were made using Wilcoxon rank-sum tests with Benjamini-Hochberg adjustment. Results with adjusted p-values