241P APOBEC3-induced PIK3CA mutations predict better clinical outcomes with PI3K inhibitors in patients with PIK3CA-mutated advanced breast cancer

APOBEC3 enzymes are a key source of mutagenesis in breast cancer. PI3K inhibitors currently used the treatment PIK3CA-mutated advanced However, whether specific PIK3CA mutations (muts) associated with better outcomes is unclear. We developed computational framework to screen for APOBEC3-induced within TCW context using whole-exome sequencing (WES) data from cancer cohort genome atlas (TCGA-BRCA) and an independent patients (pts.) ER+/HER2- who were treated aromatase (AI). Using WES 696 pts luminal disease TCGA-BRCA cohort, we identified 296 (42.5%) muts. Of these, our retrieved 104 (35.1%) muts (A3P). There was no significant difference median overall survival A3P compared non-A3P mutant (129 vs. 114 months, p=0.49), neither TMB (1.3 vs 1.17 mut/Mb, p=0.75). ESR1 protein significantly less expressed samples (log2 ratio: -0.42, p=0.04). The majority (95%) found helical domain PIK3CA. numerically higher lobular ductal subtypes (43% 32%, p=0.08). validated prioritized 65 rate A3Pm 45% (n=29) which than non-metastatic TCGA-BRCA. Pts longer progression-free on inhibitor AI (5 2 hazard 0.56, 95%CI:0.31-1.00, p=0.02) trend toward objective response (26% 5%, p=0.06). patient E453K achieved partial 11 months alpelisib AI. This mutation not routinely included companion diagnostic test. Our findings indicate that catalog could identify driver confer oncogenic addiction, hence inhibitors.