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