Mutational Landscape of PI3K-AKT-mTOR Pathway in Breast Cancer: Implications for Targeted Therapeutics

Comprehensive analysis of PI3K-AKT-mTOR pathway gene alterations in breast cancer may be helpful for targeted therapy. We performed targeted sequencing using a panel of 520 cancer-related genes to investigate gene alterations in the PI3K-AKT-mTOR pathway from 589 consecutive Chinese women diagnosed with stage I-III breast cancer. Analyses of overall survival (OS) were performed using the publicly available clinical and genomic data from METABRIC. PI3K-AKT-mTOR pathway gene alterations were detected in 62.6% (369/589) of our cohort. The most commonly altered genes were (45%), (7.5%), (5.9 %), (2.7%), and (2%). Four mutations (E545K, H1047R, E542K, and H1047L) were detected in all the breast cancer molecular subtypes. Seven mutations (E545G, E418_L422delinsV, E726K, E110del, G1049R, G118D, and D350G) were only detected in HR subtypes. Two mutations (C420R and N345K) were only detected in non-triple-negative subtypes. Most cases with mutation were HR/HER2 subtype (77.3%), followed by triple-negative subtype (18.2%). In the METABRIC breast cancer dataset, no significant OS difference was observed between the -mutant and wild-type groups. However, patients with multiple mutations (mOS: 131 vs. 159 months, = 0.029), or mutations located in the domain had significantly shorter OS (mOS, 130 vs. 154 months, =0.020) than those without the mutations. Our study reveals the heterogeneity in PI3K-AKT-mTOR pathway among the breast cancer molecular subtypes in our cohort. Moreover, the number and specific sites of mutations have distinct prognostic impact.