Journal Article

Frequency and spectrum of PIK3CA somatic mutations in breast cancer

Pascual, Tomás, Galván, Patricia, Rodríguez, Ana Belén, Martinez, Antonio, Schettini, Francesco, Adamo, Barbara, González-Farré, Blanca, Martínez-Sáez, Olga, Muñoz, Montserrat, Brasó-Maristany, Fara, Chic, Nuria, Vidal, Maria, Prat, Aleix, Sanfeliu, Esther, Martínez, Débora, Conte, Benedetta, Rodríguez, Adela

2020

Overview

Purpose The therascreen PIK3CA mutation assay and the alpha-specific PI3K inhibitor alpelisib are FDA-approved for identifying and treating patients with advanced PIK3CA- mutated ( PIK3CA mut) breast cancer (BC). However, it is currently unknown to what extend this assay detects most PIK3CA mutations in BC. This information is critical as patients and clinicians are using this and other genomic assays to indicate alpelisib. Methods Data from 6338 patients with BC was explored across 10 publicly available studies. The primary objective was to evaluate the proportion and distribution of PIK3CA mutations in BC. Secondary objectives were (1) to evaluate in silico the spectrum of PIK3CA mutations in BC that would be captured by the therascreen panel; (2) to evaluate the proportion and distribution of PIK3CA mutations in hormone receptor-positive/HER2-negative (HR+/HER2−), HER2+, and triple-negative BC (TNBC); and (3) to explore the identification of PIK3CA mutations in a cohort of 48 HR+/HER2− advanced BC patients by the Guardant B360 circulating tumor DNA (ctDNA) assay. Results Patients with PIK3CA mut tumors represented 35.7% (2261/6338). Five PIK3CA mutations comprised 73% of all PIK3CA mutations: H1047R (35%), E545K (17%), E542K (11%), N345K (6%), and H1047L (4%). Therascreen gene list would capture 72% of all PIK3CA mutations and 80% of patients with a known PIK3CA mut BC. Among patients with double PIK3CA mut tumors (12% of all PIK3CA mut), the therascreen panel would capture 78% as harboring 1 single PIK3CA mutation, 17% as PIK3CA mut undetected, and 5% as PIK3CA double-mut. PIK3CA mutation rates were lower in TNBC (16%) compared to HR+/HER2 (42%) and HER2+ (31%) BC; however, the distribution of the 4 main PIK3CA mutations across subtypes was similar. Finally, 28% of PIK3CA mutations identified in ctDNA in 48 patients with advanced HR+/HER2− BC were not part of the therascreen panel. Conclusion PIK3CA mutations in BC are heterogenous and ~ 20% of patients with a known PIK3CA mutation, and 95% with a known double PIK3CA mut tumor, would not be captured by the therascreen panel. Finally, the clinical utility of PIK3CA mutations not present in the therascreen companion diagnostic assay or identified by other sequencing-based assays needs further investigation.

• Publisher: BioMed Central,BioMed Central Ltd,Springer Nature B.V,BMC
• Subject: 1-Phosphatidylinositol 3-kinase / Alpelisib / Biomedical and Life Sciences / Biomedicine / Breast cancer / Cancer / Cancer Research / Care and treatment / Companion diagnostic / Datasets / Endocrine therapy / ErbB-2 protein / Fulvestrant / Genetic aspects / Genetic research / Hotspot mutations / Mutation / Mutation rates / Mutations / Oncology / Patients / PIK3CA / Plasma / Research Article / Surgical Oncology / Tumors