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. 2020 May 13;22(1):45.
doi: 10.1186/s13058-020-01284-9.

Frequency and spectrum of PIK3CA somatic mutations in breast cancer

Olga Martínez-Sáez  1   2   3 , Nuria Chic  1   2   3 , Tomás Pascual  1   2   3 , Barbara Adamo  1   2   3 , Maria Vidal  1   2   3 , Blanca González-Farré  1   2   3   4 , Esther Sanfeliu  1   2   3   4 , Francesco Schettini  1   2   3   5 , Benedetta Conte  1   2   3 , Fara Brasó-Maristany  1   2   3 , Adela Rodríguez  1 , Débora Martínez  2 , Patricia Galván  2 , Ana Belén Rodríguez  1 , Antonio Martinez  5 , Montserrat Muñoz  1   2   3 , Aleix Prat  6   7   8
Affiliations

Frequency and spectrum of PIK3CA somatic mutations in breast cancer

Olga Martínez-Sáez et al. Breast Cancer Res. .

Abstract

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 (PIK3CAmut) 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 PIK3CAmut 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 PIK3CAmut BC. Among patients with double PIK3CAmut tumors (12% of all PIK3CAmut), the therascreen panel would capture 78% as harboring 1 single PIK3CA mutation, 17% as PIK3CAmut 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 PIK3CAmut 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.

Keywords: Alpelisib; Breast cancer; Companion diagnostic; Hotspot mutations; Mutations; PIK3CA; Therascreen; ctDNA.

PubMed Disclaimer

Conflict of interest statement

AP reports that his institution received research funding from Nanostring Technologies, Roche, and Novartis. AP reports consulting and lecture fees from Nanostring Technologies, Roche, Novartis, Pfizer, Oncolytics Biotech, Amgen, Lilly, MSD, and PUMA.

Figures

Fig. 1
Fig. 1
The CONSORT diagram
Fig. 2
Fig. 2
Proportion of PIK3CA mutations in BC in relation to the mutations detected by therascreen. a Proportion of patients with PIK3CA mutations in the combined dataset. b Distribution of the various types of PIK3CA mutations in the combined dataset. c Proportion of PIK3CA mutations detected by the therascreen assay. d Distribution of the various types of PIK3CA mutations detected by the therascreen assay in the combined dataset
Fig. 3
Fig. 3
Proportion of the 18 most frequent PIK3CA mutations in PIK3CAmut BC in the combined dataset
Fig. 4
Fig. 4
Proportion of patients with PIK3CA mutations in BC in relation to the mutations detected by therascreen. a Proportion of patients with one, two, or three or more PIK3CA mutations in BC in the combined dataset. b Proportion of patients with a single PIK3CA mutation detected PIK3CAmut by the therascreen assay. c Proportion of patients with two or more PIK3CA mutations detected by the therascreen assay as either PIK3CA mutation “not detected,” single PIK3CA mutation or as harboring 2 or more PIK3CA mutations
Fig. 5
Fig. 5
Proportion of PIK3CA mutations across the BC subtypes. a Proportion of PIK3CA mutations in HR+/HER2-negative BC. b Proportion of PIK3CA mutations in HER2+ BC. c Proportion of PIK3CA mutations in TNBC. d Distribution of the various types of PIK3CA mutations in PIK3CAmut HR+/HER2-negative BC. e Distribution of the various types of PIK3CA mutations in PIK3CAmut HER2+ BC. f Distribution of the various types of PIK3CA mutations in PIK3CAmut TNBC
See this image and copyright information in PMC

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