Abstract
PurposeThe 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.MethodsData 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.ResultsPatients 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.ConclusionPIK3CA 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.
Highlights
Activating mutations in the PIK3CA are found in approximately 30–40% of patients with cancer and induce hyperactivation of the alpha isoform (p110α) of the phosphatidylinositol 3-kinase (PI3K) [1,2,3]
To define the potential frequency of this clinical situation, here we aimed to evaluate the distribution of PIK3CA mutations in breast cancer (BC) in relation to the therascreen PIK3CA panel
PIK3CA mutations captured by the therascreen panel In the combined dataset, the proportion of PIK3CA mutations included in the therascreen panel was 72% (Fig. 2c)
Summary
Activating mutations in the PIK3CA are found in approximately 30–40% of patients with cancer and induce hyperactivation of the alpha isoform (p110α) of the phosphatidylinositol 3-kinase (PI3K) [1,2,3]. In patients with HR+/HER2− BC, mTOR/mTOR pathway has been associated with endocrine therapy resistance [4]. Alpelisib is an orally bioavailable, small-molecule, αspecific PI3K inhibitor that inhibits p110α approximately 50 times as strongly as other isoforms [8]. Following successful preclinical and phase 1 data [4, 9], the SOLAR-1 phase III randomized trial evaluated the efficacy of alpelisib plus fulvestrant in 572 patients with HR+/HER2− advanced BC who had received prior endocrine therapy [10]. In May 2019, the FDA approved alpelisib for the treatment of patients with advanced PIK3CAmut HR+/HER2− BC
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