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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.

Frequency and spectrum of PIK3CA somatic mutations in breast cancer