PIK3CA Mutational Profiling in a Patient Cohort with HR+/HER2- Advanced Metastatic Breast Cancer at a Tertiary Cancer Center

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Abstract

Common PIK3CA gene activating mutations can be found in 20-30% of all breast cancer cases, and regarded as predictive markers for therapeutic response to PI3K inhibitors. The therascreen PIK3CA mutation companion assay and the alpha-specific PI3K inhibitor, Alpelisib, are FDA-approved for selecting and treating patients with advanced PIK3CA-mutated metastatic breast cancer. The main objective behind this report was to investigate the composition and proportion of PIK3CA mutations using a PIK3CA mutation Therascreen RT-PCR assay, in a patient cohort with receptor-positive/HER2-negative (HR+/HER2) metastatic breast cancer, who were diagnosed and treated at King Hussein Cancer Center (KHCC). Patients with PIK3CA-mutated tumors represented 39.4% (91/231) of all patients. Four PIK3CA mutations comprised 86.8% of all PIK3CA mutations; mainly H1047R (33.3%), E545K (20.9%), E542K (24.2%), and H1047L (8.8%). The four main mutations map to the helical and kinase domains of the PIK3CA encoded protein. C420R was found in only one patient, and E545A was found in two patients. Nine of the 91 mutated patients had shown double PIK3CA mutations (9.9%). In conclusion, PIK3CA is frequently mutated in multiple types of cancers at known ‘Hot-spots’, mainly in the kinase and helical modular domains, which we found consistent with our findings. PIK3CA mutational signature in our metastatic breast cancer cohort varied with a 39.4% (91/231) positivity rate. The PIK3CA mutational screening panel did not capture mutations in the remaining 140 (60.6%) cases; these patients may be mutated in other genes related to breast cancer, or in PIK3CA loci not covered by the Therascreen assay. Survival and clinical outcomes in association with PIK3CA mutational profiles shall be addressed in a follow-up investigation for this patients’ cohort.

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