PIK3CA mutations in breast cancer

Abstract Purpose: The phosphatidylinositide-3-kinase (PI3K) pathway regulates intracellular processes in relation to proliferation and apoptosis, which can be activated by somatic PIK3CA mutations. The aim of this work was to analyze the prevalence of PIK3CA mutations in an unselected cohort of patients with early stage breast cancer and their association with survival.Patients and methods: From a prospective, multicentre cohort of 1,270-breast cancer patients (PiA, Prognostic Assessment in routine application, NCT 01592825) 1,123 tumors were tested for PIK3CA-mutations in three hotspots C775 (H1047R), C763 (E545K) and C760 (E542K) by quantitative PCR. The primary objectives were the prevalence of somatic PIK3CA mutations and the associations between PIK3CA mutations and clinical and histopathological parameters. Secondary objectives were the association of PIK3CA mutations with recurrence free interval (RFI) and overall survival.Results: The overall PIK3CA mutation rate was 26.7% (300 out of 1,123). PIK3CA mutations were significantly more frequent in tumors with more favorable factors like steroid hormone receptor (HR)-positive and HER2-negative (31.4%), and G1/ G2 tumours (32.8%). We found a significant detrimental prognostic impact of PIK3CA-mutations on RFI for patients with HR-positive BCs who had only aromatase inhibitors as adjuvant therapy (adjusted HR 3.71, 95% CI 1.24-11.11), whereas PIK3CA mutations in HR-negative BCs were insignificantly associated with improved RFI (adjusted HR=0.43; 95% CI 0.10-1.82).Conclusion: The impaired prognosis for HR-positive BCs and concurrent PIK3CA mutations supports the hypothesis that the activation of PI3K might lead to endocrine resistance. Conversely, patients with HR-negative tumors and PIK3CA mutations might benefit from chemotherapy compared to patients with wildtype PIK3CA gene.