PIK3CA Mutation is Associated with Poor Response to HER2-Targeted Therapy in Breast Cancer Patients

Abstract PurposeMutations in PIK3CA gene occur frequently in patients with breast cancer. Activating PIK3CA mutations have been shown to confer resistance to human epidermal growth factor receptor (HER)2-targeted treatments. In this retrospective study, we investigated whether PIK3CA mutations were correlated with treatment response or duration in HER2-positive (HER2+) breast cancer patients.MethodsWe reviewed the clinical information of patients with HER2 + breast cancer who received HER2-targeted therapy for early stage or metastatic cancers. The pathologic complete response (pCR), progression-free survival (PFS), and overall survival were compared between patients with wild-type PIK3CA (PIK3CAw) and mutated PIK3CA (PIK3CAm), among those selected for the study. Next-generation sequencing was combined with examination of PFS associated with anti-HER2 monoclonal antibody (mAb) treatment.ResultsData from 90 patients with HER2 + breast cancer were analyzed. Overall, 34 patients had pathogenic PIK3CA mutations (37.8%). The pCR rate of the PIK3CAm group was lower than that of the PIK3CAw group among patients who received neoadjuvant chemotherapy for early stage cancer. In the metastatic setting, the PIK3CAm group showed a significantly shorter mean PFS (mPFS) with first-line anti-HER2 mAb. The mPFS of second-line T-DM1 was lower in the PIK3CAm group than in the PIK3CAw group. Sequencing revealed differences in the Mutational landscape between PIK3CAm and PIK3CAw tumors.Conclusion HER2+ breast cancer patients with activating PIK3CA mutations had lower pCR rates and shorter PFS with palliative HER2-targeted therapy than those with wild-type PIK3CA. Our results suggest that HER2+ breast cancer patients with PIK3CA mutations have an unmet clinical need.