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

Abstract

PurposeMutations in the <i>PIK3CA</i> gene occur frequently in breast cancer patients. Activating <i>PIK3CA</i> mutations confer resistance to human epidermal growth factor receptor 2 (HER2)-targeted treatments. In this study, we investigated whether <i>PIK3CA</i> mutations were correlated with treatment response or duration in patients with HER2-positive (HER2+) breast cancer.Materials and MethodsWe retrospectively 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 <i>PIK3CA</i> (<i>PIK3CAw</i>) and those with mutated <i>PIK3CA</i> (<i>PIK3CAm</i>). 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 (37.8%) patients had pathogenic <i>PIK3CA</i> mutations. The pCR rate of the <i>PIK3CAm</i> group was lower than that of the <i>PIK3CAw</i> group among patients who received neoadjuvant chemotherapy for early-stage cancer. In the metastatic setting, the <i>PIK3CAm</i> 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 <i>PIK3CAm</i> group than that in the <i>PIK3CAw</i> group. Sequencing revealed differences in the mutational landscape between <i>PIK3CAm</i> and <i>PIK3CAw</i> tumors.ConclusionPatients with HER2+ breast cancer with activating <i>PIK3CA</i> mutations had lower pCR rates and shorter PFS with palliative HER2-targeted therapy than those with wild-type <i>PIK3CA</i>. Precise targeted-therapy is needed to improve survival of patients with HER2+/PIK3CAm breast cancer.