Modulation of Mutational Landscape in HER2-Positive Breast Cancer after Neoadjuvant Chemotherapy

Abstract

Introduction: In early-stage HER2 positive breast cancer (BC) patients, tumor response to neoadjuvant chemotherapy (NACT) predict survival outcomes. Patients achieving less than pathological complete response (pCR) have a worse prognosis, however, this group is heterogeneous. Nowadays limited data on predictive/prognostic biomarkers in patients with residual cancer disease are available. Methods: Using next-generation sequencing technology, we evaluated a panel of 21 cancer genes in a group of HER2 positive BC patients with residual disease after NACT. A control group of patients who achieved the pCR was selected too. The BC mutational profile was analyzed on both the tumor diagnostic biopsy and matched residual disease. Results: Overall, the detection rate of mutations was 79% in the No-pCR group versus 90% in the pCR cohort and 98% in the residual BC. The most mutated genes were TP53 and PIK3CA. No correlations between single gene mutations and survival outcomes were found. In no-pCR cohort, 52% of patients had different mutational profile after NACT, 69% of them had an increased in the number of mutated genes. Mutational profile changes from diagnostic biopsy to residual BC were a negative prognostic factor in term of relapse free survival: recurrence probability in different gene profile sub-group was 42% vs 0% in the same profile one (P = .019). Conclusions: Treatment selective pressure on tumor cells due to NACT changed the gene mutational profile in more than half of BC patient with residual tumor disease. Treatment-induced gene mutations significantly increase the risk of relapse. Profiling primary and residual BC is a major step in order to further personalized adjuvant treatment strategy.