BRCA1 like copy number profiles to predict benefit of intensified alkylating chemotherapy in breast cancer.

Abstract

11023 Background: DNA copy number profiles can identify patients with a defect in BRCA1. We previously showed that patients with a BRCA1-like profile benefit from intensified alkylating chemotherapy (IA, 4 cycles 5-fluorouracyl, epirubicin, cyclophosphamide + 1 cycle carboplatin, thiotepa and cyclophosphamide with autologous stem cell transplantation (ASCT)). Presumably, this is because of the defect in error free homologous recombination DNA repair. Here we present an independent study of BRCA1-like profiles to predict benefit of IA chemotherapy (2 cycles induction chemotherapy consisting of 2500 mg/m2 ifosfamide and 40 mg/m2 epirubicin, followed by 12 g/m2 ifosfamide, 900 mg/m2 carboplatin, 180 mg/m2 epirubicin with ASCT) versus adriamycin-cyclophosphamide or cyclophosphamide-methotrexate-5-fluorouracyl regimens in high risk breast cancer. Methods: We isolated tumor DNA from 117 patients of a case-control study of high risk breast cancer patients to apply a marker by treatment interaction study design to assess overall survival. We generated copy number profiles and classified them to be BRCA1-like or non-BRCA1 like. We used Fisher Exact tests to calculate correlations and performed Kaplan-Meier and Cox regression analyses to investigate whether patients with a BRCA1-like tumor benefit from IA chemotherapy compared to an AC/CMF regimen. Results: 16 of 117 (14%) patients had a BRCA1-like profile. BRCA1-like status was associated with high tumor grade (p=0.03), triple negative status (p=0.0005) and high N stage (p=0.03). When corrected for hormone receptor and HER2 status, size, positive lymph nodes, and grade we found that BRCA1 like patients had a 6-fold decreased chance of death (HR: 0.15, 95% confidence interval: 0.03-0.80, p: 0.03) compared to non-BRCA1 like patients (HR: 0.94, 95% confidence interval: 0.53-1.67, p: 0.84). The interaction test between IA chemotherapy and marker status was significant (p: 0.04). Conclusions: We provide independent validation of the previous finding that breast cancer patients with a BRCA1 like copy number profile benefit highly from intensified alkylating chemotherapy.