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

Abstract

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 (IA) chemotherapy with autologous stem cell transplantation (ASCT). Here we present an independent validation of BRCA1-like profiles to predict benefit of high-dose IA chemotherapy (ifosfamide, epirubicin, carboplatin with ASCT) versus conventional chemotherapy in high risk breast cancer. Methods: Copy number profiles were generated from 117 sporadic high breast cancers and classified to either BRCAlike or non-BRCA-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. A marker by treatment interaction study design was applied to asses overall survival. Results: 14% of patients had a BRCA1-like profile, which was associated with high grade (p = 0.03), triple negative status (p = 0.0005) and high N stage (p = 0.03). When corrected for HR and HER2 status, size, positive nodes and grade we found that BRCA1-like patients had a 6-fold decreased chance of death (HR: 0.15, 95% CI: 0.03 – 0.80, p: 0.03) compared to non-BRCA1 like patients (HR: 0.94, 95% CI: 0.53 – 1.67, p: 0.84). The interaction test between treatment and BRCA1-like profile was significant (p: 0.04). Conclusions: We provide independent validation of the previous finding that breast cancers with BRCA1-like copy-number profiles benefit highly from IA chemotherapy.