BRCA-1 methylation and TP53 mutation in triple-negative breast cancer patients without pathological complete response to taxane-based neoadjuvant chemotherapy

Abstract

Triple-negative breast cancer (TNBC) patients without pathological complete response (pCR) to neoadjuvant chemotherapy have an unfavourable prognosis. TNBC harbouring BRCA-1 germline mutations may be less responsive to taxanes, while sensitivity to DNA-damaging agents is retained. A similar effect was seen in tumours with epigenetic BRCA-1 silencing. Patients without pCR to neoadjuvant chemotherapy consisting of epirubicin plus docetaxel routinely received post-operative CMF at our centre. Here, we investigated the effect of adjuvant CMF in patients with or without BRCA-1 methylation or TP53 mutation. DNA was extracted from formalin-fixed paraffin-embedded tissue. For determining BRCA-1 methylation status, quantitative methylation-specific PCR was performed. For the investigation of TP53 mutation status, DNA was PCR amplified and sequenced by Sanger sequencing. Twenty-four patients were included; BRCA-1 methylation was present in 41.7 %, while TP53 mutations were observed in 66.7 %. At a median follow-up of 27.5 months, 20 % of patients with BRCA-1 methylation had a disease-free survival (DFS) event, as compared to 64.3 % in the non-methylated group (p = 0.0472). Median DFS in the non-methylated group was 16 months and was not reached in the methylated group (n.s.). No association TP53 mutation status with clinical outcome was observed. Adjuvant CMF is of limited activity in TNBC refractory to taxane-based neoadjuvant chemotherapy. In this population, BRCA-1 methylation was associated with a significant decrease in DFS events suggesting a better prognosis and potentially retained activity of DNA-damaging agents.