Abstract

Introduction: Methylation of the BRCA1 promoter is frequent in triple negative breast cancers (TNBC) and results in a tumor phenotype similar to BRCA1-mutated tumors. BRCA1 mutation-associated cancers are more sensitive to DNA damaging agents as compared to conventional chemotherapy agents. It is not known if there is an interaction between the presence of BRCA1 promoter methylation (PM) and response to chemotherapy agents in sporadic TNBC. We sought to investigate the prognostic significance of BRCA1 PM in TNBC patients receiving standard chemotherapy.

Methods: Subjects with stage I-III TNBC treated with chemotherapy were identified and their formalin-fixed paraffin-embedded (FFPE) tumor specimens retrieved. Genomic DNA was isolated and subjected to methylation-specific PCR (MSPCR).

Results: DNA was isolated from primary tumor of 39 subjects. BRCA1 PM was detected in 30% of patients. Presence of BRCA1 PM was associated with lower BRCA1 transcript levels, suggesting epigenetic BRCA1 silencing. All patients received chemotherapy (anthracycline:90%, taxane:69%). At a median follow-up of 64 months, 46% of patients have recurred and 36% have died. On univariate analysis, African-American race, node positivity, stage, and BRCA1 PM were associated with worse RFS and OS. Five year OS was 36% for patients with BRCA1 PM vs. 77% for patients without BRCA1 PM (p=0.004). On multivariable analysis, BRCA1 PM was associated with significantly worse RFS and OS.

Conclusions: We show that BRCA1 PM is common in TNBC and has the potential to identify a significant fraction of TNBC patients who have suboptimal outcomes with standard chemotherapy.

Keywords: Triple negative breast cancer, BRCA1 promoter methylation, prognosis, chemosensitivity, biomarker