The prognostic value of promoter methylation in early stage triple negative breast cancer.

Introduction: Methylation of the promoter is frequent in triple negative breast cancers (TNBC) and results in a tumor phenotype similar to -mutated tumors. 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 promoter methylation (PM) and response to chemotherapy agents in sporadic TNBC. We sought to investigate the prognostic significance of 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. PM was detected in 30% of patients. Presence of PM was associated with lower transcript levels, suggesting epigenetic 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 PM were associated with worse RFS and OS. Five year OS was 36% for patients with PM vs. 77% for patients without PM (p=0.004). On multivariable analysis, PM was associated with significantly worse RFS and OS.

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