BRCA1 Promoter Hypermethylation is Associated with Good Prognosis and Chemosensitivity in Triple-Negative Breast Cancer

Abstract

The aberrant hypermethylation of <i>BRCA1</i> promoter CpG islands induces the decreased expression of BRCA1 <i>(</i>Breast Cancer 1<i>)</i> protein. It can be detected in sporadic breast cancer without <i>BRCA1</i> pathogenic variants, particularly in triple-negative breast cancers (TNBC). We investigated <i>BRCA1</i> hypermethylation status (by methylation-specific polymerase chain reaction (MS-PCR) and MassARRAY^® assays), and BRCA1 protein expression using immunohistochemistry (IHC), and their clinicopathological significance in 248 chemotherapy-naïve TNBC samples. Fifty-five tumors (22%) exhibited <i>BRCA1</i> promoter hypermethylation, with a high concordance rate between MS-PCR and MassARRAY^® results. Promoter hypermethylation was associated with reduced IHC BRCA1 protein expression (<i>p</i> = 0.005), and expression of Programmed death-ligand 1 protein (PD-L1) by tumor and immune cells (<i>p</i> = 0.03 and 0.011, respectively). A trend was found between promoter hypermethylation and basal marker staining (<i>p</i> = 0.058), and between BRCA1 expression and a basal-like phenotype. In multivariate analysis, relapse-free survival was significantly associated with N stage, adjuvant chemotherapy, and histological subtype. Overall survival was significantly associated with T and N stage, histology, and adjuvant chemotherapy. In addition, patients with tumors harboring <i>BRCA1</i> promoter hypermethylation derived the most benefit from adjuvant chemotherapy. In conclusion, <i>BRCA1</i> promoter hypermethylation is associated with TNBC sensitivity to adjuvant chemotherapy, basal-like features and PD-L1 expression. BRCA1 IHC expression is not a good surrogate marker for promoter hypermethylation and is not independently associated with prognosis. Association between promoter hypermethylation and sensitivity to Poly(ADP-ribose) polymerase PARP inhibitors needs to be evaluated in a specific series of patients.