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

Abstract

The aberrant hypermethylation of BRCA1 promoter CpG islands induces the decreased expression of BRCA1 (Breast Cancer 1) protein. It can be detected in sporadic breast cancer without BRCA1 pathogenic variants, particularly in triple-negative breast cancers (TNBC). We investigated BRCA1 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 BRCA1 promoter hypermethylation, with a high concordance rate between MS-PCR and MassARRAY® results. Promoter hypermethylation was associated with reduced IHC BRCA1 protein expression (p = 0.005), and expression of Programmed death-ligand 1 protein (PD-L1) by tumor and immune cells (p = 0.03 and 0.011, respectively). A trend was found between promoter hypermethylation and basal marker staining (p = 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 BRCA1 promoter hypermethylation derived the most benefit from adjuvant chemotherapy. In conclusion, BRCA1 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.

Comprehensive molecular comparison of BRCA1 hypermethylated and BRCA1 mutated triple negative breast cancers

“…In agreement with previous studies 19,23,24,47 , BRCA1 hypermethylation was strongly associated with classical features of BRCA1-null and basal-like disease. Despite this, BRCA1 promoter hypermethylation was also present in subgroups such as old patients and in molecular subtypes not commonly associated with BRCA1 deficiency in TNBC, albeit at lower frequency.…”

“…This lends support to the reproducibility and generalizability of our results in the context of the studied patient demographics for both molecular and patient outcome findings, despite limited sample numbers for some comparisons. In the total SCAN-B cohort, 24.1% of TNBC patients were BRCA1 hypermethylated, a proportion in the lower to mid-range of previous reports [14][15][16][17][18][19][20] . However, in comparison to the observed BRCA1-null rate of 10.5% among all SCAN-B patients, BRCA1 hypermethylation is more than twice as frequent.…”

“…In the SCAN-B cohort, TIL-levels did not differ between hypermethylated and BRCA1-null cases, which is consistent with the similar prognosis in these groups after adjuvant chemotherapy. PD-L1 expression is also frequent in TNBC, including BRCA1 hypermethylated tumors 19 , but studies have not found that levels of PD-L1-positive TILs in TNBC cancers are driven by a high mutation rate or by BRCA1 mutation status 52,54 . This lack of association may now be appreciated through our delineation of the BRCA1/2-wt subgroup by BRCA1 hypermethylation, forming a major subgroup of TNBC with similar genetic and immune cell phenotypes as BRCA1-null cases.…”

“…There are conflicting reports in the literature about whether BRCA1 hypermethylation is associated with a better or worse prognosis in early-stage disease (e.g., refs. 14 – 16 , 18 , 19 , 21 ). In metastatic TNBC, BRCA1 hypermethylation has been reported not to be associated with a better treatment response to carboplatin compared with docetaxel 48 (although hypermethylation in this study was measured in the primary tumor tissue, not the actual metastatic tissue) or to single-agent carboplatin effect 49 .…”

“…DNA promoter hypermethylation could be an alternative mechanism of inactivating BRCA1. BRCA1 promoter hypermethylation has been reported in 16-57% of TNBCs across studies [14][15][16][17][18][19][20] , superseding the frequency of germline BRCA1 alterations, however, with conflicting reports about association with prognosis (e.g. refs.…”