Evaluation of BRCA1 inactivation by promoter methylation as a marker of triple-negative and basal-like breast cancers.

Abstract

10510 Background: Triple-negative (ER-, PR-, and HER2-) breast cancer (TNBC) is the most aggressive form of breast disease and is overrepresented in young women and women of African ancestry. Molecular mechanisms specific for TNBC are largely unknown; there is no targeted therapy available. A subgroup of sporadic TNBCs with a basal-like phenotype (BLBC) has morphological features and gene expression profiles similar to tumors from BRCA1 mutation carriers. Promoter methylation inhibit BRCA1 expression resulting in tumor phenotypes similar to those of hereditary BRCA1-mutated tumors. We hypothesize that in sporadic tumors BRCA1inactivation by promoter methylation contributes to the development of TN and BL phenotypes. Methods: Using a combination of methylation-specific PCR, IHC and cDNA microarrays, 198 primary breast cancers were analyzed for methylation of the BRCA1 promoter and expression of ER, PR, HER2, EGFR and ck5/6. Tumor subtypes were determined in191 tumors and correlation with BRCA1 methylation and clinicopathologic features was performed using Stata 9.2 (StataCorp, College Station, TX). Results: Of the 191 tumors, 28% were TNBCs vs 72% Non-TNBCs. Of 174 tumors classified by IHC, 19% were BLBCs, 12% were HER2+/ER-, 52% were Luminal A, 12% were Luminal B and 5% were unclassified cases. BRCA1 methylation was detected in 43% (23/53) TNBCs, compared with 17% (24/138) non-TNBCs (p < 0.0001). The proportion of BRCA1 methylation differed by subtype and was predominant in BLBC (48%, p = 0.002). Luminal A and B tumors were BRCA1 methylated in 18% and 30% of the cases, respectively. In contrast, BRCA1 methylation was less likely to occur in HER2+/ER- tumors (4%). When gene expression signatures were analyzed, BLBC showed the highest proportion of BRCA1-methylated tumors (33%, 5/15) versus other tumor subtypes (5%, 2/39; p = 0.014). Conclusions: BRCA1 inactivation via promoter methylation occurs in almost half of both TNBC and BLBC, suggesting that this epigenetic event drives breast tumor progression toward the TN and BL phenotypes. Our findings justify a common targeted therapy such as PARP inhibitors for both hereditary BRCA1-mutated and sporadic BRCA1-methylated TNBCs. No significant financial relationships to disclose.