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Background  Breast Cancer 1 gene ( BRCA1 ) is known to be inactivated in breast tumors by promoter methylation. Tumor cells in patients carrying a germline mutation in  BRCA1  are sensitive to cytotoxic drugs that cause DNA double strand breaks. However, very little is known on whether patients with  BRCA1  promoter methylated tumors are similarly sensitive to cytotoxic drugs. In this study, we address this by making use of extensive follow-up data on patients treated with cyclophosphamide, methotrexate, and fluorouracil in Iceland between 1976 and 2007.    Methods  We analyzed  BRCA1  promoter methylation by pyrosequencing DNA from tumor samples from 1031 patients with primary breast cancer. Of those, 965 were sporadic cases, 61 were  BRCA2 , and five were  BRCA1  germline mutation carriers. All cases were examined with respect to clinicopathological parameters and breast cancer–specific survival in patients treated with cytotoxic drugs. Information on chemotherapy treatment in noncarriers was available for 26  BRCA1  methylated tumors and 857 unmethylated tumors.    Results    BRCA1  was promoter methylated in 29 sporadic tumors or in 3.0% of cases (29 of 965), whereas none of the tumors derived from  BRCA  germline mutation carriers were promoter methylated. Important to note, patients with  BRCA1  promoter methylation receiving chemotherapeutic drug treatment show highly improved breast cancer–specific survival compared with unmethylated controls (hazard ratio = 0.10, 95% confidence interval = 0.01 to 0.75, two-sided  P  = .02).    Conclusions    BRCA1  promoter methylation is predictive of improved disease outcome in patients receiving cyclophosphamide, methotrexate, and fluorouracil drug treatment. Our results support the use of markers indicative of “BRCAness” in sporadic breast cancers to identify patients that are likely to benefit from the use of DNA-damaging agents.

BRCA1 Promoter Methylation Status in 1031 Primary Breast Cancers Predicts Favorable Outcomes Following Chemotherapy