Brca1 promoter methylation status in 1031 primary breast cancers predicts favorable outcomes following chemotherapy

Ólafur A. Stefánsson, Hólmfridur Hilmarsdóttir, Kristrún Ólafsdóttir, Laufey Tryggvadóttir, Ásgerdur Sverrisdóttir, Óskar Þór Jóhannsson, Jón Gunnlaugur Jónasson, Jórunn Erla Eyfjörð, Stefán Þórarinn Sigurdsson*

*Corresponding author for this work

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Abstract

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.

Original languageEnglish
Article numberpkz100
Pages (from-to)pkz100
JournalJNCI Cancer Spectrum
Volume4
Issue number2
DOIs
Publication statusPublished - 11 Dec 2019

Bibliographical note

The authors would like to thank The Icelandic Research Fund (www.rannis.is) (14193–051 and 152077–051) and Gongum saman (www.gongumsaman.is) for funding.

Publisher Copyright:
© 2020 Oxford University Press. All rights reserved.

Other keywords

  • Breast cancer
  • Cancer chemotherapy

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