Family history of breast cancer in men with non-BRCA male breast cancer: implications for cancer risk counseling

Abstract

Purpose

The role of genetic predisposition in male breast cancer (MBC) patients who test negative for a BRCA mutation is unclear. The aim of this study is to define the association between MBC and family history of breast cancer in patients without mutations in BRCA1 or BRCA2.

Methods

We conducted an unmatched case–control study with men who received commercial testing for germline mutations in cancer susceptibility genes, including 3,647 MBC cases who tested negative for deleterious mutations in BRCA1/BRCA2, and 4,269 men with a personal history of colorectal cancer who tested negative for mutations in DNA mismatch repair genes to serve as controls. Associations between family history of breast cancer and MBC were estimated using unconditional multivariable logistic regression with adjustment for age, race/ethnicity and year of testing.

Results

Breast cancer in a first- or second-degree relative was associated with a four-fold increased odds of MBC (OR 4.7; 95% CI 4.1, 5.3). Associations with MBC were strongest for family history of breast cancer in 2 or more first-degree relatives (FDR) (OR 7.8; 95% CI 5.2, 11.6), for probands and FDR diagnosed at age < 45 years (OR 6.9; 95% CI 3.9, 12.4), and for family history of MBC (OR 17.9; 95% CI 7.6, 42.1). Findings were confirmed in a sensitivity analysis of MBC cases who tested negative on a 25-gene pan-cancer panel.

Conclusions

MBC patients without mutations in BRCA1/2 have significantly higher odds of a family history of breast cancer, suggesting the existence of unidentified MBC susceptibility alleles.

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Funding

Data collection and analysis was supported by Myriad Genetics Laboratories, Inc. Kent Hoskins is supported by the Eileen Lindsay Heidrick Professorship in Oncology at the University of Illinois at Chicago. Gregory Calip was supported by the National Center for Advancing Translational Sciences, National Institutes of Health, through Grant KL2TR002002. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

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Authors

Contributions

Conception and design: GC, JS, KH; Provision of study patient data: JK, HC, RB, JS, JL; Collection and assembly of data: JK, HC, RB, JS; Data analysis and interpretation: GC, JK, RB, JS, GR, KH; Manuscript writing: first draft written by GC and KH. All authors commented on previous versions of the manuscript. Final approval of manuscript: All authors.

Corresponding author

Correspondence to Gregory S. Calip.

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Conflict of interest

Mr. Kidd, Mr. Bernhisel, Dr. Cox, Mr. Evans, Dr. Saam and Dr. Lancaster received salary support and have ownership interest (stock options) in Myriad Genetics Laboratories, Inc. At the time of submission, Dr. Calip reports current employment with Flatiron Health, Inc., which is an independent subsidiary of the Roche group. Dr. Calip and Dr. Hoskins report receiving research support from Pfizer, Inc. for work unrelated to this project. Dr. Rauscher declares he has no conflict of interest.

Ethical approval

The study was performed in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. The University of Illinois at Chicago Institutional Review Board (IRB), Chicago, IL approved the study (IRB Protocol # 2015–1176). The need for informed consent was waived under the approval of the IRB due to the retrospective design.

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Calip, G.S., Kidd, J., Bernhisel, R. et al. Family history of breast cancer in men with non-BRCA male breast cancer: implications for cancer risk counseling. Breast Cancer Res Treat 185, 195–204 (2021). https://doi.org/10.1007/s10549-020-05922-w

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Keywords

  • Male breast cancer
  • Genetics
  • BRCA1
  • BRCA2
  • Family history