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.
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.
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.
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.
This is a preview of subscription content, access via your institution.
Buy single article
Instant access to the full article PDF.
Tax calculation will be finalised during checkout.
Subscribe to journal
Immediate online access to all issues from 2019. Subscription will auto renew annually.
Tax calculation will be finalised during checkout.
American Cancer Society Breast Cancer Facts & Figures 2019–2020. Atlanta: American Cancer Society, Inc. 2019.
Anderson WF, Althuis MD, Brinton LA, Devesa SS (2004) Is male breast cancer similar or different than female breast cancer? Breast Cancer Res Treat 83(1):77–86. https://doi.org/10.1023/B:BREA.0000010701.08825.2d
Ruddy KJ, Winer EP (2013) Male breast cancer: risk factors, biology, diagnosis, treatment, and survivorship. Ann Oncol 24(6):1434–1443. https://doi.org/10.1093/annonc/mdt025
Ferzoco RM, Ruddy KJ (2016) The epidemiology of male breast cancer. Curr Oncol Rep 18(1):1. https://doi.org/10.1007/s11912-015-0487-4
Giordano SH, Buzdar AU, Hortobagyi GN (2002) Breast cancer in men. Ann Intern Med 137(8):678–687
Brinton LA, Richesson DA, Gierach GL, Lacey JV Jr, Park Y, Hollenbeck AR, Schatzkin A (2008) Prospective evaluation of risk factors for male breast cancer. J Natl Cancer Inst 100(20):1477–1481. https://doi.org/10.1093/jnci/djn329
Rosenblatt KA, Thomas DB, McTiernan A, Austin MA, Stalsberg H, Stemhagen A, Thompson WD, Curnen MG, Satariano W, Austin DF et al (1991) Breast cancer in men: aspects of familial aggregation. J Natl Cancer Inst 83(12):849–854
Evans DG, Susnerwala I, Dawson J, Woodward E, Maher ER, Lalloo F (2010) Risk of breast cancer in male BRCA2 carriers. J Med Genet 47(10):710–711. https://doi.org/10.1136/jmg.2009.075176
Tai YC, Domchek S, Parmigiani G, Chen S (2007) Breast cancer risk among male BRCA1 and BRCA2 mutation carriers. J Natl Cancer Inst 99(23):1811–1814. https://doi.org/10.1093/jnci/djm203
Wooster R, Bignell G, Lancaster J, Swift S, Seal S, Mangion J, Collins N, Gregory S, Gumbs C, Micklem G (1995) Identification of the breast cancer susceptibility gene BRCA2. Nature 378(6559):789–792. https://doi.org/10.1038/378789a0
Basham VM, Lipscombe JM, Ward JM, Gayther SA, Ponder BA, Easton DF, Pharoah PD (2002) BRCA1 and BRCA2 mutations in a population-based study of male breast cancer. Breast Cancer Res 4(1):R2
Couch FJ, Farid LM, DeShano ML, Tavtigian SV, Calzone K, Campeau L, Peng Y, Bogden B, Chen Q, Neuhausen S, Shattuck-Eidens D, Godwin AK, Daly M, Radford DM, Sedlacek S, Rommens J, Simard J, Garber J, Merajver S, Weber BL (1996) BRCA2 germline mutations in male breast cancer cases and breast cancer families. Nat Genet 13(1):123–125. https://doi.org/10.1038/ng0596-123
Risch HA, McLaughlin JR, Cole DE, Rosen B, Bradley L, Fan I, Tang J, Li S, Zhang S, Shaw PA, Narod SA (2006) Population BRCA1 and BRCA2 mutation frequencies and cancer penetrances: a kin-cohort study in Ontario Canada. J Natl Cancer Inst 98(23):1694–1706. https://doi.org/10.1093/jnci/djj465
Chen S, Parmigiani G (2007) Meta-analysis of BRCA1 and BRCA2 penetrance. J Clin Oncol 25(11):1329–1333. https://doi.org/10.1200/JCO.2006.09.1066
Antoniou A, Pharoah PD, Narod S, Risch HA, Eyfjord JE, Hopper JL, Loman N, Olsson H, Johannsson O, Borg A, Pasini B, Radice P, Manoukian S, Eccles DM, Tang N, Olah E, Anton-Culver H, Warner E, Lubinski J, Gronwald J, Gorski B, Tulinius H, Thorlacius S, Eerola H, Nevanlinna H, Syrjakoski K, Kallioniemi OP, Thompson D, Evans C, Peto J, Lalloo F, Evans DG, Easton DF (2003) Average risks of breast and ovarian cancer associated with BRCA1 or BRCA2 mutations detected in case Series unselected for family history: a combined analysis of 22 studies. Am J Hum Genet 72(5):1117–1130. https://doi.org/10.1086/375033
Wasielewski M, den Bakker MA, van den Ouweland A, Meijer-van Gelder ME, Portengen H, Klijn JG, Meijers-Heijboer H, Foekens JA, Schutte M (1100delC) CHEK2 1100delC and male breast cancer in the Netherlands. Breast Cancer Res Treat 116(2):397–400. https://doi.org/10.1007/s10549-008-0162-7
Meijers-Heijboer H, van den Ouweland A, Klijn J, Wasielewski M, de Snoo A, Oldenburg R, Hollestelle A, Houben M, Crepin E, van Veghel-Plandsoen M, Elstrodt F, van Duijn C, Bartels C, Meijers C, Schutte M, McGuffog L, Thompson D, Easton D, Sodha N, Seal S, Barfoot R, Mangion J, Chang-Claude J, Eccles D, Eeles R, Evans DG, Houlston R, Murday V, Narod S, Peretz T, Peto J, Phelan C, Zhang HX, Szabo C, Devilee P, Goldgar D, Futreal PA, Nathanson KL, Weber B, Rahman N, Stratton MR, Consortium CH-BC (2002) Low-penetrance susceptibility to breast cancer due to CHEK2(*)1100delC in noncarriers of BRCA1 or BRCA2 mutations. Nat Genet 31(1):55–59. https://doi.org/10.1038/ng879
Silvestri V, Rizzolo P, Falchetti M, Zanna I, Masala G, Bianchi S, Palli D, Ottini L (2011) Mutation analysis of BRIP1 in male breast cancer cases: a population-based study in Central Italy. Breast Cancer Res Treat 126(2):539–543. https://doi.org/10.1007/s10549-010-1289-x
Silvestri V, Zelli V, Valentini V, Rizzolo P, Navazio AS, Coppa A, Agata S, Oliani C, Barana D, Castrignano T, Viel A, Russo A, Tibiletti MG, Zanna I, Masala G, Cortesi L, Manoukian S, Azzollini J, Peissel B, Bonanni B, Peterlongo P, Radice P, Palli D, Giannini G, Chillemi G, Montagna M, Ottini L (2017) Whole-exome sequencing and targeted gene sequencing provide insights into the role of PALB2 as a male breast cancer susceptibility gene. Cancer 123(2):210–218. https://doi.org/10.1002/cncr.30337
Silvestri V, Rizzolo P, Zanna I, Falchetti M, Masala G, Bianchi S, Papi L, Giannini G, Palli D, Ottini L (2010) PALB2 mutations in male breast cancer: a population-based study in Central Italy. Breast Cancer Res Treat 122(1):299–301. https://doi.org/10.1007/s10549-010-0797-z
Ding YC, Steele L, Kuan CJ, Greilac S, Neuhausen SL (2011) Mutations in BRCA2 and PALB2 in male breast cancer cases from the United States. Breast Cancer Res Treat 126(3):771–778. https://doi.org/10.1007/s10549-010-1195-2
Syrjakoski K, Kuukasjarvi T, Auvinen A, Kallioniemi OP (1100delC) CHEK2 1100delC is not a risk factor for male breast cancer population. Int J Cancer 108(3):475–476. https://doi.org/10.1002/ijc.11384
Falchetti M, Lupi R, Rizzolo P, Ceccarelli K, Zanna I, Calo V, Tommasi S, Masala G, Paradiso A, Gulino A, Giannini G, Russo A, Palli D, Ottini L (2008) BRCA1/BRCA2 rearrangements and CHEK2 common mutations are infrequent in Italian male breast cancer cases. Breast Cancer Res Treat 110(1):161–167. https://doi.org/10.1007/s10549-007-9689-2
Apostolou P, Fostira F, Papamentzelopoulou M, Michelli M, Panopoulos C, Fountzilas G, Konstantopoulou I, Voutsinas GE, Yannoukakos D (2015) CHEK2 c.1100delC allele is rarely identified in Greek breast cancer cases. Cancer Genet 208(4):129–134. https://doi.org/10.1016/j.cancergen.2015.02.006
Neuhausen S, Dunning A, Steele L, Yakumo K, Hoffman M, Szabo C, Tee L, Baines C, Pharoah P, Goldgar D, Easton D (2004) Role of CHEK2*1100delC in unselected series of non-BRCA1/2 male breast cancers. Int J Cancer 108(3):477–478. https://doi.org/10.1002/ijc.11385
Pritzlaff M, Summerour P, McFarland R, Li S, Reineke P, Dolinsky JS, Goldgar DE, Shimelis H, Couch FJ, Chao EC, LaDuca H (2017) Male breast cancer in a multi-gene panel testing cohort: insights and unexpected results. Breast Cancer Res Treat 161(3):575–586. https://doi.org/10.1007/s10549-016-4085-4
Mavaddat N, Peock S, Frost D, Ellis S, Platte R, Fineberg E, Evans DG, Izatt L, Eeles RA, Adlard J, Davidson R, Eccles D, Cole T, Cook J, Brewer C, Tischkowitz M, Douglas F, Hodgson S, Walker L, Porteous ME, Morrison PJ, Side LE, Kennedy MJ, Houghton C, Donaldson A, Rogers MT, Dorkins H, Miedzybrodzka Z, Gregory H, Eason J, Barwell J, McCann E, Murray A, Antoniou AC, Easton DF, Embrace (2013) Cancer risks for BRCA1 and BRCA2 mutation carriers: results from prospective analysis of EMBRACE. J Natl Cancer Inst 105(11):812–822. https://doi.org/10.1093/jnci/djt095
Brose MS, Rebbeck TR, Calzone KA, Stopfer JE, Nathanson KL, Weber BL (2002) Cancer risk estimates for BRCA1 mutation carriers identified in a risk evaluation program. J Natl Cancer Inst 94(18):1365–1372
Anderson DE, Badzioch MD (1992) Breast cancer risks in relatives of male breast cancer patients. J Natl Cancer Inst 84(14):1114–1117
Bevier M, Sundquist K, Hemminki K (2012) Risk of breast cancer in families of multiple affected women and men. Breast Cancer Res Treat 132(2):723–728. https://doi.org/10.1007/s10549-011-1915-2
Friedman LS, Gayther SA, Kurosaki T, Gordon D, Noble B, Casey G, Ponder BA, Anton-Culver H (1997) Mutation analysis of BRCA1 and BRCA2 in a male breast cancer population. Am J Hum Genet 60(2):313–319
von Elm E, Altman DG, Egger M, Pocock SJ, Gotzsche PC, Vandenbroucke JP, Initiative S (2008) The strengthening the reporting of observational studies in epidemiology (STROBE) statement: guidelines for reporting observational studies. J Clin Epidemiol 61(4):344–349. https://doi.org/10.1016/j.jclinepi.2007.11.008
Schulz KF, Grimes DA (2002) Case-control studies: research in reverse. Lancet 359(9304):431–434
Eggington JM, Bowles KR, Moyes K, Manley S, Esterling L, Sizemore S, Rosenthal E, Theisen A, Saam J, Arnell C, Pruss D, Bennett J, Burbidge LA, Roa B, Wenstrup RJ (2014) A comprehensive laboratory-based program for classification of variants of uncertain significance in hereditary cancer genes. Clin Genet 86(3):229–237. https://doi.org/10.1111/cge.12315
Storm HH, Olsen J (1999) Risk of breast cancer in offspring of male breast-cancer patients. Lancet 353(9148):209. https://doi.org/10.1016/S0140-6736(05)77219-6
Malone KE, Daling JR, Doody DR et al (2006) Prevalence and predictors of BRCA1 and BRCA2 mutations in a population-based study of breast cancer in white and black American women ages 35 to 64 years. Cancer Res 66(16):8297–8308
Rose S, Laan MJ (2009) Why match? Investigating matched case-control study designs with causal effect estimation. Int J Biostat. https://doi.org/10.2202/1557-4679.1127
Kerber RA, Slattery ML (1997) Comparison of self-reported and database-linked family history of cancer data in a case-control study. Am J Epidemiol 146(3):244–248
Ramsey SD, Yoon P, Moonesinghe R, Khoury MJ (2006) Population-based study of the prevalence of family history of cancer: implications for cancer screening and prevention. Genet Med 8(9):571–575. https://doi.org/10.1097/01.gim.0000237867.34011.12
Daly MB, Pilarski R, Yurgelun MB, Berry MP, Buys SS, Dickson P, Domchek SM, Elkhanany A, Friedman S, Garber JE, Goggins M, Hutton ML, Khan S, Klein C, Kohlmann W, Kurian AW, Laronga C, Litton JK, Mak JS, Menendez CS, Merajver SD, Norquist BS, Offit K, Pal T, Pederson HJ, Reiser G, Shannon KM, Visvanathan K, Weitzel JN, Wick MJ, Wisinski KB, Dwyer MA, Darlow SD (2020) NCCN guidelines insights: genetic/familial high-risk assessment: breast, ovarian, and pancreatic, version 1.2020. J Natl Compr Cancer Netw 18(4):380–391. https://doi.org/10.6004/jnccn.2020.0017
Johnson KC, Pan S, Mao Y, Canadian Cancer Registries Epidemiology Research G (2002) Risk factors for male breast cancer in Canada, 1994–1998. Eur J Cancer 11(3):253–263. https://doi.org/10.1097/00008469-200206000-00009
Ewertz M, Holmberg L, Tretli S, Pedersen BV, Kristensen A (2001) Risk factors for male breast cancer—a case-control study from Scandinavia. Acta Oncol 40(4):467–471. https://doi.org/10.1080/028418601750288181
Rothman KJ, Greenland S, Lash TL (2008) Modern epidemiology, 3rd edn. Wolters Kluwer Health/Lippincott Williams & Wilkins, Philadelphia
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.
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.
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.
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Electronic supplementary material
Below is the link to the electronic supplementary material.
About this article
Cite this article
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
- Male breast cancer
- Family history