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Risk of breast cancer in male BRCA2 carriers
  1. D G R Evans1,
  2. I Susnerwala1,
  3. J Dawson1,
  4. E Woodward2,
  5. E R Maher2,
  6. F Lalloo1
  1. 1Genetic Medicine, Manchester Academic Health Science Centre, St. Mary's Hospital, Manchester, UK
  2. 2Department of Medical and Molecular Genetics, University of Birmingham School of Medicine, and West Midlands Regional Genetics Service, Birmingham, UK
  1. Correspondence to Professor D G R Evans, Consultant Clinical Geneticist, Genetic Medicine, Manchester Academic Health Science Centre, St. Mary's Hospital, Manchester M13 0JH, UK; gareth.evans{at}cmft.nhs.uk

Abstract

The risk of breast cancer for unaffected men who test positive for a BRCA2 mutation is based on very few retrospective studies. We have used both retrospective and prospective analysis in 321 families with pathogenic BRCA2 mutations. Three breast cancers occurred in male first-degree relatives after family ascertainment in 4140 years of follow-up suggesting a risk of breast cancer to 80 years of 8.9%. A second analysis excluding index cases identified 16 breast cancers in 905 first-degree male relatives on which Kaplan–Meier analysis was performed after assigning carrier status. This analysis confirmed that breast cancer risk in men was 7.1% (SE 5.2–8.6%) by age 70 years and 8.4% (SE 6.2–10.6%) by age 80 years.

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The risk of breast cancer in male BRCA2 carriers is still in question. Only three previous studies have assessed lifetime risk in men.1–3 The second of these emphasised the need for further studies.2 We have assessed the risk of breast cancer among men in families with proven BRCA2 mutations from the adjoining health regions centralised around Manchester and Birmingham in Central North West England. Families were ascertained in the two genetic centres covering a population of around 10 million people. Testing generally starts with an affected family member in a family with more than one affected individual and was cascaded out from the index case as requested by the family. Uptake of testing in men was considerably lower than in women.3 We have developed a dedicated database that enters all male first-degree relatives (FDRs) of mutation carriers aged >20 years.4 5

There were 321 families with proven pathogenic BRCA2 mutations. In these families, there were 20 male index cases of whom 15 had developed breast cancer (age range 29–79 years median 65.3) One had bilateral breast cancer. There were 905 male FDRs of proven BRCA2 mutation carriers. Sixteen of 905 (2%) had developed breast cancer (age range 46.8–74 years median 61.7). Eight further male breast cancers occurred among second-degree relatives including one with bilateral disease; two were confirmed as mutation positive. In 4140 years of follow-up from date of family ascertainment in the genetics departments, breast cancers had occurred in 3 of 667 male FDRs (0.72 per 1000). Two hundred and thirty-eight male FDRs had died before the family ascertainment date. As all male FDRs >20 years were on the dataset, this would mean that each subject had a potential 60 years of risk. This would amount to a lifetime risk of 4.32%. However, only half of the FDRs would be mutation carriers; as such, the estimated risk in men would be 8.6%. Given the small number of male cancers in follow-up, we validated this risk by assessing male breast cancer among proven or assumed BRCA2 mutation carriers excluding the index case. In this mostly retrospective analysis in addition to all men testing positive, FDR men were assigned mutation status on a 50% basis omitting every other man on the basis of successive age at last follow-up. FDR men with breast cancer were assumed to be mutation carriers as the relative risk (RR) of breast cancer in male BRCA2 carriers is at least 100-fold,6 and male breast cancer phenocopies have not been described to our knowledge.7 Male FDRs with pancreatic and prostate cancer were assigned mutation status on a 4:1 basis omitting the fifth case in successive age order of cancer. Stomach cancers were assigned on a 2:1 basis. This decision was based on the described 2.5–5.9-fold RR in BRCA2 carriers for pancreas (3.51–5.9) and prostate cancer (2.5–4.65) and 1.2–2.59 RR of stomach cancer.2 8 After exclusion of the index case, 122 men were identified as proven carriers from family testing; six of these had breast cancer. Forty-one male FDRs had tested negative in predictive testing. Ten male FDRs of unknown mutation status were assumed to be carriers as they had suffered from breast cancer. Of 29 prostate cancers of unknown mutation status in FDRs, 24 were assigned mutation-positive status as were 5 of 6 with pancreatic cancer and 10 of 14 stomach cancers. Of the remaining 683 male FDRs of unknown status, 333 were assigned as positive (table 1). Thus, 508 male BRCA2 carriers or assumed carriers were identified. Cumulative risk of breast cancer was assessed by Kaplan–Meier analysis (figure 1). This showed a risk of 7.1% (SE 5.2–8.6%) by age 70 years and 8.4% (SE 6.2–10.6%) by age 80.

Table 1

Assignment of male FDRs based on cancer diagnosis

Figure 1

Kaplan–Meier cumulative onset of breast cancer in 508 male BRCA2 carriers and presumed carriers. Risk to age 70 years: 7.1% SE 5.2–8.6%. Risk to age 80 years: 8.4% SE 6.2–10.6%.

In the first report to assess male breast cancer risks, two large BRCA2-linked families that contained four male breast carcinoma cases were evaluated.1 The estimated cumulative risk for male breast carcinoma by age 70 years was 6.3%. In a separate study of 164 families with BRCA2 mutations, the estimated cumulative risk of breast cancer for male BRCA2 mutation carriers was 2.8% by 70 years of age and 6.9% by 80 years.2 More recently, the estimated cumulative risk of breast carcinoma for male BRCA2 mutation carriers was 6.8% (95% CI = 3.2% to 12%) by age 70 years and 8.3% to age 80 years.3 The latter study was based on 23 families ascertained through a male breast cancer. This study based risk estimates on the relative risks of male breast cancer in BRCA2 versus population risks assuming certain BRCA2 allele frequencies. A further study found that the RR of breast cancer for male BRCA2 carriers was estimated to be 102-fold.7 Our study is the first to have assessed male breast cancer risk prospectively from family ascertainment. Although the numbers are small and CIs will clearly be wide, the rates of breast cancer prospectively are in keeping with a lifetime risk to 80 years of close to 9%. To corroborate this, we carried out an analysis of cumulative risk in male FDRs taking advantage of clinical testing but excluding the bias of the index case. There are flaws in such a study in that excluding the index case alone may not be sufficient, but a contrary argument would be that there would be a tendency to preferentially test a male breast cancer case first in families with multiple affected individuals. In any case, the risks to 70 and 80 years are similar to those found in the most recent study using a different approach to analysis.3 Ours is also now the largest study of BRCA2-affected families. Based on the now four studies to assess male breast cancer risks using different study designs, it would appear appropriate to quote lifetime risks (to age 70–80 years) of breast cancer to men in the Western world of between 6% and 9%. These risks are sufficient to increase awareness of breast cancer among men in BRCA2 families and to stress the importance of early presentation with breast symptoms.

Acknowledgments

This work was supported by the Biomedical Research Centre at Central Manchester Foundation Trust and a grant from the Genesis Appeal.

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Footnotes

  • All authors contributed to the article.

  • Funding Other Funders: Genesis Appeal.

  • Competing interests None.

  • Ethics approval This study was conducted with the approval of the Central Manchester.

  • Provenance and peer review Not commissioned; externally peer reviewed.

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