—  SPECIALTY CONFERENCE  —

Breast Pathology

Case 3 - Male Breast Cancer (MBC)

David G. Hicks
University of Rochester Medical Center
Rochester , NY





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Clinical Case Presentation
An 80-year-old known carrier of a BRCA2 mutation was found to have a left breast mass at a routine health maintenance examination. Also at that time, the patient's serum level of prostate specific antigen was found to have doubled from a value obtained eight months prior. The patient underwent biopsies of both the breast mass and the prostate gland, which showed an infiltrating lobular carcinoma and adenocarcinoma, respectively. Comprehensive staging work-up and bilateral mastectomies with a left axillary sentinel lymph node dissection resulted in a final stage of T1c breast carcinoma and at least stage T2c prostatic adenocarcinoma. The prostatic adenocarcinoma was treated with anti-androgen therapy and external beam radiation.


Case 3 - Figure 1
Case 3 - Figure 2
Case 3 - Figure 3


Male Breast Cancer (MBC)
Less than 1% of breast cancer occurs in men. [1] Of these cases, greater than 90% are infiltrating ductal carcinomas. [2] Male breast tissue is rudimentary; it does not differentiate and undergo lobule formation without exposure to increased concentrations of exogenous or endogenous estrogen. Lobular carcinomas of the male breast are therefore very rare, but nonetheless have been reported in settings both with and without documented increased estrogenic exposure. [3, 4] Immunohistochemical studies have suggested that MBC is more frequently ER and PR positive while the expression of HER2 has been inconsistent across different studies.

The overall incidence of breast cancer in men is increasing, along with a rise in breast cancer seen among women. [5] Breast cancer tends to occur at an older age in men, in a unimodal distribution with peak at the age of 71. [6] Perhaps due to lack of patient and clinician awareness, male breast cancer patients often present at a more advanced stage and have a poorer prognosis. [7] Many of the risk factors for breast cancer in men are similar to those in women, including increased exposure to androgens and estrogens - whether through exogenous administration, a family history of breast cancer, liver dysfunction, obesity, testicular anomalies or genetic causes such as Klinefelter's syndrome. Ionizing radiation and alcohol consumption have also been purported to play a role. [8]

Hereditary Breast Cancer and the Breast Cancer Susceptibility BRCA Genes
Approximately 5-10% of breast cancers are hereditary and some of these tumors can be attributed to the high penetrance breast cancer susceptibility genes BRCA1 and BRCA2. While BRCA mutations carry a high lifetime risk for breast and ovarian cancers in female patients, the risk for male mutation carriers is less well understood. Germline mutations of BRCA1 have been associated with a slight increased risk for MBC in some studies, however, mutations of the BRCA2 gene carry the highest known genetic risk (approximately 80-100 times higher than in the general population in some reports). [9] Genetic linkage analysis and DNA sequencing data have demonstrated that MBC is associated with deleterious germline mutation in the BRCA2 gene. The reported frequency of BRCA2 mutations in unselected cases of MBC varies considerably in the literature and is likely dependant on the ethnic background of the population being studied. In general, mutations in the BRCA2 gene in unselected cases account for approximately 15% or greater of male breast cancer cases. [10]

BRCA2 Gene
BRCA2 is a tumor suppressor gene located on chromosome 13 (13q12.2-13), which has been shown to inhibit tumor cell proliferation in vitro, tumor growth in vivo and play an important role in DNA double-strand breakage repair by homologous recombination. [11] BRCA2 is part of a homologous recombination DNA repair complex and is responsible for the transport of the protein RAD51 to this complex. Cells lacking a functional BRCA2 are prone to replication errors and genomic instability allowing the accumulation of chromosome abnormalities and enabling mutations in genes involved in cell cycle check point activation. Such cells are usually fated for apoptosis. However, some are able to evade programmed cell death and proliferate, contributing to the formation of tumors.

The BRCA2 Gene and Risk for Other Malignancies
It has been established that the BRCA2 phenotype confers susceptibility to a variety of other malignancies in addition to breast cancer; namely, pancreatic cancer and prostate cancer. The Breast Cancer Linkage Consortium has estimated the relative risk of prostate cancer amongst carriers of a BRCA2 mutation to be 4.6. [12] Male BRCA2 mutation carriers are not only at an increased risk for breast cancer, but cancers of the pancreas, prostate and perhaps other organs as well. Interestingly, our patient had a family history of pancreatic cancer. Furthermore, studies have indicated that BRCA2 mutations are associated with a younger age of onset, higher grade and worse prognosis in prostate cancer. [13, 14, 15] Narod et al was able to show that men with BRCA2 mutations and prostate cancer had a seventy percent increased risk of death over men with prostate cancer and a BRCA1 mutation, while Mitra et al demonstrated that BRCA1 and BRCA2 mutation carriers had significantly higher Gleason scores than matched controls.

Interestingly, the association between BRCA2 mutations and the risk for prostate cancer has not been a consistent finding across all studies. Studies of high-risk prostate cancer families have suggested that BRCA2 plays at most a minimal role in these individuals, highlighting the potential genetic heterogeneity of the disease. [16] The cancer risk for individual patients may differ based on the position of the mutation and the ethnic background of the family, contributing to the phenotypic variation seen in families with BRCA2 mutations. Mutations in the central part of the BRCA2 gene termed the ovarian cancer cluster region (OCCR) are associated with a higher risk of ovarian cancer compared with breast cancer. [10] Mutations in the OCCR region of the BRCA2 gene have been associated with a lower risk of prostate cancer compared with mutation occurring outside of the OCCR. All mutations described in the study of 234 early-onset prostate cancer patients in the United Kingdom by Edwards et al were outside of the OCCR. [17]

Take Home Message
  • Hormonal, environmental, and genetic factors are involved in the pathogenesis of breast cancer in both men and women.

  • Among both sexes, the presence of a germline mutation in either the BRCA1 or BRCA2 gene figures prominently when considering lifetime cancer risk.

  • In men, BRCA2 appears to be the gene in which a mutation confers the highest risk of developing a malignancy.

  • Male BRCA2 mutation carriers are not only at an increased risk for breast cancer, but may be at an increased risk for cancers of the pancreas, prostate and perhaps other organs as well.

  • BRCA2 mutation carriers and MBC patients should undergo periodic screening and surveillance for early detection of breast cancer and other potential malignancies.

Key Words:
Male breast cancer, BRCA2, Prostate cancer

References:
  1. Jemal A, Siegel R, Ward E et al. Cancer statistics, 2008. CA Cancer J Clin. 2008;58:71-96.

  2. Nahleh ZA, Srikantiah R, Safa M, Jazieh AR, Muhleman A, Komrokji R. Male breast cancer in the veterans affairs population: a comparative analysis. Cancer. 2007;109:1471-7.

  3. Koc M, Oztas S, Erem MT, Ciftcioglu MA, Onuk MD. Invasive lobular carcinoma of the male breast: a case report. Jpn J Clin Oncol. 2001;31:444-6.

  4. Sanchez AG, Villanueva AG, Redondo C. Lobular carcinoma of the breast in a patient with Klinefelter's syndrome. A case with bilateral, synchronous, histologically different breast tumors. Cancer. 1986;57:1181-3.

  5. Speirs V, Shaaban AM. The rising incidence of male breast cancer. Breast Cancer Res Treat. 2008 May 14 [epub ahead of print].

  6. Anderson WF, Althuis MD, Brinton LA, Devesa SS. Is male breast cancer similar or different than female breast cancer? Breast Cancer Res Treat. 2004;83:77-86.

  7. Fentiman IS, Fourquet A, Hortobagyi GN. Male breast cancer. Lancet. 2006;367:595-604.

  8. Brinton LA, Richesson DA, Gierach GL et al. Prospective evaluation of risk factors for male breast cancer. J Natl Cancer Inst. 2008;100:1477-81.

  9. Karhu R, Laurila E, Kallioniemi A, Syrjakoski K. Large genomic BRCA2 rearrangements and male breast cancer. Cancer Detect Prev. 2006;30:530-4.

  10. Liede A, Karlan BY, Narod SA. Cancer risks for male carriers of germline mutations in BRCA1 or BRCA2: a review of the literature. J Clin Oncol. 2004;22:735-42.

  11. Venkitaraman AR. Cancer susceptibility and the functions of BRCA1 and BRCA2. Cell. 2002;108:171-82.

  12. Cancer risks in BRCA2 mutation carriers.The Breast Cancer Linkage Consortium. J Natl Cancer Inst. 1999;91:1310-6.

  13. Tryggvadottir L, Vidarsdottir L, Thorgeirsson T et al. Prostate cancer progression and survival in BRCA2 mutation carriers. J Natl Cancer Inst. 2007;99:929-35.

  14. Narod SA, Neuhausen S, Vichodez G et al. Rapid progression of prostate cancer in men with a BRCA2 mutation. Br J Cancer . 2008;99:371-4.

  15. Mitra A, Fisher C, Foster CS et al. Prostate cancer in male BRCA1 and BRCA2 mutation carriers has a more aggressive phenotype. Br J Cancer. 2008;98:502-7.

  16. Ostreander EA, Udler MS. The role of the BRCA2 gene in susceptibility to prostate cancer revisited. Cancer Epidemiol Biomarkers Prev. 2008;17:1843-8.

  17. Edwards SM, Kote-Jarai Z, Meitz J, et al. Two percent of men with early-onset prostate cancer harbor germline mutations in the BRCA2 gene. Am J Hum Genet. 2003;72:1-12.