Surgical Science
 Vol.5 No.7(2014), Article ID:48262,12 pages DOI:10.4236/ss.2014.57054

Males at High Risk for Breast Cancer: Who Are They and How Should We Screen Them?

Natalie Swergold1*, Vijayashree Murthy2, Ronald S. Chamberlain1,2,3

1Saint George’s University School of Medicine, Grenada, West Indies

2Department of Surgery, Saint Barnabas Medical Center, Livingston, USA

3Department of Surgery, New Jersey Medical School, Rutgers University, Newark, USA

Email: *nmswergs@gmail.com, drvijumurthy@gmail.com, rchamberlain@barnabashealth.org

Copyright © 2014 by authors and Scientific Research Publishing Inc.

This work is licensed under the Creative Commons Attribution International License (CC BY).

http://creativecommons.org/licenses/by/4.0/

Received 22 May 2014; revised 20 June 2014; accepted 15 July 2014

ABSTRACT

Background: It is estimated that 2240 males in the United States will develop invasive breast cancer (BC) in 2013, resulting in 410 deaths. Overall, male breast cancers (MBCs) are diagnosed with larger tumor size, more frequent lymphatic invasion, and advanced tumor stage compared to their female counterparts. Several risk factors have been elucidated for the development of MBC, and this paper aims to critically review the existing literature on at-risk populations and provide screening recommendations. Methods: A comprehensive search for all published studies on populations at risk for MBC using PubMed, EBSCOhost, and Google Scholar was performed (1982- 2013). The search focused specifically on genetic and epidemiologic risk factors, and screening for MBC. Keywords searched included “male breast cancer risk factors”, “male breast cancer epidemiology”, and “male breast cancer genetics”. A total of 34 studies involving 4,865,819 patients were identified. Results: Five studies (N = 327,667) focused primarily on family history of breast cancer as a risk factor for MBC. 15% - 20% of men with BC have a family history of breast or ovarian cancer, and a family history of BC among first-degree relatives confers a 2- to 3-fold increase in MBC risk (odds ratio = 3.3). Seventeen studies (N = 5451) analyzed associations between several heritable genes and MBC. Lifetime MBC risk among BRCA1 mutation carriers is 1% - 5%, while MBC risk in BRCA2 mutation carriers is higher and varies between 4% - 40%. Less clear associations between MBC and PALB2, Androgen Receptor gene, CYP17, and CHEK2 mutations have also been documented. Five studies (N = 16,667) have addressed occupational risk factors for MBC. An 8-fold increase in MBC is reported in males working in the cosmetic cream manufacturing, and the motor vehicle industries. A meta-analysis of 18 trials also identified electromagnetic field exposure as a potential MBC risk, though causation remains undocumented. Eleven studies (N = 4,843,598) analyzed the role of abnormalities in the androgen-to-estrogen ratio as a risk factor for MBC. Conditions associated with increased MBC risk include Klinefelter’s syndrome (relative risk, RR = 29.64), obesity (RR = 1.98), orchitis/epididymitis (RR = 1.84), and gynecomastia (RR = 5.86). Conclusion: Routine screening for MBC should be considered in all high risk male populations, including those with a prior history of breast carcinoma, a strong family history of BC (defined as an affected mother or sister), a positive BRCA2 mutation status (regardless of family history), and men diagnosed with Klinefelter’s syndrome, or those in the chemical or motor vehicle industries. Genetic testing for BRCA2 should be recommended for all MBC patients. Increased public and physician education on MBC is necessary to raise awareness about this rare disease and the need for screening of at-risk populations.

Keywords:Male Breast Cancer Risk Factors, Carcinoma of the Male Breast, Breast Carcinoma

1. Introduction

The American Cancer Society (ACS) estimated there will be 2240 new cases of male breast cancer (MBC) in the United States in 2013, and ~410 males will die from this disease [1] . The Surveillance, Epidemiology, and End Results registry has recorded 5494 cases of MBC between 1973 through 2005, with a median age at diagnosis of ~67 years, and an age-specific incidence rate demonstrating a single peak age at ~75 years [2] . Male breast cancers are typically diagnosed with greater tumor size, more frequent lymphatic involvement, and advanced tumor stage compared to females, which is at least in part the result of no defined screening programs for at-risk males and almost no public education on this topic [2] [3] . Given the rarity of MBC, large-scale familial, genetic, and environmental epidemiologic studies have proven difficult to conduct. This paper critically examines the existing literature on male populations at high risk for breast cancer, and provides specific screening recommendations for these populations.

2. Methods

A comprehensive search of all published studies addressing populations at risk for male breast cancer was conducted using PubMed, EBSCOhost, and Google Scholar (1982-2013). The search focused specifically on genetic and epidemiologic risk factors for male breast cancer. Keywords searched included “male breast cancer risk factors”, “male breast cancer epidemiology”, and “male breast cancer genetics”. A total of 34 studies involving 4,865,819 patients were identified. Inclusion criteria for studies included those focusing on epidemiological considerations including age, ethnicity, socioeconomic status, and occupation, as well as more traditional risk factors such as ethnicity, family history, BRCA/other genetic mutations, and genetic syndromes.

3. Family History of Breast Cancer

Five studies involving 327,667 patients (Table 1) addressed the impact of positive family history on MBC. It has been estimated that 15% - 20% of all MBC patients have a family history of breast cancer, with at least one firstor second-degree relative affected by the disease [4] [5] . In an analysis of gremline mutations in 34 MBC patients, Haraldsson et al. found a positive family history of breast cancer in 13% of MBC cases [6] . Brinton et al. conducted a prospective cohort study of 324,920 men in the National Institute of Health-AARP Diet and Health Study, of which 121 developed breast cancer (9 with in situ disease, 107 with invasive breast cancer, and 5 with unknown stage) [7] . The authors found an increased risk of breast cancer among men who reported breast cancer in a first-degree relative (RR = 1.92, 95% CI: 1.19 - 3.09), and that risk was particularly increased for individuals with an affected sister (RR = 2.25, 95% CI: 1.13 - 4.47), or both an affected mother and affected sister (RR = 9.73, 95% CI: 3.96 - 23.96) [7] . Similarly, in a population-based case-control of 81 MBC cases and 1905 male controls, Johnson et al. reported an increased risk in males with an affected mother or sister (OR = 3.65, 95% CI: 1.62 - 8.19) [8] . In a case-control study including 21 MBC cases and 82 controls, D’Avanzo et al. reported that a positive breast cancer family history in a female relative was associated with an increased risk of MBC, and an odds ratio of 8.5 (95% CI: 1.1 - 69.0) [9] . Those results were confirmed by Ewertz et al. who conducted a population-based case-control study including 156 MBC patients and 468 controls and calculated an odds ratio of 3.3 (95% CI: 2.0 - 5.6) for males with a positive family history of breast cancer [10] .

Table 1. Summary of all published studies evaluating family history as a risk factor for MBC* (1995-2008).

Abbreviations: OR = odds ratio, CI = confidence interval, MBC = male breast cancer, AR = androgen receptor gene, BRCA = breast cancer gene, RR = relative risk.

4. Genetic Mutations

Seventeen studies involving a total of 5451 patients (Table 2) analyzed the associations between heritable genetic mutations and the development of MBC. Identified cancer susceptible genes include BRCA1/2, PALB2, AR gene, and CHEK2 mutations, as well as CYP17 promotor polymorphisms [3] [4] [6] [11] -[24] .

4.1. BRCA Gene Mutations

The BRCA genes are classified as tumor-suppressor genes, in that they maintain genomic stability and cell-cycle checkpoint control [25] . Mutations in the BRCA1/2 genes results in cancer initiation, and the subsequent accumulation of genetic mutations and instabilities can ultimately engender cancer development [25] . The reported frequencies of BRCA2 germ-line mutations in MBC vary between populations, likely due to small sample sizes and varying methodologies and sensitivities of mutation screening methods [24] . Friedman et al. analyzed 54 cases of MBC from a Southern-California population and identified only 2 (4%) carriers [4] . Contrarily, Thorlacius et al. [11] reported that 40% of all MBC cases diagnosed in Iceland over a period of 40 years carried a specific BRCA2 mutation (999del5), and Couch et al. [12] reported a 14% mutation rate in their study of 50 MBC patients. Mavraki et al. screened DNA from 26 males affected with breast cancer, and identified 3 pathogenic mutations, all of which resulted in premature termination of translation, and calculated a 7% - 11% frequency of BRCA2 germ-line mutations [17] . In a population-based study of 94 MBC cases, Basham et al. identified 5 pathogenic mutations in BRCA2 and calculated a 6% carrier frequency of BRCA2 mutations (95% CI: 2 - 13) [19] . In a retrospective study of 97 men with breast carcinoma, Tai et al. estimated a 6.8% cumulative risk of MBC for BRCA2 mutation carriers at 70 years of age (95% CI: 3.2 - 12) [22] . Risch et al. observed an increased MBC relative risk of 102 for BRCA2 mutation carriers versus non-carriers (95% CI: 9.9 - 1.050) [23] . Syrjakoski et al. screened a cohort of 154 MBC patients for BRCA2 mutations, and identified previously described founder or novel mutations in 12 (7.8%) cases [18] . Additionally, the authors found that 44% of patients with a positive family history of breast cancer carried a BRCA2 mutation, as compared to the 3.6% of patients without a family history (p < 0.0001) [18] . However, this positive association between family history and BRCA mutation carrier status has not been reproduced in other analysis. While Haraldsson et al. identified BRCA2 germ-line mutations in 7 (20.6%) of 34 cases and estimated a case mutation frequency of 16%, 86% of MBC cases carrying BRCA2 mutations had no family history of breast cancer [6] . Similarly, Ding et al. identified pathogenic BRCA2 mutations in 18 of 115 MBC cases, resulting in a BRCA2-mutation prevalence of 16% (95% CI: 11 - 24), though the difference in BRCA2-mutation frequencies between cases with and without family history of breast cancer was not statistically significant (p = 0.145), further indicating that family history is a weak predictor of mutation carrier status in males [15] . Moreover, Ottini et al. [26] reported that 50% of BRCA2 pathogenic mutations were in

Table 2 . Summary of all published studies evaluating genetic mutations as a risk factor for MBC* (1996-2011).

Continued

Abbreviations: MBC = male breast cancer, AR = androgen receptor gene, BRCA = breast cancer gene, CI = confidence interval, PALB2 = partner and localizer of BRCA2 gene. *p value: statistical significance, <0.05.

MBC cases without a family history of breast cancer, and Csokay et al. [16] found that 0 of 6 MBC cases with pathogenic BRCA2 mutations had a family history of breast cancer. In an analysis of 76 men with breast cancer, Frank et al. identified deleterious mutations in 28% of the cases, of which more than one-third occurred in BRCA1 [24] . These mutations were more prevalent in men with a family history of breast or ovarian cancer and in men of Ashkenazi ancestry, although these findings failed to achieve statistical significance (p = 0.1121 and p = 0.1117, respectively) [24] . In an analysis of 261 Israeli men with a diagnosis of breast cancer, Chodick et al. observed no difference in the BRCA1 or BRCA2 mutation carrier frequencies between Ashkenazi and nonAshkenazi Jews, implicating that the increased incidence of MBC observed in Ashkenazi men cannot be accounted for by the prevalence of BRCA1/2 mutations alone [21] . Failure of BRCA mutation prevalence to reach statistical significance in men of Ashkenazi heritage is in stark contrast to the prevalence observed in their female counterpart. The prevalence of BRCA1andBRCA2 mutations among Caucasian non-Ashkenazi Jewish women with breast cancer is 2.2% - 2.9% and 2.2%, respectively, and 8.3% - 10.2% and 1.1%, respectively, among Ashkenazi Jewish women with breast cancer [25] [27] . While the prevalence of BRCA1 and BRCA2 mutations among African American women with breast cancer is noted to be 1.3% - 1.4% and 2.6%, respectively [25] [27] , the prevalence among the male African American population has yet to be specifically analyzed. However, the incidence of breast cancer is higher among black men of all ages (1.8 per 100,000) when compared to their age-related white counterparts (1.1 per 100,000), and afflicted black males display poorer prognostic features, including advanced-stage disease, with more extensive nodal involvement, larger tumor sizes, and higher tumor grade [2] . While racial disparities in outcomes in women with breast cancer are well studied, those in men warrant further investigation.

4.2. Other Genes Associated with MBC

Various additional genetic mutations have been implicated in the development of male breast cancer, however these mutations account for far less cases than the previously discussed BRCA1/2 mutations. The PALB2 gene product plays a role in the localization and stabilization of BRCA2 in nuclear chromatin, which is essential for BRCA2 to function in DNA repair. Ding et al. postulated that PALB2 may confer risk to develop MBC as a result of its close relationship to BRCA2 [15] . The authors screened for mutations in the PALB2 gene in BRCA2- negative MBC cases and identified 14 germ-line variants, which accounted for 1% - 2% of male breast cancers [15] . The CYP17 gene codes for an enzyme involved in the synthesis of androgens and estrogens. A known single base pair polymorphism creates an additional promotor motif, which has been hypothesized to lead to increased transcriptional activity and enhanced steroid hormone production. That said, Gudmundsdottir et al. investigated the association between CYP17 polymorphism and male breast cancer risk and found no difference in genotype frequencies between MBC cases and controls [14] . The CHEK2 gene located on chromosome 22 encodes a cell-cycle checkpoint kinase that is implicated in DNA repair processes involving BRCA1 and p53. Meijers-Heijboer et al. showed that a known truncating variant of the gene has a frequency of 1.1% in healthy individuals, but is present in 13.5% of individuals from families with male breast cancer (p = 0.00015) [20] . The authors estimated that this CHEK2 variant confers an ~10-fold increase in the risk of MBC that may account for ~9% of male breast cancers [20] . Haraldsson et al. surmised that mutant Androgen Receptor (AR) genes may exhibit an altered sequence-specific DNA binding, possibly having acquired the ability to bind to estrogen-  responsive elements and to activate estrogen-regulated genes, though they found no evidence of germ-line or somatic AR mutations among 34 MBC cases [6] . A region within exon 1 of the gene coding for the AR is highly polymorphic and contains a variable number of CAG repeats, with in vitro studies revealing that a short CAG repeat sequence increases the level of transactivation of the androgen receptor [13] . Young et al. investigated whether increased length of the CAG repeat sequence in the AR gene is associated with the development of MBC [13] . While the authors did not observe a significant overall difference between the median number of CAG repeat length of MBC cases and controls, sequences of 30 or more repeats were only observed in MBC cases, leading the authors to surmise that a relatively long CAG repeat sequence within the AR gene may be implicated in MBC, and a short sequence may offer protection against MBC [13] .

5. Occupational Exposures

Five studies involving a total of 16,667 patients (Table 3) have addressed occupational exposure as a risk factor from MBC. McLaughlin et al. assessed the incidence of male breast cancer by occupational and industrial categories to elucidate environmental and occupational risk factors [28] . Those industries and occupations with a significantly (p < 0.05) increased incidence of male breast cancer were determined from a sample of 333 cases of male breast cancer [28] . The highest risk (~8-fold) was observed in men employed in making soap and perfume, which the authors attributed to the production of estrogen-containing cosmetic creams by this population [26] . A meta-analysis of 7 case-control and 11 cohort studies by Sun et al. revealed a statistically significant increased risk of MBC with electromagnetic field exposure as well (pooled ORs = 1.32, 95% CI = 1.14 - 1.52, p < 0.001), and subgroup analyses also showed similar results [29] . Cocco et al. conducted a case-control of 178 MBC cases and 1041 controls to investigate whether risk of MBC is associated with workplace exposures [30] . A significant risk in MBC was associated with employment in blast furnaces, steel works, rolling mills (OR = 3.4, 95% CI: 1.1 - 10.1), and motor vehicle manufacturing (OR = 3.1, 95% CI: 1.2 - 8.2), however the authors did not hypothesize a cause for this association [30] . A case-control study of 104 MBC cases and 1901 controls by Villeneuve et al. failed to confirm the elevated risk of MBC in blast furnaces, steel works, and rolling mills [31] . However, these authors noted a two-fold increase in MBC incidence among motor vehicle mechanics (95% CI: 1.0 - 4.4), with a dose-response relationship related to duration of employment (OR = 5.9 in motor vehicle mechanics employed for 10 or more years, 95% CI: 2.4 - 14.6) [31] . Furthermore, a significantly increased odds ratio of 1.8 was observed in those cases employed in the motor vehicle sales and repairs industry (95% CI: 1.0 - 3.2) [31] . Similarly, Hansen reported a MBC odds ratio of 2.5 for males employed in trades with potential exposure to gasoline and combustion products for a period of more than 3 months (95% CI: 1.3 - 4.5), and an odds ratio of 5.4 among men younger than 40 years of age at the time of first employment (95% CI: 2.4 - 11.9) [32] . The consistently elevated risk of MBC reported in the MVI may suggest the presence of mammary carcinogens in gasoline vapors, and further investigation is warranted.

Table 3. Summary of all published studies evaluating occupational exposure as a risk factor for MBC* (1988-2013).

Abbreviations: MBC = male breast cancer, SIR = standardized incidence ratio, EMF = electromagnetic field, MVI = motor vehicle industry, OR = odds ratio, CI = confidence interval. *p value: statistical significance, <0.05.

6. Abnormalities in the Androgen-to-Estrogen Ratio

Eleven studies including a total of 4,843,598 patients (Table 4) assessed the risk of MBC in the setting of abnormal androgen-to-estrogen ratios. Nirmul et al. examined the endocrine profiles of 8 MBC patients compared to 8 healthy matched controls [33] . These authors found that the mean total serum estradiol level and the calculated mean free estradiol index were significantly increased in MBC cases compared to controls (p < 0.01 and p < 0.01, respectively) [33] . The two groups showed no significant differences in the levels of luteinizing hormone, follicle stimulating hormone, prolactin, dehydroepiandrosterone-sulfate, testosterone, or sex-hormone binding globulin [33] . Brinton et al. conducted an analysis within the U.S. Veterans Affairs (VA) medical care system database involving a total of 4,501,578 patients, from which they identified 642 MBC cases [34] . Medical conditions significantly associated with increased MBC risk in decreasing order were Klinefelter’s syndrome (RR = 29.64, 95% CI: 12.26 - 71.68), gynecomastia (RR = 5.86, 95% CI: 3.74 - 9.17), obesity (RR = 1.98, 95% CI: 1.55 - 2.54), orchitis/epididymitis (RR = 1.84, 95% CI: 1.10 - 3.08), and diabetes (RR = 1.30, 95% CI: 1.05 - 1.60) [34] . After adjusting for obesity, the association with diabetes disappeared, but that with gynecomastia persisted [34] . Notably, additional studies by Casagrande et al. [35] (N = 150) and Hsing et al. [36] (N = 690) have negated the significance of the association between gynecomastia and MBC, and Olsson et al. [37] observed no new cases of MBC in a cohort of 446 men with a diagnosis of gynecomastia after a maximum followup time of 30 years. The association between increased MBC risk and obesity has been further supported by Brinton et al. in their prospective analysis of 324,920 men, including a total of 121 MBC cases (RR = 1.79, 95% CI: 1.10 - 2.91, for body mass indices, BMI, of ≥30 versus <25 kg/m2) [7] . These authors additionally noted that physical activity during adolescence was inversely associated with MBC risk (for activity ≥5 times per week, RR = 0.59, 95% CI: 0.31 - 1.13), and that subjects who had a physically active routine were at a statistically significant lower risk of MBC (RR = 0.49, 95% CI: 0.28 - 0.87) [7] . Casagrande et al. similarly observed a significant increase in relative risk of breast cancer with increasing weight recorded at age 30 in their case-control study of 75 MBC patients [35] . Men who weighed 90 or more kilograms at age 30 years had more than 5 times

Table 4 . Summary of all published studies evaluating androgen-to-estrogen ratio abnormalities as a risk factor for MBC* (1982-2010).

Abbreviations: MBC = male breast cancer, BMI = body mass index, NIH = national institutes of health, RR = relative risk, CI = confidence interval, OR = odds ratio, LH = luteinizing hormor, FSH = follicle stimulating hormone, PRL = prolactin, DHEA-S = dehydroepiandrosterone sulfate, SHBG = sex hormone-binding globulin, SIR = standardized incidence ratio. *p value: statistical significance, <0.05.

the risk of breast cancer than men weighing less than 60 kilograms at that age (RR = 5.45 and RR = 1.00, respectively, p = 0.04) [35] . In a case-control study of 178 men who died of breast cancer, Hsing et al. reported an increased risk of MBC for men who were described by their next-of kin as very overweight (OR = 2.3, 95% CI: 1.1 - 5.0) [36] . Similarly, Ewertz et al. [10] (N = 624) reported an increased risk of MBC in males whose BMI exceeded 30 ten years prior to diagnosis (OR = 2.1, 95% CI: 1.0 - 4.5), and Altinli et al. [38] observed an average BMI of 26.54 in 40 MBC patients, with 23 (57.5%) of these patients being above their ideal weight as defined by the World Health Organization (statistical analysis not performed due to limited sample size). Johnson et al. (N = 1986) also reported a higher risk of MBC in overweight cases (OR = 2.19, 95% CI: 1.08 - 4.43) [8] .

Excessive alcohol has also been postulated to increase MBC risk as a result of its influence on hormone levels. Guenel et al. investigated the role of alcohol consumption in 74 MBC patients and 1432 age-matched controls [39] . In comparison to ageand geographically-matched controls, the risk of developing breast cancer in men increased by 16% (95% CI: 7 - 26) per 10 grams of alcohol per day (p < 0.001) [39] . Additionally, an odds ratio of 5.89 (95% CI: 2.21 - 15.69) was observed for alcohol intake greater than 90 grams per day as compared with light consumption of less than 15 grams per day, and the authors concluded that the relative risk of male breast cancer increases with consumption levels [39] . Conversely, despite a large sample size (N = 4,501,578) of VA patients with an admission diagnosis of alcoholism, Brinton et al. found no evidence of alteration in MBC risk in subgroup analysis, and further failed to detect an association of MBC with liver cirrhosis secondary to either alcohol consumption or other causes [34] . Similarly, Brinton et al. [7] and Casagrande et al. [35] found no evidence for a relationship between excessive alcohol consumption and increased MBC risk, and separate analyses by Ewertz et al. [10] and Sorensen et al. [40] (N = 11,642) involving men with liver cirrhosis also failed to detect a significant increase in MBC risk.

7. Conclusions

Male breast cancer is an uncommon disease entity which typically presents with poor prognostic features, advanced stage, large tumor size, frequent lymphatic invasion, and early chest wall spread [3] . Large-scale epidemiologic studies have been difficult to conduct as a result of the disease’s rarity. However, current published literature indicates that MBC is similar to its female counterpart clinically, in that various familial, genetic, hormonal, and environmental factors predispose at-risk populations to its development.

Public and physician awareness about male populations at risk for breast cancer is limited, if not non-existent, and men diagnosed with breast cancer are likely to suffer from psychological concerns including stigma, altered body image, lack of emotional support and feelings of isolation, and disease misperceptions [41] -[44] . As a result of poor knowledge about MBC among the public and healthcare community, there are currently no guidelines for breast cancer screening in male populations, even among those at high risk for the disease, which leads to delays in diagnosis and management. This fact, combined with data suggesting that males present with advanced stage disease, clearly implies the need for more defined screening criteria in select subgroups.

Individuals who fulfill one or more high risk criterion should be provided routine surveillance via clinical examination and imaging. Fifty to ninety percent of MBC cases present initially with a palpable breast mass [45] -[47] . This finding dictates a role for physical examination of the breast in high-risk male populations. Current National Comprehensive Cancer Network (NCCN) guidelines for men with BRCA1/2 mutations recommend that healthcare providers teach and encourage breast self-examination and perform clinical breast examinations twice a year [2] . We recommend that those guidelines be broadened to include the following five highrisk populations: 1) males with a previous personal history of breast carcinoma, 2) males with a strong family history of breast cancer (defined as an affected mother or sister), 3) confirmed BRCA2 mutation carriers (regardless of family history), 4) males with a diagnosis of Klinefelter’s syndrome, and 5) males employed in the chemical manufacturing or motor vehicle industry. Mammography should serve as an additional means of screening for the aforementioned populations. Mammographic screening has proven to be greater than 90% sensitive and specific in diagnosing malignant lesions in the male breast, with a negative predictive value of 99% for all categories of benign disease [48] . In light of this data, the five high-risk populations outlined above may benefit from annual clinical mammography in addition to bi-annual clinical examination. Lastly, there exist important management implications for BRCA2 carriers. Genetic testing for BRCA2 should be recommended for any MBC patient, regardless of family history of breast cancer, due to the large percentage of BRCA2 pathogenic mutations recorded in MBC patients lacking a family history of breast cancer.

In conclusion, select male high risk populations may benefit from routine breast cancer surveillance with bi-annual physician physical examination and yearly mammography. Public awareness of male breast cancer, particularly to those at high risk of MBC, is substantially lacking and serves as an obstacle to effective screening. Increased public and physician education on male breast cancer and the development of preventative health campaigns for at-risk populations should help to raise awareness about the rare disease and the need for screening of at-risk populations [47] [49] -[54] .

Author Disclosure Statement

No competing financial interests exist.

References

  1. American Cancer Society (2013) Breast Cancer in Men. American Cancer Society, Inc., Atlanta.
  2. Korde, L.A., Zujewski, J.A., Karmin, L., et al. (2012) Multidisciplinary Meeting on Male Breast Cancer: Summary and Research Recommendations. Journal of Clinical Oncology, 28, 2114-2122. http://dx.doi.org/10.1200/JCO.2009.25.5729
  3. Ottini, L., Palli, D., Rizzo, S., et al. (2010) Male Breast Cancer. Critical Reviews in Oncology/Hematology, 73, 141-155. http://dx.doi.org/10.1016/j.critrevonc.2009.04.003
  4. Friedman, L.S., Gayther, S.A., Kurosaki, T., et al. (1997) Mutation Analysis of BRCA1 and BRCA2 in a Male Breast Cancer Population. The American Journal of Human Genetics, 60, 313-319.
  5. Rosenblatt, K.A., Thomas, D.B., McTiernan, A., et al. (1991) Breast Cancer in Men: Aspects of Familial Aggregation. Journal of the National Cancer Institute, 83, 849-854. http://dx.doi.org/10.1093/jnci/83.12.849
  6. Haraldsson, K., Loman, N., Zhang, Q.X., et al. (1996) BRCA2 Germ-Line Mutations Are Frequent in Male Breast Cancer Patients without a Family History of the Disease. Cancer Research, 58, 1367-1371.
  7. Brinton, L.A., Richesson, D.A., Gierach, G.L., et al. (2008) Prospective Evaluation of Risk Factors for Male Breast Cancer. Journal of the National Cancer Institute, 100, 1477-1481. http://dx.doi.org/10.1093/jnci/djn329
  8. Johnson, K.C., Pan, S. and Mao, Y. (2002) Risk Factors for Male Breast Cancer in Canada, 1994-1998. European Journal of Cancer Prevention, 11, 253-263. http://dx.doi.org/10.1097/00008469-200206000-00009
  9. D’Avanzo, B. and La Vecchia, C. (1995) Risk Factors for Male Breast Cancer. British Journal of Cancer, 71, 1359-1362. http://dx.doi.org/10.1038/bjc.1995.264
  10. Ewertz, M., Holmberg, L., Tretli, S., et al. (2001) Risk Factors for Male Breast Cancer—A Case-Control Study from Scandinavia. Acta Oncologica, 40, 467-471. http://dx.doi.org/10.1080/028418601750288181
  11. Thorlacius, S., Olafsdottir, G., Tryggvadottir, L., Neuhausen, S., Jonasson, J.G., Tavtigian, S.V., Tulinius, H., Ogmundsdottir, H.M. and Eyfjord, J.E. (1996) A Single BRCA2 Mutation in Male and Female Breast Cancer Families from Iceland with Varied Cancer Phenotypes. Nature Genetics, 13, 117-119. http://dx.doi.org/10.1038/ng0596-117
  12. Couch, F.J., Farid, L.M., DeShano, M.L., Tavtigian, S.V., Calzone, K., Campeau, L., et al. (1996) BRCA2 Germline Mutations in Male Breast Cancer Cases and Breast Cancer Families. Nature Genetics, 13, 123-125. http://dx.doi.org/10.1038/ng0596-123
  13. Young, I.E., Kurian, K.M., Mackenzie, M.A.F., Kunkler, I.H., Cohen, B.B., Hooper, M.L., Wyllie, A.H. and Steel, C.M. (2000) The CAG Repeat within the Androgen Receptor Gene in Male Breast Cancer Patients. Journal of Medical Genetics, 37, 139-140. http://dx.doi.org/10.1136/jmg.37.2.139
  14. Gudmundsdottir, K., Thorlacius, S., Jonasson, J.G., Sigfusson, B.F., Tryggvadottir, L. and Eyfjord, J.E. (2003) CYP17 Promoted Polymorphisms and Breast Cancer Risk in Males and Females in Relation to BRCA2 Status. British Journal of Cancer, 88, 933-936. http://dx.doi.org/10.1038/sj.bjc.6600839
  15. Ding, Y.C., Steele, L., Kuan, C.J., Greilac, S. and Neuhausen, S.L. (2011) Mutations in BRCA2 and PALB2 in Male Breast Cancer Cases from the United States. Breast Cancer Research and Treatment, 126, 771-778. http://dx.doi.org/10.1007/s10549-010-1195-2
  16. Csokay, B., Udvarhelyi, N., Sulyok, Z., Besznyak, I., Ramus, S., Ponder, B. and Olah, E. (1999) High Frequency of Germ-Line Brca2 Mutations among Hungarian Male Breast Cancer Patients without Family History. Cancer Research, 59, 995-998.
  17. Mavraki, E., Gray, I.C., Bishop, D.T. and Spurr, N.K. (1997) Germline RBCA2 Mutations in Men with Breast Cancer. British Journal of Cancer, 76, 1428-1431. http://dx.doi.org/10.1038/bjc.1997.574
  18. Syrjakoski, K., Kuukasjarvi, T., Waltering, K., Haraldsson, K., Auvinen, A., Borg, A., Kainu, T., Kallioniemi, O.P. and Koivisto, P.A. (2004) BRCA2 Mutations in 154 Finnish Male Breast Cancer Patients. Neoplasia, 6, 541-545. http://dx.doi.org/10.1593/neo.04193
  19. Basham, V.M., Lipscombe, J.M., Ward, J.M., Gayther, S.A., Ponder, B.A.J., Easton, D.F. and Pharoah, P.D.P. (2002) BRCA1 and BRCA2 Mutations in a Population-Based Study of Male Breast Cancer. Breast Cancer Research, 4, R2. http://dx.doi.org/10.1186/bcr419
  20. Meijers-Heijboer, H., van den Ouweland, A., Kiln, J., Wasielewski, M., de Snoo, A., Oldenburg, R., et al. (2002) Low-Penetrance Susceptibility to Breast Cancer Due to CHEK2*1100delC in Noncarriers of BRCA1 or BRCA2 Mutations. Nature Genetics, 31, 55-59. http://dx.doi.org/10.1038/ng879
  21. Chodick, G., Struewing, J.P., Ron, E., Rutter, J.L. and Iscovich, J. (2008) Similar Prevalence of Founder BRCA1 and BRCA2 Mutations among Ashkenazi and Non-Ashkenazi Men with Breast Cancer: Evidence from 261 Cases in Israel, 1976-1999. The European Journal of Medical Genetics, 51, 141-147. http://dx.doi.org/10.1016/j.ejmg.2007.11.001
  22. Tai, Y.C., Domchek, S., Parmigiani, G. and Chen, S.N. (2007) Breast Cancer Risk among Male BRCA1 and BRCA2 Mutation Carriers. Journal of the National Cancer Institute, 99, 1811-1814. http://dx.doi.org/10.1093/jnci/djm203
  23. Risch, H.A., McLaughlin, J.R., Cole, D.E.C., Rosen, B., Bradley, L., Fan, I., et al. (2006) Population BRCA1 and BRCA2 Mutation Frequencies and Cancer Penetrances: A Kin-Cohort Study in Ontario, Canada. Journal of the National Cancer Institute, 98, 1694-1706. http://dx.doi.org/10.1093/jnci/djj465
  24. Frank, T.S., Deffenbaugh, A.M., Reid, J.E., Hulick, M., Ward, B.E., Lingenfelter, B., et al. (2002) Clinical Characteristics of Individuals with Germline Mutations in BRCA1 and BRCA2: Analysis of 10,000 Individuals. Journal of Clinical Oncology, 20, 1480-1490. http://dx.doi.org/10.1200/JCO.20.6.1480
  25. National Cancer Institute (2013) Genetics of Breast and Ovarian Cancer (PDQ). http://www.cancer.gov/cancertopics/pdq/genetics/breast-and-ovarian/HealthProfessional/page2
  26. Ottini, L., Rizzolo, P., Zanna, I., Falchetti, M., Masala, G., Ceccarelli, K., et al. (2009) BRCA1/BRCA2 Mutation Status and Clinical-Pathologic Features of 108 Male Breast Cancer Cases from Tuscany: A Population-Based Study in Central Italy. Breast Cancer Research and Treatment, 116, 577-586. http://dx.doi.org/10.1007/s10549-008-0194-z
  27. Malone, K.E., Daling, J.R., Doody, D.R., Hsu, L., Bernstein, L., Coates, R.J., 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 Research, 66, 8297. http://dx.doi.org/10.1158/0008-5472.CAN-06-0503
  28. McLaughlin, J.K., Malker, H.S.R., Blot, W.J., Weiner, J.A., Ericsson, J.L. and Fraumeni, J.F. (1988) Occupational Risks for Male Breast Cancer in Sweden. British Journal of Industrial Medicine, 45, 275-276.
  29. Sun, J.W., Li, X.R., Gao, H.Y., Yin, J.Y., Qin, Q., Nie, S.F. and Wei, S. (2013) Electromagnetic Field Exposure and Male Breast Cancer Risk: A Meta-Analysis of 18 Studies. Asian Pacific Journal of Cancer Prevention, 14, 523-528. http://dx.doi.org/10.7314/APJCP.2013.14.1.523
  30. Cocco, P., Figgs, L., Dosemeci, M., Hayes, R., Linet, M.S. and Hsing, A.W. (1998) Case-Control Study of Occupational Exposures and Male Breast Cancer. Occupational and Environmental Medicine, 55, 599-604. http://dx.doi.org/10.1136/oem.55.9.599
  31. Villeneuve, S., Cyr, D., Lynge, E., Orsi, L., Sabroe, S., Merletti, F., et al. (2010) Occupation and Occupational Exposure to Endocrine Disrupting Chemicals in Male Breast Cancer: A Case-Control Study in Europe. Occupational and Environmental Medicine, 67, 837-844. http://dx.doi.org/10.1136/oem.2009.052175
  32. Hansen, J. (2000) Elevated Risk for Male Breast Cancer after Occupational Exposure to Gasoline and Vehicular Combustion Products. American Journal of Industrial Medicine, 37, 349-352. http://dx.doi.org/10.1002/(SICI)1097-0274(200004)37:4<349::AID-AJIM4>3.0.CO;2-L
  33. Nirmul, D., Pegoraro, R.J., Jialal, I., Naidoo, C. and Joubert, S.M. (1982) The Sex Hormone Profile of Male Patients with Breast Cancer. British Journal of Cancer, 48, 423-427. http://dx.doi.org/10.1038/bjc.1983.208
  34. Brinton, L.A., Carreon, J.D., Gierach, G.L., McGlynn, K.A. and Gridley, G. (2010) Etiologic Factors for Male Breast Cancer in the U.S. Veterans Affairs Medical Care System Database. Breast Cancer Research and Treatment, 119, 185-192. http://dx.doi.org/10.1007/s10549-009-0379-0
  35. Casagrande, J.T., Hanisch, R., Pike, M.C., et al. (1988) A Case-Control Study of Male Breast Cancer. Cancer Research, 48, 1326-1330.
  36. Hsing, A.W., McLaughlin, J.K., Cocco, P., Co Chien, H.T. and Fraumeni Jr., J.F. (1998) Risk Factors for Male Breast Cancer (United States). Cancer Causes and Control, 9, 269-275. http://dx.doi.org/10.1023/A:1008869003012
  37. Olsson, H., Bloodstream, A. and Alm, P. (2002) Male Gynecomastia and Risk for Malignant Tumors—A Cohort Study. BMC Cancer, 2, 26.
  38. Altinli, E., Gorgun, E., Karabicak, I., Uras, C., Unal, H. and Akcal, T. (2002) Anthropometric Measurements in Male Breast Cancer. Obesity Surgery, 12, 869-870. http://dx.doi.org/10.1381/096089202320995727
  39. Guenel, P., Cyr, D., Sabroe, S., Lynge, E., Merletti, F., Ahrens, W., et al. (2004) Alcohol Drinking May Increase Risk of Breast Cancer in Men: A European Population-Based Case-Control Study. Cancer Causes and Control, 15, 571-580. http://dx.doi.org/10.1023/B:CACO.0000036154.18162.43
  40. Sorensen, H.T., Friis, S., Olsen, J.H., Thulstrup, A.M., Mellemkjaer, L., Linet, M., Trichopoulos, D., Vilstrup, H. and Olsen, J. (1998) Risk of Breast Cancer in Men with Liver Cirrhosis. American Journal of Gastroenterology, 93, 231-233. http://dx.doi.org/10.1111/j.1572-0241.1998.00231.x
  41. Al-Naggar, R.A. and Al-Naggar, D.H. (2012) Perceptions and Opinions about Male Breast Cancer and Male Breast Self-Examination: A Qualitative Study. Asian Pacific Journal of Cancer Prevention, 13, 243-246. http://dx.doi.org/10.7314/APJCP.2012.13.1.243
  42. Bunkley, D.T., Robinson, J.D., Bennett Jr., N.E. and Gordon, S. (2000) Breast Cancer in Men: Emasculation by Association? Journal of Clinical Psychology in Medical Settings, 7, 91-97. http://dx.doi.org/10.1023/A:1009553613564
  43. France, L., Michie, S., Barrett-Lee, P., Brain, K., Harper, P. and Gray, J. (2000) Male Cancer: A Qualitative Study of Male Breast Cancer. The Breast, 9, 343-348. http://dx.doi.org/10.1054/brst.2000.0173
  44. Nicholas, D.R. (2000) Men, Masculinity, and Cancer: Risk-Factor Behaviors, Early Detection, and Psychosocial Adaptation. Journal of American College Health, 49, 27-33. http://dx.doi.org/10.1080/07448480009596279
  45. Kiluk, J.V., Lee, M.C., Park, C.K., Meade, T., Minton, S., Harris, E., Kim, J. and Laronga, C. (2011) Male Breast Cancer: Management and Follow-Up Recommendations. The Breast Journal, 17, 503-509. http://dx.doi.org/10.1111/j.1524-4741.2011.01148.x
  46. Haché, K.D., Gray, S., Barnes, P.J., Dewar, R., Younis, T. and Rayson, D. (2007) Clinical and Pathological Correlations in Male Breast Cancer: Intratumoral Aromatase Expression via Tissue Microarray. Breast Cancer Research and Treatment, 105, 169-175. http://dx.doi.org/10.1007/s10549-006-9448-9
  47. Dershaw, D.D., Borgen, P.I., Deutch, B.M. and Liberman, L. (1993) Mammographic Findings in Men with Breast Cancer. American Journal of Roentgenology, 160, 267-270. http://dx.doi.org/10.2214/ajr.160.2.8424331
  48. Evans, G.F.F., Anthony, T., Appelbaum, A.H., Schumpert, T.D., Levy, K.R., Amirkhan, R.H., Cambell, T.J., Lopez, J. and Turnage, R.H. (2001) The Diagnostic Accuracy of Mammography in the Evaluation of Male Breast Disease. American Journal of Surgery, 181, 96-100. http://dx.doi.org/10.1016/S0002-9610(00)00571-7
  49. Brenner, R.J., Weitzel, J.N., Hansen, N. and Boasberg, P. (2004) Screening-Detected Breast Cancer in a Man with BRCA2 Mutation: Case Report. Radiology, 230, 553-555. http://dx.doi.org/10.1148/radiol.2302030360
  50. Estala, S.M. (2006) Proposed Screening Recommendations for Male Breast Cancer. The Nurse Practitioner, 31, 62-63. http://dx.doi.org/10.1097/00006205-200602000-00012
  51. Freedman, B.C., Keto, J. and Rosenbaum Smith, S.M. (2012) Screening Mammography in Men with BRCA Mutations: Is There a Role? The Breast Journal, 18, 73-75. http://dx.doi.org/10.1111/j.1524-4741.2011.01185.x
  52. Patterson, S.K., Helvie, M.A., Aziz, K. and Nees, A.V. (2006) Outcome of Men Presenting with Clinical Breast Problems: The Role of Mammography and Ultrasound. The Breast Journal, 12, 418-423. http://dx.doi.org/10.1111/j.1075-122X.2006.00298.x
  53. Dershaw, D.D. (1986) Male Mammography. American Journal of Roentgenology, 146, 127-131. http://dx.doi.org/10.2214/ajr.146.1.127
  54. Ruddy, K.J. and Winer, E.P. (2013) Male Breast Cancer: Risk Factors, Biology, Diagnosis, Treatment, and Survivorship. Annals of Oncology, 24, 1434-1443. http://dx.doi.org/10.1093/annonc/mdt025

NOTES

*Corresponding author.

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