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 ad- vanced 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 ex- amines the existing literature on male populations at high risk for breast cancer, and provides specific screening recommendations for these populations.

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 con- siderations including age, ethnicity, socioeconomic status, and occupation, as well as more traditional risk fac- tors such as ethnicity, family history, BRCA/other genetic mutations, and genetic syndromes.

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 first- or 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] .

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

Seventeen studies involving a total of 5451 patients (Table 2) analyzed the associations between heritable ge- netic 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] .

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 cate- gories 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.

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.

Eleven studies including a total of 4,843,598 patients (Table 4) assessed the risk of MBC in the setting of ab- normal 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 calcu- lated 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 follow- up 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 sig- nificant 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

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 age- and 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.

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 high- risk 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] .

No competing financial interests exist.