Male Breast Cancer

Epidemiology

Male breast cancer (MBC) is a rare diagnosis, with approximately 2650 estimated cases and 530 deaths in the United States in 2021. MBC accounts for less than 1% of all breast cancers and less than 0.2% of all male cancer deaths in the United States. Globally, the highest incidence of MBC is seen in Central-Eastern Europe, with a rate of 2.85/1,000,000, and Russia (2.22), while the lowest rates were seen in Australia (1.22) and Japan (0.58). The highest death rate was seen in Serbia at 4.89/1,000,000 and Bulgaria (4.14), while the lowest rates were seen in Japan (0.58) and Korea (0.43). MBC compared with female breast cancers occurs later in life, with higher stage, higher grade, and more estrogen receptor (ER)-positive tumors. The median age for presentation is in the mid-60s. According to the US Surveillance, Epidemiology and End Results (SEER) registry database from 1975 to 2011, the incidence of breast cancer was slightly increasing from 0.85 per 100,000 in 1975 to 1.43 in 2011. While MBC survival continues to improve due to improved therapeutics, it lags behind female breast cancer. Comparing patients diagnosed from 1996 to 2005 versus 1976 to 1985 and adjusting for age, stage, and grade, the rate of death due to breast cancer declined by 28% among men and 42% among women.

Race and Ethnicity

Racial and ethnic differences also exist. Black men have a higher incidence of breast cancer than non-Hispanic White men. Age-adjusted incidence rates per 100,000 men are highest in Blacks (1.65), intermediate in non-Hispanic Whites (1.31), and lowest in Hispanics (0.68) and Asian/Pacific Islanders (0.66). Black men are also diagnosed at an earlier age and at a more advanced stage compared with other ethnicities. In a study of 5972 men with breast cancer in the National Cancer Data Base, Black men demonstrated higher proportions presenting at stage II or III (stage II, 45.4% vs. 41.8%; stage III, 20.6% vs. 14.3%; P < 0.001) and were more likely to have ER-negative breast cancers (13.8% vs. 7.6%; P < 0.001). Black men were more likely to be uninsured or have Medicaid, more commonly treated in teaching or research centers, and more likely to reside in low-income areas. Younger Black men had a lower 5-year all-cause (77% vs. 86.4%) and breast cancer–specific survival rates (84% vs. 91.1%) compared to young White males.

Tumor subtypes also differ slightly across racial/ethnic groups. In a large population-based study of 606 patients with MBC, differences in receptor status did not reach statistical significance. Non-Hispanic White men had MBCs that were 82.8% hormone receptor–positive and 14.6% HER2-positive, and 2.6% had triple-negative disease. Black men had MBCs that were 73.3% hormone receptor–positive and 17.8% HER2-positive, and 8.9% had triple-negative disease. Hispanic men had MBCs that were 77.6% hormone receptor–positive and 16.4% HER2-positive, and 6% had triple-negative cancers.

Risk Factors

Several risk factors are associated with the development of MBC, including demographic, environmental, endocrine, and genetic factors. In terms of demographics, older men and those of higher socioeconomic status are at an increased risk. Black men are found to be at a greater risk of MBC compared with non-Hispanic White men. Other risks include diabetes, history of bone fracture, orchitis/epididymitis, obesity, and low physical activity.

Radiation exposure has been reported as a risk factor for breast cancer in men. The largest body of evidences comes from studies of World War II atomic bomb survivors who exhibited increased risk of MBC when followed between 1958 and 1998. A SEER database study demonstrated an increased risk for MBC as a second primary cancer after treatment for lymphoma, postulating that mantle radiation plays a role in increased risk.

Conditions associated with increased estrogen levels are associated with an increased risk of breast cancer in men. These include gynecomastia, liver disease, tobacco use, testicular abnormalities, and obesity. Gynecomastia is commonly drug-related and has been described in men taking finasteride, digoxin, thioridazine, spironolactone, or exogenous estrogen for gender reassignment.

A strong risk for breast cancer is seen in men with Klinefelter syndrome, a rare condition that results from the inheritance of an additional X chromosome (XXY). Men with this condition have atrophic testes, gynecomastia, high levels of gonadotropins (follicle-stimulating hormone, luteinizing hormone), and low plasma testosterone. Increased risk for MBC is hypothesized to be due to a high ratio of estrogen to androgen that could lead to abnormal hormonal stimulation of cell proliferation in mammary ductal epithelium. The Swedish Cancer Registry estimated the risk for MBC with Klinefelter syndrome to be increased by a factor of 50 compared with XY males. A larger cohort study in Britain consisting of 3518 men with Klinefelter syndrome demonstrated a 19-fold increase in incidence and 58-fold increase in mortality from MBC when compared to the general population, estimating the cumulative risk of MBC to be 0.9% by the age of 75 years.

Genetic mutations in the breast cancer type 1 and 2 susceptibility genes ( BRCA1 and BRCA2 ) are the most clearly delineated risk factors for breast cancer in men. Of men with breast cancer, 0% to 4% have BRCA1 mutations, while 4% to 16% have BRCA2 mutations. Compared to women with BRCA mutations who harbor a risk of 50% to 85%, the risk of MBC with these mutations is significantly lower. Men who carry BRCA1 mutations have an approximate 1.2% cumulative risk of breast cancer by age 70 years, compared to men with BRCA2 mutations, at 6.8%. In addition to increased risk, BRCA2 mutations are also more frequent than BRCA1 mutations. In an Italian series of 50 BRCA mutations carriers, 92% harbored the BRCA2 mutation compared with 8% with the BRCA1 mutation.

Mutations in genes other than BRCA may predispose males to developing breast cancer. Mutations in PALB2 have been reported in men with breast cancer, but the prevalence is reported to be low, at around 1% to 2%. Mutations in CHEK2 have also been shown to increase breast cancer risk in men. Outside of the specific truncating mutation CHEK2 *1100delC, which increased the risk of MBC by a factor of 10 per the CHEK2 Breast Cancer Consortium, the overall risk of CHEK2 mutations in MBC is not well quantified. Cowden’s disease, which results from germline mutations in the tumor suppressor gene PTEN , Li-Fraumeni syndrome caused by TP53 mutation, Lynch syndrome caused by mutations in mismatch repair genes, and single-nucleotide polymorphisms in CYP17 and RAD51B are also associated with increased risk for MBC.

Guidelines from the National Comprehensive Cancer Network (NCCN) recommend that genetic testing be offered to men who develop breast cancer, as well as to families with a known BRCA mutation, case of MBC, or the presence of female relatives with a history of breast ovarian, pancreatic, or prostate cancer that suggests the presence of an inherited breast or ovarian cancer syndrome. Furthermore, adherence to recommended screening guidelines for prostate cancer is advised for men with BRCA2 mutations and should be considered in men with BRCA1 mutations.

Clinical Features

Like breast cancer in women, MBC usually presents with a painless mass. In men, breast cancer typically presents in the subareolar position. Nipple involvement is common, at 40% to 50%, nipple retraction is seen in 9%, discharge in 6%, and skin ulceration in 6%. Due to the paucity of breast tissue compared to women, fixation to the muscle or skin is not uncommon.

Gynecomastia is the most common differential diagnosis, as it is a highly prevalent condition in men. In a review of 477 male autopsy specimens, up to 55% demonstrated gynecomastia. As opposed to MBC, gynecomastia presents as bilateral, symmetric breast enlargement with irregular borders. To make a definitive diagnosis, the American College of Radiology recommends ultrasonography for men under the age of 25 years and mammogram for those above the age of 25 years when presenting with a questionable mass. MBC on mammography is characterized by spiculated irregular masses, commonly in the subareolar position, with or without coarse calcifications. Currently there is no role for screening mammograms in men with a known genetic mutation or personal history of breast cancer.

Diagnosis

Per NCCN guidelines, the first step in the evaluation and diagnosis of a suspicious breast mass in a male is mammography. Mammography can distinguish between malignancy and gynecomastia in 80% to 90% of MBCs. Radiologic features such as a well-defined lesion that would suggest a benign finding in a female are unreliable in men and require biopsy. In one series, MBC manifested as a well-defined mass in 15% of cases using mammography and in 23% using sonography. The use of breast MRI has not been widely studied in MBC, and no prospective data exist for its use in screening of diagnosis of MBC.

Once a suspicious mass is identified, a core needle biopsy of the mass is recommended to confirm the diagnosis and ascertain the receptor status. Fine-needle aspiration (FNA) can be performed, but is less reliable in obtaining adequate tissue for study.