It is well established that inherited (ie, germline) pathogenic variants (PVs) in BRCA1 and BRCA2 (BRCA1/2) are linked to familial predisposition to early-onset breast and ovarian cancers in women. Multiple studies have demonstrated the clinical utility of early detection and risk reduction strategies for breast and ovarian cancer in female carriers of BRCA1/2 PVs. Robust clinical guidelines are available to accomplish this goal in this patient population.
Male carriers of BRCA1/2 PVs are also at increased risk of developing cancer, particularly of the prostate, pancreas, breast and stomach. Males represent half of BRCA1/2 PV carriers, but most people (including their clinicians) are unaware of their carrier status, associated cancer risks, and management recommendations, or the availability of research opportunities. In fact, males have undergone cancer-specific genetic testing at one-tenth the frequency of female individuals.
Males unaffected by cancer may meet the criteria for genetic testing if they have 1 or more blood relatives affected by certain cancer subtypes, such as acinar pancreatic cancer, triple-negative breast cancer, ovary and prostate cancer. It is important to collect family history on both maternal and paternal sides of the family, and if known, approximate age at diagnosis and whether the cancer was lethal. Inquiring about any known familial cancer risk genes is also important.
A thorough family history of cancer is necessary but not sufficient for identifying some carriers of BRCA1/2 PVs. Genetic testing is now clinically indicated for males with a personal diagnosis of pancreas adenocarcinoma, breast cancer, stomach, or prostate cancer that qualifies as high-risk or very high-risk localized disease: PSA > 20 ng/mL, Gleason grade 8-10, World Health Organization (WHO) grade group 4-5, node-positive cancer, or metastatic disease.
Male carriers of BRCA1/2 PVs are at increased risk of developing prostate cancer compared to their noncarrier counterparts, with the risk from BRCA2 PVs being higher. Carrying a BRCA1 PV has been estimated to confer up to a 3.8-fold increased risk of prostate cancer, and an absolute lifetime risk of 15% to 45%. Current guidelines recommend male BRCA2 PV carriers begin PSA screening between the ages of 40 and 45 years, although there is discordance about intervals: annual vs every 2 years.
Carriers of BRCA2 PVs have a 3.0- to 7.8-fold increased risk of developing pancreatic cancer, and a lifetime risk of up to 7%. Many professional society guidelines suggest that pancreatic cancer screening for BRCA1/2 PV carriers can be initiated at 50 years of age, or 10 years prior to the youngest age of pancreatic cancer diagnosis in the family. There is still a lack of consensus whether the screening should be offered only to individuals with pancreatic cancer in a close relative from the side of the family with the BRCA1/2 PV. Other guidelines advocate for offering pancreatic cancer screening independent of family history. Screening should typically only be offered to patients who would be surgical candidates if a high-risk lesion is identified. Screening in most centers include annual imaging with either endoscopic ultrasonography (EUS) or magnetic resonance imaging (MRI) of the abdomen with and without intravenous contrast. Recent data suggests EUS may be more effective in identifying solid lesions of the pancreas. Monitoring for the development of new-onset diabetes with annual hemoglobin A1C or fasting glucose can also be considered, because new-onset diabetes may signal developing pancreatic cancer and warrant more attentive screening. However, diabetes monitoring should only be used to complement imaging rather than to replace it.
While the lifetime incidence of breast cancer is low in males (1 in 833), the risk can be as high as 7% to 9% in male carriers of BRCA2 PVs. Male BRCA1 carriers have an estimated lifetime risk of up to 1.2% of developing breast cancer. NCCN guidelines recommend the following: breast awareness and self-examination teaching at 35 years of age, annual clinical breast examinations starting at 35 years of age, and consideration of annual mammogram for BRCA2 PV carriers starting at 50 years of age, or 10 years before the age of the earliest male breast cancer diagnosis in the family. Gynecomastia has not been shown to increase the risk of breast cancer in males and is not a requirement for screening.
Studies have demonstrated an excess risk of stomach cancer in carriers of BRCA1/2 PVs. A recent study found a strong interaction between Helicobacter pylori infection and BRCA1/2 PVs, finding that patients with both had a 45% lifetime cumulative risk of gastric cancer, with a greater effect seen in BRCA2 PV carriers. At this time, gastric cancer screening has not been included in formal guidelines, but it may be reasonable to consider baseline H pylori testing with a urea breath test or stool antigen assay, especially in areas with high H pylori prevalence, and/or if there is a family history of gastric cancer.
Genetic testing can be initiated by a primary care clinician or subspecialist, with support from genetic counselors and other cancer genetics experts. Identifying more male carriers of BRCA1/2 PVs will maximize opportunities for cancer early detection, targeted risk management, and cancer treatment, along with facilitating opportunities for risk reduction and prevention in their family members, thereby decreasing the burden of hereditary cancer.
