BRCA Mutations in Men: Important but Often Overlooked

BRCA1 and BRCA2 pathogenic variants carry well-known associations with breast and ovarian cancers in women, which has led to robust clinical guidelines for early genetic testing and risk-reduction strategies. 

Male carriers of BRCA1/2 pathogenic variants also face an increased risk for cancer, particularly of the prostate, pancreas, and breast. 

However, men often fly under the radar. 

Although males represent half of BRCA1/2 pathogenic variant carriers, men are much less likely to receive genetic testing for BRCA mutations. “Most people (including their clinicians) are unaware of their carrier status,” Heather Cheng, MD, PhD, with University of Washington, Seattle, and colleagues explained in a comprehensive review on the subject, published in JAMA Oncology. Most are also unaware of “the associated cancer risks, and management recommendations” for BRCA carriers. 

The testing gap in males may exist, in part, because of a “general lack of awareness” that BRCA gene mutations can be passed down to children from both the mother and father, Elisa Port, MD, chief of breast surgery for the Mount Sinai Health System in New York City, told Medscape Medical News.

A daughter can inherit a mutated BRCA gene that puts her at risk for breast or ovarian cancer from her mother’s or father’s family and, similarly, a son can inherit a mutated BRCA gene from either side of the family that puts him at an increased risk for developing prostate and other cancers, explained Port, director of the Center of Excellence for Breast Cancer at The Tisch Cancer Institute at Mount Sinai. 

Considering family history and genetics on both sides of the family is important when assessing cancer risk in men and women, Port said. 

BRCA Mutations in Men: What’s the Risk? 

Although fewer than 1% of all breast cancers occur in men, when men do carry a BRCA mutation, their risk for breast cancer can increase considerably. The lifetime risk for breast cancer can be as high as 9% in male BRCA2 carriers and up to 1.2% in BRCA1 carriers. 

BRCA1/2 mutations also put men at increased risk for pancreatic and prostate cancers.

For pancreatic cancer, male BRCA1 carriers have a nearly 2-fold increased risk compared with the general population, with a lifetime risk of 3%. BRCA2 carriers have a three- to nearly eightfold increased risk, with a lifetime risk up to 7%.

Male BRCA1 carriers face a nearly fourfold increased risk of developing prostate cancer and an absolute lifetime risk of 15%-45%. Male BRCA2 carriers have a five- to ninefold increased risk for prostate cancer, with an absolute lifetime risk between 27% and 60%. 

When to Test, When to Screen?

Despite the increased risk for several cancers associated with BRCA mutations, many men are not offered genetic testing.

BRCA1/2 genetic testing in men is “ultra-important but underutilized and is an evolving unmet need that the field needs to address,” Kai Tsao, MD MS, medical director of the Medical Oncology Prostate Cancer Program at Mount Sinai in New York City, told Medscape Medical News. 

For men considering genetic testing, in Tsao’s experience, barriers may include fear that insurance may not cover the test and that a positive test may increase insurance premiums, as well as concerns about what the test result may mean for them and their family.

Even for confirmed BRCA carriers, cancer screening guidelines for men vary.

For breast screening in men, there’s limited data to inform guidelines. The National Cancer Center Network currently recommends breast awareness and teaching self-examination starting at age 35 and recommends men with BRCA variants consider yearly mammograms starting at age 50, or 10 years before the earliest male breast cancer diagnosis in the family. 

Data show that screening mammography in men at high-risk for breast cancer yields similar cancer detection rates in men and women, “suggesting mammography screening may be valuable in male BRCA carriers,” the review authors noted. And, in a recent study of men with BRCA1/2 pathogenic variants, most (71%) recommended for screening mammography completed their screening. 

The European Society for Medical Oncology (ESMO) has similar screening recommendations but focuses only on men with BRCA2 mutations and suggests breast ultrasonography as well as mammography as a screening option.

The larger “issue is the general population doesn’t think of breast cancer when they think of men, which may delay seeking medical attention,” said Melissa Fana, MD, of NYU Grossman Long Island School of Medicine and NYU Langone Health, who wasn’t involved in the review. 

For pancreatic cancer, guidelines suggest BRCA1/2 carriers be screened for pancreatic cancer starting at age 50, or 10 years before the earliest known pancreatic cancer in the family, although the guidelines vary on the role family history should play.

And for prostate cancer, current guidelines recommend male BRCA carriers begin prostate-specific antigen screening between age 40 and 45 years, although recommendations on screening intervals and start age vary. ESMO recommendations are similar but only apply to BRCA2 carriers.

A male patient with a BRCA1/2 variant is typically referred for genetic counseling as well, Tsao explained. But “the challenge is that we don’t have a very good healthcare infrastructure right now” to follow through with that, he added. “Oftentimes a patient will wait many months or even more than a year for a genetic counseling appointment.”

To help improve these issues, Mount Sinai recently launched a comprehensive BRCA program for men and women that offers genetic testing and counseling for patients and family members.

Overall, identifying more male BRCA1/2 carriers will “maximize opportunities for cancer early detection, targeted risk management, and cancer treatment for males, along with facilitating opportunities for risk reduction and prevention in their family members, thereby decreasing the burden of hereditary cancer,” Cheng and colleagues concluded.

Support for the review was provided in part by BRCA Research and Cure Alliance and the Men & BRCA Program at the Basser Center for BRCA. Cheng reported grants from Promontory Pharmaceutics, Medivation, Sanofi, Janssen, royalties from UpToDate, nonfinancial support from Color Health, personal fees from AstraZeneca, BRCA Research and Cure Alliance (CureBRCA) outside the submitted work. Port, Tsao, and Fana had no conflicts of interest.