Study Finds Differences in BRCA1/2 Male Pathogenic Variant Carriers

This data may help to inform future recommendations for surveillance of BRCA1/2-associated cancers, according to researchers.

A study published in JAMA Oncology found that there are significant differences in the cancer spectrum of male BRCA2, compared with BRCA1, pathogenic variant carriers.

According to researchers, this data may help to inform future recommendations for surveillance of BRCA1/2-associated cancers, as well as possibly guide future prospective studies for estimating cancer risks in men with these pathogenic variants.

“These data may represent a step toward evidence-based guidelines and may help to refine existing recommendations in specifying distinct surveillance guidelines for men with either BRCA1 or BRCA2 [pathogenic variants],” the authors wrote.

In this retrospective cohort study, researchers evaluated 6902 men, including 3651 BRCA1 and 3251 BRCA2 pathogenic variant carriers, who were recruited from cancer genetics clinics from 1966 to 2017 by 53 study groups in 33 countries worldwide collaborating through the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA). Of the total cohort, 1634 cancers were diagnosed in 1376 men (19.9%), the 922 (67%) of which were BRCA2 pathogenic variant carriers.

Overall, being affected by any cancer was correlated with a higher probability of being a BRCA2, rather than a BRCA1, pathogenic variant carrier (OR, 3.23; 95% CI, 2.81-3.70; P < 0.001), as well as developing 2 (OR, 7.97; 95% CI, 5.47-11.60; P < 0.001) and 3 (OR, 19.60; 95% CI, 4.64-82.89; P < 0.001) primary tumors. Moreover, breast (OR, 5.47; 95% CI, 4.06-7.37; P < 0.001) and prostate (OR, 1.39; 95% CI, 1.09-1.78; P = 0.008) cancers were most often associated with a higher probability of being a BRCA2 pathogenic variant carrier.

“Intercancer intervals were shorter in male BRCA2 [pathogenic variant] carriers with a first diagnosis of breast or prostate cancers, compared with other cancers, thus suggesting that BRCA2-associated breast and prostate cancers may have a worse prognosis,” the authors wrote. “However, age difference at first diagnosis, being older for breast or prostate cancer compared with the other cancers, may affect intercancer intervals.”

Of the cancers studied outside of breast and prostate cancer, pancreatic cancer was also associated with a higher probability (OR, 3.00; 95% CI, 1.55-5.81; P = 0.001) of being a BRCA2 pathogenic variant carrier and colorectal cancer with a lower probability (OR, 0.47; 95% CI, 0.29-0.78; P = 0.003).

“Our results provide further evidence to consider screening for pancreatic cancer in male BRCA2 [pathogenic variant] carriers,” the authors wrote. “However, given the lack of data regarding the effectiveness of any pancreatic cancer screening program, male BRCA2 [pathogenic variant] carriers should be strongly encouraged to participate in clinical trials evaluating such screening strategies.”

Researchers noted that most of the commonly reported cancers in male BRCA1/2 pathogenic variant carriers are also common in the general population and may be associated with environmental or lifestyle risk factors, such as smoking – though a role of gene-environment interactions in increasing cancer risks may also be suggested. However, country-specific environmental influences and lifestyle factors cannot be altogether excluded. Nevertheless though, education and awareness regarding the signs and symptoms of these cancer types and strict adherence to population screening guidelines are incredibly necessary for male BRCA1/2 pathogenic variant carriers according to the investigators.

“Further research, ideally large prospective studies, to obtain reliable cancer risk estimates in male BRCA1/2 [pathogenic variant] carriers is urgently needed to refine clinical management strategies,” the authors wrote.


Silvestri V, Leslie G, Barnes DR. Characterization of the Cancer Spectrum in Men With Germline BRCA1 and BRCA2 Pathogenic Variants: Results From the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA). JAMA Oncology. doi:10.1001/jamaoncol.2020.2134.