Awareness Efforts Needed to Address Genetic Testing Disparities Among Male BRCA1/2 Carriers

Kara N. Maxwell, MD, PhD

Rates of genetic testing are significantly lower for males harboring germline pathogenic variants (PVs) in BRCA1/2 than females despite increasing evidence showing that men with these alterations are at an increased risk for developing prostate cancer, pancreatic cancer, and breast cancer, according to a review published in JAMA Oncology.¹ Accordingly, increasing access to and awareness of appropriate genetic testing among male carriers could improve early detection, allow for targeted risk management, and better inform treatment strategies.

“Oncologists, internists, and primary care clinicians should be vigilant about offering appropriate genetic testing to males,” lead study author Kara N. Maxwell, MD, PhD, and colleagues wrote in the review. “Identifying more male carriers of BRCA1/2 PVs 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.”

Maxwell is the director of the Men and BRCA Program at the Basser Center and an associate professor of medicine (hematology-oncology) at the Perelman School of Medicine of the University of Pennsylvania in Philadelphia.

Study Background

Although half of all carriers of hereditary cancer–predisposing BRCA1/2 PVs are male, the associated risks, management recommendations, and availability of clinical trials for these patients are underrecognized compared with their female counterparts. The estimated prevalence of BRCA1/2 PVs is 1 in 250, varying by ancestry. However, the proportion of male carriers with or without cancer remains unclear, as males undergo cancer-specific genetic testing at one-tenth the rate of females (rate ratio, 0.10 [95% CI, 0.05-0.23]).

Emerging cancer-specific risk estimates for male carriers of BRCA1/2 PVs have led to updated guidelines from key professional societies. However, these recommendations are often embedded within guidelines intended for female carriers, organ-specific guidelines, or cancer-focused guidelines, making them difficult to locate. Consequently, more work is needed to ensure male carriers receive the same access to and quality of care as female carriers. To address this issue, Maxwell and colleagues set out to compile a comprehensive reference of current guidelines and best practices.

In the review, Maxwell and colleagues note that their use of the term “males” refers to individuals assigned male sex at birth, irrespective of gender identity. This was informed by current recommendations for transgender women, gender-neutral, and gender-fluid carriers.

Indications for Genetic Testing in Male Carriers

Genetic testing is recommended for males diagnosed with pancreatic, male breast, or high-risk prostate cancer, according to the National Comprehensive Cancer Network classification (e.g. a prostate-specific antigen [PSA] level greater than 20 ng/mL, Gleason grade 8-10, and World Health Organization grade group 4-5, node-positive, or metastatic disease). These guidelines are based on research showing a high prevalence of BRCA1/2 PVs in these tumor types, as well as the expanding use of PARP inhibitors for BRCA1/2 PV carriers.

Males without a personal history of cancer may qualify for genetic testing if they have 1 or more blood relatives with breast, ovarian, prostate, or pancreatic cancer that meet testing or other specific criteria. These include gathering a detailed family history, including cancer types, age at diagnosis, cancer lethality, and known familial cancer risk genes. Testing should also be suggested for those with high-risk subtypes, including acinar pancreatic cancer and triple-negative breast cancer, regardless of ancestry. Testing should be particularly considered for individuals of European or Ashkenazi Jewish descent.

Maxwell and colleagues noted that historic data on the prevalence of PVs in prostate, pancreatic, and male breast cancers should be interpreted with caution. Many early studies focused on family histories of breast/ovarian cancer, neglecting to represent other relevant tumor types. Additionally, current data are primarily derived from cohorts comprising individuals of European or Ashkenazi Jewish ancestry, limiting applicability.

With evolving guidelines, many cancer survivors who were ineligible for genetic testing at the time of their diagnosis now meet current testing criteria. Male BRCA1/2 PV carriers are often identified outside traditional diagnostic pathways, such as through prenatal testing, direct-to-consumer testing, or tumor-normal genetic testing following a cancer diagnosis. Tumor sequencing can also reveal germline alterations otherwise missed by family history criteria.

Genetic Testing Options and Algorithms for Identifying Male Carriers

The current genetic counseling workforce is insufficient to meet the growing demand for genetic testing services, leading to disparities in access to care. Accordingly, ongoing research is focused on leveraging new technologies to reduce these disparities. Given the variability in resources across clinical settings, personalized workflows can address specific patient needs, including pretest counseling, post-test counseling after the identification of PVs, and assistance with cascade genetic testing for relatives.

Traditional algorithms for estimating the risk of BRCA1/2 PVs, which rely heavily on family histories of breast and ovarian cancers, are less effective for males. In the United States, genetic testing is recommended when the model-derived likelihood of carrying a BRCA1/2 PV is 5% or greater, although this threshold may be higher in other regions, such as Europe.

Risk Management

Male carriers of BRCA1 PV carriers have an estimated 3.8-fold and 1.9-fold increased risk of developing prostate or pancreatic cancer, respectively, vs noncarriers. The absolute lifetime risk ranges from 15% to 45% for prostate cancer, 3% for pancreatic cancer, and up to 1.2% for breast cancer. Additionally, patients with both Helicobacter pylori (H. pylori) infection and BRCA1/2 PVs have a 45% lifetime cumulative risk of gastric cancer, with a greater effect in BRCA2 PV carriers.

The risk of developing prostate or pancreatic cancers for BRCA2 PV carriers increases 4.7- to 8.6-fold and 3.0- to 7.8-fold, respectively, vs noncarriers. Absolute lifetime risks for these patients are up to 60% (95% CI, 43%-78%) and up to 7%, respectively. The lifetime incidence of breast cancer is low in males (1 in 833), but the risk of developing breast cancer is 7% to 9% in male carriers of BRCA2 PVs.

Prostate Cancer

Data from studies such as the Consortium of Investigators of Modifiers of BRCA1 and BRCA2 indicate a 27% (95% CI, 21%-35%) lifetime risk of developing prostate cancer for BRCA2 PV carriers. Moreover, prior research has shown a substantial enrichment for BRCA1/2 PVs in metastatic vs localized prostate cancer, which is even higher vs healthy controls. These findings underline the significant role these variants play in both tumorigenesis and metastatic potential.

This heightened risk has led to targeted prostate cancer screening strategies, such as those evaluated in the ongoing observational IMPACT study (NCT00261456). Data from IMPACT have shown that BRCA2 PV carriers have a higher positive predictive value for prostate biopsy and a greater likelihood of intermediate- or high-risk disease detection compared with noncarriers. Similar trends were observed for BRCA1 PV carriers, with less pronounced differences.

Based on these results, national and international guidelines recommend that male BRCA2 PV carriers begin PSA screening between ages 40 and 45 years; recommendations for BRCA1 PV carriers vary due to lower levels of evidence. Longer follow-up data from IMPACT are anticipated, and additional clinical trials are needed to further refine screening guidelines.

Pancreatic Cancer

Notably, the risk of developing pancreatic cancer in carriers of BRCA1/2 PVs increases significantly after 50 years of age. As there is high morbidity and mortality associated with pancreatic cancer, screening programs have been developed for these individuals. Guidelines from professional societies, including the American Society for Gastrointestinal Endoscopy, American Gastroenterological Association, and the Cancer of the Pancreas Screening Study consortium, suggest starting pancreatic cancer screening at age 50 years or 10 years before the youngest pancreatic cancer diagnosis in the family. However, consensus on screening specifics is lacking, and most guidelines recommend screening only for individuals with a close relative diagnosed with pancreatic cancer on the side of the family harboring BRCA1/2 PVs. However, basing eligibility for screening on family history can be limited by unknown family history, small family size, and early death from other causes that may obscure pancreatic cancer risk. As such, other guidelines advocate for offering pancreatic cancer screening regardless of family history.

Screening typically involves annual imaging with endoscopic ultrasonography (EUS) or MRI of the abdomen. Recent data indicate that EUS may be more effective for detecting solid pancreatic lesions. Additional monitoring for new-onset diabetes can complement imaging, as this may signal the development of pancreatic cancer.

Screening should be limited to patients who would be candidates for curative surgery if a high-risk lesion is found. The decision to screen should involve thorough discussions of risks, costs, and benefits, and patients should be aware that incidental findings, such as cysts, are common. When possible, screening should be conducted within clinical trials to refine approaches.

Breast, Gastric, and Other Cancers

Current guidelines for male carriers recommend breast awareness and self-examination starting at age 35 years, with annual clinical breast examinations also beginning at age 35 years. For BRCA2 PV carriers, annual mammograms are recommended starting at age 50 years or 10 years before the earliest male breast cancer diagnosis in the family. European guidelines align with these recommendations but allow for either mammography or ultrasonography. Adherence to screening recommendations among BRCA1/2 PV carriers has been reported at 71%, and mammography detection rates are comparable with those in females, supporting its value.

Although there is a lack of formal screening guidelines for BRCA1/2-mutant gastric cancer, baseline H. pylori testing and concurrent endoscopic evaluation during pancreatic cancer screening should be considered, especially in patients with H. pylori prevalence or a family history of gastric cancer.

As there is inconsistent evidence regarding the association between BRCA1/2 PVs and other cancers, the relative risk of BRCA1/2 PV carriers developing these cancers is not definitively high enough to adjust cancer screening practices in the presence of BRCA1/2 PVs alone. For instance, no increased risk for melanoma has been established for patients with BRCA1 PVs, and there are conflicting data for BRCA2. Additionally, the risk of colorectal cancer is not significantly elevated with BRCA1/2 PVs. Therefore, screening for these tumor types should follow general guidelines, as informed by personal and family history.

Treatment Implications

The role of genetic testing has expanded due to the development of novel therapies for carriers of BRCA1/2 PVs. PARP inhibitors, which were initially approved by the FDA for ovarian cancer, have since gained approvals for other BRCA1/2-associated cancers and earlier disease stages.

In metastatic castration-resistant prostate cancer, PARP inhibitors such as olaparib (Lynparza) and rucaparib (Rubraca) have improved overall survival (OS) and progression-free survival (PFS) in phase 3 trials. Recent FDA approvals include PARP inhibitor and androgen receptor signaling inhibitor combinations, which enhance radiographic PFS and OS. Platinum-based chemotherapies have traditionally had a limited role in prostate cancer, though they are increasingly being utilized in BRCA1/2-deficient tumors.

For BRCA1/2 PV carriers with pancreatic cancer who have not progressed on first-line platinum chemotherapy, maintenance therapy with PARP inhibitors is a standard of care. Retrospective data indicate that these patients may respond better to chemotherapy vs non-carriers.

In high-risk breast cancer, adjuvant olaparib demonstrated benefits in disease-free survival and OS for patients with ERBB2-negative disease in the phase 3 OlympiA trial (NCT02032823). PARP inhibitors are also FDA approved for the treatment of patients with HER2-negative metastatic breast cancer, with ongoing trials exploring their use in earlier stages and in combination with other agents.

Clinical Trials Aiding Earlier Detection

Awareness of ongoing trials and emerging technologies is vital for improving cancer detection and management in male carriers of BRCA1/2 PVs. Several ongoing early-detection clinical trials are available for male carriers of BRCA1/2 PVs across North America, including IMPACT and the observational PATROL (NCT04472338), observational PROGRESS (NCT05129605), phase 3 CAPS5 (NCT02000089), PCEDP (NCT02206360), and observational PRECEDE (NCT04970056) studies.

Novel imaging techniques and minimally invasive biomarkers from urine and blood are also under investigation. Multicancer early detection tests, developed by commercial and academic entities, are not yet included in standard guidelines but may offer future benefits. These tests should be considered in clinical trials and used to supplement, not replace, standard screening.

Research on the utility of polygenic risk scores, which aggregate common genetic variants to estimate cancer risk, is being conducted for male patients with prostate, pancreatic, and breast cancers. However, their clinical utility for modifying management approaches based on BRCA1/2 PV status is not well established outside of a clinical trial setting.

Other considerations when identifying and addressing testing disparities for male carriers of BRCA 1/2 PVs include addressing barriers to testing and cascade testing, how family planning and a preimplantation genetic diagnosis may lead to earlier testing, and general challenges incorporating genetic testing into clinical practice.

Reference

Cheng HH, Shevach JW, Castro E, et al. BRCA1, BRCA2, and associated cancer risks and management for male patients: a review. JAMA Oncol. Published online July 25, 2024. doi:10.1001/jamaoncol.2024.2185