BRCA1, BRCA2 and Associated Cancer Risks and Management for Males: A Review

Abstract

Importance:

Half of all carriers of inherited cancer-predisposing mutations in BRCA1 and BRCA2 are males, but the implications for their health are under-recognized compared to females. Germline mutations in BRCA1 and BRCA2 (also known as “pathogenic or likely pathogenic variants,” referred to here as BRCA1/2 PV) are well known to significantly increase the risk of breast and ovarian cancers in female carriers, and knowledge of BRCA1/2 PV informs established cancer screening and options for risk-reduction. While risks to male carriers of BRCA1/2 PV are less characterized, there is convincing evidence of increased risk for prostate cancer, pancreas cancer and breast cancer. There has also been rapid expansion of FDA-approved targeted cancer therapies—poly ADP-ribose polymerase (PARP) inhibitors—for breast, pancreas and prostate cancers associated with BRCA1/2 PV.

Observations:

In this narrative review, we summarize data informing cancer risks, targeted cancer therapy options, and guidelines for early cancer detection, and highlight areas of emerging research and clinical trial opportunities for male BRCA1/2 PV carriers. These developments, along with the continued relevance to family cancer risk and reproductive options, have informed changes to guideline recommendations for genetic testing and make a strong case for increased genetic testing for males.

Conclusions and Relevance:

Despite increasing clinical actionability for male carriers of BRCA1/2 PV, far fewer males than females undergo cancer genetic testing. Oncologists, internists and primary care clinicians should be alert to offering genetic testing to appropriate males. Identifying more male carriers of BRCA1/2 PV 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.

SOCIAL MEDIA POST

Half of people with inherited BRCA1/2 mutations are men, yet very few men are offered genetic testing or know the importance to their own health. We cover updated data and screening recommendations aimed to help men and their doctors take action and reduce their risk of cancer.

INTRODUCTION

In the 1990s, inherited (i.e. germline) loss-of-function mutations in BRCA1 or BRCA2, (interpreted as pathogenic or likely pathogenic variants by the American College of Medical Genetics, and henceforth referred to as BRCA1/2 PV),¹ were linked to familial predisposition to early-onset breast and ovarian cancers.^2–4 In the ensuing decades, studies demonstrated the clinical utility of early detection and risk reduction strategies for breast and ovarian cancer in female carriers of BRCA1/2 PV. Within this population, there is a substantial mortality benefit and risk reduction of breast and ovarian cancers through salpingo-oophorectomy.⁵ Moreover, poly ADP-ribose polymerase inhibitors (PARPi)—confer mortality benefit in patients with high-risk, early breast cancer and advanced ovarian cancer.^6–9 These findings have led to robust clinical guidelines for female carriers of BRCA1/2 PV, although challenges remain in improving genetic testing and ensuring equitable access for carrying out management recommendations.¹⁰

A widely overlooked group are male carriers of BRCA1/2 PV who are also at increased risk of developing cancer: particularly of the prostate, pancreas and breast. Males represent half of BRCA1/2 PV carriers, but most (along with their health care providers) are unaware of their carrier status, associated cancer risks and management recommendations, or availability of research opportunities. The population prevalence of BRCA1/2 PV carriers is roughly estimated around 1 in 250 with variance depending on specific ancestries.¹¹ The proportion with/without cancer is unknown since males have undergone cancer-specific genetic testing at one-tenth the frequency of females (RR 0.10; 95% CI: 0.05 – 0.23)¹². Patients with prostate cancer, the most common of the cancers linked with increased risk, have been far less likely to undergo genetic testing (1%) compared to patients with breast and ovarian cancer (52.3%).¹³ These differences have been attributed to a variety of causes including: lack of inclusion in national guidelines (e.g. USPSTF), less education and outreach, underrepresentation in studies of informational needs in families, and broader sex differences in health-seeking behaviors.^{14–17 18,19}

Based on emerging cancer-specific risk estimates in male carriers of BRCA1/2 PV along with treatment implications, key professional societies have updated their guidelines.^20,21 However, locating these guidelines is cumbersome as they are in disparate places and buried within guidelines for female at-risk carriers, organ-site specific guidelines, or cancer-focused guidelines. We sought address this by compiling a comprehensive reference.

In this review, “males” refers to individuals assigned male sex at birth, regardless of gender identity. While limited evidence suggests that hormonal therapies used by transgender women may affect cancer risk, at present transgender women and gender neutral/gender-fluid carriers of BRCA1/2 PV are recommended to undergo individualized cancer screening based on sex-specific organs.²²

DISCUSSION/OBSERVATIONS

CLINICAL PRESENTATION, ASSESSMENT & DIAGNOSIS

Identifying Males with BRCA1/2 PV: Family History Indications for Genetic Testing

Males unaffected by cancer may meet criteria for genetic testing if they have blood relative(s) affected by a qualifying cancer or meet other criteria (Table 1). It is important to collect family history on both maternal and paternal sides of the family, and to inquire broadly about cancer types including breast, ovary, prostate and pancreas, and, if known, approximate age at diagnoses and whether cancer was lethal. Certain cancer subtypes, such as acinar pancreas cancer and triple negative breast cancer, are additional risk factors for hereditary cancer.^23,24 These considerations apply to patients of all ancestries, not only to those for which increased risks due to BRCA1/2 PV have been better characterized (e.g. European or Ashkenazi Jewish). Inquiring about any known familial cancer risk gene is also important.

Table 1.

Clinical indications for genetic counseling and testing for BRCA1/2 PV in males^a

Personal History of Cancer Criteria (any one is sufficient without needing additional family history criteria)  • male breast cancer  • pancreas cancer  • prostate cancer that is high risk localizedb (≥cT3a, Gleason sum ≥8, Grade Group ≥4, PSA ≥20 ng/mL), lymph node positive or metastatic

Family History of Cancer Criteria  • There is a familial BRCA1/2 PV mutation (pathogenic variant)  • There is a family history of any male breast cancer, any pancreas cancer, or prostate cancer that is high risk localizedb (cT3a, Gleason sum ≥8, Grade Group ≥4, PSA ≥20 ng/mL), node positive or metastatic)  • There is a family history of early (diagnosed <50y) or triple-negative breast cancer, or multiple primary breast cancers and/or a history of ovarian cancer in close female relatives (first or second-degree)  • There is a family history of exocrine pancreas cancer in a first-degree relative  • The family is of Ashkenazi Jewish ancestry

Abbreviations: PV = pathogenic variant; PSA = prostate specific antigen;

^a These reflect the minimum criteria for considering genetic counseling and testing for BRCA1/2 PV, and should not be considered comprehensive criteria for all cancer predisposition testing. Recommend a genetic counseling referral if there are questions.

^bNCCN risk-group criteria

Identifying Males with BRCA1/2 PV: Personal Cancer History Indications for Genetic Testing

A thorough family history of cancer is necessary, but not sufficient for identifying some carriers of BRCA1/2 PV. Genetic testing criteria have been in evolution over the last 25 years, and genetic testing is now clinically indicated for males with a personal diagnosis of pancreas adenocarcinoma, breast cancer, or prostate cancer that is high-risk or very-high-risk localized based on National Cancer Center Network (NCCN) classification (defined as PSA>20, Gleason grade 8–10, WHO Grade Group 4–5), node-positive or metastatic.^20,25. These changes have resulted from studies identifying a high prevalence of BRCA1/2 PV among patients with triple negative breast, ovarian, pancreas and aggressive prostate cancer^26,27 There are also expanding indications for poly-ADP ribose polymerase inhibitors (PARPi), a class of targeted cancer therapies, for patients with ovarian, breast, pancreas and prostate cancers who carry BRCA1/2 PV.^6–8,28,29.

Published findings on the prevalence of genetic PVs in prostate, pancreas and male breast cancers gleaned from historic studies (prior to broader cancer-directed genetic testing) should be viewed with caution as testing criteria at the time relied exclusively on family history of breast/ovarian cancer without accounting for prostate, pancreas, male breast or other cancers. Another major limitation is that current data is largely derived from cohorts that are overwhelmingly of European ancestry or enriched for males of Ashkenazi Jewish ancestry, resulting in lack of genetic diversity.³⁰

Identifying Males with BRCA1/2 PV: Other Indications for Genetic Testing

Many cancer survivors may not have been eligible for genetic testing at the time of their cancer diagnosis and treatment but meet current eligibility criteria and should be offered testing. In addition, genetic testing performed over a decade ago may have missed BRCA1/2 PV identifiable on current tests. Finally, an increasing number of male BRCA1/2 PV carriers may be identified outside of traditional diagnostic pathways; for example, through prenatal testing, direct-to-consumer testing, and/or matched tumor-normal genetic testing after a cancer diagnosis. Indeed, multiple studies have reported that tumor sequencing can identify germline findings that would be missed by family history criteria^31–33.

Identifying Males with BRCA1/2 PV: Options for Genetic Testing

There are now increasing options for people to undergo genetic testing—in some cases patients have sought testing, or testing can be initiated by a primary care clinician or subspecialist, with support from genetic counselors and other cancer genetics experts. The current genetic counseling workforce cannot meet the demand for their services in most clinical settings, and there is active research investigating new strategies for genetics care delivery through new technologies to improve access and reduce disparities.^34–36 The variation in resources between clinical practice settings will require individualized workflows that can accommodate different patient needs: additional pre-test counseling, post-test counseling after identification of pathogenic variants, and/or assistance with testing relatives (i.e. cascade genetic testing). Ideally, genetic testing can identify carriers of BRCA1/2 PV before, or soon after, a cancer diagnosis to enable earlier detection of cancers and better treatment outcomes.

Algorithms for identifying BRCA1/2 PV carriers

Given the limitations discussed above, existing algorithms estimating the risk of carrying a BRCA1/2 PV that are reliant on family history of breast and ovarian cancers have less value for males.³⁷ However, if the model-derived likelihood for carrying a BRCA1/2 PV is ≥5 %, individuals in the U.S. are recommended for testing while thresholds may differ in other jurisdictions (e.g. higher in Europe).^38,39

RISKS and MANAGEMENT

Prostate Cancer-specific Risks and Clinical Recommendations for Males with BRCA1/2 PV

Male carriers of BRCA1/2 PV are at increased risk of developing prostate cancer compared to their non-carrier counterparts, with the risk from BRCA2 PV being higher. Carrying a BRCA1 PV has been estimated to confer up to a 3.8-fold increased risk of prostate cancer, and absolute lifetime risk of 15–45% (Table 2).^40,41 From a cohort of known BRCA1/2 PV carriers, a BRCA2 PV is estimated to confer a 4.7- to 8.6-fold increased risk of prostate cancer, and absolute lifetime risk of 60% (95% CI: 43–78%).⁴⁰ A retrospective analysis of families recruited based on family history of breast and ovarian cancer (CIMBA) also estimated an increased risk, albeit with a notably lower absolute lifetime risk of ~27% (95% CI: 21–35%) for BRCA2 PV carriers (Table 2).⁴² Studies of metastatic prostate cancer reveal a substantial enrichment for BRCA1/2 PV compared to localized prostate cancer and even more compared to healthy controls, indicating a contribution to both prostate tumorigenesis and to metastatic potential.^27,43,44 Taken together, these and other data are the basis for considering males who carry BRCA1/2 PV at particularly high risk for aggressive prostate cancer, although precise risk estimates for the general population of BRCA1/2 PV carriers are limited.

Table 2:

Published Cumulative Cancer Risk Estimates for Male BRCA1/2 PV Carriers (%)

	Age (y)	BRCA2		BRCA1
		Nyberg et al.40	Li et al.42	Nyberg et al.40
Prostate Cancer	50	5 (2–14)	0.2 (0.2–0.3)	4 (0.9–13)
	60	10 (5–21)	3 (2–4)	10 (5–20)
	70	27 (17–41)	13 (9–17)	21 (13–34)
	80	60 (43–78)	27 (21–35)	29 (17–45)
	Age (y)	BRCA2		BRCA1
		Li et al.42	van Asperen et al.48	Li et al.42
Pancreas Cancer	50	0.2 (0.1–0.3)	0.3 (0–1)	0.1 (<0.1–0.2)
	60	0.9 (0.5–1.4)	1 (0–3)	0.4 (0.3–0.7)
	70	2 (1–3)	4 (1–7)	1 (0.8–2)
	80	3 (2–5)	7 (4–10)	3 (2–5)
	Age (y)	BRCA2		BRCA1
		Tai et al.64	Li et al.42	Tai et al.64	Li et al.42
Male Breast Cancer	30	0.2 (<0.1–0.9)	NA	<0.1 (<0.1–0.1)	NA
	40	1 (0.3–4)	NA	0.1 (<0.1–0.6)	NA
	50	3 (1–7)	0.2 (0.1–0.5)	0.3 (<0.1–1)	<0.1 (0-<0.1)
	60	5 (2–10)	0.7 (0.4–1.5)	0.6 (0.1-?)	<0.1 (<0.1–0.3)
	70	7 (3–12)	2 (1–4)	1 (0.2–3)	0.2 (<0.1–0.7)
	80	8 (4–15)	4 (2–8)	2 (0.3–5)	0.4 (0.1–1.5)

Abbreviations: NA = not applicable; PV = pathogenic variant

IMPACT (Identification of Men with a genetic predisposition to Prostate Cancer: Targeted screening) is an ongoing international study designed to assess targeted prostate cancer screening for male carriers of BRCA1/2 PV compared to non-carriers (clinicaltrials.gov; NCT00261456). The screening strategy was annual prostate specific antigen (PSA) measurement and prostate biopsy for PSA >3.0 ng/mL. After four screening rounds, the positive predictive value (PPV) for biopsy was higher in BRCA2 PV carriers vs non-carriers (39% vs 28%), and a significant difference was observed in detecting intermediate-or high-risk disease (77% vs 40%)⁴⁵. Similarly, the PPV for biopsy was higher in BRCA1 PV carriers vs non-carriers (32% vs 20%), although no significant difference was observed in detecting intermediate- or high-risk disease. Longer follow-up is anticipated and important questions remain, such as whether PSA >3.0 ng/mL is the optimal threshold for biopsy for males with BRCA1/2 PV at all ages.

Based on the IMPACT results, national/international guidelines recommend male BRCA2 PV carriers begin PSA screening at age 40–45y, although there is discordance about intervals: annual vs every two-years (Table 3). The considerations for BRCA1 PV carriers also varies, reflecting the lower level of evidence and lower estimated risk.^20,46,47 To help define better approaches, BRCA1/2 PV carriers considering prostate cancer screening should be encouraged to do so in the context of a screening clinical trial whenever possible (Table 4).

Table 3.

Guideline-Recommended Management for Male BRCA1/2 PV Carriers

Cancer	Society/Panel	Screening Recommendations	Concordance between Guidelines	Discordance between Guidelines
Prostate	NCCN 20	Recommends annual screening for carriers of BRCA2 PV with a PSA blood test starting at age 40. Consider annual screening for carriers of BRCA1 PV with a PSA blood test starting at age 40.	All societies/panels recommend carriers of BRCA2 PV be offered screening with PSA blood test, starting at age 40–45y	BRCA2 PV vs BRCA1 PV: NCCN and ESMO both recommend screening in carriers of BRCA2 PV. ESMO does not include carriers of BRCA1 PV in recommendation for, while NCCN offers a weaker “consider” recommendation for carriers of BRCA1 PV. The AUA/SUO guidelines do not make a distinction between carriers of BRCA1 PV vs. BRCA2 PV. PSA screening interval: AUA/SUO recommend screening every 2–4 years, in contrast to yearly screening recommended by NCCN and ESMO.
	ESMO 21	Screening should be offered to carriers of BRCA2 PV with annual PSA blood test starting at age 40.
	AUA/SUO 47	Screening should be offered to carriers of BRCA1/2 PV with PSA blood test starting at age 40 to 45 every 2–4 years.
Pancreas	NCCN 20	Screening may be considered in carriers of BRCA1/2 PV who also have a first- or second-degree relative with a history of pancreas cancer, starting at age 50, or 10 years before the earliest known pancreas cancer in the family. Screening may be performed contrast-enhanced abdominal MRI and/or endoscopic ultrasound.	All societies/panels recommended consideration of screening for pancreas cancer in eligible carriers of BRCA1/2 PV starting at age-50, or 10 years before the earliest known pancreas cancer in the family. All societies/panels recommended contrast-enhanced abdominal MRI and/or endoscopic ultrasound as screening modalities.	Family history of pancreas cancer: Both NCCN and ESMO restrict recommendations to individuals who carry a BRCA1/2 PV, and also have a first- or second-degree relative with a history of pancreas cancer. CAPS Consortium and AGA restricts to individuals who carry a BRCA1/2 PV and also have a first-degree relative with a history of pancreas cancer. ASGE does not distinguish based on family history of pancreas cancer among carriers of BRCA1/2 PV. Measures of pancreatic function: CAPS also recommends a yearly assessment of insulin resistance with either HbA1c and/or fasting blood glucose.
	ESMO 21	Screening may be considered in carriers of BRCA1/2 PV who also have a first- or second-degree relative with a history of pancreas cancer, starting at age 50, or 5–10 years before the earliest known pancreas cancer in the family. Screening may be performed contrast- enhanced abdominal MRI and/or endoscopic ultrasound. Recommend screening be carried out as part of a clinical trial.
	ASGE 53	Suggests annual screening for carriers of BRCA1/2 PV at age 50, or 10 years before the earliest known pancreas cancer in the family. Screening may be performed contrast-enhanced abdominal MRI and/or endoscopic ultrasound.
	AGA 52	Consider annual screening for carriers of BRCA1/2 PV who also have a first-degree relative with a history of pancreas cancer, starting at age 50, or 10 years before the earliest known pancreas cancer in the family. Screening may be performed contrast-enhanced abdominal MRI and/or endoscopic ultrasound.
	CAPS 50	Recommends screening in carriers of BRCA1/2 PV who also have a first-degree relative with a history of pancreas cancer, starting at age 45 to 50, or 10 years before the earliest known pancreas cancer in the family. Screening may be performed contrast-enhanced abdominal MRI and/or endoscopic ultrasound as well as fasting blood glucose and/or HbA1c.
Breast	NCCN 20	Breast self-exam training, education and yearly clinical breast exam starting at age 35. Consider annual mammogram at age 50 or 10 years before the earliest known male breast cancer in the family.	Both societies/panels recommend consideration of screening in male carriers of BRCA2 PV starting at age 50 or 10 years before the earliest known male breast cancer in the family. Both societies/panels recommend annual mammogram as an acceptable screening modality. Both societies/panels emphasize patient education and awareness regarding their breast tissue and any changes patients may experience.	BRCA2 PV vs BRCA1 PV: NCCN recommends consideration of screening for males who carry BRCA1/2 PV—though places more emphases on BRCA2—while ESMO solely focuses on BRCA2. Additional breast imaging option: ESMO also considers breast ultrasonography as a method of radiologic screening, while NCCN limits screening recommendations to mammography.
	ESMO 21	In carriers of BRCA2 PV, Consider annual mammogram or at age 50 or 10 years before the earliest known male breast cancer in the family. Male carriers of BRCA2 PV should be aware of changes in their breast and seek medical attention when necessary.

Abbreviations: AGA = American Gastroenterological Association; ASGE = American Society of Gastrointestinal Endoscopy; AUA = American Urological Association; CAPS = International Cancer of the Pancreas Screening Consortium; ESMO = European Society of Medical Oncology; HbA1c = glycosylated hemoglobin; MRI = magnetic resonance imaging; NCCN = National Comprehensive Cancer Network; PV = pathogenic variant; PSA = prostate specific antigen; SUO = Society of Urologic Oncology Note: Carriers of BRCA1/2 PV should be screened for other cancers (colorectal, lung, skin cancers, etc.) according to standard population-based and individual risk-based criteria (family history, smoking, etc).

Table 4.

Ongoing Cancer Early Detection Clinical Trials in the U.S. for BRCA1/2 PV carriers

Prostate Cancer	clinicaltrials.gov
The IMPACT Study - Identification of Men With a Genetic Predisposition to ProstAte Cancer (multi-site)	NCT00261456
Men at High Genetic Risk for Prostate Cancer (National Cancer Institute)	NCT03805919
Prostate Screening Study Using MRI in BRCA Carriers (Toronto Sunnybrook Regional Cancer Centre)	NCT01990521
Prostate Screening for Men With Inherited Risk of Developing Aggressive Prostate Cancer, PATROL Study (multi-site)	NCT04472338
Prostate Cancer Genetic Risk Evaluation and Screening Study, PROGRESS (Massachusetts General)	NCT05129605
MRI Screening in Men at High Risk of Developing Prostate Cancer (University of Chicago)	NCT05608694
Pancreas Cancer	clinicaltrials.gov
CAPS5: The Cancer of the Pancreas Screening-5 Study (multi-site)	NCT02000089
PCEDP: Pancreatic Cancer Early Detection Program (White Plains Hospital)	NCT02206360
Preliminary Evaluation of Screening for Pancreatic cancer in Patients with Inherited Genetic Risk (University of Pennsylvania)	NCT02478892
A Pancreatic Cancer Screening Study in Hereditary High Risk Individuals (Western Connecticut Health Network)	NCT03250078
PRECEDE: Pancreatic Cancer Early Detection Consortium (multi-site)	NCT04970056
Pancreas Scan: Pancreatic Cancer Screening for At-risk Individuals (multi-site)	NCT05006131
Pilot Study of Pancreatic Cancer Screening (University of California, San Francisco)	NCT05058846
A Registry for BRCA Mutation Carriers With Pancreatic Ductal Adenocarcinoma (Memorial Sloan Kettering)	NCT01983410

Pancreas Cancer-specific Risks and Clinical Recommendations for Males with BRCA1/2 PV

Carriers of BRCA1 PV have a 1.9-fold increased risk of pancreas cancer compared to the general population, with a lifetime risk of pancreas cancer of 3%.⁴² Carriers of BRCA2 PV have a 3.0- to 7.8-fold increased risk of developing pancreas cancer, and a lifetime risk of up to 7%.^42,48,49 Importantly, the excess risk of pancreas cancer in carriers of BRCA1/2 PV increases significantly after the age of 50. Given the substantial morbidity and mortality associated with pancreas cancer, pancreas screening programs have been developed for BRCA1/2 PV carriers.

Many professional society guidelines suggest that pancreas cancer screening for BRCA1/2 PV carriers can be initiated at age 50, or 10 years prior to the youngest age of pancreas cancer diagnosis in the family, although there is lack of consensus on the specifics of screening (Table 3). ^{20,21,50–53} Most guidelines recommend offering screening only to individuals with pancreas cancer in a close relative from the side of the family with the BRCA1/2 PV.^20,21,50,52 How family history of pancreas cancer impacts pancreas cancer risk for BRCA1/2 PV carriers remains uncertain,⁴⁹ and basing eligibility for screening on family history has limitations, especially when family history is unknown, family size is small, and when early death from other causes may obscure pancreas cancer risk.^54,55 Other guidelines advocate for offering pancreas cancer screening independent of family history.⁵³

If pancreas cancer screening is undertaken, centers have used annual imaging with either an endoscopic ultrasound (EUS) or MRI of the abdomen with and without IV contrast. While a recent meta-analysis showed similar performance characteristics for both in detection of early-stage pancreas cancer⁵⁶, more recent data suggests EUS may be more effective in identifying solid lesions of the pancreas.⁵⁷ The decision to use EUS or MRI for screening in BRCA1/2 PV carriers is often multi-faceted, considering factors such as the need for other endoscopic or imaging procedures (i.e. pairing EUS with colonoscopy), anatomic constraints (i.e. altered upper GI anatomy preventing EUS visualization of the pancreas), local expertise and availability of EUS/MRI, and/or patient preference. Monitoring for development of new onset diabetes mellitus (DM) with annual hemoglobin A1C or fasting glucose can also be considered, since new onset DM may signal developing pancreas cancer, and warrant more attentive screening.⁵⁸ However, DM monitoring should only be used to complement imaging rather than to replace it. Some studies, but not all, have found pancreas cancer screening leads to downstaging of screen-detected pancreas cancer in high-risk individuals and increased long-term survival.^59,60 In the CAPS5 study, out of 1,461 high-risk individuals screened, invasive pancreas cancer was detected in 0.7% of individuals.⁵⁹

Importantly, since the goal of pancreas cancer screening is to identify high-risk pancreatic lesions amenable to curative intent surgical excision, screening should typically only be offered to patients who would be surgical candidates if a high-risk lesion is identified. The risks/costs vs benefits of pancreas cancer screening should be discussed in-depth prior to embarking on screening, and patients should be counseled that incidental findings in the pancreas, including cysts, are found in approximately one third of screening participants.^54,61,62 To help define better approaches, BRCA1/2 PV carriers considering pancreas screening should be encouraged to do so in the context of a screening clinical trial whenever possible (Table 4).

Breast Cancer-specific Risks and Clinical Recommendations for Males with BRCA1/2 PV

While the lifetime incidence of breast cancer is low in males (1 in 833), the risk can be as high as 7–9% in male carriers of BRCA2 PV.^63,64,65 Male BRCA1 carriers have an estimated lifetime risk of up to 1.2% of developing breast cancer. There is limited data to guide breast screening, although data showing younger age of diagnosis, higher tumor grade⁶⁶, increased risk of axillary node positive disease, and potentially decreased survival in male BRCA carriers suggest screening may be of benefit.^64,67,68 NCCN guidelines recommend: breast awareness and self-exam teaching at age 35, annual clinical breast exams starting at age 35, and consideration of annual mammogram for BRCA2 PV carriers starting at age of 50, or 10 years before the age of the earliest male breast cancer diagnosis in the family.²⁰ ESMO guidelines recommend similar age to start screening, although allows for either annual mammogram or ultrasound.²¹ Of note, gynecomastia has not been shown to increase risk of breast cancer in males and is not a requirement for screening.^20,21 A recent study of male carriers of BRCA1/2 PV reported that while breast cancer screening recommendations varied, adherence was 71% (10/14) among those who were recommended to undergo screening mammography⁶⁹. Further, screening mammography in high-risk males has been shown to yield a similar cancer detection rate in males as in females, suggesting mammography screening may be valuable in male BRCA carriers⁷⁰.

Gastric Cancer-specific Risks and Clinical Recommendations for Males with BRCA1/2 PV

Studies have demonstrated an excess risk of gastric cancer in carriers of BRCA1/2 PV.^42,71,72 Usui et al. recently reported a strong interaction between Helicobacter pylori (H. pylori) infection and BRCA1/2 PV, finding that patients with both had a 45% lifetime cumulative risk of gastric cancer, with a greater effect seen in BRCA2 PV carriers.⁷² These studies may be confounded by variance in regional prevalence of H. pylori and potential misassignment of gastric cancer (vs advanced ovarian cancer). 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. If a BRCA1/2 PV carrier opts for pancreas cancer screening and undergoes EUS, concurrent endoscopic evaluation of gastric mucosa for gastric neoplasia should be considered.⁷³

Other Cancer-specific Risks and Clinical Recommendations for Males with BRCA1/2 PV

Some cancers have inconsistently been reported to have modest association with BRCA1/2 PV. The observed potential associations may result from ascertainment bias due to increased multi-gene panel testing in people affected by cancers associated with non-BRCA1/2 PV cancer syndromes. While these cancers can occasionally be observed in true association with BRCA1/2 PV, the relative risk of BRCA1/2 PV carriers developing these cancers has not been established to be sufficiently high to support modifying cancer screening due to BRCA1/2 PV alone. For example, no studies have shown an increased risk of melanoma or skin cancers with BRCA1, and there are conflicting data regarding the risk of BRCA2 and melanoma along with other skin cancers.^74,75 In a study of cancer types not recognized in association with BRCA1/2 PV, melanoma tumorigenesis appeared to be independent of the BRCA1/2 PV.⁷⁵ Thus, it is reasonable to follow population screening guidance and consider annual skin exam if there is a family history of melanoma. For colorectal cancer, studies carried out without ascertainment bias find no increased risk of colon cancer associated with BRCA1/2 PV.^76–78 PVs in other genes (e.g. Lynch Syndrome) can increase risk of colon cancer. Therefore, colorectal cancer screening should be considered independent of BRCA1/2 PV status and be informed by personal and family history—consistent with American Gastroenterological Association guidelines⁷⁹.

Treatment implications for cancers in males with cancer and BRCA1/2 PV

An increasing role for genetic testing is the expanding indications for life-prolonging therapies approved for patients with BRCA1/2 PV-associated cancers, which are sensitive to DNA damage by platinum-based chemotherapy and PARPi.⁸⁰ PARP inhibitors as a class gained initial FDA-approval for third- and subsequent line treatment for BRCA1/2 PV-associated ovarian cancer, followed by maintenance therapy in advanced ovarian cancer, paving the way for subsequent approvals for other BRCA1/2 PV-associated cancers and in earlier disease settings. ^8,9,81–83

In patients with metastatic castration-resistant prostate cancer (mCRPC)—the latest stage of disease—who are carriers of BRCA1/2 PV, PARPis have been shown in phase III trials to improve overall survival (olaparib) and PFS (olaparib, rucaparib).^28,29. Additionally, PARPi and androgen receptor signaling inhibitor combinations (niraparib/abiraterone, talazoparib/enzalutamide, olaparib/abiraterone) have recently been FDA-approved for biomarker-selected patients with mCRPC due to improved radiographic PFS and OS.^84–88 Importantly, while platinum chemotherapies are frequently used in ovarian, pancreas and breast cancers, they have historically had a limited role in prostate cancer, but are also an option for advanced prostate cancer patients with BRCA1/2 deficiency.^89,90

For patients with BRCA1/2 PV and pancreas cancer that has not progressed on first-line platinum chemotherapy, maintenance PARPi can be considered.^91–93 Retrospective data suggests that patients with pancreas cancer who carry BRCA1/2 PV may have better responses to platinum-based chemotherapy in the first-line setting compared to their non-carrier counterparts.^94,95

In patients with high-risk breast cancer who carry BRCA1/2 PV, adjuvant olaparib has demonstrated disease-free and OS benefits among patients with HER2-negative disease in OlympiA trial.^6,7 PARPis are also FDA-approved in the HER2-negative metastatic breast cancer setting based on OlympiAD and EMBRACA.^96–99

Ongoing therapeutic clinical trials are testing use of PARPi in earlier cancer settings and in combination with other agents, while also developing novel targeted therapies for patients whose cancers are associated with BRCA1/2 PV.

Clinical Trials of Early Cancer Detection

A number of early detection clinical trials are available for male BRCA1/2 PV carriers of (Table 4). These trials seek to improve management and optimize screening and risk reduction interventions for at-risk people. Better awareness of available options for tailored management approaches for BRCA1/2 PV carriers as well as opportunities to explore novel early cancer detection approaches and interception strategies may provide further motivation for males to consider genetic testing.

Other Investigational Screening Strategies

There is keen interest in new technologies that may improve early cancer detection, including novel imaging approaches and minimally invasive circulating biomarkers, e.g. from urine and blood. Among these are multicancer early detection tests (MCED), which are being developed by commercial companies and academic laboratories. To date, none have established clinical utility and therefore are not included in current recommended guidelines or standard of care. Pending better understanding of performance characteristics and clinical utility, these tests should be undertaken as part of prospective clinical trials when possible. At most, they should supplement—but not replace—standard screening tests.

Attention has been given to polygenic risk scores (PRS), which combine common genetic variants found in all individuals (not just those at high risk) into a single continuous variable intended to quantify genetic risk of cancer. PRS have historically been studied largely in European populations, and non-cancer PRS have conflated environmental and social risk factors with biological risk of disease.^100,101 While PRS is being studied for prostate, pancreas and male breast cancers, ¹⁰² there remains no established clinical utility for modified management of BRCA1/2 PV status based on PRS outside of research trials.

Other Considerations

Additional key considerations for identifying and caring for male carriers of BRCA1/2 PV and reviewed elsewhere include genetic testing implementation challenges ^103,104, strategies to overcome to barriers to testing and cascade testing ¹⁰⁵, family planning and pre-implantation genetic diagnosis considerations which may motivate testing at an earlier age¹⁰⁶.

CONCLUSIONS

Males who carry BRCA1/2 PV are at increased risk for prostate cancer, pancreas cancer and breast cancer. Despite the increasing clinical actionability, males are currently much less likely to be offered or complete genetic testing, resulting in lost opportunities to impact health ^15,107. Identifying more male carriers of BRCA1/2 PV 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.