BRCA2 and prostate cancer

Germline mutation of the BRCA2 tumour suppressor gene substantially increases the lifetime risk of developing prostate cancer (PCa)

• in BRCA2-mutation carriers, localized PCa rapidly progresses to metastatic castrate-resistant prostate cancer (mCRPC) with 5-year cancer-specific survival rates of from 50-60% (1,2)
• BRCA2-mutant tumours also exhibit an increased frequency of intraductal carcinoma (IDC), a pathology that predicts adverse outcome in both familial and sporadic PCa (3,4)

Prostate tumours arising in men with an inactivating BRCA2 germline mutation (BRCA2-mutant PCa) are uniquely aggressive, associated with younger age of onset, have higher rates of lymph node and distant metastasis, and increased mortality relative to sporadic, non-BRCA2-mutant disease (2,4,5)

The molecular origins of the clinical aggressiveness of BRCA2-mutant PCa are unknown.

Screening using PSA in patients with BRCA2 (5):

• demonstrated that after 3 yr of prostate-specific antigen (PSA) testing, detected more serious prostate cancers in men with BRCA2 mutations than in those without these mutations.
• study also showed BRCA2 carriers were diagnosed at a younger age (61 vs 64yr; p = 0.04) and were more likely to have clinically significant disease than BRCA2 noncarriers (77% vs 40%; p = 0.01)
• cancer incidence rate per 1000 person years was higher in BRCA2 carriers than in noncarriers (19.4 vs 12.0; p = 0.03)
• no differences in age or tumour characteristics were detected between BRCA1 carriers and BRCA1 noncarriers
• study authors recommended that male BRCA2 carriers are offered systematic PSA screening

Notes:

• evidence supports that pathogenic variants in BRCA1 and BRCA2 lead to increased risk for prostate cancer, pancreatic cancer, and breast cancer in males

Reference:

1. Castro, E. et al. Effect of BRCA mutations on metastatic relapse and causespecific survival after radical treatment for localised prostate cancer. Eur. Urol. 2015; 68:186-193.
2. Castro, E. et al. Germline BRCA mutations are associated with higher risk of nodal involvement, distant metastasis, and poor survival outcomes in prostate cancer. J. Clin. Oncol. 2013; 31: 1748-1757.
3. Risbridger, G. P. et al. Patient-derived xenografts reveal that intraductal carcinoma of the prostate is a prominent pathology in BRCA2 mutation carriers with prostate cancer and correlates with poor prognosis. Eur. Urol. 2015; 67: 496-503
4. Liede, A., Karlan, B. Y. & Narod, S. A. Cancer risks for male carriers of germline mutations in BRCA1 or BRCA2: a review of the literature. J. Clin. Oncol. 2004; 22: 735-742
5. Page EC et al. Interim Results from the IMPACT Study: Evidence for Prostate-specific Antigen Screening in BRCA2 Mutation Carriers. European Journal of Urology (in Press - September 19th 2019)
6. 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