BRCA2 and prostate cancer

The evidence base suggests a more pronounced increased risk of prostate cancer associated with mutations of the BRCA2 gene than the BRCA1 gene. The evidence is reviewed below:

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)

Cheng et al note that males who carry BRCA1/2 PV (pathogenic or likely pathogenic variants) are at increased risk for prostate cancer, pancreas cancer and breast cancer.

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:

• BRCA1 versus BRCA2 and prostate cancer risk
  • Nyberg et al found that carriers of BRCA2 mutations have a high risk of developing prostate cancer, particularly more aggressive prostate cancer
    • BRCA2 carriers had an SIR (standardised incidence ratio) of 4.45 (95% confidence interval [CI] 2.99-6.61) and absolute prostate cancer risk of 27% (95% CI 17-41%) and 60% (95% CI 43-78%) by ages 75 and 85 yr, respectively
    • BRCA1 carriers had a prostate cancer SIR of 2.35; absolute risk of prostate cance was 21% by age 75 yr and 29% by age 85 yr
  • Li et al showed that BRCA2 variants were associated with increased risk of prostate cancer; but BRCA1 variants were not
  • an evidence-based evaluation of the association of germline pathogenic/likely pathogenic (P/LP) was was conducted using data from the UK Biobank and Johns Hopkins School of Medicine, including 22,052 Pca patients and 191,055 unaffected controls found (9):
    • the analysis and large published studies provide statistical evidence that P/LP mutations in HOXB13, BRCA2, ATM, CHEK2, and MSH2 are associated with PCa risk, with estimated ORs for PCa between 1.81 and 4.05
    • evidence is consistent and strongest for BRCA2, weak for BRCA1
    • demonstrate that P/LP mutations in BRCA2 and ATM are associated with aggressive PCa

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.
7. Nyberg T et al. Prostate Cancer Risks for Male BRCA1 and BRCA2 Mutation Carriers: A Prospective Cohort Study. Eur Urol. 2020 Jan;77(1):24-35.
8. Li S et al. Cancer Risks Associated With BRCA1 and BRCA2 Pathogenic Variants. J Clin Oncol. 2022 May 10;40(14):1529-1541.
9. Xu J et al. Germline Testing for Prostate Cancer Patients: Evidence-Based Evaluation of Genes Recommended by NCCN Guidelines. Prostate. 2025 Sep;85(12):1087-1095