Men with BRCA2 mutations are more likely be diagnosed with clinically significant prostate cancer than those without, according to new data published in European Urology. Thus, men with germline pathogenic BRCA2 mutations might benefit from systematic PSA screening.
The IMPACT study is an international trial involving men at increased risk of developing prostate cancer as they harbour pathogenic mutations in BRCA1 and BRCA2. BRCA2 mutations in men are known to be associated with an increased risk of early-onset and clinically significant prostate cancer. Furthermore, germline BRCA2 status is an independent prognostic factor for prostate cancer outcomes. However, the influence of BRCA1 mutations on prostate cancer is unclear. Participants included in the IMPACT study receive targeted annual PSA screening to determine the prostate cancer incidence in men who have these germline mutations.
The recently reported interim analysis included 2,932 unique individuals, comprising 919 men with BRCA1 mutations and 709 without; 902 men with BRCA2 mutations and 497 without — 95 men without BRCA2 mutations who were sequenced for both BRCA1 and BRCA2 mutations were included in both control cohorts.
Overall, 2,932 men had a PSA screening test at baseline. Of these men, 228 (7.7%) had serum PSA levels >3.0 ng/ml and cancer was diagnosed in 69 (2.4%) via biopsy sampling. After four PSA screening tests, PSA levels >3.0 ng/ml were found in 527 men (18%) and prostate cancer was diagnosed in 112 men using biopsy sampling. The overall prostate cancer detection rate was 3.8% (112/2,932) and the rate of prostate cancer incidence per 1,000 person years was 15.
Analysis by cohort showed that, in the BRCA2 group, prostate cancer was diagnosed in 47 men with mutations and in 15 without. Prostate cancer incidence rate per 1,000 person years was 19 in men with mutations and 12 in those without, which was significantly different (P = 0.031). Positive predictive value (PPV) of PSA >3 ng/ml was 31% in BRCA2 mutation carriers versus 18% in noncarriers (P = 0.025). In comparison, PPV of prostate biopsy was 39% and 28% in mutation carriers and noncarriers, respectively.
In the BRCA1 group, 31 men with mutations and 19 men without were diagnosed with cancer. The rate of prostate cancer per 1,000 person years was 14 in men with mutations and 11 in those without, which was not significantly different (P = 0.300). The PPV of PSA >3 ng/ml was 23% and 15% in BRCA1 mutation carriers and noncarriers, respectively. By contrast, PPV of prostate biopsy was 32% in men with BRCA1 mutations and 20% in men without.
Prostate cancer was diagnosed at a younger age in men with BRCA2 mutations (61 years) than in men without (64 years). Furthermore, 37 of 48 BCRA2 carriers with prostate cancer were diagnosed with intermediate-risk or high-risk disease compared with 6 of 15 noncarriers. Age and risk category at diagnosis did not differ between men with and without mutations in the BRCA1 cohort.
“Men with BRCA2 mutations had a significantly increased cancer incidence rate per 1,000 person years”
These interim results show that the trends seen at baseline screening strengthen after 3 years of follow-up monitoring. The role of screening in men with BRCA1 mutations is still unclear. Men with BRCA2 mutations had a significantly increased cancer incidence rate per 1,000 person years, are diagnosed at a young age and are likely to have clinically significant disease. Thus, these men might benefit from systematic PSA screening.
Page, E. C. et al. Interim results from the IMPACT study: evidence for prostate-specific antigen screening in BRCA2 mutation carriers. Eur. Urol. https://doi.org/10.1016/j.eururo.2019.08.019 (2019)
Taylor, R. A. et al. The influence of BRCA2 mutation on localized prostate cancer. Nat. Rev. Urol. 16, 281–290 (2019)
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Stone, L. The IMPACT of BRCA2 in prostate cancer. Nat Rev Urol 16, 639 (2019). https://doi.org/10.1038/s41585-019-0249-4