Interim Results from the IMPACT Study: Evidence for Prostate-specific Antigen Screening in BRCA2 Mutation Carriers

Abstract

BackgroundMutations in BRCA2 cause a higher risk of early-onset aggressive prostate cancer (PrCa). The IMPACT study is evaluating targeted PrCa screening using prostate-specific-antigen (PSA) in men with germline BRCA1/2 mutations.ObjectiveTo report the utility of PSA screening, PrCa incidence, positive predictive value of PSA, biopsy, and tumour characteristics after 3 yr of screening, by BRCA status.Design, setting, and participantsMen aged 40–69 yr with a germline pathogenic BRCA1/2 mutation and male controls testing negative for a familial BRCA1/2 mutation were recruited. Participants underwent PSA screening for 3 yr, and if PSA > 3.0 ng/ml, men were offered prostate biopsy.Outcome measurements and statistical analysisPSA levels, PrCa incidence, and tumour characteristics were evaluated. Statistical analyses included Poisson regression offset by person-year follow-up, chi-square tests for proportion t tests for means, and Kruskal-Wallis for medians.Results and limitationsA total of 3027 patients (2932 unique individuals) were recruited (919 BRCA1 carriers, 709 BRCA1 noncarriers, 902 BRCA2 carriers, and 497 BRCA2 noncarriers). After 3 yr of screening, 527 men had PSA > 3.0 ng/ml, 357 biopsies were performed, and 112 PrCa cases were diagnosed (31 BRCA1 carriers, 19 BRCA1 noncarriers, 47 BRCA2 carriers, and 15 BRCA2 noncarriers). Higher compliance with biopsy was observed in BRCA2 carriers compared with noncarriers (73% vs 60%). Cancer incidence rate per 1000 person years was higher in BRCA2 carriers than in noncarriers (19.4 vs 12.0; p = 0.03); BRCA2 carriers were diagnosed at a younger age (61 vs 64 yr; p = 0.04) and were more likely to have clinically significant disease than BRCA2 noncarriers (77% vs 40%; p = 0.01). No differences in age or tumour characteristics were detected between BRCA1 carriers and BRCA1 noncarriers. The 4 kallikrein marker model discriminated better (area under the curve [AUC] = 0.73) for clinically significant cancer at biopsy than PSA alone (AUC = 0.65).ConclusionsAfter 3 yr of screening, compared with noncarriers, BRCA2 mutation carriers were associated with a higher incidence of PrCa, younger age of diagnosis, and clinically significant tumours. Therefore, systematic PSA screening is indicated for men with a BRCA2 mutation. Further follow-up is required to assess the role of screening in BRCA1 mutation carriers.Patient summaryWe demonstrate that after 3 yr of prostate-specific antigen (PSA) testing, we detect more serious prostate cancers in men with BRCA2 mutations than in those without these mutations. We recommend that male BRCA2 carriers are offered systematic PSA screening.

Hereditary Predisposition to Prostate Cancer: From Genetics to Clinical Implications

“…Carrier men ≤55 years old seem to be considerably more susceptible to PrCa development, with an RR ranging from 7.8 to 23 [ 55 , 58 ]. Moreover, germline alterations in the BRCA2 gene have been appointed as independent predictors of a younger age of diagnosis, more aggressive phenotype, and higher mortality rate compared with non-carriers [ 55 , 59 , 60 , 61 , 62 ]. The study of germline alterations in the BRCA1/2 genes is particularly important in the identification of population-specific founder variants, e.g., in the Ashkenazim Jewish population, it is estimated that approximately 2% of the population carries at least one of three founder mutations in BRCA1 (185delA or 5382insC) and BRCA2 (6174delT) [ 63 ].…”

Clinical Applications of Molecular Biomarkers in Prostate Cancer

“…International guidelines recommend annual PSA screening for PCa in the general population between 40-45 years of age [64]. The IMPACT study evaluated the efficacy of this screening approach in patients with BRCA germline mutations [65]. That study found that patients with the BRCA2 mutation were diagnosed at a younger age and also more likely to present clinically-significant disease at diagnosis (intermediate or high-risk PCa in 77% of BRCA2 carriers versus 40% in controls).…”

Cancer Genetics and Therapeutic Opportunities in Urologic Practice

“…Following the first round of screening, it has shown no difference between BRCA1/2 mutation carriers and controls in the rate of detection of prostate cancer or the positive predictive value of prostate biopsy in men with a PSA ≥ 3 ng/mL. However, no conclusions can be made until more follow-up data are collected [95].…”