Targeted prostate cancer screening in BRCA1 and BRCA2 mutation carriers: results from the initial screening round of the IMPACT study.

BACKGROUND: Men with germline breast cancer 1, early onset (BRCA1) or breast cancer 2, early onset (BRCA2) gene mutations have a higher risk of developing prostate cancer (PCa) than noncarriers. IMPACT (Identification of Men with a genetic predisposition to ProstAte Cancer: Targeted screening in BRCA1/2 mutation carriers and controls) is an international consortium of 62 centres in 20 countries evaluating the use of targeted PCa screening in men with BRCA1/2 mutations. OBJECTIVE: To report the first year's screening results for all men at enrollment in the study. DESIGN, SETTING AND PARTICIPANTS: We recruited men aged 40-69 yr with germline BRCA1/2 mutations and a control group of men who have tested negative for a pathogenic BRCA1 or BRCA2 mutation known to be present in their families. All men underwent prostate-specific antigen (PSA) testing at enrollment, and those men with PSA >3 ng/ml were offered prostate biopsy. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: PSA levels, PCa incidence, and tumour characteristics were evaluated. The Fisher exact test was used to compare the number of PCa cases among groups and the differences among disease types. RESULTS AND LIMITATIONS: We recruited 2481 men (791 BRCA1 carriers, 531 BRCA1 controls; 731 BRCA2 carriers, 428 BRCA2 controls). A total of 199 men (8%) presented with PSA >3.0 ng/ml, 162 biopsies were performed, and 59 PCas were diagnosed (18 BRCA1 carriers, 10 BRCA1 controls; 24 BRCA2 carriers, 7 BRCA2 controls); 66% of the tumours were classified as intermediate- or high-risk disease. The positive predictive value (PPV) for biopsy using a PSA threshold of 3.0 ng/ml in BRCA2 mutation carriers was 48%-double the PPV reported in population screening studies. A significant difference in detecting intermediate- or high-risk disease was observed in BRCA2 carriers. Ninety-five percent of the men were white, thus the results cannot be generalised to all ethnic groups. CONCLUSIONS: The IMPACT screening network will be useful for targeted PCa screening studies in men with germline genetic risk variants as they are discovered. These preliminary results support the use of targeted PSA screening based on BRCA genotype and show that this screening yields a high proportion of aggressive disease. PATIENT SUMMARY: In this report, we demonstrate that germline genetic markers can be used to identify men at higher risk of prostate cancer. Targeting screening at these men resulted in the identification of tumours that were more likely to require treatment.

BRCA1, BRCA2 and TP53 mutations in very early-onset breast cancer with associated risks to relatives.

Pathological mutations in BRCA1, BRCA2 and TP53 are associated with an increased risk of breast cancer. This study evaluated mutation frequency of these genes in early-onset breast cancer patients, and correlated this with family history and determined relative risks to family members. Patients with breast adenocarcinoma diagnosed 30 years were ascertained between 1980 and 1997. Family history was established and mutation screening of BRCA1, BRCA2 and TP53 genes was performed. Estimates of penetrance and relative risk were undertaken. DNA was obtained from 100/139 women. 17/36 familial cases had a BRCA1, BRCA2 or TP53 mutation. Of 64 non-familial cases, one BRCA2, two BRCA1 and two TP53 mutations were detected. Penetrance estimates (by age 70) for breast cancer were 84% for BRCA1 mutations and 91% for BRCA2 mutations and for ovarian cancer, 60% and 26%, respectively. Relative risks associated with mutations were consistent with previous studies. BRCA1 and BRCA2 mutations in patients with breast cancer 30 years are predicted strongly by family history. The majority of families with ovarian cancer were due to mutations in BRCA1/2 whereas these mutations only accounted for 30-50% of the excess breast cancers.