Targeted Prostate Cancer Screening in BRCA1 and BRCA2 Mutation Carriers: Results from the Initial Screening Round of the IMPACT Study

Supplementary data associated with this article can be\ud
found, in the online version, at http://dx.doi.org/10.1016/\ud
j.eururo.2014.01.003.Background\ud
\ud
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.\ud
\ud
Objective\ud
\ud
To report the first year's screening results for all men at enrolment in the study.\ud
\ud
Design, setting and participants\ud
\ud
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 enrolment, and those men with PSA >3 ng/ml were offered prostate biopsy.\ud
\ud
Outcome measurements and statistical analysis\ud
\ud
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.\ud
\ud
Results and limitations\ud
\ud
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.\ud
\ud
Conclusions\ud
\ud
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.\ud
\ud
Patient summary\ud
\ud
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.This research is coordinated by the Institute of Cancer Research, London, UK, and is supported by grants from the Ronald and Rita McAulay Foundation and Cancer Research UK (grant references C5047/A15007 and C5047/A13232). In Australia, this project was cofunded by Cancer Council Tasmania and Cancer Australia, grant number 1006349 (2011–2013); Prostate Cancer Foundation of Australia, grant number PCFA PR04 (2008); Cancer Councils of Victoria and South Australia, grant number 400048 (2006–2008); the Victorian Cancer Agency Clinical Trial Capacity CTCB08_14; and Translational grants EOI09_50. The Association of International Cancer Research funded data collection in The Netherlands (AICR 10–0596). The authors received funding from the NIHR to the Biomedical Research Center at the Institute of Cancer Research and the Royal Marsden NHS Foundation Trust, and at Central Manchester Foundation Trust; the Basser Research Centre (to Susan Domchek); the National Cancer Institute (R01CA160816, R01 CA175491, and P50-CA92629); the Sidney Kimmel Center for Prostate and Urologic Cancers; David H. Koch through the Prostate Cancer Foundation, the National Institute for Health Research (NIHR) Oxford Biomedical Research Centre Program, Swedish Cancer Society project no. 11–0624, a FiDIPro-program award from TEKES in Finland, and Fundacion Federico SA; and the Slovenian Research Agency, research programme P3–0352.Peer-reviewedPublisher Versio