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

Elizabeth K Bancroft, Elizabeth C Page, Elena Castro, Hans Lilja, Andrew Vickers, Daniel Sjoberg, Melissa Assel, Christopher S Foster, Gillian Mitchell, Kate Drew, Lovise Mæhle, Karol Axcrona, D Gareth Evans, Barbara Bulman, Diana Eccles, Donna McBride, Christi van Asperen, Hans Vasen, Lambertus A Kiemeney, Janneke Ringelberg, Cezary Cybulski, Dominika Wokolorczyk, Christina Selkirk, Peter J Hulick, Anders Bojesen, Anne-Bine Skytte, Jimmy Lam, Louise Taylor, Rogier Oldenburg, Ruben Cremers, Gerald Verhaegh, Wendy A van Zelst-Stams, Jan C Oosterwijk, Ignacio Blanco, Monica Salinas, Jackie Cook, Derek J Rosario, Saundra Buys, Tom Conner, Margreet G Ausems, Kai-ren Ong, Jonathan Hoffman, Susan Domchek, Jacquelyn Powers, Manuel R Teixeira, Sofia Maia, William D Foulkes, Nassim Taherian, Marielle Ruijs, Apollonia T Helderman-van den Enden, Louise Izatt, Rosemarie Davidson, Muriel A Adank, Lisa Walker, Rita Schmutzler, Kathy Tucker, Judy Kirk, Shirley Hodgson, Marion Harris, Fiona Douglas, Geoffrey J Lindeman, Janez Zgajnar, Marc Tischkowitz, Virginia E Clowes, Rachel Susman, Teresa Ramón y Cajal, Nicholas Patcher, Neus Gadea, Allan Spigelman, Theo van Os, Annelie Liljegren, Lucy Side, Carole Brewer, Angela F Brady, Alan Donaldson, Vigdis Stefansdottir, Eitan Friedman, Rakefet Chen-Shtoyerman, David J Amor, Lucia Copakova, Julian Barwell, Veda N Giri, Vedang Murthy, Nicola Nicolai, Soo-Hwang Teo, Lynn Greenhalgh, Sara Strom, Alex Henderson, John McGrath, David Gallagher, Neil Aaronson, Audrey Ardern-Jones, Chris Bangma, David Dearnaley, Philandra Costello, Jorunn Eyfjord, Jeanette Rothwell, Alison Falconer, Henrik Gronberg, Freddie C Hamdy, Oskar Johannsson, Vincent Khoo, Zsofia Kote-Jarai, Jan Lubinski, Ulrika Axcrona, Jane Melia, Joanne McKinley, Anita V Mitra, Clare Moynihan, Gad Rennert, Mohnish Suri, Penny Wilson, Emma Killick, Sue Moss, Rosalind A Eeles
European Urology 2014, 66 (3): 489-99

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.

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