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

Abstract

BACKGROUND:

Mutations 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.

OBJECTIVE:

To 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 PARTICIPANTS:

Men 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 ANALYSIS:

PSA 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 LIMITATIONS:

A 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).

CONCLUSIONS:

After 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 SUMMARY:

We 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.

• Authors: Elizabeth C Page, Elizabeth K Bancroft, Mark N Brook, Melissa Assel, Mona Hassan Al Battat, Sarah Thomas, Natalie Taylor, Anthony Chamberlain, Jennifer Pope, Holly Ni Raghallaigh, D Gareth Evans, Jeanette Rothwell, Lovise Maehle, Eli Marie Grindedal, Paul James, Lyon Mascarenhas, Joanne McKinley, Lucy Side, Tessy Thomas, Christi van Asperen, Hans Vasen, Lambertus A Kiemeney, Janneke Ringelberg, Thomas Dyrsø Jensen, Palle J S Osther, Brian T Helfand, Elena Genova, Rogier A Oldenburg, Cezary Cybulski, Dominika Wokolorczyk, Kai-Ren Ong, Camilla Huber, Jimmy Lam, Louise Taylor, Monica Salinas, Lidia Feliubadaló, Jan C Oosterwijk, Wendy van Zelst-Stams, Jackie Cook, Derek J Rosario, Susan Domchek, Jacquelyn Powers, Saundra Buys, Karen O'Toole, Margreet G E M Ausems, Rita K Schmutzler, Kerstin Rhiem, Louise Izatt, Vishakha Tripathi, Manuel R Teixeira, Marta Cardoso, William D Foulkes, Armen Aprikian, Heleen van Randeraad, Rosemarie Davidson, Mark Longmuir, Mariëlle W G Ruijs, Apollonia T J M Helderman van den Enden, Muriel Adank, Rachel Williams, Lesley Andrews, Declan G Murphy, Dorothy Halliday, Lisa Walker, Annelie Liljegren, Stefan Carlsson, Ashraf Azzabi, Irene Jobson, Catherine Morton, Kylie Shackleton, Katie Snape, Helen Hanson, Marion Harris, Marc Tischkowitz, Amy Taylor, Judy Kirk, Rachel Susman, Rakefet Chen-Shtoyerman, Allan Spigelman, Nicholas Pachter, Munaza Ahmed, Teresa Ramon Y Cajal, Janez Zgajnar, Carole Brewer, Neus Gadea, Angela F Brady, Theo van Os, David Gallagher, Oskar Johannsson, Alan Donaldson, Julian Barwell, Nicola Nicolai, Eitan Friedman, Elias Obeid, Lynn Greenhalgh, Vedang Murthy, Lucia Copakova, Sibel Saya, John McGrath, Peter Cooke, Karina Rønlund, Kate Richardson, Alex Henderson, Soo H Teo, Banu Arun, Karin Kast, Alexander Dias, Neil K Aaronson, Audrey Ardern-Jones, Chris H Bangma, Elena Castro, David Dearnaley, Diana M Eccles, Karen Tricker, Jorunn Eyfjord, Alison Falconer, Christopher Foster, Henrik Gronberg, Freddie C Hamdy, Vigdis Stefansdottir, Vincent Khoo, Geoffrey J Lindeman, Jan Lubinski, Karol Axcrona, Christos Mikropoulos, Anita Mitra, Clare Moynihan, Gadi Rennert, Mohnish Suri, Penny Wilson, Tim Dudderidge, IMPACT Study Collaborators, Judith Offman, Zsofia Kote-Jarai, Andrew Vickers, Hans Lilja, Rosalind A Eeles
• Journal: European urology (Eur Urol) Vol. 76 Issue 6 Pg. 831-842 (12 2019) ISSN: 1873-7560 [Electronic] Switzerland
• PMID: 31537406 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2019 The Authors. Published by Elsevier B.V. All rights reserved.

Chemical References

• KLK3 protein, human
• Kallikreins
• Prostate-Specific Antigen

Topics

• Adult
• Aged
• Early Detection of Cancer (methods)
• Genes, BRCA1
• Genes, BRCA2
• Genetic Carrier Screening (methods)
• Germ-Line Mutation
• Humans
• Kallikreins (blood)
• Male
• Middle Aged
• Prospective Studies
• Prostate-Specific Antigen (blood)
• Prostatic Neoplasms (blood, diagnosis, genetics)