E U R O P E A N U RO L O GY 76 ( 2 019 ) 8 31 – 8 4 2 available at www.sciencedirect.com journal homepage: www.europeanurology.com Prostate Cancer Interim Results from the IMPACT Study: Evidence for Prostate-specific Antigen Screening in BRCA2 Mutation Carriers Elizabeth C. Page a,y, Elizabeth K. Bancroft a,b,y, Mark N. Brook a, Melissa Assel c, Mona Hassan Al Battat d, Sarah Thomas b, Natalie Taylor b, Anthony Chamberlain a, Jennifer Pope a, Holly Ni Raghallaigh a, D. Gareth Evans e, Jeanette Rothwell e, Lovise Maehle f, Eli Marie Grindedal f, Paul James g,h,i, Lyon Mascarenhas g, Joanne McKinley g, Lucy Side j, Tessy Thomas j, Christi van Asperen k, Hans Vasen l, Lambertus A. Kiemeney m, Janneke Ringelberg l, Thomas Dyrsø Jensen n, Palle J.S. Osther o, Brian T. Helfand p, Elena Genova p, Rogier A. Oldenburg q, Cezary Cybulski r, Dominika Wokolorczyk r, Kai-Ren Ong s, Camilla Huber s, Jimmy Lam t, Louise Taylor u, Monica Salinas v, Lidia Feliubadaló v, Jan C. Oosterwijk w, Wendy van Zelst-Stams m, Jackie Cook x, Derek J. Rosario y, Susan Domchek z, Jacquelyn Powers z, Saundra Buys A, Karen O’Toole A, Margreet G.E.M. Ausems B, Rita K. Schmutzler C, Kerstin Rhiem C, Louise Izatt D, Vishakha Tripathi D, Manuel R. Teixeira E,F, Marta Cardoso E, William D. Foulkes G,H, Armen Aprikian G, Heleen van Randeraad l, Rosemarie Davidson I, Mark Longmuir I, Mariëlle W.G. Ruijs J, Apollonia T.J.M. Helderman van den Enden K, Muriel Adank L, Rachel Williams M,N, Lesley Andrews M,N, Declan G. Murphy h,O, Dorothy Halliday P, Lisa Walker P, Annelie Liljegren Q, Stefan Carlsson Q, Ashraf Azzabi R, Irene Jobson R, Catherine Morton S, Kylie Shackleton S, Katie Snape T, Helen Hanson T, Marion Harris U, Marc Tischkowitz V,W, Amy Taylor V, Judy Kirk X,Y, Rachel Susman Z, Rakefet Chen-Shtoyerman aa, Allan Spigelman ab,ac,ad, Nicholas Pachter ae,af, Munaza Ahmed ag, Teresa Ramon y Cajal ah, Janez Zgajnar ai, Carole Brewer aj,ak, Neus Gadea al, Angela F. Brady am, Theo van Os an, David Gallagher ao, Oskar Johannsson ap, Alan Donaldson aq, Julian Barwell ar,as, Nicola Nicolai at, Eitan Friedman au, Elias Obeid av, Lynn Greenhalgh aw, Vedang Murthy ax, Lucia Copakova ay, Sibel Saya a, John McGrath ak,az, Peter Cooke Aa, Karina Rønlund n, Kate Richardson g, Alex Henderson R,Ab, Soo H. Teo Ac, Banu Arun Ad, Karin Kast Ae, Alexander Dias a,Af, Neil K. Aaronson J, Audrey Ardern-Jones b, Chris H. Bangma Ag, Elena Castro Ah, David Dearnaley Ai, Diana M. Eccles Aj,j, Karen Tricker e, Jorunn Eyfjord Ak, Alison Falconer Al, Christopher Foster Am, Henrik Gronberg An, Freddie C. Hamdy Ao,Ap, Vigdis Stefansdottir ap, Vincent Khoo b,T,Ai,Aq, Geoffrey J. Lindeman S,Aq,Ar, Jan Lubinski r, y These authors are joint first authors. z See Appendix 1. * Corresponding author. The Institute of Cancer Research and Royal Marsden NHS Foundation Trust, 15 Cotswold Road, Sutton SM2 5NG, UK. Tel. +44 208 722 4094, Fax: +44 208 722 4110. E-mail address: rosalind.eeles@icr.ac.uk (R.A. Eeles). https://doi.org/10.1016/j.eururo.2019.08.019 0302-2838/© 2019 The Authors. Published by Elsevier B.V. on behalf of European Association of Urology. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). 832 E U RO P E A N U RO L O GY 76 ( 2 019 ) 8 31 – 8 4 2 Karol Axcrona As, Christos Mikropoulos At, Anita Mitra Au, Clare Moynihan a, Gadi Rennert Av, Mohnish Suri Aw, Penny Wilson Ax, Tim Dudderidge Ay, The IMPACT Study Collaboratorsz, Judith Offman Az, Zsofia Kote-Jarai a, Andrew Vickers c, Hans Lilja d,Ap,ba, Rosalind A. Eeles a,b,* a Oncogenetics Team, Institute of Cancer Research, London, UK; b Cancer Genetics Unit and Academic Urology Unit, Royal Marsden NHS Foundation Trust, London, UK; c Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, NY, USA; d Department of Translational Medicine, Lund University, Malmö, Sweden; e Genetic Medicine, Manchester Academic Health Sciences Centre, Central Manchester University Hospitals NHS Foundation Trust, Manchester, UK; f Department of medical genetics, Oslo University Hospital, 0424 Oslo, Norway; g Parkville Familial Cancer Centre, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia; h The Sir Peter MacCallum Department of Oncology, University of Melbourne, VIC, Australia; i Genetic Medicine, The Royal Melbourne Hospital, Parkville, VIC, Australia; j Wessex Clinical Genetics Service, Princess Anne Hospital, Southampton, UK; k Leiden University Medical Center, Leiden, The Netherlands; l The Foundation for the Detection of Hereditary Cancer, Leiden, The Netherlands; m Radboud University Medical Center, Nijmegen, The Netherlands; Department of Clinical Genetics, Vejle Hospital, Vejle, Denmark; Department of Urology, Vejle Hospital, Vejle, Denmark; p John n o and Carol Walter Center for Urological Health, Division of Urology, NorthShore University HealthSystem, Evanston, IL, USA; q Department of clinical genetics, r Erasmus University Medical Center, Rotterdam, The Netherlands; International Hereditary Cancer Center, Department of Genetics and Pathology, Pomeranian Medical University in Szczecin, Szczecin, Poland; Clinical Genetics Unit, Birmingham Women's Hospital, Birmingham, UK; t Department of s Urology, Flinders Medical Centre, Bedford Park, SA, Australia; u Department of Urology, Repatriation General Hospital, Daw Park, SA, Australia; v Hereditary w Cancer Program, ICO-IDIBELL (Bellvitge Biomedical Research Institute, Catalan Institute of Oncology), CIBERONC, Barcelona, Spain; University of x Groningen, University Medical Center Groningen, Groningen, The Netherlands; Sheffield Clinical Genetics Service, Sheffield Children's Hospital, Sheffield, UK; y Royal Hallamshire Hospital, Sheffield, UK; z Basser Research Center, University of Pennsylvania, Philadelphia, PA, USA; A Huntsman Cancer Institute, University of Utah, Salt Lake City, UT, USA; B Division of Laboratories, Pharmacy and Biomedical Genetics, Department of Genetics, University Medical Centre, Utrecht, The Netherlands; C Center for Familial Breast and Ovarian Cancer, Center for Integrated Oncology (CIO), University of Cologne, Faculty of Medicine D E and University Hospital Cologne, Cologne, Germany; Clinical Genetics Service, Guy’s and St Thomas’ NHS Foundation Trust, London, UK; Genetics Department and Research Center, Portuguese Oncology Institute (IPO Porto), Porto, Portugal; F Biomedical Sciences Institute (ICBAS), Porto University, Porto, Portugal; G Cancer Research Program, Research Institute of McGill University Health Centre, Montreal, Quebec, Canada; H Lady Davis Institute, Jewish General Hospital, McGill University, Montreal, QC, Canada; I West of Scotland Genetic Service, Queen Elizabeth University Hospital, Glasgow, UK; J Netherlands Cancer Institute, Amsterdam, The Netherlands; K Department of Clinical Genetics, Maastricht University Medical Center, Maastricht, The Netherlands; L VU University Medical Center, Amsterdam, The Netherlands; M Prince of Wales Clinical School, Faculty of Medicine, University of New South Wales, Sydney, NSW, Australia; N O Hereditary Cancer Centre, Prince of Wales Hospital, Randwick, NSW, Australia; Division of Cancer Surgery, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia; P Oxford Centre for Genomic Medicine, Oxford University Hospitals NHS Trust, Oxford, UK; Q Karolinska University Hospital and Karolinska R S Institutet, Stockholm, Sweden; Northern Genetics Service, Newcastle upon Tyne Hospitals, UK; Familial Cancer Centre, The Royal Melbourne Hospital, T U V Grattan St, Parkville, VIC, Australia; St George’s Hospital, Tooting, London, UK; Familial Cancer Centre, Monash Health, Clayton, VIC, Australia; East Anglian Medical Genetics Service, Cambridge University Hospitals NHS Trust, Cambridge, UK; W Academic Department of Medical Genetics, NIHR Cambridge X Biomedical Research Centre, Level 6 Addenbrooke's Treatment Centre, Cambridge Biomedical Campus, University of Cambridge, Cambridge, UK; Familial Cancer Service, Crown Princess Mary Cancer Centre, Westmead Hospital, Westmead, Sydney, NSW, Australia; Y Sydney Medical School, University of Sydney, Centre for Cancer Research, The Westmead Institute for Medical Research, Westmead, Sydney, NSW, Australia; Z Genetic Health Queensland, Royal Brisbane & Women's Hospital, Herston, QLD, Australia; aa The Genetic Institute, Kaplan Medical Center, Rehovot, Israel; ab Hunter Family Cancer Service, Waratah, NSW, ac ad Australia; University of New South Wales, St Vincent’s Clinical School, NSW, Australia; Cancer Genetics Clinic, The Kinghorn Cancer Centre, St Vincent's Hospital, Sydney, NSW, Australia; ae Genetic Services of WA, King Edward Memorial Hospital, Subiaco, WA, Australia; af Department of Paediatrics, University of Western Australia, Perth, WA, Australia; ag NE Thames Regional Genetics Service, Institute of Child Health, London, UK; ah Hospital de Sant Pau, Barcelona, ai aj ak Spain; Institute of Oncology, Ljubljana, Slovenia; Peninsular Genetics, Derriford Hospital, Plymouth, UK; Royal Devon and Exeter Hospital, Exeter, UK; al am Hospital Vall d'Hebron, Barcelona, Spain; North West Thames Regional Genetics Service, Kennedy-Galton Centre, London North West University an ao ap Healthcare NHS Trust, Harrow, UK; Academic Medical Center, Amsterdam, The Netherlands; St James's Hospital, Dublin, Ireland; Landspitali—the National University Hospital of Iceland, Reykjavik, Iceland; aq St Michael’s Hospital, Bristol, UK; ar University of Leicester, Leicester, UK; as University Hospitals at au av Leicester, Leicester, UK; Istituto Nazionale dei Tumori, Milano, Italy; Chaim Shema Medical Center, Tel-Hashomer, Israel; Fox Chase Cancer Center, aw ax ay Philadelphia, PA, USA; Clinical Genetics Service, Liverpool Women’s Hospital, Liverpool, UK; Tata Memorial Centre, Mumbai, India; National Cancer az Aa Institute, Bratislava, Slovak Republic; University of Exeter Medical School, St Luke’s Campus, Exeter, UK; New Cross Hospital, Wolverhampton, UK; Ab Ac West Cumberland Infirmary, Whitehaven, UK; Cancer Research Initiatives Foundation, Subang Jaya Medical Centre, Selangor, Darul Ehsan, Malaysia; Ad Ae The University of Texas, MD Anderson Cancer Center, Houston, TX, USA; Department of Gynecology and Obstetrics, Medical Faculty and University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany; Af Instituto Nacional de Cancer Jose de Alencar Gomes da Silva (INCA), Rio de Ag Ah Janeiro, Brazil; Department of urology, Erasmus University Medical Center, Rotterdam, The Netherlands; Spanish National Cancer Research Center, Ai Aj Madrid, Spain; Division of Radiotherapy and Imaging, The Institute of Cancer Research, Sutton, UK; The University of Southampton Medical School, Ak Al Southampton, UK; Faculty of Medicine, School of Health Sciences, University of Iceland, Reykjavik, Iceland; Imperial College Healthcare NHS Trust, Am An Ao Ap London, UK; HCA Pathology Laboratories, London, UK; University Hospital, Umea, Sweden; Churchill Hospital, Headington, Oxford, UK; Nuffield Aq Department of Surgical Sciences, University of Oxford, Oxford, UK; Department of Medicine, The University of Melbourne, Parkville, VIC, Australia; Ar As Cancer Biology and Stem Cells Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, Australia; Department of Urology, Akershus University Hospital, Lørenskog, Norway; At Medway Hospital, Kent, UK; Au University College London Hospitals NHS Foundation Trust, London, UK; Av Aw Ax CHS National Cancer Control Center, Carmel Medical Center, Haifa, Israel; Nottingham City Hospital, Nottingham, UK; Innovate UK, Polaris House, Ay Az Swindon, UK; University Hospital Southampton, Southampton, UK; School of Cancer and Pharmaceutical Sciences, Faculty of Life Sciences & Medicine, ba King’s College London, Guy’s Cancer Centre, Guy’s Hospital, London, UK; Departments of Laboratory Medicine, Surgery, and Medicine, Memorial Sloan- Kettering Cancer Center, New York, NY, USA E U R O P E A N U RO L O GY 76 ( 2 019 ) 8 31 – 8 4 2 833 Article info Abstract Article history: Background: Mutations in BRCA2 cause a higher risk of early-onset aggressive prostate Accepted August 12, 2019 cancer (PrCa). The IMPACT study is evaluating targeted PrCa screening using prostate- specific-antigen (PSA) in men with germline BRCA1/2 mutations. Associate Editor: Objective: To report the utility of PSA screening, PrCa incidence, positive predictive T. Morgan 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 Statistical Editor: recruited. Participants underwent PSA screening for 3 yr, and if PSA > 3.0 ng/ml, men Emily Zabor were offered prostate biopsy. Outcome measurements and statistical analysis: PSA levels, PrCa incidence, and tumour Keywords: 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- BRCA1 Wallis for medians. BRCA2 Results and limitations: A total of 3027 patients (2932 unique individuals) were Prostate-specific-antigen recruited (919 BRCA1 carriers, 709 BRCA1 noncarriers, 902 BRCA2 carriers, and 497 Prostate cancer BRCA2 noncarriers). After 3 yr of screening, 527 men had PSA > 3.0 ng/ml, 357 biopsies Targeted prostate screening 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 discrim- inated 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. © 2019 The Authors. Published by Elsevier B.V. on behalf of European Association of Urology. This is an open access article under the CC BY-NC-ND license (http://creati- vecommons.org/licenses/by-nc-nd/4.0/). 1. Introduction documented, but PSA remains the most effective PrCa biomarker currently available [10–12]. Efforts to improve It is well established that BRCA2 gene mutations cause a sensitivity and specificity of PSA by incorporating other higher risk of prostate cancer (PrCa), with an estimated biological markers, such as the 4 kallikrein (4 K) marker relative risk of 2.5–8.6-fold by age 65 yr [1,2], and are panel [13,14], PrCa risk calculators [15,16], magnetic associated with earlier-onset, clinically significant disease. A resonance imaging (MRI) [17,18], and genetic markers number of retrospective studies report higher rates of lymph [19,20], into screening algorithms are under evaluation. node involvement, distant metastasis at diagnosis, and The IMPACT study (Identification of Men with a genetic higher mortality rates in mutation carriers [3–6]. Germline predisposition to ProstAte Cancer: Targeted screening in men BRCA2 mutation status is reported to be an independent at higher genetic risk and controls; http://impact.icr.ac.uk/) is prognostic factor for poorer outcome [3]. Furthermore, an international, multicentre study evaluating targeted PrCa tumours of BRCA2 mutation carriers with localised PrCa screening in men with BRCA1/2 mutations. IMPACT aims to have been demonstrated to exhibit genomic instability more evaluate the utility of PSA screening in detecting clinically typically seen in metastatic castration-resistant PrCa [7]. significant PrCa (defined as intermediate- or high-risk disease There is debate about whether there is an increased risk of using the National Institute for Health and Care Excellence PrCa for BRCA1 mutation carriers, with an estimated relative [NICE] guidelines [21]), PrCa incidence, positive predictive risk of 1.8–3.75-fold by age 65 yr [8] and some evidence of value (PPV) of biopsy using a PSA threshold of 3.0 ng/ml, and more clinically significant disease [3,9]; however, this tumour characteristics in order to establish whether PSA warrants further research. It is hypothesised that targeted screening detects clinically significant disease in this screening in BRCA1/2 carriers facilitates early detection. population compared with the noncarrier control group. The controversies of using prostate-specific antigen An analysis of the baseline screen for nearly 2500 men (PSA) screening in the general population are well enrolled in IMPACT supported the use of targeted PSA 834 E U RO P E A N U RO L O GY 76 ( 2 019 ) 8 31 – 8 4 2 screening in BRCA1/2 mutation carriers, suggesting that [29] (Fig. 1). The local histopathologist at each centre screening detects a high proportion of clinically significant reported the biopsy results to guide treatment in accor- tumours [22]. Moreover, we have also demonstrated that dance with local guidelines. Cancers were defined using the PSA is more predictive of PrCa in BRCA1/2 carriers than in NICE criteria, and were deemed “clinically significant” if noncarriers [23]. It has been reported that men with classified as of intermediate or high risk according to these germline BRCA1/ BRCA2 mutations, on active surveillance guidelines [21]. Whenever high-grade prostate intraepithe- for low-risk PrCa, are at a higher risk of reclassification to lial neoplasia or atypical small acinar proliferation was higher-grade PrCa than noncarriers [24]. detected, the biopsy was repeated within 3–6 mo. National Comprehensive Cancer Network guidelines The IMPACT results have been compared with the advise PrCa screening to begin at 45 yr for male BRCA2 Göteborg cohort of the ERPSC study. This Swedish general carriers, consider the same for BRCA1 carriers, and perform population cohort of men aged 50–64 yr was offered routine BRCA1/2 testing for men with high-risk PrCa, family biennial PSA screening with further investigations for history, or metastatic disease [25,26]. PSA > 3.0 ng/ml and therefore were the closest general The aims of this study were to evaluate the utility of PSA population group available for comparison. screening, by assessing PrCa prevalence/incidence, PPV of biopsy, and tumour characteristics. A secondary aim was to 2.1. Statistical analysis evaluate the addition of 4 K markers to the algorithm predicting biopsy outcome (full details of this analysis can Statistical analyses were undertaken using Stata 14.2 Stata- be found in the Supplementary material). Corp. 2015. Stata Statistical Software: Release 14. College Station, TX: StataCorp LP and GraphPad QuickCalcs Web 2. Patients and methods site: https://www.graphpad.com/quickcalcs (accessed Au- gust 2019). The IMPACT study design has been reported previously PrCa prevalence for individuals with PSA > 3.0 ng/ml at [22,27,28] and is summarised in Fig. 1. The protocol was the first PSA test was calculated. The cumulative incidence approved by the West-Midlands Research and Ethics was calculated at the fourth screening round, stratified by Committee in the UK (reference: 05/MRE07/25) and age group, tumour-node-metastasis stage, and Gleason subsequently by each participating institution’s local score, and compared by mutation status using Poisson committee. All participants provided written consent, and regression offset by person-year follow-up, adjusted for age, interim analyses are presented to the Independent Data and ethnicity, and country. Proportions of screen-detected Safety Monitoring Committee biannually. disease and PPV of PB were compared between groups The target sample is 500 BRCA1 and 350 BRCA2 mutation using the chi-square test. Fisher’s exact and Kruskal-Wallis carriers, and a control group of 850 men who have undergone tests were used to compare median age, PSA, and tumour predictive testing and tested negative for a pathogenic characteristics between groups. BRCA1/2 mutation known to be present in their family. Analyses were performed on the whole cohort and by IMPACT has been powered to detect a two-fold PrCa risk over BRCA status. Secondary analyses were conducted excluding 5 yr of screening, with 80% power at the p < 0.01 level. prevalent cancers (cancers diagnosed within <12 mo of Between October 2005 and February 2013, men aged 45– enrolment). A p value of <0.05 was considered statistically 69 yr in The Netherlands and 40–69 yr in all other countries significant. were recruited from families with known pathogenic BRCA1 or BRCA2 mutations. Further detail of the inclusion criteria 3. Results were described previously [22,27,28]. Participants were screened annually in all centres except for those in 3.1. Study population The Netherlands, which screened biennially in accordance with local regulations. Recruitment was extended to A total of 3027 persons (2932 unique individuals) were December 2015, and a subset of 95 BRCA2 noncarriers recruited from 65 centres in 20 countries over 120 mo was sequenced for BRCA1/2 mutations and used as the (Supplementary Table 1): 919 BRCA1 carriers, 709 BRCA1 control group to cover the loss of numbers that resulted in noncarriers, 902 BRCA2 carriers, and 497 BRCA2 noncarriers. removing The Netherlands cohort from cumulative analyses Ninety-five BRCA2 noncarriers sequenced for both BRCA1/2 and include them as BRCA1 noncarriers. mutations were included in both control cohorts. The All participants underwent annual PSA testing for four cohorts were overrecruited, as advised by the study’s screening rounds. If PSA was >3.0 ng/ml, transrectal Independent Data Monitoring Committee. The rationale ultrasound–guided prostate biopsy (PB) was recommended. was that overrecruitment would only strengthen the data Decision to biopsy was based on this single PSA level; PSA and would compensate for any participants who withdrew was not repeated prior to biopsy unless clinically indicated. from the study. Centres were requested to follow a standard biopsy The majority of participants were Caucasian (97%), highly protocol, consisting of 10 and 12 biopsy cores taken from educated, and in work (Supplementary Table 2); median specific locations within the prostate gland. Individuals enrolment age was 54 yr; 24% of men reported urinary with a benign PB continued annual PSA follow-up. A repeat symptoms and 36% previously had at least one PSA test; and PB was recommended if PSA was >50% of the pre-PB PSA 31% reported a family history of PrCa. No statistically E U R O P E A N U RO L O GY 76 ( 2 019 ) 8 31 – 8 4 2 835 [(Fig._1)TD$IG] Fig. 1 – Study design algorithm. ASAP = atypical small acinar proliferation; FU = follow-up; MRI = magnetic resonance imaging; PIN = prostate intraepithelial neoplasia; PrCa = prostate cancer; PSA = prostate-specific-antigen; Re-BX = repeat biopsy. 836 E U RO P E A N U RO L O GY 76 ( 2 019 ) 8 31 – 8 4 2 Table 1 – Prostate cancer detection rates after four rounds of screening. Total cohorta Mutation status BRCA2+ BRCA2– BRCA1+ BRCA1– Baseline (“yr 1”) Unique individuals, n (%) 2932 902 (30) 497(16) 919 (30) 709 (24) Total PSAs taken, n 2931 902 497 919 708 Median PSA (IQR) 0.9 (0.6-1.5) 0.9 (0.5-1.5) 0.9 (0.6-1.4) 0.9 (0.5-1.4) 1.0 (0.6-1.7) PSA > 3 ng/ml, n (%) 228 (7.5) 68 (7.5) 29 (5.8) 73 (7.9) 61 (8.6) PSA > 3 ng/ml requiring action, n 228 68 29 73 61 Biopsies, n (biopsy rate %) 180 (79) 56 (82) 19 (66) 57 (78) 49 (75) Including repeats, n 195 61 21 62 52 Benign, n 107 29 12 32 35 ASAP/HG PIN, n 13 5 0 6 2 Malignant (PrCa incidence), n (%, 95 CI) 69 (2.4, 1.8-3.0) 25 (2.8, 1.7-3.8) 7 (1.4, 3.7-2.4) 24 (2.6, 1.6-3.6) 13 (1.8, 0.8-2.8) Diff. in detection rate: BRCA + vs BRCA– (%, 95 CI) (1.4, -0.1-2.9) (0.8, -0.6-2.2) p value for detection rate: BRCA + vs BRCA– 0.10 0.3 Diagnosed within 6 mo of entry, n 65 25 6 22 12 Diagnosed within 12 mo of entry, n 68 25 7 23 13 PPV of biopsy (%, 95 CI) (35, 29-43) (41, 29-53) (33, 13-53) (39, 27-51) (25, 13-37) Diff. in PPV, biopsy: BRCA + vs BRCA– (%, 95 CI) (8, 16-31) (14, 3-31) p value for PPV, biopsy: BRCA + vs BRCA– 0.5 0.12 PPV of PSA > 3 ng/ml requiring action (%, 95 CI) (30, 24-37) (37, 25-48) (24, 9-40) (33, 22-44) (21, 11-32) Diff. in PPV, PSA > 3: BRCA + vs BRCA– (%, 95 CI) (13, 7-32) (12, 3-26) p value for PPV, PSA > 3: BRCA + vs BRCA– 0.2 0.14 3-yr follow-up (“yr 4”) Total PSAs taken, n (%) 9363 3108 (32) 1600 (16) 2847 (29) 2183 (22) Median PSA (IQR) 0.9 (0.6-1.5) 0.9 (0.6-1.5) 0.9 (0.6-1.5) 0.9 (0.5-1.5) 1.0 (0.6-1.7) PSA > 3 ng/ml, n (%) 695 (7.4) 200 (6.4) 117 (7.3) 218 (7.7) 182 (8.3) PSA > 3 ng/ml requiring action, n (%) 527 (5.6) 150 (4.8) 84 (5.3) 138 (4.8) 126 (5.8) Biopsies, n (biopsy rate%) 332 (63) 110 (73) 50 (60) 93 (67) 89 (71) Including repeats, n 357 122 54 98 95 Benign, n 208 59 32 60 67 ASAP/HG PIN, n 26 10 5 7 6 Malignant (PrCa incidence), n (%, 95 CI) 112 (3.8, 3.2-4.6) 47 (5.2, 3.8-6.7) 15 (3.0, 1.5-4.5) 31 (3.4, 2.2-4.5) 19 (2.7, 1.5-3.9) Diff. in detection rate: BRCA + vs BRCA– (%, 95 CI) (2.2, 0.1-4.2) (0.7, 0.9-2.3) p value for detection rate: BRCA + vs BRCA– 0.057 0.4 PPV of biopsy (%, 95 CI) (31, 27-36) (39, 30-47) (28, 16-40) (32, 22-41) (20, 12-28) Diff. in PPV, biopsy: BRCA + vs BRCA– (%, 95 CI) (11, 4-25) (12, 0.6-24) p value for PPV, biopsy: BRCA + vs BRCA– 0.17 0.065 PPV of PSA > 3 ng/ml requiring action (%, 95 CI) (21, 18-25) (31, 24-39) (18, 10-26) (23, 16-29) (15, 9-21) Diff. in PPV, PSA > 3: BRCA + vs BRCA– (%, 95 CI) (13, 2-25) (7, 2-17) p value for PPV, PSA > 3: BRCA + vs BRCA– 0.025 0.13 Prevalence of PrCa in all PSAs (%, 95 CI) (1.2, 1-1.4) (1.5, 1.1-1.9) (0.9, 0.5-1.4) (1.1, 0.7-1.5) (0.9, 0.5-1.2) Diff. in prevalence of PrCa: BRCA + vs BRCA– (%, 95 CI) (0.6, 0.1-1.2) (0.2, 0.3-0.8) p value for prevalence of PrCa: BRCA + vs BRCA– 0.10 0.4 Follow-up time (yr), median (IQR) Noncancers 3.0 (2.18, 3.12) 3.0 (2.91, 3.14) 3.0 (2.17, 3.11) 3.0 (2.09, 3.12) 3.0 (2.12, 3.10) Cancers 0.3 (0.12, 2.05) 0.4 (0.18, 2.27) 1.0 (0.12, 2.28) 0.2(0.10, 1.12) 0.2 (0.06, 1.43) Total follow-up time, person yrs Noncancers 7185 2371 1227 2206 1674 Cancers 110 57 20 19 14 Cancer incidence rate (per 1000 person yrs) 15 19 12 14 11 Incidence rate ratio (crude), (95 CI) 1.61 (0.90-2.88) 1.24 (0.70-2.19) IRR, adjusted for age, ethnicity, country (95 CI) (p value) 1.95 (1.06-3.56) (0.031) 1.36 (0.75-2.45) (0.3) ASAP = atypical small acinar proliferation; CI = confidence interval; Diff. = difference; HG PIN = high-grade prostate intraepithelial neoplasia; IQR = interquartile range; IRR = incidence rate ratio; PPV = positive predictive value; PrCa = prostate cancer; PSA = prostate-specific antigen. a A total of 95 individuals contribute to both BRCA1 and BRCA2 controls; therefore, the sum of mutation status will not match the total cohort. significant differences were observed in sociodemographic Cumulatively, after four PSA screens, 527 individuals variables, symptoms, or previous screening between groups. (18%) had PSA > 3.0 ng/ml and 112 cancers diagnosed from 357 biopsies. In the BRCA2 cohort, 47 (5.2%) cancers were 3.2. PrCa detection rates after 3 yr of screening and PPV of diagnosed in carriers and 15 (3.0%) in noncarriers; biopsy 31 cancers (3.4%) were diagnosed in BRCA1 carriers compared with 19 (2.7%) in noncarriers (Table 1 and Fig. 2). At baseline, 2932 participants had a PSA test, 228 (7.7%) had Overall PrCa detection rate was 3.8% (112/2932), and the PSA > 3.0 ng/ml, and 69 (2.4%) had cancers diagnosed from cancer incidence rate per 1000 person years was 15. The 195 biopsies. cancer incidence rates were 19 and 12 in BRCA2 carriers and E U R O P E A N U RO L O GY 76 ( 2 019 ) 8 31 – 8 4 2 837 [(Fig._2)TD$IG] Fig. 2 – A consort diagram of the IMPACT study after four screening rounds. ASAP = atypical small acinar proliferation; PIN = prostate intraepithelial neoplasia; PPV = positive predictive value; PSA = prostate-specific-antigen. a Controls were men who had a negative predictive genetic test for the BRCA mutation in their family. b Biopsy—abnormal refers to high-grade PIN and ASAP. noncarriers, respectively (incidence rate ratio [IRR] = 1.95, outlier, the analyses were repeated combining the control p = 0.031), and 14 and 11 in BRCA1 carriers and noncarriers, groups, and all significant differences remained. respectively (IRR = 1.36, p = 0.3). Analyses were repeated removing cancers diagnosed Overall, PPV of PB was 31%, with 39% and 28% in BRCA2 within <12 mo of study entry (Supplementary Table 5). These carriers and noncarriers, respectively (p = 0.17), and 32% and analyses show increased PrCa incidence in BRCA2 carriers; 20% in BRCA1 carriers and noncarriers, respectively (p = 0.065). however, these analyses are currently underpowered. The overall PPV of PSA > 3.0 ng/ml was 21%, with 31% and During the first four screening rounds, the biopsy 18% in BRCA2 carriers and noncarriers, respectively (p = compliance rate for raised PSA (>3) was 73% in BRCA2 0.025), and 23% and 15% in BRCA1 carriers and noncarriers, carriers, 60% in BRCA2 noncarriers, 67% in BRCA1 carriers, and respectively (p = 0.13). 71% in BRCA1 noncarriers. From the 357 biopsies performed To compare results with the population-based Göteborg including repeat biopsies, the median age at biopsy of BRCA2 cohort [30], we restricted the IMPACT cohort to entry ages 50– carriers was 60 yr, compared with 64 yr in BRCA2 noncarriers 64 yr (Supplementary Table 3). The Göteborg study report 2.5% (p  0.001). No differences were observed in the BRCA1 PrCa incidence (confidence interval [CI]: 2.2%, 2.8%) after 4 yr cohort (Table 2). When comparing by genetic status, no [30,31] compared with 5.3% (CI: 4.2–6.5) in IMPACT. differences were seen in median PSA, which triggered biopsy, PPV for PB is 30% in the Göteborg cohort and is 26% for time (in days) between PSA test and biopsy, age at biopsy, and PSA (above threshold). PPV for PB is 33% in IMPACT, number of diagnostic cores taken at biopsy. restricted to the Göteborg age range, and 24% for PSA > 3.0 ng/ml. When comparing PPVs in the Göteborg cohort with 3.3. Cancer characteristics IMPACT for clinically significant disease, we see a higher incidence in the BRCA2 carriers for both PSA (p  0.001) and Table 3 and Supplementary Table 6 show the characteristics PB (p  0.001). of all screen-detected PrCa cases diagnosed in patients with As a sensitivity analysis, analyses were repeated excluding a PSA level of >3.0 ng/ml during the first four screening centres in The Netherlands (Supplementary Table 4) that rounds. screened patients biennially. No differences in the distribu- The median age at PrCa diagnosis was 61 yr (interquartile tions of cancer incidence, incidence rate, or PPV of PB were range [IQR]: 56, 64) in BRCA2 carriers and 64 yr (IQR: 60, 66) observed. To rule out the BRCA2 control group being an in BRCA2 noncarriers (p = 0.044, Kruskal-Wallis). In the 838 E U RO P E A N U RO L O GY 76 ( 2 019 ) 8 31 – 8 4 2 Table 2 – Summary of characteristics of men who underwent biopsies in the first four screening rounds of the IMPACT study. Total BRCA1+ BRCA1– p value BRCA2+ BRCA2– p value Total biopsies (n) 357a 98 95 122 54 Biopsy compliance (%) 68 71 75 81 64 Median PSA (ng/ml) to trigger biopsy (IQR) 4.2 (3.5–5.6) 4.2 (3.7–5.6) 4.0 (3.5–4.8) 0.1 4.5 (3.5–5.9) 4.2 (3.4–6.2) 0.8 Median age (yr) at biopsy (IQR) 61 (56–65) 61 (56–64) 61 (56–65) 0.9 60 (56–64) 64 (60–67) <0.001 Median time difference (d) PSA to biopsy (IQR) 51 (27–89) 56 (28–72) 42 (22–79) 0.3 57 (28–94) 50 (25–87) 0.1 Median cores taken, n (IQR) 10 (8–12) 10 (9–12) 10 (8–12) 0.5 10 (8–12) 10 (8–12) 1 IQR = interquartile range; PSA = prostate-specific antigen. a Twelve biopsies contribute to both BRCA1 and BRCA2 controls, therefore the sum of mutation status will not match total cohort. Table 3 – Summary of cancer characteristics of PSA detected cancers using final clinical pathology (ie, if available after prostatectomy)a. Genetic status BRCA2+ (n = 48) BRCA2– (n = 15) p value BRCA1+ (n = 33) BRCA1– (n = 20) p value Median age (yr) at diagnosis 61 (56, 64) 64 (60, 66) 0.044 62 (57, 66) 61 (58, 62) 0.3 Median PSA (ng/ml) at diagnosis (IQR) 4.5 (3.6, 5.5) 4.2 (3.4, 6.1) 0.9 4.4(3.8, 5.9) 4.4 (3.6, 5.3) 0.7 Gleason score 6 18 (38) 11 (73) 0.019b 18 (55) 13 (65) 0.6a Gleason score 7 (3 + 4) 15 (31) 1 (7) 9 (27) 4 (20) Gleason score 7 (4 + 3) 9 (19) 2 (13) 4 (12) 3 (15) Gleason score 8+ 6 (12) 1 (7) 2 (6) 0 T stage—T1/T2a 16 (35) 8 (57) 0.2b 9 (31) 8 (40) 0.6a T Stage—T2b 2 (4) 2 (14) 0 1 (5) T Stage—T2c/T3 28 (61) 4 (29) 20 (69) 11 (55) Risk categoryc—low 11 (23) 9 (60) 0.011b 10 (30) 4 (20) 0.5a Risk categoryc—intermediate 7 (14.5) 1 (7) 3 (9) 6 (30) Risk categoryc—high 30 (62.5) 5 (33) 20 (61) 10 (50) Screening round diagnosed—1 25 (52) 7 (47) 23 (70) 13 (65) Screening round diagnosed—2 7 (14.5) 1 (7) 3 (9) 3 (15) Screening round diagnosed—3 9 (19) 5 (33) 6 (18) 2 (10) Screening round diagnosed—4 7 (14.5) 2 (13) 1 (3) 2 (10) Active surveillance 8 (17) 7 (47) 5 (17) 6 (30) Radical prostatectomy 32 (70) 6 (40) 22 (76) 12 (60) Nonsurgical treatment 6 (13) 2 (13) 2 (7) 2 (10) IQR = interquartile range; NICE = National Institute for Health and Care Excellence; PSA = prostate-specific antigen. Some pathology information is not available from sites yet. Values are presented as median (IQR) and n (%). a Note four cancers included in this analysis were diagnosed as a result of additional off-protocol repeat biopsies in men with high PSA. b p values calculated on difference between clinically significant disease and non–clinically significant disease. c Risk category classification system using NICE guidelines [21]. BRCA1 cohort, there was no difference in median age at BRCA1/2 mutations. IMPACT will screen all but the Dutch diagnosis (p = 0.33). patients for a total of five screening rounds, and collect Looking at the overall risk category, 37/48 (77%) BRCA2 cancer incidence and mortality data for a further 5 yr. carriers had intermediate- or high-risk PrCa (clinically Controversy about PSA level that used to trigger PB significant disease), compared with six/15 (40%) BRCA2 continues, and we have demonstrated that using a PSA level noncarriers (p = 0.011, Fisher’s exact). There were no of >3.0 ng/ml, after four screening rounds, 13% of the total statistically significant differences between BRCA1 carriers cohort was recommended to have a PB with a 3.8% cancer (70%) and noncarriers (80%; Fig. 3). detection rate. The IMPACT study continues to collect Limiting to incident cases, 48 cancers were diagnosed: 23 in screening data, and a further component of the protocol is to BRCA2 carriers, eight in BRCA2 noncarriers, 10 in BRCA1 offer men the option of undergoing PB after the completion carriers, and seven in BRCA1 noncarriers; there is no significant of five screening rounds, irrespective of the PSA level. This difference by carrier status. No significant difference was also will provide the opportunity to evaluate the number of seen when limiting to incident cases and excluding men who clinically significant cancers missed in carriers and non- had had a previous benign biopsy (n = 9). carriers when using a PSA threshold of 3.0 ng/ml. After four screening rounds, no deaths from PrCa were We have demonstrated that the trends reported after the reported in the IMPACT study participants. baseline screen are strengthened after 3 yr of follow-up. The PPV of PSA > 3.0 ng/ml was significantly higher in 4. Discussion BRCA2 mutation carriers (31%) compared with noncarriers (18%; p = 0.025). When compared with the Göteborg cohort, The IMPACT study is the only international prospective PrCa the PPV of PB in BRCA2 carriers was 41% compared with 30%, screening study conducted exclusively in families with therefore biopsying fewer men unnecessarily. As previously E U R O P E A N U RO L O GY 76 ( 2 019 ) 8 31 – 8 4 2 839 [(Fig._3)TD$IG] Fig. 3 – (A) Pie charts showing the overall prostate cancer risk category (as defined by the NICE guidelines—www.nice.org.uk: low: PSA < 10 and Gleason 6 and T1/T2a; intermediate: PSA 10–20 or Gleason 7 or T2b; and high: PSA > 20 or Gleason 8–10 or  T2c), for all study PSA-detected cancers in screening rounds 1–4 and broken down by genetic status. (B) Pie charts showing the overall Gleason score, for all study PSA-detected cancers in screening rounds 1–4 and broken down by genetic status. NICE = National Institute for Health and Care Excellence; PSA = prostate-specific-antigen. reported, no significant differences were detected between high-risk cancers were detected in BRCA2 carriers than in BRCA1 carriers and noncarriers [19]. noncarriers (p = 0.074). Owing to the relatively small After four screening rounds, BRCA2 carriers have a number of cancers diagnosed in the BRCA2 noncarriers, statistically significantly higher cancer incidence rate (19) we also re-ran these analyses combining the two noncarrier per 1000 person years compared with noncarriers (12; p = control groups, and statistically significant differences in 0.03). With a higher number of cancers detected than tumour characteristics remained. In addition, clinically reported previously [22], we have confirmed that significant cancers were diagnosed at every screening BRCA2 carriers are diagnosed at a younger age (p = 0.044) round, supporting the use of systematic PSA screening. than BRCA2 noncarriers and that a significantly greater After 3 yr of follow-up, it is possible that disease was proportion of cancers were intermediate- or high-risk present, but not detectable by PSA, at study entry. A further disease (p = 0.011). Overall, 77% of cancers diagnosed in aim of the IMPACT study is to offer PB to all men after five BRCA2 carriers were clinically significant, compared with screening rounds, to evaluate the utility of a baseline biopsy 49% in the general population [11]. The youngest age of irrespective of the PSA level with respect to cancer diagnosis of clinically significant disease was 41 yr for prevalence and tumour characteristics. However, it is BRCA2 carriers and 43 yr for BRCA1 carriers, which may reassuring to see from the data presented that using a suggest screening from an early age. Regarding the number cut-off of 3 ng/ml, the majority of the tumours detected of men needed to screen to detect one clinically significant were at an early stage. PrCa after four screening rounds, screening 60 BRCA2 No statistically significant differences were detected in carriers aged 40–54 yr and 13 carriers aged 55–69 yr will age of onset or cancer characteristics between BRCA1 detect one clinically significant PrCa, respectively. Eventu- carriers and noncarriers. Further follow-up is required to ally, long-term follow-up data on the clinical benefit of early conclude the clinical management of BRCA1 carriers. detection are needed to determine the best starting age. Similar to our report for the IMPACT baseline screen [22], Analyses of the cancer detection rates, PPV, and the ProtecT score using the 4 K panel (Supplementary characteristics were repeated excluding prevalent cancers material) was able to predict PB outcome, with a (PrCa diagnosed within 12 mo of baseline PSA). It was found discrimination of 0.73 for high-grade disease. This adds that whilst not statistically significant, there was greater further evidence to support the use of additional biological PrCa incidence in BRCA2 carriers than in noncarriers (9.1 vs markers, such as the 4 K panel in improving the detection of 6.4), and substantially higher numbers of intermediate- and clinically significant PrCa. 840 E U RO P E A N U RO L O GY 76 ( 2 019 ) 8 31 – 8 4 2 4.1. Limitations PrCa, are diagnosed at a younger age, and present with more clinically significant tumours than BRCA2 noncarriers. A limitation of IMPACT is that not all men comply with the Further follow-up is required to assess the role of screening study protocol, and therefore cancers may be missed either in in BRCA1 mutation carriers. Therefore, these data support men who refuse PB, or in men who are advised locally to have the use of systematic PSA screening in male BRCA2 carriers. MRI or repeat PSA instead of a PB. Genetic status may play a role in protocol compliance with fewer noncarriers, particu- Author contributions: Rosalind A. Eeles had full access to all the data in larly BRCA2 noncarriers, proceeding with a PB (73% vs 60%). the study and takes responsibility for the integrity of the data and the This differential biopsy rate is likely to have underestimated accuracy of the data analysis. the PrCa incidence in both BRCA2 carriers and noncarriers. Complete data would be expected to strengthen the power to Study concept and design: Aaronson, Ardern-Jones, Bancroft, Bangma, detect the difference in clinically significant disease between Castro, Dearnaley, Eccles, Evans, Eyfjord, Falconer, Foster, Gronberg, these groups. As follow-up will continue for a further 5 yr, Hamdy, Johannsson, Khoo, Kote-Jarai, Lilja, Lindeman, Lubinski, Mahle, these data will become available as part of future analyses. Mikropoulos, Mitra, Moynihan, Page, Rennert, Suri. Acquisition of data: All authors. The higher observed biopsy rate within BRCA2 carriers could Analysis and interpretation of data: All authors. represent variation in how health professionals counsel men Drafting of the manuscript: All authors. with high PSA levels, with a bias towards encouraging biopsy Critical revision of the manuscript for important intellectual content: All in BRCA2 carriers. Of note, no variation was seen between the authors. number of cores taken at biopsy and mutation status. Statistical analysis: Page, Bancroft, Brook, Assel, Vickers, Lilja. Variation was observed between sites and across the course Obtaining funding: Eeles and all IMPACT collaborating sites obtained their of the study as the protocol increased from 10 to 12 biopsy own funding for running the study at their site. cores as standard practice changed. Administrative, technical, or material support: All authors. Given the rarity of BRCA1/2 mutations, it was not possible Supervision: Eeles. to restrict the protocol to those with no prior urinary Other: None. symptoms or PSA testing. Those with a prior PB were excluded. There was no difference in cancer incidence rates Financial disclosures: Rosalind A. Eeles certifies that all conflicts of in those with symptoms or prior PSA testing. interest, including specific financial interests and relationships and In comparing with the Göteborg cohort, we acknowledge affiliations relevant to the subject matter or materials discussed in the manuscript (eg, employment/affiliation, grants or funding, consultan- that this general population cohort is not stratified for BRCA cies, honoraria, stock ownership or options, expert testimony, royalties, status; however, the population frequency of BRCA1/2 or patents filed, received, or pending), are the following: Hans Lilja holds mutations is low. This study also used biennial rather than patents for intact PSA assays, and is named, along with Andrew J. Vickers, yearly PSA and was restricted to sextant PB, and therefore on a patent application for a statistical method to detect prostate cancer. cancer detection rates at PB may be lower than that in The patents have been licensed and commercialised as the 4 Kscore by IMPACT. OPKO Health. Drs. Vickers and Lilja receive royalties from sales of this IMPACT started in 2005, prior to the implementation of test. Additionally, Dr. Lilja owns stock and Dr. Vickers owns stock options multiparametric MRI in PrCa screening [17,18]. Without a in OPKO. Professor Rosalind Eeles: Royal Marsden Hospital—Nov 2017; systematic evaluation of the use of MRI in men at support from Janssen; honorarium as speaker £1100; University of genetically high risk, it is difficult to extrapolate general Chicago invited talk May 2018; honorarium as speaker $1000. The population data to this setting and needs further research. remaining authors have no other conflict of interest to declare. The Dutch protocol, as outlined above, screened men every 2 yr, and also included digital rectal examination and Funding/Support and role of the sponsor: This research is coordinated by the Institute of Cancer Research, London, UK, and is supported by grants PCA3 in the algorithm of whether to proceed to biopsy or from Cancer Research UK (grant references C5047/A21332, C5047/ not. Therefore, some men with PSA < 3.0 ng/ml were A13232, and C5047/A17528) and the Ronald and Rita McAulay Founda- biopsied, some of whom were diagnosed with cancer. tion. Judith Offman is supported by Cancer Research UK Programme Grant However, despite this differing protocol in this cohort, reference C8161/A16892. Mr. and Mrs. Jack Baker are acknowledged for sensitivity analyses excluding the Dutch data demonstrate supporting the study in NorthShore University HealthSystem, Evanston, that this approach did not affect the overall results. IL, USA and Myriad Genetics Laboratory, Salt Lake City, UT, USA, for A challenge of a longitudinal study such as IMPACT is in providing research BRCA testing rates for NorthShore University balancing the standardisation of procedures and changes in HealthSystem patients. We acknowledge funding from the National practice. For example, there have been changes in PB during Institute for Health Research (NIHR) to the Biomedical Research Center at the course of this study; the protocol has been updated to the Institute of Cancer Research and the Royal Marsden NHS Foundation increase the number of diagnostic cores from 10 to 12 during Trust, at Manchester University Foundation Trust (IS-BRC-1215-20007), the Oxford Biomedical Research Centre Program, and the Cambridge the study’s duration. Some centres have used the transper- Clinical Research Centre, NIHR Cambridge Biomedical Research Centre. ineal approach in line with local practice guidelines. We acknowledge that in Australia, this project was cofunded by Cancer Council Tasmania and Cancer Australia (grant number 1006349 [2011– 5. Conclusions 2013]), Prostate Cancer Foundation of Australia (grant number PCFA PRO4 [2008]), Cancer Councils of Victoria and South Australia (grant number We demonstrate that, after four annual PSA screening 400048 [2006–2008]), the Victorian Cancer Agency Clinical Trial Capacity rounds, BRCA2 mutation carriers have a higher incidence of CTCB08_14, Cancer Australia and Prostate Cancer Foundation of Australia E U R O P E A N U RO L O GY 76 ( 2 019 ) 8 31 – 8 4 2 841 (2014–2016; grant number 1059423), and Translational grants EOI09_50. [7] Taylor RA, Fraser M, Livingstone J, et al. Germline BRCA2 mutations The Association of International Cancer Research funded data collection drive prostate cancers with distinct evolutionary trajectories. Nat in The Netherlands (AICR 10-0596). We acknowledge funding from the Commun 2017;8:13671. Basser Center for BRCA (to Susan Domchek). This work was supported in [8] Leongamornlert D, Mahmud N, Tymrakiewicz M, et al. Germline part by the National Institutes of Health/National Cancer Institute (NIH/ BRCA1 mutations increase prostate cancer risk. Br J Cancer NCI) with a Cancer Center Support Grant to Memorial Sloan Kettering 2012;106:1697–701. Cancer Center (P30 CA008748), a SPORE grant in Prostate Cancer to Dr. H. [9] Giusti RM, Rutter JL, Duray PH, et al. A twofold increase in BRCA Scher (P50-CA92629), the Sidney Kimmel Center for Prostate and Urologic mutation related prostate cancer among Ashkenazi Israelis is not Cancers, David H. Koch through the Prostate Cancer Foundation. This associated with distinctive histopathology. J Med Genet work was also supported in part by the NIHR Oxford Biomedical Research 2003;40:787–92. Centre Program in UK, the Swedish Cancer Society (CAN 2017/559), the [10] Pinsky PF, Yu K, Kramer BS, et al. Extended mortality results for Swedish Research Council (VR-MH project no. 2016-02974), and General ovarian cancer screening in the PLCO trial with median 15 years Hospital in Malmö Foundation for Combating Cancer. We acknowledge follow-up. Gynecol Oncol 2016;143:270–5. funding from the Slovenian Research Agency, Research programme P3- [11] Schroder FH, Hugosson J, Roobol MJ, et al. Screening and prostate 0352. We thank CERCA Program/Generalitat de Catalunya for their cancer mortality: results of the European Randomised Study of institutional support. Elena Castro acknowledges funding from Prostate Screening for Prostate Cancer (ERSPC) at 13 years of follow-up. Cancer Foundation. We acknowledge the support of the Asociación Lancet 2014;384:2027–35. Española Contra el Cáncer (AECC), the Instituto de Salud Carlos III [12] Martin RM, Donovan JL, Turner EL, et al. Effect of a low-intensity (organismo adscrito al Ministerio de Economía y Competitividad), “Fondo PSA-based screening intervention on prostate cancer mortality: the Europeo de Desarrollo Regional (FEDER), una manera de hacer Europa” CAP randomized clinical trial. JAMA 2018;319:883–95. (PI10/01422, PI13/00285, PIE13/00022, PI16/00563, JR18/00011 and [13] Assel M, Sjoblom L, Murtola TJ, et al. A four-kallikrein panel and CIBERONC), and the Institut Català de la Salut and Autonomous beta-microseminoprotein in predicting high-grade prostate cancer Government of Catalonia (2009SGR290, 2014SGR338 and PERIS Project on biopsy: an independent replication from the Finnish section of MedPerCan). We acknowledge funding support from Fundação para a the European Randomized Study of Screening for Prostate Cancer. Ciência e a Tecnologia to the IPO Porto study (project grant PTDC/DTP-PIC/ Eur Urol Focus 2017. http://dx.doi.org/10.1016/j.euf.2017.11.002. 1308/2014 to Manuel R. 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