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

      research-article
      a , b , b , b , c , d , e , f , g , h , h , h , i , j , k , j , l , l , m , m , n , n ,   o , p , q , p , r , r , s , s , t , u , u , v , v , w , q , q , q , x , y , y , z , aa , bb , bb , cc , dd , dd , ee , ee , ff , gg , ff , hh , hh , ii , jj , kk , ll , mm , nn , oo , pp , qq , rr , ss , tt , uu , vv , ww , xx , yy , zz , aaa , bbb , aaa , bbb , ccc , ddd , eee , fff , ggg , hhh , iii , jjj , kkk , lll , mmm , nnn , ooo , ppp , qqq ,   rrr , sss , ttt , uuu , vvv , www , xxx ,   yyy , zzz , aaaa , bbbb , cccc , dddd , vv , ooo , eeee , ii , a , w , a , b , n , ffff , m , gggg , hhhh , e , nn , rrr , a , b , r , l , bbb , j , b , iiii , b , jjjj , kkkk , llll , a , b , The IMPACT Collaborators , mmmm , b , a , *
      European Urology
      Elsevier Science
      BRCA1, BRCA2, Prostate cancer, Prostate-specific antigen, Targeted screening

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          Abstract

          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 enrolment 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 enrolment, 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.

          Take Home Message

          This report demonstrates that germline genetic markers can be used to identify men at higher risk of prostate cancer. Targeting screening at these higher-risk men resulted in the identification of tumours that were more likely to require treatment.

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          Most cited references27

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          The 2005 International Society of Urological Pathology (ISUP) Consensus Conference on Gleason Grading of Prostatic Carcinoma.

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            Mortality results from a randomized prostate-cancer screening trial.

            The effect of screening with prostate-specific-antigen (PSA) testing and digital rectal examination on the rate of death from prostate cancer is unknown. This is the first report from the Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial on prostate-cancer mortality. From 1993 through 2001, we randomly assigned 76,693 men at 10 U.S. study centers to receive either annual screening (38,343 subjects) or usual care as the control (38,350 subjects). Men in the screening group were offered annual PSA testing for 6 years and digital rectal examination for 4 years. The subjects and health care providers received the results and decided on the type of follow-up evaluation. Usual care sometimes included screening, as some organizations have recommended. The numbers of all cancers and deaths and causes of death were ascertained. In the screening group, rates of compliance were 85% for PSA testing and 86% for digital rectal examination. Rates of screening in the control group increased from 40% in the first year to 52% in the sixth year for PSA testing and ranged from 41 to 46% for digital rectal examination. After 7 years of follow-up, the incidence of prostate cancer per 10,000 person-years was 116 (2820 cancers) in the screening group and 95 (2322 cancers) in the control group (rate ratio, 1.22; 95% confidence interval [CI], 1.16 to 1.29). The incidence of death per 10,000 person-years was 2.0 (50 deaths) in the screening group and 1.7 (44 deaths) in the control group (rate ratio, 1.13; 95% CI, 0.75 to 1.70). The data at 10 years were 67% complete and consistent with these overall findings. After 7 to 10 years of follow-up, the rate of death from prostate cancer was very low and did not differ significantly between the two study groups. (ClinicalTrials.gov number, NCT00002540.) 2009 Massachusetts Medical Society
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              Cancer risks in BRCA2 mutation carriers.

              (1999)
              Carriers of germline mutations in the BRCA2 gene are known to be at high risk of breast and ovarian cancers, but the risks of other cancers in mutation carriers are uncertain. We investigated these risks in 173 breast-ovarian cancer families with BRCA2 mutations identified at 20 centers in Europe and North America. Other cancer occurrence was determined in a final cohort of 3728 individuals, among whom 681 persons had breast or ovarian cancer and 3047 persons either were known mutation carriers, were first-degree relatives of known mutation carriers, or were first-degree relatives of breast or ovarian cancer patients. Incidence rates were compared with population-specific incidence rates, and relative risks (RRs) to carriers, together with 95% confidence intervals (CIs), were estimated by use of a maximum likelihood approach. Three hundred thirty-three other cancers occurred in this cohort. Statistically significant increases in risks were observed for prostate cancer (estimated RR = 4.65; 95% CI = 3.48-6.22), pancreatic cancer (RR = 3.51; 95% CI = 1. 87-6.58), gallbladder and bile duct cancer (RR = 4.97; 95% CI = 1. 50-16.52), stomach cancer (RR = 2.59; 95%CI = 1.46-4.61), and malignant melanoma (RR = 2.58; 95% CI = 1.28-5.17). The RR for prostate cancer for men below the age of 65 years was 7.33 (95% CI = 4.66-11.52). Among women who had already developed breast cancer, the cumulative risks of a second, contralateral breast cancer and of ovarian cancer by the age of 70 years were estimated to be 52.3% (95% CI = 41.7%-61.0%) and 15.9% (95% CI = 8.8%-22.5%), respectively. In addition to the large risks of breast and ovarian cancers, BRCA2 mutations may be associated with increased risks of several other cancers.
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                Author and article information

                Contributors
                Journal
                Eur Urol
                Eur. Urol
                European Urology
                Elsevier Science
                0302-2838
                1873-7560
                1 September 2014
                September 2014
                : 66
                : 3
                : 489-499
                Affiliations
                [a ]Cancer Genetics Unit and Academic Urology Unit, Royal Marsden NHS Foundation Trust, London, UK
                [b ]Oncogenetics Team, Institute of Cancer Research, London, UK
                [c ]Spanish National Cancer Research Centre, Madrid, Spain
                [d ]Departments of Laboratory Medicine, Surgery, and Medicine, Memorial Sloan-Kettering Cancer Center, New York, NY, USA
                [e ]Nuffield Department of Surgical Sciences, University of Oxford, Oxford, UK
                [f ]Institute of Biomedical Technology, University of Tampere, Tampere, Finland
                [g ]Department of Laboratory Medicine, Lund University, Malmö, Sweden
                [h ]Department of Epidemiology and Biostatistics, Memorial Sloan-Kettering Cancer Center, New York, NY, USA
                [i ]HCA Healthcare Laboratories, London, WC1E 6JA, UK
                [j ]Familial Cancer Centre, Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia
                [k ]Sir Peter MacCallum Department of Oncology, University of Melbourne, Melbourne, Victoria, Australia
                [l ]Norwegian Radium Hospital, Oslo, Norway
                [m ]Genetic Medicine, Manchester Academic Health Sciences Centre, Central Manchester University Hospitals NHS Foundation Trust, Manchester, UK
                [n ]Wessex Clinical Genetics Service, Princess Anne Hospital, Southampton, UK
                [o ]Leiden University Medical Center, Leiden, The Netherlands
                [p ]Foundation for the Detection of Hereditary Tumours, Leiden, The Netherlands
                [q ]Radboud University Medical Centre, Nijmegen, The Netherlands
                [r ]International Hereditary Cancer Center, Pomeranian Medical University, Szczecin, Poland
                [s ]Center for Medical Genetics, NorthShore University HealthSystem, Evanston, IL, USA
                [t ]Priztker School of Medicine, University of Chicago, Chicago, IL, USA
                [u ]Vejle Hospital, Vejle, Denmark
                [v ]Department of Urology, Repatriation General Hospital, Daw Park, South Australia, Australia
                [w ]Erasmus Medical Center, Rotterdam, The Netherlands
                [x ]University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
                [y ]Hereditary Cancer Program, Catalonian Institute of Oncology, L’Hospitalet, Barcelona, Spain
                [z ]Sheffield Clinical Genetics Service, Sheffield Children's Hospital, Sheffield, UK
                [aa ]Royal Hallamshire Hospital, Sheffield, UK
                [bb ]Huntsman Cancer Institute, University of Utah, Salt Lake City, UT, USA
                [cc ]Department of Medical Genetics, University Medical Centre Utrecht, The Netherlands
                [dd ]Clinical Genetics Unit, Birmingham Women's Hospital, Birmingham, UK
                [ee ]Basser Research Center, University of Pennsylvania, Philadelphia, PA, USA
                [ff ]Genetics Department and Research Center, Portuguese Oncology Institute, Porto, Portugal
                [gg ]Biomedical Sciences Institute (ICBAS), Porto University, Porto, Portugal
                [hh ]McGill Program in Cancer Genetics, Departments of Oncology and Human Genetics, McGill University, Montreal, Quebec, Canada
                [ii ]The Netherlands Cancer Institute, Amsterdam, The Netherlands
                [jj ]Maastricht University Medical Center, Department of Clinical Genetics, Maastricht, The Netherlands
                [kk ]South East Thames Genetics Service, London, UK, Guy's Hospital, London, UK
                [ll ]Duncan Guthrie Institute of Medical Genetics, Yorkhill NHS Trust, Glasgow, UK
                [mm ]VU University Medical Center, Amsterdam, The Netherlands
                [nn ]Churchill Hospital, Headington, Oxford, UK
                [oo ]Center of Familial Breast and Ovarian Cancer, University Hospital of Cologne, Cologne, Germany
                [pp ]Hereditary Cancer Clinic, Prince of Wales Hospital, Randwick, New South Wales, Australia
                [qq ]Faculty of Medicine, University of New South Wales, Sydney, New South Wales, Australia
                [rr ]Familial Cancer Service, Westmead Hospital, Westmead, Sydney, New South Wales, Australia
                [ss ]Sydney Medical School (University of Sydney) at Westmead Millennium Institute, Sydney, NSW, Australia
                [tt ]St. George's Hospital, Tooting, London, UK
                [uu ]Familial Cancer Centre, Monash Health, Clayton, Victoria, Australia
                [vv ]Northern Genetics Service, Newcastle upon Tyne Hospitals, Newcastle upon Tyne, UK
                [ww ]Familial Cancer Centre, The Royal Melbourne Hospital, Parkville, Victoria, Australia
                [xx ]Stem Cells and Cancer Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, Australia
                [yy ]Department of Medicine, The University of Melbourne, Parkville, Victoria, Australia
                [zz ]Institute of Oncology, Ljubljana, Slovenia
                [aaa ]Addenbrooke's Hospital, Cambridge, UK
                [bbb ]The University of Cambridge, Cambridge, UK
                [ccc ]Genetic Health Queensland, Royal Brisbane and Women's Hospital, Herston, Queensland, Australia
                [ddd ]Hospital de Sant Pau, Barcelona, Spain
                [eee ]Genetic Services of WA, King Edward Memorial Hospital, Subiaco, WA, Australia
                [fff ]Department of Paediatrics, University of Western Australia, Perth, WA, Australia
                [ggg ]Hospital Vall d’Hebron, Barcelona, Spain
                [hhh ]Hunter Family Cancer Service, Waratah, New South Wales, Australia
                [iii ]University of New South Wales, St. Vincent's Clinical School, Darlinghurst, New South Wales, Australia
                [jjj ]Hereditary Cancer Clinic, The Kinghorn Cancer Centre, St. Vincent's Hospital, Sydney, New South Wales, Australia
                [kkk ]Academic Medical Center, Amsterdam, The Netherlands
                [lll ]Karolinska University Hospital and Karolinska Institute, Stockholm, Sweden
                [mmm ]NE Thames Regional Genetics Service, Institute of Child Health, London, UK
                [nnn ]Peninsular Genetics, Derriford Hospital, Plymouth, UK
                [ooo ]Royal Devon and Exeter Hospital, Exeter, UK
                [ppp ]North West Thames Regional Genetics Service, Kennedy-Galton Centre, North West London Hospitals NHS Trust, Harrow, UK
                [qqq ]St. Michael's Hospital, Bristol, UK
                [rrr ]Landspitali–the National University Hospital of Iceland, Reykjavik, Iceland
                [sss ]Chaim Shema Medical Center, Tel-Hashomer, Israel
                [ttt ]The Genetic Institute, Kaplan Medical Center, Rehovot, Israel
                [uuu ]Murdoch Childrens Research Institute, Parkville, Victoria, Australia
                [vvv ]National Cancer Institute, Bratislava, Slovak Republic
                [www ]University of Leicester, Leicester, UK
                [xxx ]University Hospitals Leicester, Leicester, UK
                [yyy ]Fox Chase Cancer Center, Philadelphia, PA, USA
                [zzz ]Tata Memorial Centre, Mumbai, India
                [aaaa ]Istituto Nazionale dei Tumori, Milano, Italy
                [bbbb ]Cancer Research Initiatives Foundation, Subang Jaya Medical Centre, Selangor, Darul Ehsan, Malaysia
                [cccc ]Clinical Genetics, Royal Liverpool Children's Hospital, Liverpool, UK
                [dddd ]The University of Texas, MD Anderson Cancer Center, Houston, TX, USA
                [eeee ]Mater Misericordiae University Hospital, Dublin, Ireland
                [ffff ]Faculty of Medicine, School of Health Sciences, University of Iceland, Reykjavik, Iceland
                [gggg ]Imperial College Healthcare NHS Trust, London, London, UK
                [hhhh ]University Hospital, Umea, Sweden
                [iiii ]University College London Hospitals NHS Foundation Trust, London, UK
                [jjjj ]CHS National Cancer Control Center, Carmel Medical Center, Haifa, Israel
                [kkkk ]Nottingham City Hospital, Nottingham, UK
                [llll ]BioZenix, Altrincham, Cheshire, UK
                [mmmm ]Queen Mary University of London, London, UK
                Author notes
                [* ]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. rosalind.eeles@ 123456icr.ac.uk
                [†]

                See online Supplement.

                Article
                S0302-2838(14)00004-9
                10.1016/j.eururo.2014.01.003
                4105321
                24484606
                b883283d-13dd-4f09-905b-6929339d9583
                © 2014 Elsevier B.V. on behalf of European Association of Urology. All rights reserved.
                History
                : 2 January 2014
                Categories
                Platinum Priority – Prostate Cancer
                Editorial by Ola Bratt on pp. 500–501 of this issue

                Urology
                brca1,brca2,prostate cancer,prostate-specific antigen,targeted screening
                Urology
                brca1, brca2, prostate cancer, prostate-specific antigen, targeted screening

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