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


METHODS
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.


METHODS
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.


CONCLUSIONS
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.


RESULTS
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.
Cancer Genetics Unit and Academic Urology Unit, Royal Marsden NHS Foundation Trust, London, UK; Oncogenetics Team, Institute of Cancer Research, London, UK.
Elizabeth K
EK
Bancroft
Oncogenetics Team, Institute of Cancer Research, London, UK.
Elizabeth C
EC
Page
Oncogenetics Team, Institute of Cancer Research, London, UK; Spanish National Cancer Research Centre, Madrid, Spain.
Elena
E
Castro
Departments of Laboratory Medicine, Surgery, and Medicine, Memorial Sloan-Kettering Cancer Center, New York, NY, USA; Nuffield Department of Surgical Sciences, University of Oxford, Oxford, UK; Institute of Biomedical Technology, University of Tampere, Tampere, Finland; Department of Laboratory Medicine, Lund University, Malmö, Sweden.
Hans
H
Lilja
Department of Epidemiology and Biostatistics, Memorial Sloan-Kettering Cancer Center, New York, NY, USA.
Andrew
A
Vickers
Department of Epidemiology and Biostatistics, Memorial Sloan-Kettering Cancer Center, New York, NY, USA.
Daniel
D
Sjoberg
Department of Epidemiology and Biostatistics, Memorial Sloan-Kettering Cancer Center, New York, NY, USA.
Melissa
M
Assel
HCA Healthcare Laboratories, London, WC1E 6JA, UK.
Christopher S
CS
Foster
Familial Cancer Centre, Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia; Sir Peter MacCallum Department of Oncology, University of Melbourne, Melbourne, Victoria, Australia.
Gillian
G
Mitchell
Familial Cancer Centre, Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia.
Kate
K
Drew
Norwegian Radium Hospital, Oslo, Norway.
Lovise
L
Mæhle
Norwegian Radium Hospital, Oslo, Norway.
Karol
K
Axcrona
Genetic Medicine, Manchester Academic Health Sciences Centre, Central Manchester University Hospitals NHS Foundation Trust, Manchester, UK.
D Gareth
DG
Evans
Genetic Medicine, Manchester Academic Health Sciences Centre, Central Manchester University Hospitals NHS Foundation Trust, Manchester, UK.
Barbara
B
Bulman
Wessex Clinical Genetics Service, Princess Anne Hospital, Southampton, UK.
Diana
D
Eccles
Wessex Clinical Genetics Service, Princess Anne Hospital, Southampton, UK.
Donna
D
McBride
Leiden University Medical Center, Leiden, The Netherlands.
Christi
C
van Asperen
Foundation for the Detection of Hereditary Tumours, Leiden, The Netherlands.
Hans
H
Vasen
Radboud University Medical Centre, Nijmegen, The Netherlands.
Lambertus A
LA
Kiemeney
Foundation for the Detection of Hereditary Tumours, Leiden, The Netherlands.
Janneke
J
Ringelberg
International Hereditary Cancer Center, Pomeranian Medical University, Szczecin, Poland.
Cezary
C
Cybulski
International Hereditary Cancer Center, Pomeranian Medical University, Szczecin, Poland.
Dominika
D
Wokolorczyk
Center for Medical Genetics, NorthShore University HealthSystem, Evanston, IL, USA.
Christina
C
Selkirk
Center for Medical Genetics, NorthShore University HealthSystem, Evanston, IL, USA; Priztker School of Medicine, University of Chicago, Chicago, IL, USA.
Peter J
PJ
Hulick
Vejle Hospital, Vejle, Denmark.
Anders
A
Bojesen
Vejle Hospital, Vejle, Denmark.
Anne-Bine
AB
Skytte
Department of Urology, Repatriation General Hospital, Daw Park, South Australia, Australia.
Jimmy
J
Lam
Department of Urology, Repatriation General Hospital, Daw Park, South Australia, Australia.
Louise
L
Taylor
Erasmus Medical Center, Rotterdam, The Netherlands.
Rogier
R
Oldenburg
Radboud University Medical Centre, Nijmegen, The Netherlands.
Ruben
R
Cremers
Radboud University Medical Centre, Nijmegen, The Netherlands.
Gerald
G
Verhaegh
Radboud University Medical Centre, Nijmegen, The Netherlands.
Wendy A
WA
van Zelst-Stams
University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
Jan C
JC
Oosterwijk
Hereditary Cancer Program, Catalonian Institute of Oncology, L'Hospitalet, Barcelona, Spain.
Ignacio
I
Blanco
Hereditary Cancer Program, Catalonian Institute of Oncology, L'Hospitalet, Barcelona, Spain.
Monica
M
Salinas
Sheffield Clinical Genetics Service, Sheffield Children's Hospital, Sheffield, UK.
Jackie
J
Cook
Royal Hallamshire Hospital, Sheffield, UK.
Derek J
DJ
Rosario
Huntsman Cancer Institute, University of Utah, Salt Lake City, UT, USA.
Saundra
S
Buys
Huntsman Cancer Institute, University of Utah, Salt Lake City, UT, USA.
Tom
T
Conner
Department of Medical Genetics, University Medical Centre Utrecht, The Netherlands.
Margreet G
MG
Ausems
Clinical Genetics Unit, Birmingham Women's Hospital, Birmingham, UK.
Kai-ren
KR
Ong
Clinical Genetics Unit, Birmingham Women's Hospital, Birmingham, UK.
Jonathan
J
Hoffman
Basser Research Center, University of Pennsylvania, Philadelphia, PA, USA.
Susan
S
Domchek
Basser Research Center, University of Pennsylvania, Philadelphia, PA, USA.
Jacquelyn
J
Powers
Genetics Department and Research Center, Portuguese Oncology Institute, Porto, Portugal; Biomedical Sciences Institute (ICBAS), Porto University, Porto, Portugal.
Manuel R
MR
Teixeira
Genetics Department and Research Center, Portuguese Oncology Institute, Porto, Portugal.
Sofia
S
Maia
McGill Program in Cancer Genetics, Departments of Oncology and Human Genetics, McGill University, Montreal, Quebec, Canada.
William D
WD
Foulkes
McGill Program in Cancer Genetics, Departments of Oncology and Human Genetics, McGill University, Montreal, Quebec, Canada.
Nassim
N
Taherian
The Netherlands Cancer Institute, Amsterdam, The Netherlands.
Marielle
M
Ruijs
Maastricht University Medical Center, Department of Clinical Genetics, Maastricht, The Netherlands.
Apollonia T
AT
Helderman-van den Enden
South East Thames Genetics Service, London, UK, Guy's Hospital, London, UK.
Louise
L
Izatt
Duncan Guthrie Institute of Medical Genetics, Yorkhill NHS Trust, Glasgow, UK.
Rosemarie
R
Davidson
VU University Medical Center, Amsterdam, The Netherlands.
Muriel A
MA
Adank
Churchill Hospital, Headington, Oxford, UK.
Lisa
L
Walker
Center of Familial Breast and Ovarian Cancer, University Hospital of Cologne, Cologne, Germany.
Rita
R
Schmutzler
Hereditary Cancer Clinic, Prince of Wales Hospital, Randwick, New South Wales, Australia; Faculty of Medicine, University of New South Wales, Sydney, New South Wales, Australia.
Kathy
K
Tucker
Familial Cancer Service, Westmead Hospital, Westmead, Sydney, New South Wales, Australia; Sydney Medical School (University of Sydney) at Westmead Millennium Institute, Sydney, NSW, Australia.
Judy
J
Kirk
St. George's Hospital, Tooting, London, UK.
Shirley
S
Hodgson
Familial Cancer Centre, Monash Health, Clayton, Victoria, Australia.
Marion
M
Harris
Northern Genetics Service, Newcastle upon Tyne Hospitals, Newcastle upon Tyne, UK.
Fiona
F
Douglas
Familial Cancer Centre, The Royal Melbourne Hospital, Parkville, Victoria, Australia; Stem Cells and Cancer Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, Australia; Department of Medicine, The University of Melbourne, Parkville, Victoria, Australia.
Geoffrey J
GJ
Lindeman
Institute of Oncology, Ljubljana, Slovenia.
Janez
J
Zgajnar
Addenbrooke's Hospital, Cambridge, UK; The University of Cambridge, Cambridge, UK.
Marc
M
Tischkowitz
Addenbrooke's Hospital, Cambridge, UK; The University of Cambridge, Cambridge, UK.
Virginia E
VE
Clowes
Genetic Health Queensland, Royal Brisbane and Women's Hospital, Herston, Queensland, Australia.
Rachel
R
Susman
Hospital de Sant Pau, Barcelona, Spain.
Teresa
T
Ramón y Cajal
Genetic Services of WA, King Edward Memorial Hospital, Subiaco, WA, Australia; Department of Paediatrics, University of Western Australia, Perth, WA, Australia.
Nicholas
N
Patcher
Hospital Vall d'Hebron, Barcelona, Spain.
Neus
N
Gadea
Hunter Family Cancer Service, Waratah, New South Wales, Australia; University of New South Wales, St. Vincent's Clinical School, Darlinghurst, New South Wales, Australia; Hereditary Cancer Clinic, The Kinghorn Cancer Centre, St. Vincent's Hospital, Sydney, New South Wales, Australia.
Allan
A
Spigelman
Academic Medical Center, Amsterdam, The Netherlands.
Theo
T
van Os
Karolinska University Hospital and Karolinska Institute, Stockholm, Sweden.
Annelie
A
Liljegren
NE Thames Regional Genetics Service, Institute of Child Health, London, UK.
Lucy
L
Side
Peninsular Genetics, Derriford Hospital, Plymouth, UK; Royal Devon and Exeter Hospital, Exeter, UK.
Carole
C
Brewer
North West Thames Regional Genetics Service, Kennedy-Galton Centre, North West London Hospitals NHS Trust, Harrow, UK.
Angela F
AF
Brady
St. Michael's Hospital, Bristol, UK.
Alan
A
Donaldson
Landspitali-the National University Hospital of Iceland, Reykjavik, Iceland.
Vigdis
V
Stefansdottir
Chaim Shema Medical Center, Tel-Hashomer, Israel.
Eitan
E
Friedman
The Genetic Institute, Kaplan Medical Center, Rehovot, Israel.
Rakefet
R
Chen-Shtoyerman
Murdoch Childrens Research Institute, Parkville, Victoria, Australia.
David J
DJ
Amor
National Cancer Institute, Bratislava, Slovak Republic.
Lucia
L
Copakova
University of Leicester, Leicester, UK; University Hospitals Leicester, Leicester, UK.
Julian
J
Barwell
Fox Chase Cancer Center, Philadelphia, PA, USA.
Veda N
VN
Giri
Tata Memorial Centre, Mumbai, India.
Vedang
V
Murthy
Istituto Nazionale dei Tumori, Milano, Italy.
Nicola
N
Nicolai
Cancer Research Initiatives Foundation, Subang Jaya Medical Centre, Selangor, Darul Ehsan, Malaysia.
Soo-Hwang
SH
Teo
Clinical Genetics, Royal Liverpool Children's Hospital, Liverpool, UK.
Lynn
L
Greenhalgh
The University of Texas, MD Anderson Cancer Center, Houston, TX, USA.
Sara
S
Strom
Northern Genetics Service, Newcastle upon Tyne Hospitals, Newcastle upon Tyne, UK.
Alex
A
Henderson
Royal Devon and Exeter Hospital, Exeter, UK.
John
J
McGrath
Mater Misericordiae University Hospital, Dublin, Ireland.
David
D
Gallagher
The Netherlands Cancer Institute, Amsterdam, The Netherlands.
Neil
N
Aaronson
Cancer Genetics Unit and Academic Urology Unit, Royal Marsden NHS Foundation Trust, London, UK.
Audrey
A
Ardern-Jones
Erasmus Medical Center, Rotterdam, The Netherlands.
Chris
C
Bangma
Cancer Genetics Unit and Academic Urology Unit, Royal Marsden NHS Foundation Trust, London, UK; Oncogenetics Team, Institute of Cancer Research, London, UK.
David
D
Dearnaley
Wessex Clinical Genetics Service, Princess Anne Hospital, Southampton, UK.
Philandra
P
Costello
Faculty of Medicine, School of Health Sciences, University of Iceland, Reykjavik, Iceland.
Jorunn
J
Eyfjord
Genetic Medicine, Manchester Academic Health Sciences Centre, Central Manchester University Hospitals NHS Foundation Trust, Manchester, UK.
Jeanette
J
Rothwell
Imperial College Healthcare NHS Trust, London, London, UK.
Alison
A
Falconer
University Hospital, Umea, Sweden.
Henrik
H
Gronberg
Nuffield Department of Surgical Sciences, University of Oxford, Oxford, UK; Churchill Hospital, Headington, Oxford, UK.
Freddie C
FC
Hamdy
Landspitali-the National University Hospital of Iceland, Reykjavik, Iceland.
Oskar
O
Johannsson
Cancer Genetics Unit and Academic Urology Unit, Royal Marsden NHS Foundation Trust, London, UK.
Vincent
V
Khoo
Oncogenetics Team, Institute of Cancer Research, London, UK.
Zsofia
Z
Kote-Jarai
International Hereditary Cancer Center, Pomeranian Medical University, Szczecin, Poland.
Jan
J
Lubinski
Norwegian Radium Hospital, Oslo, Norway.
Ulrika
U
Axcrona
The University of Cambridge, Cambridge, UK.
Jane
J
Melia
Familial Cancer Centre, Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia.
Joanne
J
McKinley
Oncogenetics Team, Institute of Cancer Research, London, UK; University College London Hospitals NHS Foundation Trust, London, UK.
Anita V
AV
Mitra
Oncogenetics Team, Institute of Cancer Research, London, UK.
Clare
C
Moynihan
CHS National Cancer Control Center, Carmel Medical Center, Haifa, Israel.
Gad
G
Rennert
Nottingham City Hospital, Nottingham, UK.
Mohnish
M
Suri
BioZenix, Altrincham, Cheshire, UK.
Penny
P
Wilson
Cancer Genetics Unit and Academic Urology Unit, Royal Marsden NHS Foundation Trust, London, UK; Oncogenetics Team, Institute of Cancer Research, London, UK.
Emma
E
Killick
Queen Mary University of London, London, UK.
Sue
S
Moss
Oncogenetics Team, Institute of Cancer Research, London, UK; Cancer Genetics Unit and Academic Urology Unit, Royal Marsden NHS Foundation Trust, London, UK. Electronic address: rosalind.eeles@icr.ac.uk.
Rosalind A
RA
Eeles
D000328:Adult; D000368:Aged; D001706:Biopsy; D055088:Early Detection of Cancer; D019398:Genes, BRCA1; D024522:Genes, BRCA2; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation; D018579:Patient Selection; D011237:Predictive Value of Tests; D011467:Prostate / Q000473:pathology*; D017430:Prostate-Specific Antigen / Q000097:blood*; D011471:Prostatic Neoplasms / Q000097:blood / Q000235:genetics* / Q000473:pathology*
D017430:Prostate-Specific Antigen
BRCA1; BRCA2; Prostate cancer; Prostate-specific antigen; Targeted screening