Germline mutation in BRCA1 or BRCA2 and ten-year survival for women diagnosed with epithelial ovarian cancer.
OBJECTIVE
To analyze the effect of germline mutations in BRCA1 and BRCA2 on mortality in patients with ovarian cancer up to 10 years after diagnosis.


METHODS
We used unpublished survival time data for 2,242 patients from two case-control studies and extended survival time data for 4,314 patients from previously reported studies. All participants had been screened for deleterious germline mutations in BRCA1 and BRCA2. Survival time was analyzed for the combined data using Cox proportional hazard models with BRCA1 and BRCA2 as time-varying covariates. Competing risks were analyzed using Fine and Gray model.


RESULTS
The combined 10-year overall survival rate was 30% [95% confidence interval (CI), 28%-31%] for non-carriers, 25% (95% CI, 22%-28%) for BRCA1 carriers, and 35% (95% CI, 30%-41%) for BRCA2 carriers. The HR for BRCA1 was 0.53 at time zero and increased over time becoming greater than one at 4.8 years. For BRCA2, the HR was 0.42 at time zero and increased over time (predicted to become greater than 1 at 10.5 years). The results were similar when restricted to 3,202 patients with high-grade serous tumors and to ovarian cancer-specific mortality.


CONCLUSIONS
BRCA1/2 mutations are associated with better short-term survival, but this advantage decreases over time and in BRCA1 carriers is eventually reversed. This may have important implications for therapy of both primary and relapsed disease and for analysis of long-term survival in clinical trials of new agents, particularly those that are effective in BRCA1/2 mutation carriers.
Department of Gynecology and Obstetrics, Ribeirao Preto Medical School, University of Sao Paulo, Sao Paulo, Brazil.
Francisco J
FJ
Candido-dos-Reis
Centre for Cancer Genetic Epidemiology, University of Cambridge, Cambridge, United Kingdom.
Honglin
H
Song
Mayo Clinic, Rochester, Minnesota.
Ellen L
EL
Goode
Mayo Clinic, Rochester, Minnesota.
Julie M
JM
Cunningham
University of Kansas Medical Center, Kansas City, Kansas.
Brooke L
BL
Fridley
Mayo Clinic, Rochester, Minnesota.
Melissa C
MC
Larson
The Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia.
Kathryn
K
Alsop
Centre for Cancer Genetic Epidemiology, University of Cambridge, Cambridge, United Kingdom.
Ed
E
Dicks
Centre for Cancer Genetic Epidemiology, University of Cambridge, Cambridge, United Kingdom.
Patricia
P
Harrington
Department of Preventive Medicine, Keck School of Medicine, University of Southern California Norris Comprehensive Cancer Center, Los Angeles, California.
Susan J
SJ
Ramus
Department of Gynaecological Oncology, Crown Princess Mary Cancer Centre and Westmead Institute for Cancer Research, University of Sydney at Westmead Millennium Institute, Westmead Hospital, Sydney NSW, Australia.
Anna
A
de Fazio
The Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia.
Gillian
G
Mitchell
The Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia.
Sian
S
Fereday
Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, Maryland.
Kelly L
KL
Bolton
University of Edinburgh Cancer Research UK Centre, MRC IGMM, Edinburgh, United Kingdom.
Charlie
C
Gourley
Ninewells Hospital and Medical School, Dundee, United Kingdom.
Caroline
C
Michie
Women's Cancer Program at the Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, California.
Beth
B
Karlan
Women's Cancer Program at the Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, California.
Jenny
J
Lester
Women's Cancer Program at the Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, California.
Christine
C
Walsh
Women's Cancer Program at the Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, California.
Ilana
I
Cass
Departments of Cancer Epidemiology and Oncology, Lund University, Lund, Sweden.
Håkan
H
Olsson
Royal Marsden NHS Foundation Trust, London, United Kingdom.
Martin
M
Gore
Human Genetics Group and Human Genotyping Unit Spanish National Cancer Research Centre (CNIO), Madrid, Spain.
Javier J
JJ
Benitez
Human Genetics Group and Human Genotyping Unit Spanish National Cancer Research Centre (CNIO), Madrid, Spain.
Maria J
MJ
Garcia
Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital; Departments of Molecular Genetics and Laboratory Medicine and Pathobiology, University of Toronto, Ontario, Canada.
Irene
I
Andrulis
Laboratory Medicine Program, University Health Network; Department of Laboratory Medicine and Pathobiology, University of Toronto, Ontario, Canada.
Anna Marie
AM
Mulligan
Laboratory Medicine Program, University Health Network; Department of Laboratory Medicine and Pathobiology, University of Toronto, Ontario, Canada.
Gord
G
Glendon
Hereditary Cancer Program, Catalan Institute of Oncology, L'Hospitalet, Barcelona, Spain.
Ignacio
I
Blanco
Hereditary Cancer Program, Catalan Institute of Oncology, L'Hospitalet, Barcelona, Spain.
Conxi
C
Lazaro
Department of Health Research and Policy-Epidemiology, Stanford University School of Medicine, Stanford, California.
Alice S
AS
Whittemore
Department of Health Research and Policy-Epidemiology, Stanford University School of Medicine, Stanford, California.
Valerie
V
McGuire
Department of Health Research and Policy-Epidemiology, Stanford University School of Medicine, Stanford, California.
Weiva
W
Sieh
Immunology and Molecular Oncology Unit, Istituto Oncologico Veneto IOV-IRCCS, Padua, Italy.
Marco
M
Montagna
Immunology and Molecular Oncology Unit, Istituto Oncologico Veneto IOV-IRCCS, Padua, Italy.
Elisa
E
Alducci
Gertner Institute for Epidemiology and Health Policy Research, Sheba Medical Center, Tel Hashomer, Israel.
Siegal
S
Sadetzki
Gertner Institute for Epidemiology and Health Policy Research, Sheba Medical Center, Tel Hashomer, Israel.
Angela
A
Chetrit
The Hong Kong Hereditary Breast Cancer Family Registry, Cancer Genetics Center, Hong Kong, Hong Kong.
Ava
A
Kwong
Department of Virus, Lifestyle and Genes, Danish Cancer Society Research Center, Copenhagen, Denmark.
Susanne K
SK
Kjaer
Department of Virus, Lifestyle and Genes, Danish Cancer Society Research Center, Copenhagen, Denmark.
Allan
A
Jensen
Molecular Unit, Department of Pathology, Herlev Hospital, University of Copenhagen, Copenhagen, Denmark.
Estrid
E
Høgdall
Department of Population Sciences, Beckman Research Institute of the City of Hope, Duarte, California.
Susan
S
Neuhausen
University of California San Francisco, Cancer Risk Program, San Francisco, California.
Robert
R
Nussbaum
Department of Clinical Genetics, Fox Chase Cancer Center, Philadelphia, Pennsylvania.
Mary
M
Daly
Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, Maryland.
Mark H
MH
Greene
Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, Maryland.
Phuong L
PL
Mai
Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, Maryland.
Jennifer T
JT
Loud
Department of Cancer Prevention and Control, Roswell Park Cancer Institute, Buffalo, New York.
Kirsten
K
Moysich
Departments of Internal Medicine and Molecular Virology, Immunology, and Medical Genetics, The Comprehensive Cancer Center, Ohio State University, Columbus, Ohio.
Amanda E
AE
Toland
VIB Vesalius Research Center, University of Leuven, Leuven, Belgium.
Diether
D
Lambrechts
Centre for Cancer Genetic Epidemiology, University of Cambridge, Cambridge, United Kingdom.
Steve
S
Ellis
Centre for Cancer Genetic Epidemiology, University of Cambridge, Cambridge, United Kingdom.
Debra
D
Frost
Departments of Oncology and Radiology, Cambridge University Hospitals Foundation Trust, Cambridge, United Kingdom. CR-UK Cambridge Institute, University of Cambridge; NIHR Cambridge Biomedical Research Centre, Cambridge, United Kingdom. Cambridge Experimental Cancer Medicine Centre, Cambridge, United Kingdom.
James D
JD
Brenton
Department of Medical Genetics, University of Cambridge, Cambridge, United Kingdom.
Marc
M
Tischkowitz
Centre for Cancer Genetic Epidemiology, University of Cambridge, Cambridge, United Kingdom.
Douglas F
DF
Easton
Centre for Cancer Genetic Epidemiology, University of Cambridge, Cambridge, United Kingdom.
Antonis
A
Antoniou
QIMR Berghofer Medical Research Institute, Herston, Australia.
Georgia
G
Chenevix-Trench
Department of Preventive Medicine, Keck School of Medicine, University of Southern California Norris Comprehensive Cancer Center, Los Angeles, California.
Simon A
SA
Gayther
The Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia.
David
D
Bowtell
Centre for Cancer Genetic Epidemiology, University of Cambridge, Cambridge, United Kingdom. paul.pharoah@srl.cam.ac.uk.
Paul D P
PD
Pharoah
D000368:Aged; D000077216:Carcinoma, Ovarian Epithelial; D005260:Female; D019398:Genes, BRCA1; D024522:Genes, BRCA2; D018095:Germ-Line Mutation; D006801:Humans; D008875:Middle Aged; D060787:Neoplasm Grading; D009367:Neoplasm Staging; D009375:Neoplasms, Glandular and Epithelial / Q000235:genetics* / Q000401:mortality* / Q000473:pathology; D010051:Ovarian Neoplasms / Q000235:genetics* / Q000401:mortality* / Q000473:pathology; D011379:Prognosis; D016019:Survival Analysis