Association Between BRCA1 and BRCA2 Mutations and Survival in Women With Invasive Epithelial Ovarian Cancer

Kelly L. Bolton, PhD;
Georgia Chenevix- Trench, PhD;
Cindy Goh, BA;
Siegal Sadetzki, MD, MPH;
Susan J. Ramus, PhD;
Beth Y. Karlan, MD;
Diether Lambrechts, PhD;
Evelyn Despierre, MD;
Daniel Barrowdale, BSc;
Lesley McGuffog;
Sue Healey, BSc;
Douglas F. Easton, PhD;
Olga Sinilnikova, PhD;
Javier Benítez, PhD;
María J. García, PhD;
Susan Neuhausen, PhD;
Mitchell H. Gail, MD, PhD;
Patricia Hartge, ScD;
Susan Peock, PhD;
Debra Frost, ONC;
D. Gareth Evans, MBBS, MRCP, MD, FRCP;
Rosalind Eeles, PhD, MA, FRCP, FRCR;
Andrew K. Godwin, PhD;
Mary B. Daly, MD, PhD;
Ava Kwong, MBBS, FRCS;
Edmond S. K. Ma, MD;
Conxi Lázaro, PhD;
Ignacio Blanco, MD, PhD;
Marco Montagna, PhD;
Emma D'Andrea, MD, PhD;
Maria Ornella Nicoletto, MD;
Sharon E. Johnatty, PhD;
Susanne Krüger Kjær, MD, DMSc;
Allan Jensen, PhD;
Estrid Høgdall, PhD;
Ellen L. Goode, PhD;
Brooke L. Fridley, PhD;
Jennifer T. Loud, DNP;
Mark H. Greene, MD;
Phuong L. Mai, MD;
Angela Chetrit, MSc;
Flora Lubin, MSc;
Galit Hirsh-Yechezkel, PhD;
Gord Glendon, MSc;
Irene L. Andrulis, PhD;
Amanda E. Toland, PhD;
Leigha Senter, MS;
Martin E. Gore, MBBS, PhD, FRCP;
Charlie Gourley, PhD, FRCP;
Caroline O. Michie, MD;
Honglin Song, PhD;
Jonathan Tyrer, PhD;
Alice S. Whittemore, PhD;
Valerie McGuire, PhD;
Weiva Sieh, MD, PhD;
Ulf Kristoffersson, MD, PhD;
Håkan Olsson, MD, PhD;
Åke Borg, PhD;
Douglas A. Levine, MD;
Linda Steele, BS;
Mary S. Beattie, MD, MAS;
Salina Chan, BSc;
Robert L. Nussbaum, MD;
Kirsten B. Moysich, PhD;
Jenny Gross, MPH;
Ilana Cass, MD;
Christine Walsh, MD;
Andrew J. Li, MD;
Ronald Leuchter, MD;
Ora Gordon, MD, MS;
Montserrat Garcia-Closas, MD, DrPH;
Simon A. Gayther, PhD;
Stephen J. Chanock, MD;
Antonis C. Antoniou, PhD;
Paul D. P. Pharoah, BM, BCh, PhD
for the EMBRACE, kConFab Investigators, and The Cancer Genome Atlas Research Network

[+] Author Affiliations

Author Affiliations: Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, Maryland (Drs Bolton, Gail, Chanock, and Hartge); David Geffen School of Medicine, University of California, Los Angeles (Dr Bolton); Queensland Institute of Medical Research, Royal Brisbane Hospital, Herston, Australia (Drs Chenevix-Trench and Johnatty and Ms Healey); Addenbrooke's Hospital, Cambridge, England (Ms Goh); Gertner Institute for Epidemiology and Health Policy Research, Sheba Medical Center, Tel Hashomer, Israel (Drs Sadetzki and Hirsh-Yechezkel and Mss Chetrit and Lubin); Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel (Dr Sadetzki); Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles (Drs Ramus and Gayther); Women's Cancer Program, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, California (Drs Karlan, Cass, Walsh, Li, Leuchter, and Gordon and Ms Gross); VIB Vesalius Research Center, University of Leuven, Leuven, Belgium (Dr Lambrechts); Department of Obstetrics and Gynaecology, University Hospitals Leuven, University of Leuven, Leuven, Belgium (Dr Despierre); Center for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, England (Drs Easton, Peock, and Antoniou and Mr Barrowdale and Mss McGuffog and Frost); Unit of Genetic Predisposition to Common Cancers, Hospices Civils de Lyon−Center Léon Bérard, Lyon, and INSERM U1052, CNRS UMR5286, University Lyon 1, Cancer Research Center of Lyon, Lyon, France (Dr Sinilnikova); Human Genetics Group (Dr García), Human Cancer Genetics Program and Genotyping Unit, Spanish National Cancer Research Center (Dr Benítez), and CIBERER (Drs Benítez and García), Madrid, Spain; Department of Population Sciences, Beckman Research Institute of the City of Hope, Duarte, California (Dr Neuhausen and Ms Steele); Genetic Medicine, Manchester Academic Health Sciences Center, Central Manchester University Hospitals NHS Foundation Trust, Manchester, England (Dr Evans); Oncogenetics Team, The Institute of Cancer Research and Royal Marsden NHS Foundation Trust, Sutton, Surrey, United Kingdom (Dr Eeles); Department of Pathology and Laboratory Medicine, University of Kansas Medical Center, Kansas City (Dr Godwin); Department of Clinical Genetics, Fox Chase Cancer Center, Philadelphia, Pennsylvania (Dr Daly); The Hong Kong Hereditary Breast Cancer Family Registry, Cancer Genetics Center (Drs Kwong and Ma), and Division of Molecular Pathology (Dr Ma), Hong Kong Sanatorium and Hospital, Central Block, Hong Kong; Division of Breast Surgery, University of Hong Kong, Queen Mary Hospital, Hong Kong (Dr Kwong); Hereditary Cancer Program, Catalan Institute of Oncology, L’Hospitalet, Barcelona, Spain (Drs Lázaro and Blanco); Immunology and Molecular Oncology Unit (Dr Montagna) and Medical Oncology Unit 1 (Dr Nicoletto), Istituto Oncologico Veneto IRCCS, Padua, Italy; Department of Oncology and Surgical Sciences, Istituto Oncologico Veneto IOV - IRCCS, Padua, Italy (Dr D’Andrea); Department of Virus, Hormones, and Cancer, Danish Cancer Society, and Department of Gynecology, Rigshospitalet, University of Copenhagen (Drs Kjær, Jensen, and Høgdall), Copenhagen, Denmark; Department of Health Sciences Research, Mayo Clinic College of Medicine, Rochester, Minnesota (Drs Goode and Fridley); Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, Maryland (Drs Loud, Greene, and Mai); Ontario Cancer Genetics Network, Cancer Care Ontario (Dr Andrulis and Mr Glendon), and Samuel Lunenfeld Research Institute, Mount Sinai Hospital (Dr Andrulis), Toronto, Ontario, Canada; Departments of Internal Medicine and Molecular Virology, Immunology, and Medical Genetics, The Comprehensive Cancer Center, Ohio State University, Columbus (Dr Toland); Clinical Cancer Genetics Program, Department of Internal Medicine, The Comprehensive Cancer Center, Ohio State University, Columbus (Ms Senter); Gynecological Oncology Unit, The Royal Marsden Hospital, London, England (Dr Gore); University of Edinburgh Cancer Research Center, Institute of Genetics and Molecular Medicine, Western General Hospital, Edinburgh, Scotland (Drs Gourley and Michie); Cancer Research United Kingdom, Departments of Oncology and Public Health and Primary Care, University of Cambridge, Strangeway's Research Laboratory, Cambridge, England (Drs Song, Tyrer, and Pharoah); Department of Health Research and Policy, Stanford University School of Medicine, Stanford, California (Drs Whittemore, McGuire, and Sieh); Department of Clinical Genetics, University and Regional Laboratories Skåne and Lund University, Lund, Sweden (Dr Kristoffersson); Department of Oncology, Lund University, Lund, Sweden (Drs Olsson and Borg); Department of Surgery, Memorial Sloan-Kettering Cancer Center, New York, New York (Dr Levine); University of California San Francisco Cancer Risk Program, San Francisco (Drs Beattie and Nussbaum and Ms Chan); Department of Medicine, University of California, San Francisco (Drs Beattie and Nussbaum); Department of Cancer Prevention and Control, Roswell Park Cancer Institute, Buffalo, New York (Dr Moysich); and Sections of Epidemiology and Genetics, Institute of Cancer Research and Breakthrough Breast Cancer Research Center, London, England (Dr Garcia-Closas).

Abstract

Context Approximately 10% of women with invasive epithelial ovarian cancer (EOC) carry deleterious germline mutations in BRCA1 or BRCA2. A recent article suggested that BRCA2 -related EOC was associated with an improved prognosis, but the effect of BRCA1 remains unclear.

Objective To characterize the survival of BRCA carriers with EOC compared with noncarriers and to determine whether BRCA1 and BRCA2 carriers show similar survival patterns.

Design, Setting, and Participants A pooled analysis of 26 observational studies on the survival of women with ovarian cancer, which included data from 1213 EOC cases with pathogenic germline mutations in BRCA1 (n = 909) or BRCA2 (n = 304) and from 2666 noncarriers recruited and followed up at variable times between 1987 and 2010 (the median year of diagnosis was 1998).

Main Outcome Measure Five-year overall mortality.

Results The 5-year overall survival was 36% (95% CI, 34%-38%) for noncarriers, 44% (95% CI, 40%-48%) for BRCA1 carriers, and 52% (95% CI, 46%-58%) for BRCA2 carriers. After adjusting for study and year of diagnosis, BRCA1 and BRCA2 mutation carriers showed a more favorable survival than noncarriers (for BRCA1: hazard ratio [HR], 0.78; 95% CI, 0.68-0.89; P < .001; and for BRCA2: HR, 0.61; 95% CI, 0.50-0.76; P < .001). These survival differences remained after additional adjustment for stage, grade, histology, and age at diagnosis (for BRCA1: HR, 0.73; 95% CI, 0.64-0.84; P < .001; and for BRCA2: HR, 0.49; 95% CI, 0.39-0.61; P < .001). The BRCA1 HR estimate was significantly different from the HR estimated in the adjusted model (P for heterogeneity = .003).

Conclusion Among patients with invasive EOC, having a germline mutation in BRCA1 or BRCA2 was associated with improved 5-year overall survival. BRCA2 carriers had the best prognosis.

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