Germline mutation in BRCA1 or BRCA2 and ten-year survival for women diagnosed with epithelial ovarian cancer

Francisco J Candido-dos-Reis¹, Honglin Song², Ellen L Goode³, Julie M Cunningham³, Brooke L Fridley⁴, Melissa C Larson³, Kathryn Alsop⁵, Ed Dicks², Patricia Harrington², Susan J Ramus⁶, Anna de Fazio⁷, Gillian Mitchell⁵, Sian Fereday⁵, Kelly L Bolton⁸, Charlie Gourley⁹, Caroline Michie¹⁰, Beth Karlan¹¹, Jenny Lester¹¹, Christine Walsh¹¹, Ilana Cass¹¹, Håkan Olsson¹², Martin Gore¹³, Javier J Benitez¹⁴, Maria J Garcia¹⁴, Irene Andrulis¹⁵, Anna Marie Mulligan¹⁶, Gord Glendon¹⁶, Ignacio Blanco¹⁷, Conxi Lazaro¹⁷, Alice S Whittemore¹⁸, Valerie McGuire¹⁸, Weiva Sieh¹⁸, Marco Montagna¹⁹, Elisa Alducci¹⁹, Siegal Sadetzki²⁰, Angela Chetrit²⁰, Ava Kwong²¹, Susanne K Kjaer²², Allan Jensen²², Estrid Høgdall²³, Susan Neuhausen²⁴, Robert Nussbaum²⁵, Mary Daly²⁶, Mark H Greene⁸, Phuong L Mai⁸, Jennifer T Loud⁸, Kirsten Moysich²⁷, Amanda E Toland²⁸, Diether Lambrechts²⁹, Steve Ellis², Debra Frost², James D Brenton³⁰, Marc Tischkowitz³¹, Douglas F Easton², Antonis Antoniou², Georgia Chenevix-Trench³², Simon A Gayther⁶, David Bowtell⁵, Paul D P Pharoah³³; for EMBRACE; kConFab Investigators; Australian Ovarian Cancer Study Group

Affiliations

¹ Department of Gynecology and Obstetrics, Ribeirao Preto Medical School, University of Sao Paulo, Sao Paulo, Brazil.
² Centre for Cancer Genetic Epidemiology, University of Cambridge, Cambridge, United Kingdom.
³ Mayo Clinic, Rochester, Minnesota.
⁴ University of Kansas Medical Center, Kansas City, Kansas.
⁵ The Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia.
⁶ Department of Preventive Medicine, Keck School of Medicine, University of Southern California Norris Comprehensive Cancer Center, Los Angeles, California.
⁷ 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.
⁸ Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, Maryland.
⁹ University of Edinburgh Cancer Research UK Centre, MRC IGMM, Edinburgh, United Kingdom.
¹⁰ Ninewells Hospital and Medical School, Dundee, United Kingdom.
¹¹ Women's Cancer Program at the Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, California.
¹² Departments of Cancer Epidemiology and Oncology, Lund University, Lund, Sweden.
¹³ Royal Marsden NHS Foundation Trust, London, United Kingdom.
¹⁴ Human Genetics Group and Human Genotyping Unit Spanish National Cancer Research Centre (CNIO), Madrid, Spain.
¹⁵ Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital; Departments of Molecular Genetics and Laboratory Medicine and Pathobiology, University of Toronto, Ontario, Canada.
¹⁶ Laboratory Medicine Program, University Health Network; Department of Laboratory Medicine and Pathobiology, University of Toronto, Ontario, Canada.
¹⁷ Hereditary Cancer Program, Catalan Institute of Oncology, L'Hospitalet, Barcelona, Spain.
¹⁸ Department of Health Research and Policy-Epidemiology, Stanford University School of Medicine, Stanford, California.
¹⁹ Immunology and Molecular Oncology Unit, Istituto Oncologico Veneto IOV-IRCCS, Padua, Italy.
²⁰ Gertner Institute for Epidemiology and Health Policy Research, Sheba Medical Center, Tel Hashomer, Israel.
²¹ The Hong Kong Hereditary Breast Cancer Family Registry, Cancer Genetics Center, Hong Kong, Hong Kong.
²² Department of Virus, Lifestyle and Genes, Danish Cancer Society Research Center, Copenhagen, Denmark.
²³ Molecular Unit, Department of Pathology, Herlev Hospital, University of Copenhagen, Copenhagen, Denmark.
²⁴ Department of Population Sciences, Beckman Research Institute of the City of Hope, Duarte, California.
²⁵ University of California San Francisco, Cancer Risk Program, San Francisco, California.
²⁶ Department of Clinical Genetics, Fox Chase Cancer Center, Philadelphia, Pennsylvania.
²⁷ Department of Cancer Prevention and Control, Roswell Park Cancer Institute, Buffalo, New York.
²⁸ Departments of Internal Medicine and Molecular Virology, Immunology, and Medical Genetics, The Comprehensive Cancer Center, Ohio State University, Columbus, Ohio.
²⁹ VIB Vesalius Research Center, University of Leuven, Leuven, Belgium.
³⁰ 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.
³¹ Department of Medical Genetics, University of Cambridge, Cambridge, United Kingdom.
³² QIMR Berghofer Medical Research Institute, Herston, Australia.
³³ Centre for Cancer Genetic Epidemiology, University of Cambridge, Cambridge, United Kingdom. paul.pharoah@srl.cam.ac.uk.

PMID: 25398451
PMCID: PMC4338615
DOI: 10.1158/1078-0432.CCR-14-2497

Germline mutation in BRCA1 or BRCA2 and ten-year survival for women diagnosed with epithelial ovarian cancer

Francisco J Candido-dos-Reis et al. Clin Cancer Res. 2015.

. 2015 Feb 1;21(3):652-7.

doi: 10.1158/1078-0432.CCR-14-2497. Epub 2014 Nov 14.

Authors

Affiliations

¹ Department of Gynecology and Obstetrics, Ribeirao Preto Medical School, University of Sao Paulo, Sao Paulo, Brazil.
² Centre for Cancer Genetic Epidemiology, University of Cambridge, Cambridge, United Kingdom.
³ Mayo Clinic, Rochester, Minnesota.
⁴ University of Kansas Medical Center, Kansas City, Kansas.
⁵ The Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia.
⁶ Department of Preventive Medicine, Keck School of Medicine, University of Southern California Norris Comprehensive Cancer Center, Los Angeles, California.
⁷ 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.
⁸ Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, Maryland.
⁹ University of Edinburgh Cancer Research UK Centre, MRC IGMM, Edinburgh, United Kingdom.
¹⁰ Ninewells Hospital and Medical School, Dundee, United Kingdom.
¹¹ Women's Cancer Program at the Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, California.
¹² Departments of Cancer Epidemiology and Oncology, Lund University, Lund, Sweden.
¹³ Royal Marsden NHS Foundation Trust, London, United Kingdom.
¹⁴ Human Genetics Group and Human Genotyping Unit Spanish National Cancer Research Centre (CNIO), Madrid, Spain.
¹⁵ Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital; Departments of Molecular Genetics and Laboratory Medicine and Pathobiology, University of Toronto, Ontario, Canada.
¹⁶ Laboratory Medicine Program, University Health Network; Department of Laboratory Medicine and Pathobiology, University of Toronto, Ontario, Canada.
¹⁷ Hereditary Cancer Program, Catalan Institute of Oncology, L'Hospitalet, Barcelona, Spain.
¹⁸ Department of Health Research and Policy-Epidemiology, Stanford University School of Medicine, Stanford, California.
¹⁹ Immunology and Molecular Oncology Unit, Istituto Oncologico Veneto IOV-IRCCS, Padua, Italy.
²⁰ Gertner Institute for Epidemiology and Health Policy Research, Sheba Medical Center, Tel Hashomer, Israel.
²¹ The Hong Kong Hereditary Breast Cancer Family Registry, Cancer Genetics Center, Hong Kong, Hong Kong.
²² Department of Virus, Lifestyle and Genes, Danish Cancer Society Research Center, Copenhagen, Denmark.
²³ Molecular Unit, Department of Pathology, Herlev Hospital, University of Copenhagen, Copenhagen, Denmark.
²⁴ Department of Population Sciences, Beckman Research Institute of the City of Hope, Duarte, California.
²⁵ University of California San Francisco, Cancer Risk Program, San Francisco, California.
²⁶ Department of Clinical Genetics, Fox Chase Cancer Center, Philadelphia, Pennsylvania.
²⁷ Department of Cancer Prevention and Control, Roswell Park Cancer Institute, Buffalo, New York.
²⁸ Departments of Internal Medicine and Molecular Virology, Immunology, and Medical Genetics, The Comprehensive Cancer Center, Ohio State University, Columbus, Ohio.
²⁹ VIB Vesalius Research Center, University of Leuven, Leuven, Belgium.
³⁰ 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.
³¹ Department of Medical Genetics, University of Cambridge, Cambridge, United Kingdom.
³² QIMR Berghofer Medical Research Institute, Herston, Australia.
³³ Centre for Cancer Genetic Epidemiology, University of Cambridge, Cambridge, United Kingdom. paul.pharoah@srl.cam.ac.uk.

PMID: 25398451
PMCID: PMC4338615
DOI: 10.1158/1078-0432.CCR-14-2497

Abstract

Purpose: To analyze the effect of germline mutations in BRCA1 and BRCA2 on mortality in patients with ovarian cancer up to 10 years after diagnosis.

Experimental design: 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.

PubMed Disclaimer

Figures

**Figure 1. Kaplan-Meier Estimates of Cumulative Survival According to BRCA1/2 Mutation Status**

See this image and copyright information in PMC

References

1. Ferlay J, Shin HR, Bray F, Forman D, Mathers C, Parkin DM. Estimates of worldwide burden of cancer in 2008: GLOBOCAN 2008. Int J Cancer. 2010;127:2893–917. - PubMed
1. Ledermann JA, Raja FA, Fotopoulou C, Gonzalez-Martin A, Colombo N, Sessa C, et al. Newly diagnosed and relapsed epithelial ovarian carcinoma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2013;24(Suppl 6):vi24–vi32. - PubMed
1. Zhang S, Royer R, Li S, McLaughlin JR, Rosen B, Risch HA, et al. Frequencies of BRCA1 and BRCA2 mutations among 1,342 unselected patients with invasive ovarian cancer. Gynecol Oncol. 2011;121:353–7. - PubMed
1. Pal T, Permuth-Wey J, Betts JA, Krischer JP, Fiorica J, Arango H, et al. BRCA1 and BRCA2 mutations account for a large proportion of ovarian carcinoma cases. Cancer. 2005;104:2807–16. - PubMed
1. Soegaard M, Kjaer SK, Cox M, Wozniak E, Hogdall E, Hogdall C, et al. BRCA1 and BRCA2 mutation prevalence and clinical characteristics of a population-based series of ovarian cancer cases from Denmark. Clin Cancer Res. 2008;14:3761–7. - PubMed

Publication types

Actions
Actions
Actions

MeSH terms

Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions

Grants and funding

LinkOut - more resources

Full Text Sources
Other Literature Sources
- scite Smart Citations
Medical
- MedlinePlus Health Information
Molecular Biology Databases
- NIAID Data Ecosystem - Find datasets on Infectious and Immune-mediated Diseases
Miscellaneous
- NCI CPTAC Assay Portal

Save citation to file

Email citation

Add to Collections

Add to My Bibliography

Your saved search

Create a file for external citation management software

Your RSS Feed

Germline mutation in BRCA1 or BRCA2 and ten-year survival for women diagnosed with epithelial ovarian cancer

Affiliations

Germline mutation in BRCA1 or BRCA2 and ten-year survival for women diagnosed with epithelial ovarian cancer

Authors

Affiliations

Abstract

Figures

References

Publication types

MeSH terms

Grants and funding

LinkOut - more resources

Full Text Sources

Other Literature Sources

Medical

Molecular Biology Databases

Miscellaneous