Cancer Risks for BRCA1 and BRCA2 Mutation Carriers: Results From Prospective Analysis of EMBRACE

 

Source:  http://jnci.oxfordjournals.org/content/early/2013/04/26/jnci.djt095

Cancer Risks for BRCA1 and BRCA2 Mutation Carriers: Results From Prospective Analysis of EMBRACE

1. Nasim Mavaddat,
2. Susan Peock,
3. Debra Frost,
4. Steve Ellis,
5. Radka Platte,
6. Elena Fineberg,
7. D. Gareth Evans,
8. Louise Izatt,
9. Rosalind A. Eeles,
10. Julian Adlard,
11. Rosemarie Davidson,
12. Diana Eccles,
13. Trevor Cole,
14. Jackie Cook,
15. Carole Brewer,
16. Marc Tischkowitz,
17. Fiona Douglas,
18. Shirley Hodgson,
19. Lisa Walker,
20. Mary E. Porteous,
21. Patrick J. Morrison,
22. Lucy E. Side,
23. M. John Kennedy,
24. Catherine Houghton,
25. Alan Donaldson,
26. Mark T. Rogers,
27. Huw Dorkins,
28. Zosia Miedzybrodzka,
29. Helen Gregory,
30. Jacqueline Eason,
31. Julian Barwell,
32. Emma McCann,
33. Alex Murray,
34. Antonis C. Antoniou,
35. Douglas F. Easton,
36. on behalf of EMBRACE

+ Author Affiliations

1. Affiliations of authors: Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care (NM, SP, DF, SE, RP, EF, ACA, DFE); Genetic Medicine, Manchester Academic Health Sciences Centre, Central Manchester University Hospitals NHS Foundation Trust, Manchester, UK (DGE); South East Thames Regional Genetics Service, Guy’s Hospital, London, UK (LI); Oncogenetics Team, Institute of Cancer Research and Royal Marsden NHS Foundation Trust, London, UK (RAE); Yorkshire Regional Genetics Service, Leeds, UK (JA); Ferguson-Smith Centre for Clinical Genetics, Yorkhill Hospitals, Glasgow, UK (RD); Wessex Clinical Genetics Service, Princess Anne Hospital, Southampton, UK (DE); West Midlands Regional Genetics Service, Birmingham Women’s Hospital Healthcare NHS Trust, Edgbaston, Birmingham, UK (TC); Sheffield Clinical Genetics Service, Sheffield Children’s Hospital, Sheffield, UK (JC); Department of Clinical Genetics, Royal Devon & Exeter Hospital, Exeter, UK (CB); Department of Clinical Genetics, East Anglian Regional Genetics Service, Addenbrookes Hospital, Cambridge, UK (MT); Institute of Genetic Medicine, Centre for Life, Newcastle Upon Tyne Hospitals NHS Trust, Newcastle upon Tyne, UK (FD); Clinical Genetics Department, St.Georges University of London, Tooting, London, UK (SH); Oxford Regional Genetics Service, Churchill Hospital, Oxford, UK (LW); South East of Scotland Regional Genetics Service, Western General Hospital, Edinburgh, UK (MEP); Northern Ireland Regional Genetics Centre, Belfast City Hospital, Belfast, UK (PJM); North East Thames Regional Genetics Service, Great Ormond Street Hospital for Children NHS Trust, London, UK (LES); Academic Unit of Clinical and Molecular Oncology, Trinity College Dublin and St James’s Hospital, Dublin, Ireland (MJK); Cheshire & Merseyside Clinical Genetics Service, Liverpool Women’s NHS Foundation Trust, Liverpool, UK (CH); South West Regional Genetics Service, Bristol, UK (AD); All Wales Medical Genetics Services, University Hospital of Wales, Cardiff, UK (MTR); North West Thames Regional Genetics Service, Kennedy-Galton Centre, Harrow, UK (HD); North of Scotland Regional Genetics Service, NHS Grampian & University of Aberdeen, Foresterhill, Aberdeen, UK (ZM, HG); Nottingham Clinical Genetics Service, Nottingham University Hospitals NHS Trust, UK (JE); Leicestershire Clinical Genetics Service, University Hospitals of Leicester NHS Trust, Leicester, UK (JB); All Wales Medical Genetics Service, Glan Clwyd Hospital, Rhyl, UK (EM, AM).

1. Correspondence to: Nasim Mavaddat, MBBS, PhD, Strangeways Research Laboratory, Worts Causeway, Cambridge, CB1 8RN, UK (e-mail: nasim@srl.cam.ac.uk).

• Received July 24, 2012.
• Revision received March 20, 2013.
• Accepted March 22, 2013.

Abstract

Background Reliable estimates of cancer risk are critical for guiding management of BRCA1 and BRCA2 mutation carriers. The aims of this study were to derive penetrance estimates for breast cancer, ovarian cancer, and contralateral breast cancer in a prospective series of mutation carriers and to assess how these risks are modified by common breast cancer susceptibility alleles.

Methods Prospective cancer risks were estimated using a cohort of 978 BRCA1 and 909 BRCA2 carriers from the United Kingdom. Nine hundred eighty-eight women had no breast or ovarian cancer diagnosis at baseline, 1509 women were unaffected by ovarian cancer, and 651 had been diagnosed with unilateral breast cancer. Cumulative risks were obtained using Kaplan–Meier estimates. Associations between cancer risk and covariables of interest were evaluated using Cox regression. All statistical tests were two-sided.

Results The average cumulative risks by age 70 years for BRCA1 carriers were estimated to be 60% (95% confidence interval [CI] = 44% to 75%) for breast cancer, 59% (95% CI = 43% to 76%) for ovarian cancer, and 83% (95% CI = 69% to 94%) for contralateral breast cancer. For BRCA2 carriers, the corresponding risks were 55% (95% CI = 41% to 70%) for breast cancer, 16.5% (95% CI = 7.5% to 34%) for ovarian cancer, and 62% (95% CI = 44% to 79.5%) for contralateral breast cancer. BRCA2 carriers in the highest tertile of risk, defined by the joint genotype distribution of seven single nucleotide polymorphisms associated with breast cancer risk, were at statistically significantly higher risk of developing breast cancer than those in the lowest tertile (hazard ratio = 4.1, 95% CI = 1.2 to 14.5; P = .02).

Conclusions Prospective risk estimates confirm that BRCA1 and BRCA2 carriers are at high risk of developing breast, ovarian, and contralateral breast cancer. Our results confirm findings from retrospective studies that common breast cancer susceptibility alleles in combination are predictive of breast cancer risk for BRCA2 carriers.

Related articles

• 'The "87%" BRCA breast cancer claim is a myth!'
• Angelina Jolie Undergoes Preventive Double Mastectomy
• What Angelina Jolie's decision means to you: Seacoast doctors explain - Seacoastonline.com
• What Angelina Jolie Forgot to Mention About Her Breast Removal
• What does a 'mutation in BRCA1′ actually mean?
• Doctor Says Angelina Jolie Double Mastectomy Story 'Not Relevant To More Than 99% of American Women'
• Did Angelina Jolie Make A Mistake By Acting On The 'Breast Cancer Gene' Theory?
• Mark E. Robson, M.D.: The Choice
• What is BRCA1?
• The quack view of preventing breast cancer versus reality and Angelina Jolie [Respectful Insolence]