title: Cancer risks for BRCA1 and BRCA2 mutation carriers: results from prospective analysis of EMBRACE.
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.
authors.affiliation: Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, Manchester, UK.
authors.forename: Nasim
authors.initials: N
authors.lastname: Mavaddat
authors.forename: Susan
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authors.lastname: Peock
authors.forename: Debra
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authors.forename: Steve
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authors.lastname: Ellis
authors.forename: Radka
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authors.lastname: Platte
authors.forename: Elena
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authors.lastname: Fineberg
authors.forename: D Gareth
authors.initials: DG
authors.lastname: Evans
authors.forename: Louise
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authors.lastname: Izatt
authors.forename: Rosalind A
authors.initials: RA
authors.lastname: Eeles
authors.forename: Julian
authors.initials: J
authors.lastname: Adlard
authors.forename: Rosemarie
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authors.lastname: Davidson
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authors.lastname: Eccles
authors.forename: Trevor
authors.initials: T
authors.lastname: Cole
authors.forename: Jackie
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authors.lastname: Cook
authors.forename: Carole
authors.initials: C
authors.lastname: Brewer
authors.forename: Marc
authors.initials: M
authors.lastname: Tischkowitz
authors.forename: Fiona
authors.initials: F
authors.lastname: Douglas
authors.forename: Shirley
authors.initials: S
authors.lastname: Hodgson
authors.forename: Lisa
authors.initials: L
authors.lastname: Walker
authors.forename: Mary E
authors.initials: ME
authors.lastname: Porteous
authors.forename: Patrick J
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authors.lastname: Morrison
authors.forename: Lucy E
authors.initials: LE
authors.lastname: Side
authors.forename: M John
authors.initials: MJ
authors.lastname: Kennedy
authors.forename: Catherine
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authors.lastname: Houghton
authors.forename: Alan
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authors.lastname: Donaldson
authors.forename: Mark T
authors.initials: MT
authors.lastname: Rogers
authors.forename: Huw
authors.initials: H
authors.lastname: Dorkins
authors.forename: Zosia
authors.initials: Z
authors.lastname: Miedzybrodzka
authors.forename: Helen
authors.initials: H
authors.lastname: Gregory
authors.forename: Jacqueline
authors.initials: J
authors.lastname: Eason
authors.forename: Julian
authors.initials: J
authors.lastname: Barwell
authors.forename: Emma
authors.initials: E
authors.lastname: McCann
authors.forename: Alex
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authors.lastname: Murray
authors.forename: Antonis C
authors.initials: AC
authors.lastname: Antoniou
authors.forename: Douglas F
authors.initials: DF
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mesh_terms: D000328:Adult; D000368:Aged; D019313:BRCA1 Protein / Q000235:genetics*; D024682:BRCA2 Protein / Q000235:genetics*; D001943:Breast Neoplasms / Q000453:epidemiology* / Q000235:genetics*; D015986:Confounding Factors, Epidemiologic; D005260:Female; D020022:Genetic Predisposition to Disease; D006579:Heterozygote; D006801:Humans; D015994:Incidence; D007494:Ireland / Q000453:epidemiology; D053208:Kaplan-Meier Estimate; D008875:Middle Aged; D009154:Mutation; D016017:Odds Ratio; D010051:Ovarian Neoplasms / Q000453:epidemiology* / Q000235:genetics* / Q000517:prevention & control; D010052:Ovariectomy; D020641:Polymorphism, Single Nucleotide; D011322:Primary Prevention / Q000379:methods; D016016:Proportional Hazards Models; D011446:Prospective Studies; D018570:Risk Assessment; D012307:Risk Factors; D058994:Salpingectomy; D011795:Surveys and Questionnaires; D006113:United Kingdom / Q000453:epidemiology
chemical_list: D019313:BRCA1 Protein; D024682:BRCA2 Protein