Cancer Risks for BRCA1 and BRCA2 Mutation Carriers

Results From Prospective Analysis of EMBRACE

Nasim Mavaddat; Susan Peock; Debra Frost; Steve Ellis; Radka Platte; Elena Fineberg; D. Gareth Evans; Louise Izatt; Rosalind A. Eeles; Julian Adlard; Rosemarie Davidson; Diana Eccles; Trevor Cole; Jackie Cook; Carole Brewer; Marc Tischkowitz; Fiona Douglas; Shirley Hodgson; Lisa Walker; Mary E. Porteous; Patrick J. Morrison; Lucy E. Side; M. John Kennedy; Catherine Houghton; Alan Donaldson; Mark T. Rogers; Huw Dorkins; Zosia Miedzybrodzka; Helen Gregory; Jacqueline Eason; Julian Barwell; Emma McCann; Alex Murray; Antonis C. Antoniou; Douglas F. Easton

Disclosures

J Natl Cancer Inst. 2013;105(11):812-822. 

In This Article

Abstract and Introduction

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.

Introduction

Pathogenic mutations in the BRCA1 and BRCA2 genes confer high risks of breast, ovarian, and contralateral breast cancer (CBC). However, the precise magnitude of these risks is uncertain. Most penetrance studies to date have been retrospective in design, using either families ascertained on the basis of multiple affected individuals or population-based studies of cancer patients. Estimates in the range of 40% to 87% for BRCA1 and 18% to 88% for BRCA2 mutation carriers have been reported for breast cancer, and estimates in the range of 22% to 65% for BRCA1 and 10% to 35% for BRCA2 mutation carriers have been reported for ovarian cancer.[1–25] Such studies require adjustment for ascertainment to address nonrandom sampling of families and individuals with respect to their disease status. Estimates of CBC risk also vary across studies, with 10-year cumulative risk after unilateral breast cancer ranging from 16% to 35%.[26–31] Although some of the observed variation may be explained by different study methods and populations, other factors contribute to variation in risk. Cancer risks in BRCA1 and BRCA2 carriers vary by age at diagnosis or site of the cancer in index patient,[2,4,32] family history,[25,31] type and site of the mutation,[2,15,33,34] and lifestyle factors such as parity.[35–37] Furthermore, the higher risk in individuals with strong family history is consistent with the existence of genetic modifiers or other familial factors that influence risk.[3] Recently, several common alleles have been reported to be associated with breast cancer risk for BRCA1 and/or BRCA2 carriers in large retrospective studies.[38–45] The effect associated with each of these single nucleotide polymorphisms (SNPs) is small, but in combination these alleles may be useful in stratifying individuals into distinct risk categories.[42] Cohort studies, in which unaffected mutation carriers are followed up prospectively, provide penetrance estimates that are free of ascertainment bias. However such studies to date have generally been limited in size or follow-up time.[46–51]

The Epidemiological Study of BRCA1 and BRCA2 mutation carriers (EMBRACE) is an ongoing collaborative study established in 1998 that recruits from 28 centers from across the United Kingdom and Ireland. Participants included in these analyses were carriers of pathogenic BRCA1 or BRCA2 mutations who were unaffected at date of baseline questionnaire or diagnosed with unilateral breast cancer. We used prospective follow-up data on these individuals to estimate age-specific incidence of breast, ovarian, and contralateral breast cancer and the corresponding cumulative risks. We also examined the effect of bilateral prophylactic oophorectomy on cancer risks. We further constructed genetic profiles, defined by the joint distribution of SNPs previously found to modify cancer risks for mutation carriers in retrospective studies, and assessed their associations with prospective cancer risk.

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