BRCA1- and BRCA2-mutation carriers have high risks of early onset breast cancer and ovarian cancer. Age-specific cancer risks vary strongly between individuals and among families. In this project we collected data and conducted analyses to develop and validate a comprehensive risk prediction tool that provides individualized cancer risk estimates.
The study group comprised 9,863 BRCA1/2 mutation carries, of which 5,162 women were eligible for prospective follow-up. Information on BRCA1/ BRCA2 mutations, common genetic variants, hormonal/lifestyle risk factors, and risk-reducing surgeries was available for 5,969 BRCA1/2 mutation carriers, pedigree data for 4,983 women and consecutive series of mammograms for 3,661 women.
We examined the absolute risks of breast and ovarian cancer for BRCA1- and BRCA2-mutation carriers, prospectively. Through the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA) polygenic risk scores (PRS), consisting of relevant common genetic variants for breast and ovarian cancer for BRCA1- and BRCA2-mutation carriers, were established. The associations of hormonal/lifestyle risk factors and breast density with risk of breast cancer for BRCA1- and BRCA2-mutation carriers were found to be consistent with those known for the general population, with the potential exception of reproductive risk factors. A risk reducing salpingo-oophorectomy (RRSO) caused a decrease in percent breast density. An integrated version of the risk prediction BOADICEA model was developed, which includes the explicit effects of BRCA1/2 mutations, pedigree-based family history information, BRCA1- and BRCA2-specific incidence rates, the combined effects of common genetic variants in terms of a 313-SNP PRS, hormonal/reproductive risk factors, and breast density. In a prospective validation study, the model showed already adequate discrimination and calibration properties even without breast density. It is likely that the model will further improve, if breast density and change of breast density during follow-up are taken into account.
The online CanRisk tool, including the comprehensive BOADICEA model, is now available for clinical implementation.