Development of a Comprehensive Risk Prediction Model for BRCA1 and BRCA2 mutation carriers
BRCA1/2 mutation carriers have high risks of early onset Breast Cancer (BC) and ovarian cancer (OvC), but age-specific risks vary strongly between and among families. Currently, we are rapidly generating knowledge on genetic and hormonal modifiers of BC and OvC risks among BRCA1/2 carriers. However, the new risk modifiers cannot yet be used in the counselling of BRCA1/2 mutation carriers as the current risk prediction models do not take them into account. Hence, wide ranges of future cancer risks are communicated and, rather than a personalized risk prediction, other factors, like distress and social/professional acceptation of the procedures, determine if a BRCA1/2 mutation carrier opts for a risk reducing surgery. As a result the uptake of risk reducing strategies varies greatly within Europe. In this project we aim 1. to assess the independent and combined associations of common genetic variants, reproductive/hormonal risk factors, breast density and risk reducing surgeries and risks of breast and ovarian cancer in BRCA1 and BRCA2 mutation carriers, 2. To examine if a (lack of) decrease in breast density after a risk reducing oophorectomy may help to define a hormone-(in) sensitive group, and 3. to develop a novel online comprehensive risk prediction tool that provides valid individualized age-specific cancer risk estimates and uses for the first time the combined information of common genetic variants, reproductive/hormonal factors, breast density and risk reducing surgeries. This project is based on the International BRCA1/2 mutation Carrier Cohort Study, the largest available prospective BRCA1/2 cohort study. So far, 4,670 BRCA1 and 2,805 BRCA2 mutation carriers completed questionnaires on reproductive/hormonal risk factors. This project will enable expanded follow-up till October 2015. We will further enrich the dataset with a DNA sample, breast density, clinico-pathological information and new enrolment. We expect 479 cases of breast cancer and 224 cases of ovarian cancer during follow-up. We will use retrospective data on 5,304 BRCA1/2 mutation carriers for informing the risk model construction and we will use prospective data on 3,641 BRCA1/2 mutation carriers for the risk model validation. Personalized prediction of the risk of breast or ovarian cancer for the next 10 years for BRCA1 and BRCA2 mutation carriers will help to decide if risk reducing surgeries should be considered at a specific age, might be postponed or might not be necessary. The risk prediction tool will be updated regularly. Predicted 10-year risks may direct primary as well as secondary prevention strategies.
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.
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This project has received funding from the European Union’s Horizon 2020 Research and Innovation Programme under grant agreement No. 964264.