TRANsIBCCS

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.