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Women who carry a pathogenic variant (mutation) in the BRCA1 or BRCA2 genes have a high lifetime risk of breast and ovarian cancer. The high lifetime breast and ovarian cancer risks among BRCA1 and BRCA2 mutation carriers shows a wide variation. Knowing the modifiers of this variation is of high clinical relevance to distinguish high-risk women from moderate risk women and to personalize screening strategy and preventive options. With this thesis we aim to contribute to knowledge about the use of various exogenous hormones as potential modifiers of breast and ovarian cancer risk in BRCA1 and BRCA2 mutation carriers. The exogenous hormones assessed in this thesis were oral contraceptive preparations (OCPs) ovarian stimulation with in vitro fertilization (IVF) and hormone replacement therapy (HRT) around (artificial) menopause. More specifically for OCP use, we aim to help BRCA1 and BRCA2 mutation carriers to make informed decisions regarding OCPs when used to prevent unwanted pregnancies. We studied the association between OCP use and the risk of breast and ovarian cancer for BRCA1 and BRCA2 mutation carriers. We concluded that, so far, there is no clear evidence that the associations (measured in terms of relative risk) between OCP use and risks of breast and ovarian cancer are different for BRCA1 and BRCA2 mutation carriers compared with the general population. This implies that current use of 5 years of OCP reduces the risks of ovarian cancer (RR=0.52-0.61), and slightly increases the risk of breast cancer (RR=1.17-1.27). Both the increased and decreased relative risks are stronger with longer durations of use and attenuate over time after stopping of OCP use. To help BRCA1 and BRCA2 mutation carriers make informed decisions regarding OCP use, we calculated absolute cancer risk-benefit estimates, specifically for breast, ovarian, and endometrial cancer. We examined 18 realistic scenarios with respect to OCP use (timing, duration of use), preventive surgery (risk-reducing salpingo-oophorectomy (RRSO), risk-reducing bilateral mastectomy (RRM), or both). In addition, we conducted several sensitivity analyses, for instance considering hormone-replacement therapy (HRT) following RRSO. For both BRCA1 and BRCA2 mutation carriers OCP use strongly decreased lifetime cancer risk, but initially increased breast/ovarian/endometrial cancer risk. An RRSO after OCP use reduced the risk of ovarian cancer and, thereby, decreased the lifetime benefit from OCP use. Furthermore, we studied the association between exposure to ovarian stimulation for IVF and risk of breast cancer in BRCA1 and BRCA2 mutation carriers. IVF exposure was not associated with risk of breast cancer (HR 0.79 95%CI 0.46–1.36), but the small number of exposed women resulted in wide confidence intervals. Since not all potential mutation carriers choose to undergo DNA-testing, we assessed the potential selection bias in observational BRCA mutation carrier studies, by comparing tested and untested relatives in BRCA1/2 families, stratified by personal breast/ovarian cancer history. We concluded that DNA-test uptake is higher for women with a personal breast or ovarian cancer history than for unaffected relatives (87% versus 42%, respectively). Whereas affected women generally opt for DNA-testing, the uptake by unaffected relatives in BRCA families may not be independent of the risk factors of interest in observational studies. Therefore, because of the difference between affected and unaffected relatives, selection bias may occur in retrospective observational studies on clinically-tested BRCA1/2 mutation carriers. This type of selection will not bias prospective observational BRCA1/2 mutation carrier studies as only unaffected women are eligible. |
