Long-term effects of prophylactic oophorectomy in women at high familial risk of breast and ovarian cancer

This thesis describes the results of two studies: first, the HARMOny study on long-term health effects of risk-reducing salpingo-oophorectomy before natural menopause on sexual functioning, urogenital functioning and neurocognitive functioning. To summarize the results of the HARMOny study; we found that, at least 15 years after RRSO, timing of RRSO (i.e. premenopausal versus postmenopausal, and early premenopausal versus later premenopausal) did not influence sexual pleasure, urge urinary incontinence, and objective cognitive functioning. We did observe, however, more vaginal dryness, sexual discomfort, more stress urinary incontinence and worse subjective cognitive functioning in women with a premenopausal RRSO compared with women with a postmenopausal RRSO. However, these differences were small, and although they were statistically significant, it can be debated whether they are clinically relevant. Within the premenopausal group we found no differences between women with an early premenopausal RRSO and women with a later premenopausal RRSO. MHT use did influence the results: women who used MHT at time of study reported less vaginal dryness, but more subjective complaints of forgetfulness. Women who formerly used MHT reported more urinary incontinence. These results can be explained by the working mechanism of MHT, or by confounding by indication. Overall, these results are reassuring for all women undergoing RRSO. In the second study that is part of this thesis, we investigated if BC patients carrying a BRCA1/2pv are at higher risk to develop ischemic heart disease or heart failure after treatment for BC than BC patients who do not carry a pathogenic variant in BRCA1/2 genes. After a median follow-up of 14.0 years since BC treatment, we showed that BC patients with BRCA1/2pv had a slightly, but non-significantly increased risk of ischemic heart disease. We specifically looked at interaction between a pathogenic variant in BRCA1/2 and radiotherapy to the internal mammary chain in the development of ischemic heart disease, as the heart and major blood vessels are located directly in this radiation field. We found no evidence of such an interaction. We also found no evidence for an increased risk of heart failure in BRCA carriers. Nor did we find interaction between a pathogenic variant in BRCA1/2 and anthracycline-based chemotherapy when considering heart failure as an outcome. Our data does not support a greater sensitivity of BRCA1/2pv carriers to the cardiotoxicity of BC radiotherapy or chemotherapy. Overall, the risks of developing BC treatment-associated ischemic heart disease and heart failure are similarly increased in women carrying a BRCA1/2pv and other patients with BC. These results are reassuring for patients carrying a BRCA1/2pv. In general, clinicians should be alert to the increased risk of CVD in patients with BC treated with anthracycline-based chemotherapy and/or radiotherapy to the internal mammary chain, both in BRCA1/2pv carriers and in other patients with BC.