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Long term outcomes of risk reducing salpingo-oophorectomy in the general population and in women with pathogenic variants in BRCA1 and BRCA2 https://doi.org/10.17863/CAM.120722 Hassan, Hend Antoniou, Antonis Abstract Background Ovarian cancer is the most lethal gynaecological malignancy. To date there is no approved screening method for ovarian cancer and the only recommended method for prevention is bilateral sapling- oophorectomy (BSO). BSO is associated with more than 90% reduction in the risk of ovarian cancer. However, the benefit of ovarian cancer risk reduction should be balanced against the health sequalae caused by the pre-mature loss of oestrogen in premenopausal women. In my PhD I aimed to investigate the association between BSO and long-term health outcomes using population scale linked electronic health records. Objectives Examine the association between BSO and long-term health outcomes in: (1) women with a general population-level risk of ovarian cancer; (2) women with personal history of breast cancer; and (3) women with germline pathogenic variants in BRCA1 or BRCA2 and a personal history of breast cancer. Methodology I first examined the existing literature on the long-term outcomes of BSO at the time of hysterectomy for benign indications in a systemic review. I have updated a previous systematic review by searching the literature using PubMed, Web of Science, and Embase for publications between January 2015 and August 2022. Then conducted meta-analyses for the associations between BSO and the long- term outcomes stratified by the age at BSO. The CanGene-CanVar research programme facilitated novel linkage of the National cancer registration dataset (NCRD), the Hospital Episode Statistics-Admitted Patient Care (HES-APC) dataset and data from the genetic testing laboratories of England. The NCRD was used to identify cohorts with personal history of breast cancer and cancer outcomes, HES-APC was used to identify the delivery of BSO, other relevant procedures and non-cancer long-term outcomes and the genetic testing data were used to identify BRCA1 and BRCA2 PV carriers. For women with general population level risk, the analysis included 777,675 women who had hysterectomy for benign indications of whom 342,567 women had a BSO. For women with personal history of breast cancer I identified 568,883 breast cancer patients of whom 23,401 had undergone BSO. Finally, for women with pathogenic variants (PV) in BRCA1 or BRCA2 and personal history of breast cancer the analysis included 3,423 women of whom 1,855 had BSO. I used multivariable Cox-regression to assess the association between BSO and the long-term outcomes, with BSO modelled as a time-dependent covariate. Analyses were adjusted for deprivation index, ethnicity, Charlson comorbidity index and in the cohorts including women with personal history of breast cancer analyses were also adjusted for age at breast cancer diagnosis, tumour characteristics and breast cancer treatments. Analyses were stratified by the age at BSO. Multiple imputation was used to impute missing tumour characteristics in the analyses including women with personal history of breast cancer. Key findings The systematic review added 26 studies with more than 7 million women to the previously published one. It showed that BSO at the time of hysterectomy was associated with reduced risk of ovarian cancer in all age groups and reduced risk of breast cancer in women having BSO at a young age (<45y). Additionally, BSO at a young age (<50y) was associated with increased risk of cardiovascular diseases (CVD), depression, dementia, parkinsonism and all-cause mortality. In my PhD thesis general population analysis, similar associations were observed with breast cancer, CVD and all-cause mortality. Additionally, the analysis confirmed an increased risk of depression, dementia and parkinsonism in a cohort larger than any previously reported in studies of these outcomes. In women with personal history of breast cancer, BSO before and after the age of 55 years was associated with increased risk of long-term outcomes including CVD, cancer and depression. There was a small reduction in the risk of all-cause mortality in the older group. In BRCA1 and BRCA2 PV carriers with personal history of breast cancer the uptake of BSO was lower among the Black, Asian and most deprived women and BSO was associated with marked reduction in the risk of all-cause mortality, breast cancer specific mortality and second non-breast cancer risk. There was no evidence in this cohort that BSO was associated with cardiovascular diseases, depression or contralateral breast cancer. These are the largest studies to examine this wide range of long-term outcomes of BSO among the three specified cohorts. The analyses also addressed some of the methodological limitations in previous studies on BRCA1 and BRCA2 PV carriers including potential confounding by tumour characteristics and treatment, immortal time bias and cancer-induced testing bias. Conclusion This work using linked population scale level data highlights the critical need to balance the reduction in ovarian cancer risk against the potential long-term health outcomes of oestrogen cessation caused by the BSO. Personalised, evidence-based counselling is essential for different groups of women. importantly, women at high risk of developing ovarian cancer appear to derive the greatest benefit from undergoing BSO. Additionally, this novel data linkage demonstrates the potential of using data from genetic testing laboratories to assess the role of various prevention and treatment options in cancer patients with underlying genetic susceptibility. University of Cambridge 2025-01-24 Thesis Doctoral Doctor of Philosophy (PhD) eng https://www.repository.cam.ac.uk/handle/1810/388324 https://www.repository.cam.ac.uk/bitstreams/c838f4c2-ebb1-4bdb-b652-64d8c1243655/download 845b483e61a39c3b785386ab92995154 https://www.repository.cam.ac.uk/bitstreams/7d40fd9f-7ef9-4db5-827e-c666feba73ed/download 87eda9de84448d1f82354d60eee3eb5f https://creativecommons.org/licenses/by/4.0/ Ovarian cancer Breast cancer Saplingo-oophorectomy BSO RRSO BRCA1 BRCA2