1. Hormonal and metabolic exposures and cancers of the breast and endometrium : risk, clinical outcomes and survival
- Author
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McVicker, Lauren, McMenamin, Una, and Cardwell, Christopher
- Subjects
Breast cancer ,hypothyroidism ,hormone replacement therapy ,cardiovascular disease ,aromatase inhibitors ,Tamoxifen ,survival ,endometrial cancer ,diabetes ,metabolic syndrome ,population-based study ,electronic health records - Abstract
Breast and endometrial cancer are the first and sixth most common female cancers worldwide, and they make up over one quarter of the cancer burden in females. Epidemiological and trial data have observed a role for hormones, particularly oestrogen and insulin, and metabolic dysfunction in the aetiology and progression of breast and endometrial cancers. The overall aim of this thesis was to investigate hormonal and metabolic exposures, specifically those resulting from conditions and medication use, in regard to breast and endometrial cancer risk, clinical outcomes and survival. To meet these aims, five distinct studies were carried out; three relating to breast cancer and two relating to endometrial cancer. Although incidence rates remain high, breast cancer mortality rates are declining and the 10-year survival rate after diagnosis has increased to around 70% in Europe. An increased survival for breast cancer patients represents an increased opportunity for new or existing comorbidities, and medication use, to detrimentally affect quality of life as well as breast cancer prognosis. Particularly if these conditions or medications modulate hormonal and metabolic factors. Epidemiological studies have indicated a higher prevalence of hypothyroidism in breast cancer patients, possibly related to shared risk factors and breast cancer treatments. However, few studies have evaluated how hypothyroidism, a condition which results in reduced thyroid hormones and disrupted metabolic homeostasis, impacts survival outcomes in breast cancer patients. In this thesis, a population-based cohort study was conducted comparing survival outcomes in breast cancer patients with and without hypothyroidism, and reassuringly did not find any negative associations. In addition, between 79% and 95% of breast cancer patients experience menopausal symptoms, some as a result of cancer treatments. Although contraindicated, some breast cancer patients will use vaginal or systemic hormone replacement therapy (HRT) and there are concerns about how exogenous oestrogen administration may impact the risk of their cancer recurring and their survival. In another population-based cohort study, this thesis observed little evidence of a worse cancer-specific mortality for breast cancer patients who used vaginal HRT after diagnosis compared to those who used no HRT. However, due to the small number of breast cancer patients who used systemic HRT, no conclusions could be confidently drawn regarding the safety of systemic HRT use in breast cancer patients. Furthermore, breast cancer patients have a high burden of cardiovascular disease (CVD) as the two conditions share a number of risk factors and breast cancer patients receive cardio-toxic cancer treatments. The gold standard treatment for postmenopausal oestrogen receptor (ER) positive breast cancer, a drug that reduces systemic oestrogen production called an aromatase inhibitor (AI), has been shown to increase the risk of CVD in a number of epidemiological studies relative to other hormone modulating treatments (tamoxifen), but not consistently. This thesis compared the risk of any CVD event, and specific CVD types, among AI and tamoxifen users in a large cohort of postmenopausal ER-positive breast cancer patients and saw no difference in CVD risk between the two medications. There are large gaps in the knowledge of endometrial cancer aetiology and pathogenesis, but most have been shown to develop and progress in the context of metabolic dysfunction and hypo-estrogenic pathologies such as obesity. Diabetes, particularly type 2, is associated with an increased risk of endometrial cancer, but its impact on prognosis is unclear and epidemiological studies to date have produced inconsistent results. In a systematic review and meta-analysis, this thesis observed that diabetes was associated with a worse cancer-specific and overall survival. Another condition with altered metabolic and hormonal features includes the metabolic syndrome, characterised as the co-occurrence of obesity, elevated triglycerides, reduced high-density lipoprotein (HDL) cholesterol, elevated blood pressure and abnormal glucose metabolism. Whilst a metabolic syndrome diagnosis has traditionally been utilised to identify those at a high risk of diabetes and CVD, numerous studies have observed an association between metabolic syndrome and endometrial cancer risk. Using data from the UK Biobank, this thesis investigated if postmenopausal women with metabolic syndrome, according to three clinically relevant and up-to-date definitions, had a higher risk of endometrial cancer. An over two-fold increased risk of endometrial cancer was observed for women with metabolic syndrome compared to without and each individual component of the metabolic syndrome was associated with endometrial cancer, of which obesity was most prominent. In summary, this thesis has contributed evidence on hormonal and metabolic exposures, including hypothyroidism, HRT, endocrine therapies (AIs and tamoxifen), diabetes and metabolic syndrome, and the risk of and survival from breast and endometrial cancer, plus the risk of CVD in a breast cancer population. Additional studies are required to enable strong and potentially causal conclusions to be drawn in the future, with the aim of informing intervention strategies that reduce the public health burden of breast and endometrial cancer.
- Published
- 2023