Metformin and statins in relation to ovarian cancer: implications for risk and potential etiologic pathways

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Background: Metabolic factors, including obesity, diabetes, and circulating lipids are associated with increased risk of ovarian cancer, the most fatal gynecologic malignancy. Drugs targeting these conditions have drawn interest as potential chemopreventive agents, but limited studies have examined relationships with ovarian cancer overall, by possible benefit groups or with regards to related etiologic pathways. This dissertation examined medications that target metabolic abnormalities with risk of ovarian cancer, and expression of a pro-tumorigenic lipid pathway in ovarian cancer tissue.Methods: Nested case-control studies of metformin (Aim 1) and statin (Aim 2) use in relation to ovarian cancer (cases n=9,207 and 10:1 frequency-matched controls n=92,070) were conducted in Clinical Practice Research Datalink (CPRD) (1987-2020), a primary care database in the United Kingdom. Aim 3 was a case-only analysis from The Polish Ovarian Cancer Study (POCS) (2001-2003, n=166) determining expression of sphingosine-1-phosphate receptors S1PR1 and S1PR3 in ovarian cancer tissue. Multivariable logistic regression estimated odds ratios (ORs) and 95% confidence intervals (CI) for associations between medication use and ovarian cancer in CPRD (Aims 1 and 2), and cancer characteristics with marker expression in POCS (Aim 3). Results: Within the CPRD analyses, metabolic conditions such as obesity (OR 1.19, 95% CI 1.11-1.28) and polycystic ovarian syndrome (OR 1.66, 95% CI 1.17-2.35) were significantly associated with increased ovarian cancer risk. However, neither metformin (OR 1.01, 95% CI 0.91-1.13) nor statin use (OR 1.02, 95% CI 0.96-1.08) was associated with ovarian cancer risk. Associations did not differ by drug indications (pint >0.05), individual statin or class. In Aim 3, strong expression of lipid markers in ovarian cancer tissue significantly differed by histotype (p<0.01). Lower marker expression was observed in non-serous tumors compared to serous, but expression was not associated with cancer risk factors or survival. Conclusion: Findings from this dissertation do not support use of metformin or statins as chemopreventive agents. However, as most CPRD users had an indication, it remains unclear whether findings are generalizable to the at-risk population for ovarian cancer. Strong expression of lipid markers in ovarian cancer tissue suggests involvement in carcinogenesis; additional molecular studies are needed to elucidate their role.