Statin use and risk of endometrial cancer: a nationwide registry-based case–control study CECILIE D. SPERLING1, FREIJA VERDOODT1, SØREN FRIIS2,3,4, CHRISTIAN DEHLENDORFF2 & SUSANNE K. KJAER1,5 1Virus, Lifestyle and Genes, Danish Cancer Society Research Center, Copenhagen, 2Unit of Statistics, Bioinformatics and Registry, Danish Cancer Society Research Center, Copenhagen, 3Department of Public Health, University of Copenhagen, Copenhagen, 4Department of Clinical Epidemiology, Aarhus University Hospital, Aarhus, and 5Department of Gynecology, Rigshospitalet University Hospital, University of Copenhagen, Copenhagen, Denmark ACTA Obstetricia et Gynecologica Scandinavica Journal Club -Gynecology- February 2017 Edited by Francesco D’Antonio

Background Endometrial cancer is the fourth most common cancer in women worldwide and the most common malignancy of the female genital tract in developed countries. Laboratory studies of human cell lines and in vivo animal models have demonstrated anti-cancer properties of statins, including induction of apoptosis, inhibition of angiogenesis, and suppression of tumor growth and metastasis . However, these findings have not been confirmed by epidemiological studies which have reported mainly null associations between statin use and endometrial cancer risk. A recent meta-analysis reported a non significant reduction in risk of endometrial cancer associated with overall statin use, although it was based on a small number of cases.

Aim of the study To examine the association between statin use and risk of endometrial cancer and to evaluate whether the association varies by duration and intensity of statin use, type of endometrial cancer, or patient characteristics.

Methodology Women with endometrial cancer were identified in the Danish Cancer Registry. Only women aged 30–84 years with histologically verified type I or II endometrial cancer an no history of cancer were considered eligible for the inclusion. For each case, 15 controls matched on date of birth using risk-set sampling and applying the same selection criteria as for cases were selected. Use of statin was defined as two or more filled prescriptions on separate dates and non-use as fewer than two prescriptions. Recent use was defined as two or more prescriptions during one to three years while former use as fewer than 2 prescriptions during one to three years before the index date (defined as the time of diagnosis of cancer). Duration of statin use was defined as the time between the first and last filled statin prescription plus 60 days and categorized as short-term (less than five years) or long-term (five or more years) use. Intensity of statin use as the cumulative number of defined daily doses divided by the duration in days.

Methodology (Statistical analysis) Conditional logistic regression was used to compute the odds ratios (ORs) for endometrial cancer associated with statin use. Sub-analyses assessing the association between type of statin user (recent vs former) , duration and intensity of statin use and endometrial cancer was also performed. Potential effect measure modification among women with high susceptibility of endometrial cancer, defined by nulliparity, hormone replacement therapy (HRT) use, diabetes and obesity was explored.

Results (Study population) 5382 endometrial cancer cases and 72 127 population controls were included in the study. The majority of cases (88.5%) had type I endometrial cancer. More cases than controls were nulliparous, and cases were more likely to use HRT and have a history of obesity or diabetes. Use of statins was observed among 11.3% of the cases and 9.7% of the controls.

Results (Association between statins and endometrial cancer) FHR baseline, agreement and reliability were high and similar in all groups No association between ever use of statin and endometrial cancer risk (OR 1.03, 95% CI 0.94–1.14). No substantial variation in ORs between recent (OR 1.02, 95% CI 0.93–1.13) and former (OR 1.27, 95% CI 0.90–1.78) use of statins. Endometrial cancer risk did not vary substantially with duration and intensity of statin use. Stratification by type of endometrial cancer also showed no difference in ORs (type I, OR 1.03 95% CI 0.93–1.15; type II, OR 1.04 95% CI 0.80–1.35).

Results (potential effect measure modification ) FHR baseline, agreement and reliability were high and similar in all groups No difference in the risk of endometrial cancer was observed when the analysis was stratified by parity, diabetes, obesity and HRT. Women <50 years exhibited similar associations to those of the main analysis after additional adjustment for oral contraceptive use

Strengths Limitations Large sample size. Long study period with a prescription history up to 15 years. Use of continuously updated nationwide registries. All statins used during the study period were eligible for the analyses, as statins can only be obtained by a prescription in Denmark. Cancer diagnoses were restricted to histologically verified cases. Limitations History of obesity based on hospital and outpatient diagnoses and prescription use. No information on the patients’ compliance with statin therapy. Statin users might differ from non-users in term of lifestyle and health-seeking behavior. Left truncation of the prescription data might have introduced misclassification of statin use.

Statins use was not associated with endometrial cancer risk. Conclusion Statins use was not associated with endometrial cancer risk. This null association persisted across various levels of duration and intensity of statin use, and for type I and II endometrial cancer.