International Journal of Epidemiology

Statins and the risk of gynecological cancer: a Norwegian population-based cohort study

Abstract Background Endometrial, ovarian, and cervical cancers are the most common gynecological cancers, with 1.4 million diagnoses worldwide in 2022. Statins are widely used for cardiovascular conditions and have been studied for their association with gynecological cancer risk, but results to date have been inconclusive. Methods We conducted a population-based cohort study including data from the Norwegian Prescription Database and the Cancer Registry of Norway, and followed women aged ≥50 years from 2004 to 2018. We examined the association between statin use overall and by type (lipophilic, hydrophilic), and the risk of endometrial, ovarian, and cervical cancers overall and by age groups and histologic subgroup using Cox proportional hazard models. Results The cohort study included 1 083 629 women. During a median follow-up of 11.6 years, 334 582 (31%) used statins at least once. There were 7709 cases of endometrial, 4415 cases of ovarian, and 1603 cases of cervical cancers. Statin use was associated with reduced risk of endometrial cancer [current use hazard ratio (HR) = 0.90, 95% confidence interval (CI): 0.85–0.96; past use HR = 0.79, 95% CI: 0.71–0.88]; associations were observed only for the lipophilic statins, and with similar associations by age groups and for type I and II endometrial cancer. No consistent associations were found for ovarian or cervical cancers. We found no trends for cumulative defined daily doses of current use or time since cessation for any cancer type. Conclusion Statin use was associated with a reduced risk of endometrial cancer but not with the risk of ovarian cancer or cervical cancer.

Early life exposure to tobacco smoke and ovarian cancer risk in adulthood

AbstractBackgroundOvarian cancer risk in adulthood may be affected by early life exposure to tobacco smoke. We investigated this relationship in two large prospective cohorts, the Nurses’ Health Study (NHS) and NHSII.MethodsIn total, analyses included 110 305 NHS participants (1976–2016) and 112 859 NHSII participants (1989–2017). Self-reported early life smoking exposures were queried at baseline or follow-up questionnaires. Cox proportional hazards models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for risk of ovarian cancer overall and by tumour histotype.ResultsOverall, ovarian cancer risk was not different among participants whose mothers did versus did not smoke during pregnancy (HR = 1.05, 95% CI: 0.87–1.27); however, an increased risk was observed among women who themselves were never smokers (HR = 1.38, 95% CI: 1.05–1.81) but not among ever smokers (HR = 0.86, 95% CI: 0.66–1.14; Pheterogeneity = 0.02). Compared with women who never smoked, ovarian cancer risk was similar for women who started to smoke at age <18 (HR = 0.98, 95% CI: 0.86–1.11) or ≥18 (HR = 1.02, 95% CI: 0.93–1.12). These associations did not differ by histotype (Pheterogeneity ≥0.35). Parental smoking in the home during childhood/adolescence was related to a 15% increased risk of ovarian cancer in adulthood (HR = 1.15, 95% CI: 1.04–1.27) and this association was suggestively stronger among women with non-serous/low-grade serous tumours (HR = 1.28, 95% CI: 1.02–1.61) versus high-grade serous/poorly differentiated tumours (HR = 1.09, 95% CI: 0.93–1.28; Pheterogeneity = 0.25).ConclusionsExposure to parental tobacco smoke in the home, but not early initiation of smoking, was associated with a modest elevated risk of ovarian cancer. Further investigations are required to confirm these findings and elucidate underlying mechanisms.

Use of an emulated trial to investigate the association between use of nitrogen-based bisphosphonates and risk of epithelial ovarian cancer

Abstract Background Epithelial ovarian cancer (EOC) is the eighth most common cancer in women, with poor survival outcomes. Observational evidence suggests that nitrogen-based bisphosphonate (NBB) use may be associated with reduced risk of EOC, particularly the endometrioid and serous histotypes; however, confounding by indication is a concern. An alternative approach to investigate the chemo-preventive potential of NBBs is to emulate a target trial by identifying all women who initiate use of NBBs and investigate the risk of EOC for continued users compared with discontinued users. Methods Using population-based linked data, we identified all Australian women aged over 50 years who first used NBBs over 2004–12. We used the year after first use to define treatment for each woman as either continued or discontinued use. We emulated randomization using stabilized inverse probability weights to balance the treatment groups using covariates including age, comorbidities and socioeconomic status. We followed women from treatment assignment until EOC diagnosis, death or 31 December 2013. We assessed the risk of EOC (overall and by histotype) using flexible parametric time-to-event models allowing for time-varying effects, and produced time-varying coefficients. Results Of the 313 383 women in the study, 472 were diagnosed with EOC during follow-up (261 serous EOC), with an average age at diagnosis of 72 years. Continued use of NBBs was associated with reduced risk of EOC overall (HR = 0.87, 95% CI: 0.69, 1.10), and serous EOC (HR = 0.71, 95% CI: 0.53, 0.96), compared with discontinued treatment, with estimates remaining constant over the 9-year follow-up. Conclusions Results from our emulated trial suggest that in women who initiated NBB treatment, those who continued use had 13% and 29% lower hazards of being diagnosed with EOC overall and serous EOC, respectively, compared with women who discontinued use.

Commentary: Could microchimerism play a role in ovarian carcinogenesis?

Male origin microchimerism and ovarian cancer

Abstract Background Reduced risk of ovarian cancer is commonly ascribed to reduced exposure to endogenous hormones during pregnancy, using oral contraceptives or not using hormone replacement therapy. However, exposure to hormones alone account for less than half of all cases. Many women carry small amounts of male cells—known as male origin microchimerism—in their circulation and remarkable impacts of these cells on women’s health are being published. Here, we pursue the possibility that male origin microchimerism has a role in reducing ovarian cancer risk. Methods We conducted a prospective case-cohort study using blood samples and questionnaire data from 700 women participating in the Danish Diet, Cancer, and Health cohort. Blood samples were analysed for Y chromosome presence as a marker of male microchimerism. We evaluated the association between male microchimerism and ovarian cancer, using weighted Cox regression models reporting hazard ratios (HRs) and corresponding 95% confidence intervals (CIs). Results Male microchimerism was detected in 46% of cases and 65.9% of controls. Women testing positive for male microchimerism had a reduced hazard rate of ovarian cancer compared with women testing negative (HR = 0.44, 95% CI: 0.29-0.68). We found no evidence of interaction with measures of hormonal exposures (P = 0.50). Conclusions For the first time we report that women who test positive for male microchimerism in their circulation have reduced rates of ovarian cancer compared with women who test negative. Although the underlying mechanisms are presently unknown, we believe male microchimerism is potent in preventing ovarian cancer.

Cohort Profile: The Ovarian Cancer Cohort Consortium (OC3)

Evaluating the effectiveness of the human papillomavirus vaccination programme in England, using a regression discontinuity design

Abstract Background In England, the national human papillomavirus (HPV) immunization programme was introduced in 2008 to prevent cervical cancer. Girls aged 12–13 years were offered routine vaccination and those aged 14–18 years in 2008 were offered ‘catch-up’ vaccination. We evaluate the effect of the HPV catch-up vaccination programmes on cervical cancer and cervical dysplasia diagnoses, and provide an estimate of the vaccine effectiveness. Methods Using the 2011 Census, Hospital Episode Statistics, and mortality data for the population of England, we exploit the cut-off in eligibility and apply a regression discontinuity design to assess the impact of HPV vaccination on cervical disease. Results Vaccination reduced the incidence of cervical dysplasia and cancer diagnoses by 31% and 75%, respectively, at ages 23–30 years in girls offered catch-up vaccination at ages 17–18 years compared with those who were just above the eligibility age for the catch-up vaccination, with a clear discontinuity. Reductions continued amongst girls offered routine vaccination. Conclusion These estimates, obtained by using a quasi-experimental approach, are similar to vaccine effectiveness estimates based on more traditional approaches. This approach provides further evidence of the HPV vaccination programme reducing adverse cervical outcomes in young women and could be used for future studies to evaluate major changes in HPV vaccination policy and for studies of longer-term outcomes including other cancers and deaths.

Multidimensional penalized splines for survival models: illustration for net survival trend analyses

Abstract Background In descriptive epidemiology, there are strong similarities between incidence and survival analyses. Because of the success of multidimensional penalized splines (MPSs) in incidence analysis, we propose in this pedagogical paper to show that MPSs are also very suitable for survival or net survival studies. Methods The use of MPSs is illustrated in cancer epidemiology in the context of survival trends studies that require specific statistical modelling. We focus on two examples (cervical and colon cancers) using survival data from the French cancer registries (cases 1990–2015). The dynamic of the excess mortality hazard according to time since diagnosis was modelled using an MPS of time since diagnosis, age at diagnosis and year of diagnosis. Multidimensional splines bring the flexibility necessary to capture any trend patterns while penalization ensures selecting only the complexities necessary to describe the data. Results For cervical cancer, the dynamic of the excess mortality hazard changed with the year of diagnosis in opposite ways according to age: this led to a net survival that improved in young women and worsened in older women. For colon cancer, regardless of age, excess mortality decreases with the year of diagnosis but this only concerns mortality at the start of follow-up. Conclusions MPSs make it possible to describe the dynamic of the mortality hazard and how this dynamic changes with the year of diagnosis, or more generally with any covariates of interest: this gives essential epidemiological insights for interpreting results. We use the R package survPen to do this type of analysis.

Associations of life course obesity with endometrial cancer: could alternative categorization of BMI change improve inference about cumulative risks?

Use of antidepressants and endometrial-cancer risk: a nationwide nested case–control study

AbstractBackgroundPreclinical studies have suggested that antidepressant drugs may possess antineoplastic properties. In a nationwide case–control study, we examined the association between use of antidepressants and endometrial-cancer risk with a particular focus on selective serotonin reuptake inhibitors (SSRIs).MethodsFrom the Danish Cancer Registry, we identified all women with a histologically verified diagnosis of endometrial cancer between 2000 and 2016, and, for each woman, 15 age-matched controls. We obtained information on use of SSRIs, tricyclic antidepressants (TCAs) and other antidepressants based on records of filled prescriptions from the National Prescription Register. Using conditional logistic regression, we calculated adjusted odds ratios (ORs) and 95% confidence intervals (CIs) for associations between use of antidepressants and endometrial-cancer risk compared with non-use. In active comparator analyses, SSRI use was compared with TCA use.ResultsThe study population comprised 8164 cases and 122 432 controls. Compared with non-use, SSRI use was associated with an OR of 0.88 (95% CI 0.82–0.96) for endometrial cancer, whereas the association with TCA use was close to unity (OR 1.05, 95% CI 0.90–1.22). Use of other antidepressants yielded an OR of 0.86 (95% CI 0.71–1.03). We observed no apparent trends in associations according to cumulative amount. The inverse association with SSRI use persisted when compared with TCA use (OR 0.81, 95% CI 0.66–0.99).ConclusionsUse of SSRIs was associated with a decreased risk of endometrial cancer, whereas no inverse association appeared with use of TCAs. The antineoplastic potential of SSRIs should be investigated in future studies.