Ovarian and endometrial cancers are the most common gynecologic malignancies and emerging evidence suggests that lipid metabolism and subsequent inflammation are important etiologic factors for both tumors. Statins (HMG-CoA reductase inhibitors) are the most widely prescribed lipid-lowering drugs in the United States and are used by 25% of adults aged 40+ years. In addition to their cardio-protective actions, statins have anti-inflammatory effects and have demonstrated antiproliferative and apoptotic properties in cancer cell lines, supporting a potential role in cancer prevention. To appropriately quantify potential public health impact of statin use for cancer prevention, there is a great need to understand the potential risk reduction among individuals at a higher risk of gynecologic cancers, the group that will likely need to be targeted to effectively balance risk/benefit of medications repurposed for cancer prevention. In this commentary, we focus on summarizing emerging evidence suggesting that the anti-inflammatory and lipid-lowering mechanisms of statins may provide important cancer-preventive benefits for gynecologic cancers as well as outline important unanswered questions and future research directions.

Ovarian and endometrial cancer are gynecologic cancers with high mortality rates (1). Because the recommended treatment for both cancers is surgical with high degrees of adverse effects—salpingo-oophorectomy for ovarian cancer and total hysterectomy for endometrial cancer, the necessity for nonsurgical options is pervasive. Currently, the clinically approved nonsurgical option for prevention of ovarian and endometrial cancer is hormonal (oral contraceptives and progesterone, respectively; refs. 2, 3), which has limited acceptability by potential users due to side effects and potential increased risk of breast cancer among current users (4). Thus, it is imperative to investigate more suitable options for nonsurgical prevention of ovarian and endometrial cancers.

Statins were first introduced in the late 1980s to reduce risk of recurrent cardiovascular disease (CVD) events (Fig. 1; ref. 5). On the basis of their cholesterol- and inflammation-lowering effects, statins were later approved for primary cardio-prevention to reduce incident CVD morbidity and mortality (5). As a result, statin use has increased dramatically in recent years (6) with approximately 25% of U.S. females aged 40 and older reporting current use, based on recent cycles of the National Health and Nutrition Examination Survey (NHANES; ref. 7).

Figure 1.

Overview of timeline of statin use in the United States.

Figure 1.

Overview of timeline of statin use in the United States.

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Statins block activity of HMG-CoA (3-hydroxy-3-methyglutaryl COA) reductase, which catalyzes the conversion of HMG-CoA to mevalonic acid, a precursor of cholesterol. Preclinical and clinical studies have demonstrated that statins also possess antiproliferative and proapoptotic effects, as well as anti-invasion and anti-inflammatory properties, making them promising agents for cancer prevention and/or treatment. Statin use is associated with relatively low risk of major adverse events. Myopathy occurs in approximately 5% of statin users and although it is classified as a minor adverse event, it is the most commonly reported reason for changing or stopping statin therapy (8). Other reported side effects (e.g., fatigue, headache, nausea, and indigestion) are rare and considered mild (8). In this commentary, we focus on the role of statins as preventive interventions for ovarian and endometrial cancers.

The potential cancer preventive effect of statins was originally identified in analyses of randomized control trials that were investigating statin effects on CVD. In these trials, safety and follow-up measurements revealed that statin use was associated with decreased cancer incidence, consistent reductions were also reported in observational studies (9). Mechanistic studies have revealed that dysregulation of the mevalonate pathway is associated with various tumorigenic mechanisms in both cholesterol-dependent and -independent manners (10).

While cholesterol is primarily known to serve as a structural component of plasma membranes, it and its associated metabolites have also been demonstrated to modulate various immune processes involved in carcinogenesis, including T-cell signaling, macrophage function, and interferon signaling (11). Cholesterol has also been shown to activate cancer-associated signaling pathways such as the Hedgehog pathway, among others, promoting cell differentiation and proliferation (12). Statin use inhibits cholesterol synthesis, thereby demonstrating anticancer properties by inhibiting activation of these and other protumorigenic pathways.

Statins also affect non–cholesterol-related mechanisms that contribute to carcinogenesis (13). Statin inhibition of HMG-CoA reductase interferes with isoprenoid synthesis. Isoprenoids such as farnesyl pyrophosphate (FPP) and geranylgeranyl pyrophosphate (GGPP) activate numerous intracellular signaling proteins involved in transformation, including the Ras and Rho family of proteins. Statin inhibition of these pathways affect both antiproliferative and proapoptotic cellular mechanisms, such as cell-cycle progression and cell motility/invasion (ref. 14; Fig. 2).

Figure 2.

Schematic of statin inhibition of mevalonate pathway and possible downstream effects related to reduced mevalonate pathway metabolism.

Figure 2.

Schematic of statin inhibition of mevalonate pathway and possible downstream effects related to reduced mevalonate pathway metabolism.

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Statins also reduce inflammation, including lowering levels of C-reactive protein (CRP), TNFα, and IFNγ, independent of their role in cholesterol reduction (15, 16). CRP is a systemic marker of inflammation and increased levels are known to be associated with increased CVD risk, CRP, and other systemic inflammatory markers have also been shown to be correlated with increased endogenous estrogen levels (17), as well as increased risks of both ovarian cancer (18) and endometrial cancer (19). These findings indicate a potential link between inflammation and ovarian cancer as well as obesity-related cancers, and suggest a role for statins in preventing the inflammatory processes that may be driving carcinogenesis. Unlike other cancers, the incidence of some obesity-related cancers like endometrial cancers are increasing over time, warranting additional research to better elucidate the mechanism(s) by which statin use decreases circulating inflammatory marker levels.

Several studies have evaluated the association between statin use and risk of ovarian and endometrial cancers. Numerous meta-analyses have investigated the association between statin use and ovarian cancer risk. The majority reported relative risks that were consistently inverse [RR (95% confidence interval (CI) = 0.79 (0.64–0.98); ref. 20; RR (95% CI) = 0.88 (0.76–1.03); ref. 21; RR (95% CI) = 0.87 (0.74–1.03); ref. 22; RR (95% CI) = 0.92 (0.85–1.00); ref. 23], and suggest that statin use is associated with lower risk of developing ovarian cancer. Associations across the included individual studies were heterogenous (I2 > 42%) which may, at least in part, explain the lack of statistical significance in some of the published meta-analyses. Multiple factors contribute to the between study heterogeneity such as study design and follow-up time together with a likely complex relationship between statin use and ovarian cancer that may be modulated by statin type, dose, duration, age at initiation, and ovarian cancer histotypes. The largest risk reductions were suggested among long-term statin users (>5 years of use; RR range: 0.48–0.73; refs. 20–22). Results from subgroup analyses investigating differences by geographical region (i.e., restricted to White and Asian populations) are incomplete, with some reports of inverse associations in White populations and inconclusive findings in Asian populations. Irvin and colleagues conducted several subgroup analyses taking into account statin use patterns and ovarian cancer histotypes (22). They reported reduced risk of ovarian cancer after exposure to lipophilic statins [RR (95% CI) = 0.88 (0.69–1.12)] and no association with hydrophilic statins [RR (95% CI) = 1.06 (0.72–1.57)]. When considering ovarian cancer histotypes, no association was observed between statin use and risk of serous [RR (95% CI) = 0.95 (0.69–1.30)] or clear cell tumors [RR (95% CI) = 1.17 (0.74–1.86)]. As few studies reported on mucinous or endometroid tumors, age at statin use initiation, and statin indication, no meta-analyses could be conducted. Of the observational studies summarized in Irvin and colleagues, statin use was based on prescription records in the majority of studies (75%) and self-report (interview-based prescription medication inventory) in the remaining two studies (25%). While prescription records have some limitations in terms of being able to assess completeness of coverage of the population of interest and adherence, most studies were based in large health care organizations or in entire countries (i.e., Denmark, Finland) with near complete registry coverage and implemented a stringent exposure definition (e.g., ≥2 prescriptions redeemed on separate dates, based on filled prescriptions vs. prescriptions written) to reduce exposure misclassification due to unfilled prescriptions.

To date, only one randomized controlled trial (RCT) has been published evaluating ovarian cancer risk after statin use, supporting a reduction in risk of ovarian cancer for statin users, albeit based on only two ovarian cancer cases (24). The trial was designed to evaluate the use of lovastatin in primary coronary heart disease prevention. As such, the study did not intend to evaluate cancer outcomes, included women with preexisting cancer, and followed participants for an average of 5.2 years. While included in the referenced meta-analyses, this trial contributes little weight (<1%) given the limited cases identified. A valid comparison of the RCT trial results to observational studies is limited given methodologic considerations as well as lack of diversity in statin type.

Additional evidence supporting a protective effect of statin use on ovarian cancer incidence comes from a Mendelian Randomization study which showed that genetically proxied HMG-CoA reductase (i.e., genetic variants related to lower function of HMG-CoA reductase, the target of statins) equivalent to a 1-mmol/L reduction in LDL cholesterol was associated with lower odds of epithelial ovarian cancer in the general population [OR (95% CI) = 0.60 (0.43–0.83)] and among BRCA1/2 mutation carriers [HR (95% CI) = 0.69 (0.51–0.93); ref. 25]. Interestingly, genetically proxied LDL cholesterol levels were not associated with ovarian cancer risk [OR (95% CI) = 0.98 (0.91–1.05)] suggesting that the effect of statins on ovarian cancer is not likely driven by its ability to lower LDL cholesterol. Indeed, several studies report statin use is associated with changes in other lipid species [triglycerides, sphingomyelins, lysophospholipids, cholesterol esters; refs. 26–28], which are associated with ovarian cancer risk (29–31).

Similar to ovarian cancer, multiple meta-analyses have investigated the association between statin use and risk of endometrial cancer. While earlier studies reported similar inverse associations between statin use and endometrial cancer risk [RR (95% CI) = 0.90 (0.75–1.07); ref. 20, RR (95% CI) = 0.94 (0.82–1.07); ref. 32, RR (95% CI) = 0.88 (0.78–1.00); ref. 21], the most recent analysis estimated a 19% lower relative risk of endometrial cancer among statin users [RR (95% CI) = 0.81 (0.70–0.94); ref. 23]. Study heterogeneity was substantial in these meta-analyses as well (I2 > 58%) suggesting multiple factors, such as geographic location, statin use patterns, and endometrial cancer histotype, play an important role in the association between statin use and endometrial cancer risk. Analyses stratified by cohort or case–control study design suggested limited differences in associations. However, the only RCT to evaluate endometrial cancer risk published to date reported a reduced risk of endometrial cancer (24). As noted previously, it is not possible to compare this RCT with the observational studies given methodologic concerns, notably the limited number of cancer diagnoses. Few subgroup analyses focused on clinical and pharmacologic factors have been conducted. Two studies investigated associations by statin use duration and report potential inverse associations [RR (95% CI) = 0.69 (0.44–1.10); ref. 20; RR (95% CI) = 0.79 (0.58–1.08); ref. 21] among long-term users. Analyses by statin type and endometrial cancer histotype are also needed.

A recent Mendelian Randomization analysis found genetically predicted increased LDL cholesterol levels and genetically predicted lower HDL cholesterol levels, but not genetically predicted triglycerides, to be associated with lower endometrial cancer risk, specifically the more fatal non-endometrioid endometrial tumors, and independent of obesity (33). These findings suggest that any reduction in endometrial cancer risk among statin users is likely due to other mechanisms than lowering LDL-cholesterol or offset the unexplained inverse association between genetically predicted LDL-cholesterol levels and endometrial cancer risk. A recent review found that multiple lipid species (e.g., phosphatidylcholines and sphingomyelins) and fatty acids were altered in endometrial cancer cases compared with controls (34) while other studies show that statin use can alter lipid profiles, including phosphatidylcholines and sphingomyelins (26–28).

There are many challenges to studying the potential cancer preventive benefits of statins for gynecologic cancer prevention. First, gynecologic cancers are rare. As such, large studies are needed to accumulate sufficient cancer diagnoses for a well powered investigation. Leveraging existing resources and pooling data across large population-based studies is one approach that has the potential to address unanswered questions about the role of statin use in gynecologic cancer prevention. The ability to accrue sufficient numbers of patients and controls to RCTs of commonly used medications is also challenging (35). Assessing statin use is also challenging given that adherence to statin prescriptions is reported to be low (8). It is estimated that 33%–50% of prescriptions are not filled and that of the prescriptions filled, many stop taking their statin prescription within 6 months due to cost, lack of tangible benefits, and/or side effects (8). Thus, it will be important for observational studies of statin use to collect updated information on prescription use to most accurately characterize usage patterns and address questions related to potential risk reductions.

Studies of statin use and gynecologic cancers need to carefully consider both confounding and effect modification. Given that many factors associated with statin use are also associated with increased and/or decreased risk of ovarian or endometrial cancer, or both, potential confounders should be defined a priori, and controlled for either in study design or statistical analyses. Studies also need to consider confounding by indication—confounding that arises due to the fact that individuals who are prescribed a medication or who take a given medication are inherently different from those who do not take the drug—because they are taking the drug for a reason. Indications for statin use are time-dependent and include CVD and related-comorbidities (dyslipidemia, hypertension, heart disease, type 2 diabetes; ref. 8). Dyslipidemia and type 2 diabetes are associated with altered risk of both endometrial and ovarian cancers in some studies, and associations with CVD need to be more thoroughly evaluated. Potential adverse events associated with statin use in this context should also be considered. In addition to known side-effects, statins have been shown to decrease insulin sensitivity and increase risk of or progression to type 2 diabetes in some individuals (36). This may be particularly relevant for endometrial cancer, as type 2 diabetes is an endometrial cancer risk factor, but also some patients with endometrial cancer are at increased risk of diabetes and other comorbidities, so balancing the risk-benefit of statin use by patient characteristics is likely going to be critically necessary.

Several factors could plausibly alter the association between statin use and cancer risk. For ovarian and endometrial cancers, potential effect modifiers of the statin-cancer association likely include body mass index (BMI), menopausal status, and/or menopausal hormone therapy (MHT) use. Furthermore, ovarian cancer risk reduction among statin users is likely not due to lowering LDL-cholesterol (25). This relationship is more complex for endometrial cancer because obesity, a strong risk factor for endometrial cancer but not for ovarian cancer, is also strongly associated with cholesterol levels (total, LDL, and HDL). Further research is needed to identify and disentangle the common and distinct biological mechanisms underlying the reduction in risk of ovarian and endometrial cancer among statin users.

Evaluations of statin use in ovarian or endometrial cancers require additional accommodation for sources of bias seen in similar cancer prevention studies, such as those of immortal time, the effect of prevalent medication use, and healthy initiator or adherer biases that can lead to seemingly improbable protective effects. Study designs, such as the active comparator, new user (ACNU) design or target trial emulation methodology can be applied to observational data to drastically reduce these biases and mimic estimates from RCTs (37). ANCU studies tackle issues of confounding by indication, healthy initiator, prevalent user, and even potential biases caused by lack of prescription filling by eliminating the untreated comparator group and including only new and indicated medication users. Applying target trial methodology to observational data and requiring that follow-up is aligned with eligibility and categorization into statin or non-statin groups can eliminate immortal time biases by excluding the time period before or after exposure categorization where the subject could not experience the event of interest (i.e., either ovarian or endometrial cancer) (38). Recent analyses for statin use in cancer prevention proved this idea by showing that large reductions in colorectal cancer risk after statin use were due to a period of immortal time that was not accounted for in the original analyses, and risk estimates were null after reducing or eliminating immortal time using a target trial emulation (38). For ovarian and endometrial cancers, which are rare, these methodologies may be difficult to implement, as selection based on target trial criteria may limit the pool of eligible participants and require extensive follow-up times given their long induction periods, but nevertheless these additional methodologic approaches should be considered in large-population based data sources given the potential impact on public health decision making.

Additional research is needed to determine whether there is a role for statins in the prevention of ovarian and endometrial cancers. While existing epidemiologic literature points to possible benefits, extensive gaps remain in determining whether effects seen in observational studies translate to clinical use. Large epidemiologic analyses in prescription databases linkable to cancer registry data are critical for providing context, but require careful execution to account for potential exposure misclassification and biases outlined above. The effect of statins on risks of ovarian or endometrial cancers, particularly in the most common histologic subtypes, should be established in well-powered data sources, compared with existing literature, and evaluated for consistency. Most importantly, research is needed to demonstrate that risk reductions associated with statin use are apparent for those at highest risk (e.g., high genetic risk and/or multiple epidemiologic risk factors) to provide evidence that targeted cancer prevention could be feasible. Given that all medications have some risk of side effects, it will be important to understand the potential risk reduction among individuals at higher-risk of ovarian and/or endometrial cancer, the groups that will likely need to be targeted to effectively balance risk/benefits of medications repurposed for cancer prevention. Future studies should also evaluate histotype-specific effects of statins, given the known heterogeneity of both cancer types, which can inform etiology and possibly demonstrate risk reductions in less prevalent cancer groups.

Cancer risk may differ according to medication use characteristics and needs further assessment. Evaluation processes similar to that of aspirin in the prevention of colorectal cancer are applicable to statin use in gynecologic cancer prevention (39, 40). For instance, determination of optimal age(s) at initiation, dose, duration, and frequency of use are essential to providing clinically relevant information. Because there are multiple statins with different pharmacokinetic properties, whether statin type or intensity (a combination of statin type and dose) heterogeneously influence cancer risk must also be established. As most women taking a statin are indicated for use given either CVD or combinations of CVD-risk factors, future studies should determine how indication(s) impact potential benefits, including severity of the indication(s) and concomitant medication use for CVD-related complications. For women taking statins for primary CVD prevention, the atherosclerotic cardiovascular disease (ASCVD) 10-year risk estimate could be applied for use in determining effects within risk groups and evaluating exposure time period effects pre-and post-2013 when the American College of Cardiology prescribing guidelines were updated. Cancer risk factors such as high BMI, MHT use, and smoking behaviors commonly occur together with CVD indications and require consideration as potential confounders or effect modifiers. Finally, future research efforts should implement study designs that address complex biases, such as the ACNU or target trial methodologies. Combined with careful consideration of adverse events associated with use characteristics, a picture may emerge that depicts how statins are best applied with minimal harm.

Finally, because most individuals taking statins have an underlying indication and are at-risk for CVD, the generalizability of observational findings to the population on a wider scale is not well understood. Although statins appear to reduce CVD risk for those with low cholesterol, little is known regarding the benefit statins provide with respect to gynecologic cancer risk for CVD-naïve women or women with low 10-year ASCVD risk. Future work should consider addressing these points in conjunction with well-designed clinical trials or ancillary components to observational studies across all CVD-risk levels.

Statins are the most widely prescribed lipid-lowering drugs in the United States and have also demonstrated anti-inflammatory, antiproliferative, and apoptotic effects, suggesting a potential cancer preventive role. Ovarian and endometrial cancers have high mortality rates and are treated with life-changing surgeries; therefore, non-surgical preventive options such as statins are appealing preventative interventions for these cancers. Statins ability to reduce cancer risk may be related to immune-related and anti-proliferative mechanisms, among other potential pathways. Epidemiologic studies investigating the association between statin use and ovarian or endometrial cancer risk support a potential inverse relationship, although the variability between the studies necessitate additional research with increased power to draw more definitive conclusions. Additional well-powered studies are critically needed to address whether statin use is associated with reduced cancer risk among higher-risk individuals, including among individuals with higher genetic risk of ovarian and/or endometrial cancer. Ultimately, risk and benefit analyses are the most critical consideration when developing a preventative intervention; a large number of healthy individuals will need to be treated with an agent that must have a very low adverse event profile, such that an acceptable number of adverse events will justify the prevention of endometrial and/or ovarian cancer. It is critical to understand the biological mechanisms driving associations between statin use and lower risk of ovarian or endometrial cancer which will result in a better selection of women who will benefit the most from this intervention. Importantly, studies should investigate differences in associations by race/ethnicity and ovarian or endometrial cancer histotypes. Finally, new and ongoing studies should collect expanded information on prescription use (e.g., different types of statins, dosage and duration of treatment) to better characterize actual usage patterns. Prevention for ovarian and endometrial cancers remains elusive, but is not a lost cause. For statins, as we have outlined, there is much more work to be done.

No disclosures were reported.

This material should not be interpreted as representing the viewpoint of the U.S. Department of Health and Human Services, the NIH, or the NCI.

B. Trabert received funding support from the Huntsman Cancer Institute/Huntsman Cancer Foundation. This work was supported in part by the Intramural Research Program of the NCI, NIH.

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