Lipophilic Statin Use Is Associated With Decreased Mortality in Epithelial Ovarian Cancer

Kala Visvanathan, MD, MBBS, MHS

Findings from an observational study of more than 10,000 women with ovarian cancer showed that lipophilic statins, a class of medicine used to lower blood cholesterol, were associated with a 43% overall reduction in epithelial ovarian cancer mortality, with declines seen across subtypes.¹

“The goal of this study was to examine whether statins could be an effective strategy to improve survival in women with epithelial ovarian cancer,” said Kala Visvanathan, MD, MBBS, MHS, lead author of the study.¹ “Our results provide further evidence in support of the clinical evaluation of lipophilic statins as part of the treatment of ovarian cancer. These drugs are appealing as they are widely used, inexpensive, and well-tolerated [by] most patients. The associated reduction in ovarian cancer mortality is promising.”²

Visvanathan, director of Clinical Cancer Genetics and Prevention Service at the Johns Hopkins Kimmel Cancer Center in Baltimore, Maryland, presented the results during a press briefing in advance of the virtual American Association for Cancer Research Annual Meeting II. In time-updated models, statin use of any kind, at any time and at any dose, corresponded with a 40% reduction in ovarian cancer mortality compared with no statin use (HR, 0.60; 95% CI, 0.54-0.66). At 5 years, the HR was 0.63 (95% CI, 0.56-0.70).¹

Lipophilic statin use improved survival across epithelial ovarian cancer subtypes at varying magnitudes: the HR was 0.43 (95% CI, 0.33-0.76), 0.65 (95% CI, 0.34-0.78), 1.02 (95% CI, 0.98-1.98), 0.60 (95% CI, 0.45-0.95), 0.30 (95% CI, 0.25-0.87), in high-grade serous carcinoma, endometrioid, clear cell, mucinous, and borderline disease, respectively.1 The most significant reductions in mortality occurred in the endometroid ovarian cancer patient (50%) and high-grade serous carcinoma patient subsets (40%; 95% CI, 32-47).^1,2

Patient advantage also differed based on the type of care and statin received. For example, the benefit from statin use was greater in women treated with curative intent (HR, 0.19; 95% CI, 0.18-0.20) versus palliative intent (HR, 0.41; 0.39-0.40) The lipophilic statins, atorvastatin (Lipitor) and simvastatin (Zocor) were specifically associated with a reduction in mortality, with reported HRs of 0.35 (95% CI, 0.22-0.50) and 0.25 (95% CI, 0.22-0.34). Survival improvements were seen with either atorvastatin or simvastatin versus no statin use. Increasing the dose of the given lipophilic statin was also associated with a drop in epithelial ovarian cancer death (P = .06).¹

Methods and Patient Characteristics

Investigators linked data from the Finnish National Cancer Registry and National Prescription Claims database on 10,062 women diagnosed with ovarian cancer between 1995 and 2015 to examine the clinical relationship between pre- and postdiagnostic statin use and ovarian cancer mortality. In the analysis, investigators adjusted for several factors, including age at diagnosis; stage; epithelial ovarian cancer subtype; treatments; year of diagnosis; and concurrent receipt of beta blockers and cardiac, diabetes, and non-statin cholesterol medications.¹

Of the 10,062 patients in the database, 2621 used statins and 80% used lipophilic statins. The median duration of statin use was 7.5 years and the median age at diagnosis was 67 among patients who received statins at any point.¹

In the 2621 patients who ever used statins, serous carcinoma was the most prevalent subtype (42.6%), followed by borderline (19.6%), other (13.7%), endometroid (12.1%), mucinous (8.5%), and clear cell (3.4%). Serous carcinoma was also the most common subtype in the remaining 7441 patients who never used statins.²

Statins

Statins are widely used to lower individuals’ total and low-density lipoprotein cholesterol in the United States and other countries. Approximately 28% of United States adults older than 40 years routinely take the statins.¹ The medication is classified by its solubility: whereas lipophilic statins such as atorvastatin and simvastatin dissolve in fats, hydrophilic statins dissolve in water. Statins are also available in a combination lipophilic and hydrophilic form.²

Mechanistically, statins inhibit the first enzyme in the mevalonate pathway, the β-Hydrozy β-methylglutaryl-CoA reductase.¹ “Products of the pathway have been implicated in tumorigenesis, including tumor growth, proliferation, and angiogenesis,” Visvanathan said. Specifically, lipophilic statins have “demonstrated prominent immunologic effects and can impact immunosurveillance,” she added.

In ovarian cancer, statins have been an investigative focus of several small studies that have sought to define the association of statin use and mortality in patients with ovarian cancer, but findings from these past evaluations have been inconsistent, Visvanathan explained. “The prior observational studies that have examined the association between statin use and ovarian[-specific mortality] or total mortality have reported mixed results,” she said.

For example, findings from a retrospective population-based study of postdiagnostic statin use in 5416 patients with epithelial ovarian cancer showed that that statin use reduced overall mortality by 19% compared with patients who did not use statins (adjusted HR, 0.81; 95% CI, 0.72-0.90; P <.001). The data, published in 2017, also indicated that postdiagnostic statin use led to a significant decline (18%) in ovarian cancer specific-mortality (adjusted HR, 0.82; 95% CI, 0.72-0.93; P = .002).³ In contrast, results from a separate retrospective analysis of statin use and ovarian cancer mortality in 60 propensity-matched patients with advanced-stage disease failed to show an improvement in overall survival.⁴

Visvanathan said the large sample size of this observational study allowed her and fellow investigators to study the effect of statin use on ovarian cancer mortality across a greater number of subtypes than prior evaluations, but noted that the promising results seen in this study must first be confirmed in randomized clinical trials before becoming standard-of-care. However, conducting long-term studies in ovarian cancer is difficult due to the lethality of the disease, Visvanathan added. Ovarian cancer accounts for an estimated 1.2% of cancer cases diagnosed annually in the United States and has a 5-year survival rate below 50% in the United States and other developed countries.² As incidence continues to rise worldwide, “there is an urgent need to find cheaper [and] effective treatment alternatives,” Visvanathan concluded.

References:

1. Visvanathan K, Modur S, Artama M, et al. Lipophilic statins show promise for treatment of epithelial ovarian cancer. Presented at: American Association for Cancer Research Virtual Annual Meeting II; June 19-22, 2020. Poster 5872.
2. Use of lipophilic statins is associated with lower mortality from ovarian cancer. News release. The American Association for Cancer Research. June 22, 2020. Accessed June 19, 2020. https://aacr.ent.box.com/s/297kev1xj8rd6yuann89tri3nhs00xms
3. Couttenier A, Lacroix O, Vaes E. Statin use is associated with improved survival in ovarian cancer: a retrospective population-based study. PLoS One. 2017;12(12):e0189233. doi:10.1371/journal.pone.0189233
4. Chen H-Y, Wang Q, Xu Q-H, et al. Statin as a combined therapy for advanced ovarian cancer: a propensity score matched analysis. Biomed Res Int. 2016;2016:9125238. doi:10.1155/2016/9125238