Statins & Ovarian Cancer
They’re not just for lowering cholesterol.
Each year, roughly 20,000 women in the United States are diagnosed with ovarian cancer, with older women being more likely than younger women to develop the disease. Among women in the United States, ovarian cancer is the eighth most common cancer and fifth-leading cause of cancer death. And while most patients with ovarian cancer respond initially to chemotherapy agents, many experience relapse along with the subsequent development of resistance to chemotherapy treatment. With only a 48% five-year survival rate, there’s a tremendous need for new treatment options for women suffering from ovarian cancer.1 Of particular interest is the potential role of the widely used cholesterol-lowering class of medications known as statins (also known as hydroxymethylglutarate coenzyme-A [HMG-CoA] reductase inhibitors) to help prevent or treat ovarian and several other cancers.
Types of ovarian cancer includes epithelial tumors, which begin in the thin layer of tissue that covers the outside of the ovaries; stromal tumors, which begin in the ovarian tissue that contains hormone-producing cells; and germ cell tumors, which begin in the egg-producing cells. Approximately 90% of ovarian cancers involve epithelial tumors. Stromal tumors represent about 7% of ovarian tumors, while germ cell tumors are significantly more rare. While the five-year relative survival rate for these three types of tumors is only 44%, early detection generally results in a better outlook.3 When the cancer is diagnosed and treated in stage 1, the five-year relative survival rate is 92%; however, only about 15% of ovarian cancers are diagnosed in stage 1.
Women should be aware of risk factors that are believed to increase their chance of developing epithelial ovarian cancer. (These don’t apply to other less common types of ovarian cancer such germ cell tumors and stromal tumors.) Greater risk of ovarian cancer is associated with women who3:
• are middle-aged or older;
• have close family members (such as a mother, sister, aunt, or grandmother) on either their mother’s or father’s side who have had ovarian cancer;
• have a genetic mutation of the breast cancer susceptibility genes BRCA1 or BRCA2 or other gene mutations, such as those associated with Lynch syndrome;
• have had breast, uterine, or colorectal cancer;
• have an Eastern European or Ashkenazi Jewish background;
• have endometriosis, a condition in which tissue from the lining of the uterus grows elsewhere in the body;
• have never given birth or have had trouble getting pregnant; and
• have taken estrogen by itself (without progesterone) for 10 or more years.
It’s also thought that continuous or “incessant” ovulation, uninterrupted by pregnancy or oral contraceptive use, has the strongest correlation with the disease.4
Role of Cholesterol in Cancer
Role of Statins in Cancer
HMG-CoA Genetic Study
Evaluated during the study were 63,347 women between the ages of 20 and 100 years old, of whom 22,406 had ovarian cancer, as well as an additional 31,448 women who carried the BRCA1/2 gene fault, of whom 3,887 had ovarian cancer. The study used an approach called Mendelian randomization, which involves analyzing the genetic data from thousands of people. The study concluded that those women whose genetics allowed for more effective inhibition of HMG-CoA had significantly lower odds of epithelial ovarian cancer than did the general population. Those women with enhanced genetics were found to have genetic HMG-CoA reductase inhibition equivalent to a 38.7-mg/dL reduction in LDL cholesterol and had significantly lower odds (odds ratio [OR] 0.6) of epithelial ovarian cancer. Benefits were also seen among BRCA1/2 mutation carriers (hazard ratio, 0.69).
While keeping in mind that the findings come from looking at gene variation rather than use of statins themselves, the data suggest that long-term statin use could be associated with an estimated 40% reduction in ovarian cancer risk in the general population.
New England Case Control Study
Overall, women who used statins had 32% lower risk of ovarian cancer compared with nonusers, adjusting for the matching factors and other covariates. The risk of ovarian cancer was 37% lower in statin users between the ages of 50 and 59 compared with nonusers (OR 0.63, 95% CI 0.46–0.87). Among women age 60 and older, the risk of ovarian cancer was 39% lower among statin users vs nonusers (OR 0.61, 95% CI 0.44–0.85). The decreased risk was seen for all types of ovarian cancer, including serous invasive cancers, high-grade serous cancer, all nonserous invasive cancers, and mucinous cancers.
The specific statins taken during the study period were not provided; however, statistics about the statins’ lipophilic or hydrophilic nature were presented. Lipophilic statins include lovastatin, atorvastatin, pitavastatin, and simvastatin, whereas hydrophilic statins include pravastatin, fluvastatin, and rosuvastatin. The reduced risk of ovarian cancer was most apparent in women taking a lipophilic statin who began use after age 49 and who had used it for two to 4.9 years. The use of a statin (hydrophilic or lipophilic) was associated with a 25% reduction in overall ovarian risk, with the reduction in risk being statistically significant only with the use of a lipophilic statin. The researchers pointed out that this difference may be a simple matter of study power since most of the study participants were using a lipophilic statin (88% vs 12%). It was also noted that other studies have suggested that lipophilic statins are associated with a greater reduction in risk of cancer recurrence and improved survival, while another study found no difference. Regardless, the choice of statin is likely an important issue to consider and report on in future epidemiologic studies of statins and ovarian cancer.
Additionally, the benefit of taking a statin on ovarian cancer risk was greater for women who used both a statin and either an NSAID or a statin plus aspirin. In contrast, the reduction in ovarian cancer risk with statin use was apparent only in women who did not have obesity, who had a body mass index of less than 30 kg/m2, and who did not have either type 1 or type 2 diabetes.
Statin Use Following Diagnosis
The researchers indicated that for effective cancer therapy the right statin is needed, that it must be used at the right dose and interval, and that diet needs to be controlled to reduce sources of geranylgeraniol, which can limit pitavastatin’s effect on cancer cells. The research found that the tumor inhibiting effects of pitavastatin in mice were limited when dietary geranylgeraniol was present. This indicates that statins appear to work in cancer by not only lowering cholesterol but also preventing cancer cells from making geranylgeraniol, both of which occur as part of the mevalonate pathway. Dietary considerations including limiting geranylgeraniol (found in various foods including sunflower oil and some rice) are likely warranted in future trials.
Pitavastatin was found to be effective in all of the cell lines tested, with potencies differing by approximately 10-fold between different cell lines. Researchers wrote that statins’ effectiveness may reflect a fundamental role of the mevalonate pathway in ovarian cancer cell biology. Furthermore, it was observed that the increased expression of wild-type and gain-of-function variants of TP53 resulted in an increase in HMG-CoA reductase expression. Because of the widespread dysregulation of TP53 in ovarian cancer and the detection of HMG-CoA reductase expression in a large proportion of ovarian cancer tumors, the researchers suggest that a significant proportion of ovarian cancer patients may be candidates for treatment with pitavastatin. Additionally, it was noted that pitavastatin retained its activity in matched cells obtained from patients both before and after the onset of drug resistance, suggesting the usefulness of statins to treat patients with chemotherapy-resistant cancer.
There are no clinical guidelines recommending the use of statins for ovarian cancer treatment, so additional studies of statins are needed. However, the use of statins is promising, as the studies to date strongly suggest they likely will play a role in the development of future treatment options for ovarian cancer patients.
— Mark D. Coggins, PharmD, BCGP, FASCP, is vice president of pharmacy services and medication management for skilled nursing centers operated by Diversicare in nine states and is a past director on the board of the American Society of Consultant Pharmacists. He was nationally recognized by the Commission for Certification in Geriatric Pharmacy with the 2010 Excellence in Geriatric Pharmacy Practice Award.
2. Signs and symptoms of ovarian cancer. American Cancer Society website. https://www.cancer.org/cancer/ovarian-cancer/detection-diagnosis-staging/signs-and-symptoms.html. Updated April 11, 2018.
3. Ovarian cancer. Drugs.com website. https://www.drugs.com/mcd/ovarian-cancer. Updated July 25, 2019.
4. Fathalla MF. Incessant ovulation and ovarian cancer — a hypothesis re-visited. Facts Views Vis Obgyn. 2013;5(4):292-297.
5. Batetta B, Sanna F. Cholesterol metabolism during cell growth: which role for the plasma membrane? Eur J Lipid Sci Technol. 2006;108(8):687-699.
6. Göbel A, Rauner M, Hofbauer LC, Rachner TD. Cholesterol and beyond — the role of the mevalonate pathway in cancer biology. Biochim Biophys Acta Rev Cancer. 2020;1873(2):188351.
7. Yarmolinsky J, Bull CJ, Vincent EE, et al. Association between genetically proxied inhibition of HMG-CoA reductase and epithelial ovarian cancer. JAMA. 2020;323(7):646-655.
8. Akinwunmi B, Vitonis AF, Titus L, Terry KL, Cramer DW. Statin therapy and association with ovarian cancer risk in the New England Case Control (NEC) study. Int J Cancer. 2019;144(5):991-1000.
9. Harding BN, Delaney JA, Urban RR, Weiss NS. Use of statin medications following diagnosis in relation to survival among women with ovarian cancer. Cancer Epidemiol Biomarkers Prev. 2019;28(7):1127-1133.
10. de Wolf E, Abdullah MI, Jones SM, et al. Dietary geranylgeraniol can limit the activity of pitavastatin as a potential treatment for drug-resistant ovarian cancer. Sci Rep. 2017;7(1):5410.