"Off-target"; Effects? The Role of Statins in Cancer Biology
March 1, 2013
By Robert L. Coleman, MD, Professor, University of Texas; M.D. Anderson Cancer Center, Houston, is Associate Editor for OB/GYN Clinical Alert.
Dr. Coleman reports no financial relationships relevant to this field of study.
Synopsis: Statin use among cancer patients with diverse malignancies is associated with reduced cancer-related mortality. The mechanism is plausible since statins inhibit cholesterol synthesis, which reduces the pool of compounds necessary in cellular proliferation and maintenance of critical cellular functions, such as membrane integrity, signaling, protein synthesis, and cell cycle progression. Prospective clinical trials are warranted.
Source: Nielsen SF, et al. Statin use and reduced cancer-related mortality. N Engl J Med 2012;367:1792-1802.
Cholesterol-reducing statin agents have been associated preclinically with cancer cell growth inhibition and metastases prevention. Given the ubiquitous use of statins in the general population for reduction in cardiovascular risk, the authors evaluated statin use in cancer patients for effects on cancer-specific mortality. They assessed mortality among patients from the entire Danish population who had received a diagnosis of cancer between 1995 and 2007, accompanied by a minimum follow-up of 2 years. Among patients 40 years of age or older, 18,721 had used statins regularly before the cancer diagnosis and 277,204 had never used statins. Multivariable-adjusted hazard ratios for statin users, as compared with patients who had never used statins, were 0.85 (95% confidence interval [CI], 0.83-0.87) for death from any cause and 0.85 (95% CI, 0.82-0.87) for death from cancer. Adjusted hazard ratios for death from any cause according to the defined daily statin dose (the assumed average maintenance dose per day) were 0.82 (95% CI, 0.81-0.85) for a “low” dose (0.01-0.75 defined daily dose per day), 0.87 (95% CI, 0.83-0.89) for “average” dose (0.76-1.50 defined daily dose per day), and 0.87 (95% CI, 0.81-0.91) for “high” dose (> 1.50 defined daily dose per day); the corresponding hazard ratios for death from cancer were 0.83 (95% CI, 0.81-0.86), 0.87 (95% CI, 0.83-0.91), and 0.87 (95% CI, 0.81-0.92), respectively. The reduced cancer-related mortality among statin users as compared with those who had never used statins was observed for each of 13 cancer types. A nested case-control study matched statin cancer patients to three non-statin using cancer patients to control for changes in staging and cancer treatment. The effects were similar to the larger general population analysis. The authors concluded that statin use in patients with cancer is associated with reduced cancer-related mortality. Further study of mechanism and effect in prospective studies is warranted.
Commentary
As a complement to last issue’s commentary on the use of metformin and its effect on ovarian cancer mortality, we have this provocative report of statin use. To summarize, statin use was associated with reduced cancer-specific mortality across 13 different malignancies. The data were derived from a unique resource, the enviable National Registry of Patients, which has nearly unbelievable quality control within the Danish health care system. Lending credibility to the study’s conclusions are the 98% capture of index cancers associated with nearly 100% complete follow-up and prescriptive practices over a 13-year period among the entire Danish population. Also, to confront changes in the cancer classifications, staging, and treatment over the study period, a nested 1:3 matched case-control study was also conducted. In that analysis, statin users with cancer were matched to three non-statin users with cancer controlling for cancer type, gender, age at diagnosis, and year of diagnosis. The consistency of effect in “all-cause” death and “cancer-specific” death in the two analyses provide legitimacy to the hypothesis that statin use in patients developing cancer may provide up to a 15% reduction in the cumulative risk of these events. This is bolstered by a credible link to the mechanism of action of the statins, which is to perturb cholesterol synthesis. As is recognized, cholesterol is a fundamental structural component of mammalian cell membranes and structures. It is also critical to many cellular processes that govern proliferation, and in cancer cells, processes that are involved in tumor growth, invasion, and metastases.1,2 In particular, the mevalonate pathway (cholesterol synthesis pathway) is up-regulated in P53 mutated cancers, where cholesterol metabolites serve as important signaling substrates promoting the malignant phenotype.3 Statin use in preclinical experiments has been shown to inhibit cellular growth and metastases. There is also evidence that statins can block the P-glycoprotein pump, which serves as a mechanism of resistance to some chemotherapeutics.4
Since the sample is so large and homogeneous, the clinical impact may be trivial in some cancers and not easily extrapolated to other ethnic groups. In addition, the combination of statins (which are metabolized via intestinal and hepatic cytochrome P450 oxygenases) with chemotherapy needs to be carefully considered, as they may compete for metabolic clearance. Further, there are gaps in the analysis, such as the consideration of important cofactors (tobacco use, balance of screening/early detection practices, cholesterol levels) and the observed lack of a dose effect, which may suggest a minimal dose could be just as important to mortality reduction but with fewer side effects. Nevertheless, the results are thought-provoking and support more definitive clinical investigation into the role of statins in cancer therapy and their effect on long-term survival.
References
- Agarwal B, et al. Mechanism of lovastatin-induced apoptosis in intestinal epithelial cells. Carcinogenesis 2002;23:521-528.
- Gruenbacher G, et al. IL-2 costimulation enables statin-mediated activation of human NK cells, preferentially through a mechanism involving CD56+ dendritic cells. Cancer Res 2010;70:9611-9620.
- Freed-Pastor WA, et al. Mutant p53 disrupts mammary tissue architecture via the mevalonate pathway. Cell 2012;148:244-258.
- Follet J, et al. The association of statins and taxanes: An efficient combination trigger of cancer cell apoptosis. Br J Cancer 2012;106:685-692.
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