Originally published as JCO Early Release 10.1200/JCO.2006.07.9673 on September 25 2006

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Statin and Cancer Risks: From Tasseomancy of Epidemiologic Studies to Meta-Analyses

Kyungmann Kim

University of Wisconsin–Madison, Madison, WI

Statins have been developed as a treatment for lowering cholesterol and have been shown to prevent cardiac events, not only in patients with hypercholesterolemia, but also in patients with a wide range of cholesterol levels in a number of large clinical trials. These latter findings are believed to result from possible independent effects of statins beyond their cholesterol-lowering effect alone. Bonetti at al¹ provided a comprehensive review of the so-called pleiotropic effects of statins on multiple targets such as dementia, bone fractures and cancer, among many. More recently Chan et al² provided a brief review of the potential mechanisms of action for statins, specifically as anticancer agents.

In this issue of the Journal of Clinical Oncology, Bonovas et al³ report a meta-analysis of the relative risk of any cancer and of respiratory cancer based on 35 published randomized controlled trials of statins with 109,143 patients treated for cardiovascular outcomes. The authors conclude that "[o]ur findings do not support a protective effect of statins against cancer." Obviously, there are a number of limitations in this meta-analysis. As the authors acknowledge, the follow-up periods were relatively short considering the long latency of typical cancer. Also it was a meta-analysis of nonprimary outcome data in the contributing randomized controlled trials. Despite these limitations, this is the most extensive and inclusive meta-analysis of its kind relating statin use and cancer risk. It will be helpful to interpret the conclusions drawn in this publication in the light of previous findings from epidemiologic studies on the effects of statins on cancer risk and other meta-analyses.

A number of epidemiologic studies on the effects of statins on cancer risk have been published in the literature, some showing positive effects on reducing site-specific cancer incidence as well as overall cancer incidence^4-7 and others showing lack of any effects of statins in cancer risk or even an increase.^8-10

In a nested case-control study based on the administrative health databases in Québec (Canada), Blais et al⁴ found a 28% reduction in the risk of any cancer among users of statins as compared to users of bile acid-binding resins, but found no statistically significant associations with site-specific cancers. In a nested case-control study based on a database linking drug dispensing records and hospital discharge records in the Netherlands, Graaf et al⁵ found a 20% reduction associated with statin use and a 36% reduction with longer than 4 years of statin use, but again found no statistically significant associations with site-specific cancers, except for kidney cancer. In a cohort study based on the Pharmacoepidemiological Prescription Database, Cancer Registry and Central Population Register of North Jutland in Denmark, Friis et al⁶ found a 14% risk reduction among statin users as compared to nonusers and a 27% reduction as compared to other lipid-lowering drugs, but did not find any statistically significant association with site-specific cancers. It was the publication by Poynter et al⁷ that captured the most attention in the literature, with a 47% reduction in the risk of colorectal cancer based on a case-control study in Israel with an accompanying editorial stating that it is perhaps time for a paradigm shift in chemoprevention to "beyond the one drug, one disease model."¹¹

In a case-control study based on the Case-Control Surveillance Study of Drugs and Serious Illnesses in New York, Coogan et al⁸ found a statistically significant 50% increase in the risk of breast cancer among statin users, largely accounted for by a 80% increase in the risk of carcinoma in situ, and a 20% increase in the risk of prostate cancer and a 40% increase in the risk of stage A prostate cancer, albeit statistically insignificant. In a case-control study using the General Practice Research Database, Kaye and Jick⁹ found no statistically significant associations between current statin use and any of 13 studied cancers and a slight, but statistically significant increase, in the risk of colon and rectal cancers with current statin use of 5 years or longer. In contrast to the findings by Poyner et al of a 47% reduction in the risk of colorectal cancer with statin use, Jacobs et al¹⁰ in a nested case-control study based on the Cancer Prevention Study II Nutrition Cohort found no association between current use of cholesterol-lowering drugs and the incidence of colorectal cancer with a relative risk of 1.03 (95% CI, 0.85 to 1.26) and also found no association between current use of cholesterol-lowering drugs for 5 years or longer and the colorectal cancer incidence (a relative risk of 1.09; 95% CI, 0.83 to 1.43), and concluded that the hypothesis that statin use strongly reduces risk of colorectal cancer is not supported by their results.

These epidemiologic studies, whether they showed beneficial effects of statin use on cancer risk or lack thereof, all appear to suffer from limitations resulting from residual confounding and unaccounted effect modifications. As is usually the case in any epidemiologic study, there are limits to how much one can do to reduce unmeasured or unknown sources of bias. At least on the basis of the findings, both positive and neutral, it is unclear what to make of these studies.

A number of meta-analyses have been reported in the literature, investigating the association between statins and cancer risk.^12-16 In contrast to epidemiologic studies, these meta-analyses all report negative associations between statins and cancer risk. Of course, all these meta-analyses are chronologically built on an ever-expanding array of randomized controlled trials, and so there are inherent correlations from an earlier meta-analysis to a later meta-analysis. Hebert et al¹² report a meta-analysis of 16 trials that included approximately 29,000 patients with an average follow-up of 3.3 years, and found no reduction in the risk of cancer with statin use with a relative risk of 1.03 (95% CI, 0.90 to 1.17). Bjere and LeLorier¹³ report a meta-analysis of the five largest trials—including more than 30,000 patients in total—each with a minimum of 4,000 patients and a minimum treatment duration of 4 years; they found no difference in absolute risk between statin and placebo: 0.0% (95% CI, –0.8% to 0.8%) for all nonfatal cancers; –0.1% (95% CI, –0.7% to 0.4%) for all fatal cancers; –0.1% (95% CI, –1.0% to 0.7%) for all fatal and nonfatal cancers combined; and –1.5% (95% CI, –2.8% to 0.2%) for all-cause mortality. Pfeffer et al¹⁴ report a meta-analysis of three large trials in 19,592 patients with more than 112,000 person-years of exposure comparing pravastatin and placebo and found no reduction in the risk of any cancers with an incidence ratio of 1.03 (95% CI, 0.95 to 1.13). Instead, they found a statistically significant increase in the risk of cancer in musculoskeletal/connective tissue with an incidence ratio of 8.98 (95% CI, 1.13 to 70.3) and a marginally significant increase in the risk of cancer in endocrine/metabolic/electrolyte imbalance with an incidence ratio of 1.99 (0.998 to 3.99) with statin use. Bonovas et al¹⁵ reported a meta-analysis of seven randomized controlled trials and nine observational studies and found no reduction in the risk of breast cancer with a relative risk of 1.02 (95% CI, 0.89 to 1.18). Most recently, Dale et al¹⁶ reported a meta-analysis of 26 randomized controlled trials including 86,936 patients, each with a minimum follow-up of 1 year and a minimum of 100 patients and found an odds ratio of 1.02 (95% CI, 0.97 to 1.07) for cancer incidence based on 20 studies and an odds ratio of 1.01 (95% CI, 0.93 to 1.09) for cancer mortality based on 22 studies.

According to epidemiologic studies and meta-analyses of cancer risks in clinical trials, including the current publication, the only sensible conclusion one can draw at this stage appears to be (1) that the association between statin use and cancer risk is inconclusive at best and (2) that at worst, there are no effects at all. Coming on the heels of inconclusive epidemiologic studies and meta-analyses all showing no effects of statin on cancer risk, the findings reported by Bonovas et al³ are particularly informative because they are consistent with findings from other meta-analyses.

With these findings, where do we as a clinical community go? Is a series of meta-analyses going to provide us with a definitive answer to the question? How many such meta-analyses would be required before the question can be settled in the light of all the meta-analyses that showed lack of effects of statins on cancer risk? What should and can be done next? According to the Physician Data Query (PDQ) clinical trials registry as of this writing, there are five active early-phase clinical trials of statins registered with the US National Institutes of Health (Bethesda, MD), two treatment protocols, one each in multiple myeloma and metastatic colorectal cancer, and three chemoprevention protocols, two in breast cancer and one in colorectal neoplasia. There is one additional chemoprevention trial of statin in dysplatic nevi soon to be activated. But these are all very early-phase trials. The US National Cancer Institute (National Institutes of Health) appears to be taking very cautious steps by supporting only a few early-phase chemoprevention trials, which seems to be prudent considering inconsistent epidemiologic study findings and negative meta-analyses results.

If—and a big "if" at that—these studies provide reliable preliminary data, the obvious and simple solution for the dilemma would be to conduct a definitive randomized controlled trial or two. The statistical theory known as the law of the iterated logarithm tells us that by increasing the sample size of a study indefinitely, one can detect any arbitrarily small treatment effect. The critical question is how small a treatment effect is clinically relevant and, from a public health perspective, to be detected in a clinical trial. The window of opportunity to conduct definitive randomized controlled trials appears to be narrowing rapidly. Because of widespread use of statins, it will be difficult to identify suitable patient populations. A necessarily long duration of such trials will pose many challenges because of probable contamination. Perhaps the genie is already out of the bottle.

Author's Disclosures of Potential Conflicts of Interest

The author indicated no potential conflicts of interest.

NOTES

published online ahead of print at www.jco.org on September 25, 2006.

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