Perspectives in clinical gastroenterology and hepatology
Statins and Colorectal Cancer

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The 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors, more commonly referred to as statins, comprise a family of lipid-lowering drugs that are prescribed on a global scale on account of their proven safety and efficacy in reducing mortality from cardiovascular disease. Beyond their potent pharmacologic inhibition of cholesterol biosynthesis, statins appear to have pleiotropic effects, including modulation of cell growth, apoptosis, and inflammation. Through modulation of these pathways, statins have the potential to influence a wide range of disease processes, including cancer. Much attention has focused on the association between statins and colorectal cancer, raising the prospect that these well-tolerated compounds could form the basis of future chemopreventive strategies. Herein, we review the epidemiologic, clinical, and preclinical data relevant to statins and colorectal neoplasia, and discuss the current status and future potential of statins as chemopreventive agents.

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Experimental Evidence: Anticancer Mechanisms of Statins

The interest in statins as modifiers of cancer risk spawned a large number of experimental studies examining the antineoplastic effects of statins in cellular and animal models of human cancer.10, 11 Inhibition of HMG-CoA reductase by statins leads not only to a decrease in cholesterol synthesis, but also to reduced generation of other intermediates of the mevalonate pathway, including the nonsterol isoprenoids, farnesyl pyrophosphate and geranylgeranyl pyrophosphate.5 Farnesyl pyrophosphate

Statins and Colorectal Cancer Risk in Randomized Trials

As a result of numerous large RCTs of lipid-lowering and major vascular events, a wealth of clinical data on statin use has accrued. Most statin RCTs have reported data on overall cancer incidence, and some studies have reported site-specific incidence (Table 1).17, 53, 54, 55, 56, 57, 58, 59, 60 Thus, cardiovascular RCTs represent a valuable resource for assessing differences in cancer incidence between groups in which statin use has been randomly assigned. Several tabular meta-analyses of RCT

Case-Control Studies

Case-control studies are generally able to efficiently examine associations between remote exposures and risk of disease, whereas cohort studies can be valuable in dissecting time-dependent associations between exposures and outcomes. A large number of observational studies have assessed the association between statin use and colorectal cancer (Table 2). Perhaps the most publicized and highly cited of these studies is the analysis by Poynter et al,26 based on the Molecular Epidemiology of

Statins and Risk of Colorectal Adenomas

Even short-term statin use may be sufficient to influence the evolution or progression of colorectal adenomas, the precursors to the vast majority of colorectal cancers (Table 3). In a retrospective analysis conducted in more than 2500 veterans with a history of colonoscopic polypectomy for adenomas, Siddiqui et al87 showed a 49% reduction in the incidence of recurrent adenomas, and a 29% reduction in the incidence of advanced adenomas, associated with continuous statin use over 3 to 5 years.

Statin Use After a Diagnosis of Colorectal Cancer

Another high-risk group, in whom it may be possible to show benefit from statin use in shorter-term studies, are individuals who have already developed colorectal cancer. In a retrospective cohort study of 1309 male veterans with colorectal cancer,92 more than 3 years of prediagnosis statin use was associated with lower tumor stage, lower prevalence of metastases, and higher frequency of proximal cancers, compared with nonusers. Survival analysis showed more favorable 5-year cancer-specific

Statins and Combination Chemoprevention

Even if statins, when used alone, are judged to be ineffective at reducing the risk of colorectal neoplasia, their use in combination with other agents, such as NSAIDs or aspirin, may still prove to be a successful chemopreventive strategy.98 Experimental evidence suggests that statins act synergistically with NSAIDs, and cyclooxygenase-2 inhibitors, to induce cell-cycle arrest and apoptosis in human colorectal cancer cell lines.40, 99 In an animal model, statins, in combination with NSAIDs or

Summary and Future Perspectives

An abundance of experimental data have provided a variety of biologically plausible mechanisms through which statins might affect the initiation or evolution of colorectal neoplasia. Evidence from clinical studies is, however, conflicting. Studies supporting a chemopreventive role for statins in colorectal neoplasia are relatively few in number and are almost exclusively of retrospective observational design. Although the magnitude of risk reduction observed in the case-control study by Poynter

Acknowledgment

The content is solely the responsibility of the authors.

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    This article has an accompanying continuing medical education activity on page e13. Learning Objectives—At the end of this activity, the successful learner will be able to appraise the current evidence relating to statins in the prevention and treatment of colorectal neoplasia.

    Conflicts of interest This author discloses the following: Andrew Chan has consulted for Bayer Healthcare, Millennium Pharmaceuticals, and Pfizer, Inc. The remaining author discloses no conflicts.

    Funding Supported by a Clinical Academic Fellowship from the Chief Scientist Office of the Scottish Government (P.L.), and a Damon Runyon Clinical Investigator award (A.C.).

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