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Journal of Clinical Oncology, Vol 25, No 23 (August 10), 2007: pp. 3395-3396 © 2007 American Society of Clinical Oncology. DOI: 10.1200/JCO.2007.11.9511
Can Statins Pass the Aspirin Litmus Test in Cancer?Winship Cancer Institute, Emory University, Atlanta, GA Much like aspirin has found new roles during the years (from headache remedy to cardiovascular disease prevention), new potential benefits for 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins) are coming to light. Statins limit the biosynthesis of the cholesterol precursor mevalonate. In addition to cholesterol biosynthesis, mevalonate is also a precursor of farnesyl and geranylgeranyl moieties, which are critical to post-translational modification of intracellular signaling pathway proteins such as Ras. Inhibition of farnesylation and geranylgeranylation of messenger molecules have been major targets of cancer drug development. The farnesyl transferase inhibitor tipifarnib is in active development for the treatment of acute myelogenous leukemia, and the farnesyl transferase inhibitor lonafarnib is being developed for myelodysplastic syndrome. Statins have been observed as having protean properties such as antiangiogenesis and apoptosis induction. In vivo mouse models have reported potential chemopreventive effects of statins in colorectal carcinogenesis.1 There have been multiple retrospective and prospective studies reporting the connection between statins and colorectal cancer prevention. Only two published studies have reported a benefit.2,3 A case-control study by Friis et al3 reported a 20% risk reduction for the development of cancers, in general, associated with statin use. Poynter et al2 reported an Israeli case-control study that demonstrated a 47% risk reduction for colon cancer development in users of statins. Unfortunately, multiple other studies3-9 have failed to corroborate the results from the studies by Friis et al and Poynter et al. In this issue of the Journal of Clinical Oncology, Bonovas et al10 present a comprehensive meta-analysis of the major studies, consisting of more than 1.5 million patients, which have reported the relationship between HMG-CoA reductase inhibitors and colorectal cancer incidence. The study used validated and well-accepted statistical methods for meta-analyses.11,12 Analysis of six large randomized control trials with 55,000 patients that were randomly assigned to treatment with either a statin or placebo/observation revealed no significant protective effect of statin use in terms of colorectal cancer prevention. Half of the trials reported a lower risk with statin use, whereas the other half reported a relative increase. This result is in contrast to the nine case-control studies and three cohort studies that demonstrated a significant reduction in colorectal cancer risk (relative risk [RR] = 0.92). However, when four studies, presented in abstract form only, were removed from the analysis, statins continued to have a marginally protective effect (RR = 0.90), but the effect was no longer statistically significant. The combined analysis of randomized controlled trials, case-control trials, and cohort studies did not yield a statistically significant result in favor of the use of statins in colorectal cancer prevention. The authors concluded that the use of statins for colorectal cancer prevention cannot be recommended based on the meta-analysis results, although they state, "a modest protective effect cannot be excluded." In the Discussion within the article by Bonovas et al,10 it is astutely pointed out that statin use may reflect the socioeconomic status of patients. Patients with health insurance can afford expensive drugs such as statins, whereas underinsured or uninsured patients cannot. Given this fact, underinsured patients are also unlikely to have access to preventive healthcare such as routine screening colonoscopies, which theoretically could lower the incidence of colorectal cancer by removing premalignant polyps. This is one possible explanation for why some retrospective trials demonstrated protective effects of statins and randomized controlled trials have not. The evidence surrounding HMG-CoA reductase inhibitors in preventing colorectal cancer, at best, is modest. If statins truly have a 47% risk reduction as initially reported in the study by Poynter et al,2 one would have expected to see a benefit in the randomized control trials, albeit the primary end point of the trials was related to cardiovascular effects and not cancer. Although the results of the study by Poynter et al cannot be refuted, the majority of studies have not demonstrated benefits of statins. In addition, two thirds of the patients in the study by Poynter et al were of Ashkenazi Jewish heritage, and one wonders if the beneficial effects could have been attributable to pharmacogenomic interactions specific to this patient population. So, are statins the next aspirin? At present, the data suggest this is not quite the case yet. Given the inconclusive nature of the data surrounding statins as chemopreventive agents, it would be wise to restrict the use of statins to the prevention of cardiovascular disease. The chemoprevention question could be answered definitely with a trial similar in design to the Celecoxib for the Prevention of Sporadic Colorectal Adenomas study, in which patients with a history of colorectal polyps were randomly assigned to receive either celecoxib or placebo, with recurrence of polyps as the primary end point.13 Until and unless the trials with statins are carried out in a way that can establish definitive chemopreventive benefit, these compounds will join a long list of agents with promising initial epidemiologic data that failed the cancer chemoprevention Litmus test. Alternatively, success would provide the statins membership to an exclusive circle of agents that, to date, is restricted to tamoxifen and raloxifene in breast cancer, finasteride in prostate cancer, and celecoxib in colon polyp prevention.14-17 AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST Although all authors completed the disclosure declaration, the following authors or their immediate family members indicated a financial interest. No conflict exists for drugs or devices used in a study if they are not being evaluated as part of the investigation. For a detailed description of the disclosure categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors. Employment or Leadership Position: None Consultant or Advisory Role: John Kauh, Amgen (C); Fadlo R. Khuri, sanofi-aventis (C), Genentech (C) Stock Ownership: None Honoraria: Fadlo R. Khuri, sanofi-aventis Research Funding: Fadlo R. Khuri, sanofi-aventis, Novartis Expert Testimony: None Other Remuneration: None AUTHOR CONTRIBUTIONS Conception and design: John Kauh Manuscript writing: John Kauh Final approval of manuscript: John Kauh, Fadlo R. Khuri REFERENCES 1. Narisawa T, Fukaura Y, Tanida N, et al: Chemopreventive efficacy of low dose of pravastatin, an HMG-CoA reductase inhibitor, on 1,2-dimethylhydrazine-induced colon carcinogenesis in ICR mice. Tohoku J Exp Med 180:131-138, 1996[CrossRef][Medline] 2. Poynter JN, Gruber SB, Higgins PD, et al: Statins and the risk of colorectal cancer. N Engl J Med 352:2184-2192, 2005 3. Friis S, Poulsen AH, Johnsen SP, et al: Cancer risk among statin users: A population-based cohort study. Int J Cancer 114:643-647, 2005[CrossRef][Medline] 4. Setoguchi S, Glynn RJ, Avorn J, et al: Statins and the risk of lung, breast, and colorectal cancer in the elderly. Circulation 115:27-33, 2007 5. Coogan PF, Smith J, Rosenberg L: Statin use and risk of colorectal cancer. J Natl Cancer Inst 99:32-40, 2007 6. Kaye JA, Jick H: Statin use and cancer risk in the General Practice Research Database. Br J Cancer 90:635-637, 2004[CrossRef][Medline] 7. Blais L, Desgagne A, LeLorier J: 3-Hydroxy-3-methylglutaryl coenzyme A reductase inhibitors and the risk of cancer: A nested case-control study. Arch Intern Med 160:2363-2368, 2000 8. Strandberg TE, Pyorala K, Cook TJ, et al: Mortality and incidence of cancer during 10-year follow-up of the Scandinavian Simvastatin Survival Study (4S). Lancet 364:771-777, 2004[CrossRef][Medline] 9. Bonovas S, Filioussi K, Tsavaris N, et al: Statins and cancer risk: A literature-based meta-analysis and meta-regression analysis of 35 randomized controlled trials. J Clin Oncol 24:4808-4817, 2006 10. Bonovas S, Filioussi K, Flordellis CS, et al: Statins and the risk of colorectal cancer: A meta-analysis of 18 studies involving more than 1.5 million patients. J Clin Oncol 25:3462-3468, 2007 11. Stroup DF, Berlin JA, Morton SC, et al: Meta-analysis of observational studies in epidemiology: A proposal for reporting—Meta-analysis of Observational Studies in Epidemiology (MOOSE) group. JAMA 283:2008-2012, 2000 12. Moher D, Cook DJ, Eastwood S, et al: Improving the quality of reports of meta-analyses of randomised controlled trials: The QUOROM statement—Quality of Reporting of Meta-Analyses. Lancet 354:1896-1900, 1999[CrossRef][Medline] 13. Bertagnolli MM, Eagle CJ, Zauber AG, et al: Celecoxib for the prevention of sporadic colorectal adenomas. N Engl J Med 355:873-884, 2006 14. Arber N, Eagle CJ, Spicak J, et al: Celecoxib for the prevention of colorectal adenomatous polyps. N Engl J Med 355:885-895, 2006 15. Fisher B, Costantino JP, Wickerham DL, et al: Tamoxifen for prevention of breast cancer: Report of the National Surgical Adjuvant Breast and Bowel Project P-1 Study. J Natl Cancer Inst 90:1371-1388, 1998 16. Vogel VG, Costantino JP, Wickerham DL, et al: Effects of tamoxifen vs raloxifene on the risk of developing invasive breast cancer and other disease outcomes: The NSABP Study of Tamoxifen and Raloxifene (STAR) P-2 trial. JAMA 295:2727-2741, 2006 17. Thompson IM, Goodman PJ, Tangen CM, et al: The influence of finasteride on the development of prostate cancer. N Engl J Med 349:215-224, 2003 Related Article
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Copyright © 2007 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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