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Journal of Clinical Oncology, Vol 24, No 13 (May 1), 2006: pp. 2128-2129 © 2006 American Society of Clinical Oncology. DOI: 10.1200/JCO.2005.05.1649
Lipophilic Statins Merit Additional Study for Breast Cancer ChemopreventionThe Johns Hopkins University School of Medicine, Baltimore, MD To the Editor: Bonovas et al 1reported that statins did not appear to protect users against breast cancer in their recent article in the Journal of Clinical Oncology. Pravastatin, the agent tested in four of seven randomized clinical trials (RCTs) included in the meta-analysis, is the only commercially available statin that is lipophobic. As expected, the lipophilic statins have greater cell permeability due to increased lipid solubility. In vitro data have established that all of the lipophilic statins inhibit proliferation of MCF-7 breast cancer cell lines by up to 90%, whereas pravastatin has no such antiproliferative effect.2 In vivo data using murine models indicate that the lipophilic statins, but not pravastatin, inhibit mammary tumor growth by 50% at doses equivalent to those used in humans for cholesterol lowering.3 When one excludes the pravastatin RCTs from the meta-analysis, only three trials of lipophilic statins remain, with a total of 123 cases of breast cancer. The results of these trials were not statistically significant, with relative risks of 0.75, 1.44, and 1.44. These divergent results based on the small numbers of cases suggest that there is insufficient power to draw clear conclusions regarding statins' potential as chemopreventive agents for breast cancer. In addition to reporting bias, the observational studies are limited by the use of multiple statins, doses, and treatment durations, as noted by Bonovas et al.1 This can create a misclassification bias that tends to drive the observed relative risk values toward 1.0. Furthermore, if pravastatin is not protective, but the other statins are, combining them in observational studies will mask a protective effect. Despite these concerns, it is worth noting that a very large epidemiologic study of statins for breast cancer prevention was presented at the 2005 Annual Meeting of the American Society of Clinical Oncology, but has not yet been published, and thus was not included in the meta-analysis of Bonovas et al. In this retrospective case-control study of 40,421 females with 556 cases of breast cancer, Kochhar et al4 found that statin users were half as likely to develop breast cancer as nonusers (odds ratio, 0.49; 95% CI, 0.38 to 0.62; P < .0001). Let us learn from the experience of our colleagues in other disciplines. Were it not for well-designed RCTs with prospectively defined, disease-specific end points, we might still be teaching medical students that beta-blockers are contraindicated in heart failure and routinely prescribing hormone replacement therapy to postmenopausal women. Given the limitations of epidemiologic studies, the favorable safety profile of the statins, the preclinical data that suggest chemopreventive activity is likely limited to the lipophilic statins, and the fact that the RCTs of statins to date have been designed with cardiovascular end points in mind and were underpowered to detect small changes in breast cancer risk, we believe that the lipophilic statins merit additional study in high-risk populations with well-designed RCTs using prospectively defined, breast cancer-related end points. Authors' Disclosures of Potential Conflicts of Interest The authors indicated no potential conflicts of interest. REFERENCES
1. Bonovas S, Filioussi K, Tsavaris N, et al: Use of statins and breast cancer: A meta-analysis of seven randomized clinical trials and nine observational studies. J Clin Oncol 23:8606-8612, 2005 2. Seeger H, Wallwiener D, Mueck AO: Statins can inhibit proliferation of human breast cancer cells in vitro. Exp Clin Endocrinol Diabetes 111:47-48, 2003[CrossRef][Medline] 3. Esserman L, Campbell M, Shoemaker M, et al: Breast cancer inhibition by statins. J Clin Oncol 23:97s, 2004 (suppl; abstr 1003) 4. Kochhar R, Khurana V, Bejjanki H, et al: Statins to reduce breast cancer risk: A case control study in U.S. female veterans. J Clin Oncol 23:7s, 2005 (suppl; abstr 514) Related Reply
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Copyright © 2006 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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