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Journal of Clinical Oncology, Vol 24, No 13 (May 1), 2006: pp. 2129 © 2006 American Society of Clinical Oncology. DOI: 10.1200/JCO.2006.05.8867
In ReplyDepartments of Pharmacology and Pathophysiology, School of Medicine, University of Athens, Athens, Greece We appreciate the comments by Prowell, Stearns, and Trock in regard to our article1 published in the Journal of Clinical Oncology. They make some points with which we certainly agree and others we would like to discuss. Our meta-analysis provides evidence that statin use is not associated with a substantially decreased or increased risk of breast cancer. However, Prowell et al suggest that lipophilic statins may have a different chemopreventive potential than lipophobic (pravastatin). To investigate this hypothesis, we performed additional subgroup analyses. We restricted the meta-analysis of randomized clinical trials to the three trials of lipophilic statins.2-4 Approximately 7,000 women were randomly assigned in these trials, with an average follow-up of approximately 5.5 years. The overall incidence of breast cancer was 1.78% (123 incident cases). The association of statin use with breast cancer was once again not statistically significant (random effects model: relative risk [RR], 0.97; 95% CI, 0.60 to 1.55; fixed effects model: RR, 0.89; 95% CI, 0.63 to 1.27; I2 = 25%). However, the small number of cases limited the statistical power and resulted in wide confidence intervals. Prowell et al correctly mention that the observational studies included in our meta-analysis are limited by the use of multiple statins, doses, and treatment durations. They state that this can create a misclassification bias that tends to drive the observed RRs toward 1.0; masking a potential protective effect of statins. However, this applies only in the case of nondifferential exposure misclassification. Even slight deviations from completely nondifferential misclassification can lead to large biases away from the null.5 Regarding the retrospective case-control study of Kochhar et al6 presented at the 41st Annual Meeting of the American Society of Clinical Oncology in 2005, we have to mention that our study was completed in April 2005, in accordance with the study protocol. Thus, it was impossible to have included this abstract in our meta-analysis. For the same reason, a very large study of 75,828 women,7 with 6 to 12 years of follow-up and 3,177 incident breast cancer cases, was also not included in our meta-analysis. This prospective study suggested that statin use is not significantly associated with breast cancer risk (RR, 0.91; 95% CI, 0.76 to 1.08). Clearly, laboratory investigation should be conducted to further define the biologic mechanisms by which statins induce apoptosis and reduce cell invasiveness in various cell lines, including breast carcinoma cells. However, the question of whether the current epidemiologic data provide a basis for randomized clinical trials needs to be examined carefully. 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. 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] 3. Downs JR, Clearfield M, Weis S, et al: Primary prevention of acute coronary events with lovastatin in men and women with average cholesterol levels: Results of AFCAPS/TexCAPS Air Force/Texas Coronary Atherosclerosis Prevention Study. JAMA 279:1615-1622, 1998 4. Heart Protection Study Collaborative Group: MRC/BHF heart protection study of cholesterol lowering with simvastatin in 20,536 high-risk individuals: A randomised placebo-controlled trial. Lancet 360:7-22, 2002[CrossRef][Medline] 5. Brenner H: Inferences on the potential effects of presumed nondifferential exposure misclassification. Ann Epidemiol 3:289-294, 1993[Medline] 6. Kochhar R, Khurana V, Bejjanki H, et al: Statins reduce beast cancer risk: A case control study in U.S. female veterans. J Clin Oncol 23:7s, 2005 (suppl; abstr 514) 7. Eliassen AH, Colditz GA, Rosner B, et al: Serum lipids, lipid-lowering drugs, and the risk of breast cancer. Arch Intern Med 165:2264-2271, 2005
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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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