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Journal of Clinical Oncology, Vol 24, No 13 (May 1), 2006: pp. 2129-2130 © 2006 American Society of Clinical Oncology. DOI: 10.1200/JCO.2005.05.5392
Statins and Breast Cancer Prevention: Time for Randomized Controlled TrialsUniversity of Vermont and Fletcher Allen Healthcare, Burlington, VT To the Editor: Bonovas et al1 conclude from their meta-analysis of seven large randomized controlled trials (RCTs) and nine observational trials (four cohort and five case-control) that no association exists between statin monotherapy and breast cancer risk. Their article has the ambitious goal of discerning an effect of a drug (statins) on the prevention or causation of a disease (breast cancer) that the clinical trials analyzed were not designed to study (in the case of the RCTs), or that only a small percentage of the study population is actually taking (in the case of the observational trials). The RCTs all had cardiovascular end points for which mortality due to cancer of any type was a subgroup analysis. A total of 17,049 women were included in these studies with a total of 254 cases of breast cancer reported, divided roughly equally between statin users and nonusers, 132 versus 122, respectively. For the seven RCTs this is a low number of statin users with breast cancer from which to draw any firm conclusions. Furthermore, nearly 60% of patients were taking pravastatin, a hydrophilic statin optimized for liver uptake. This choice of agent may be suboptimal in a breast cancer prevention strategy because of the decreased systemic distribution compared with lipophilic statins, such as simvastatin.2 Thus, grouping all statins together in a meta-analysis may mask effects. Only three of the nine observational studies were specifically designed to study breast cancer with one fourth a mix between breast and prostate cancer. The total number of breast cancer patients in these studies is identified but not the statin user population. Statin users tended to be older and have more medical interaction because of statin monitoring. For instance in the study by Beck et al3 the number of statin users with breast cancer younger than 55 years was 25 cases versus 163 for the older than 55 age group. Statin type is not controlled, and hormone replacement therapy was used by more than 50% of statin users. Experimental models have shown that replacement of estrogen negates the effects of statins on cell cycle progression.4 Theoretically this could reduce preventative effects. We applaud Bonovas et al for their efforts to quantify the effects of statins on breast cancer prevention across multiple disparate studies. Statins are safe, nontoxic, and effective drugs for the vast majority of the patients who use them to lower their cholesterol. There is compelling laboratory evidence both in cell culture5 and animal models6 that statins have anticancer effects. However, until a randomized placebo controlled trial is designed specifically for breast cancer prevention, we will continue to be unsatisfied by the current data. We are currently accruing to a randomized, placebo controlled pilot trial of the effect of statins on mammographic breast density, as well as on serum and tissue biomarkers in premenopausal women at high risk for breast cancer. This and other ongoing trials will begin to fulfill the need for randomized placebo controlled trials designed to ask the question: do statins help to prevent breast cancer? The current epidemiologic data should not discourage enthusiasm for accrual to these types of studies. 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. Hamelin BA, Turgeon J: Hydrophilicity/lipophilicity: Relevance for the pharmacology and clinical effects of HMG-CoA reductase inhibitors. Trends Pharmacol Sci 19:26-37, 1998[CrossRef][Medline] 3. Beck P, Wysowski D, Downey W, et al: Statin use and the risk of breast cancer. J Clin Epidemiol 56:280-285, 2003[CrossRef][Medline] 4. Addeo R, Altucci L, Battista T, et al: Stimulation of human breast cancer MCF-7 cells with estrogen prevents cell cycle arrest by HMG-CoA reductase inhibitors. Biochem Biophys Res Commun 220:864-870, 1996[CrossRef][Medline] 5. Denoyelle C, Vasse M, Korner M, et al: Cerivastatin, an inhibitor of HMG-CoA reductase, inhibits the signaling pathways involved in the invasiveness and metastatic properties of highly invasive breast cancer cell lines: An in vitro study. Carcinogenesis 22:1139-1148, 2001 6. Shibata MA, Ito Y, Morimoto J, et al: Lovastatin inhibits tumor growth and lung metastasis in mouse mammary carcinoma model: A p53-independent mitochondrial-mediated apoptotic mechanism. Carcinogenesis 25:1887-1898, 2004
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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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