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In Reply

Departments of Pharmacology and Pathophysiology, School of Medicine, University of Athens, Athens, Greece

The letter by Drs Sprague and Wood raises a number of issues that are relevant both to the randomized controlled trials and the observational studies included in our meta-analysis.¹

The seven large-scale randomized clinical trials (RCTs) of statins for cardiovascular outcomes assessed the incidence of breast cancer as a secondary end point. Approximately 17,000 women were randomly assigned and observed for an average period of 5 years. Each separate trial apparently had limited statistical power to assess the particular outcome of breast cancer. However, one could say that this is the specific role of meta-analysis. It serves as a valuable tool for studying rare and unintended effects of a treatment, by permitting synthesis of data and providing more stable estimates of effect.

Regarding the comment that grouping all statins together may mask a potential different effect of lipophilic statins, we have now attempted to investigate this hypothesis by further restricting the meta-analysis of RCTs to the three trials of lipophilic statins.^2-4 The association of statin use with breast cancer risk was once again not statistically significant (random effects model: relative risk, 0.97; 95% CI, 0.60 to 1.55).

On the subject of the observational studies included in our meta-analysis, we certainly agree that they were different in terms of study design and definitions of drug exposure. Moreover, the control for potential confounders was highly variable across these studies. However, these are the realities of both meta-analysis and working with data as they are available in the published literature.

Though the primary studies had varying study designs with different potential biases, it is noteworthy that the findings were similar in both meta-analyses of RCTs and observational studies, not supporting a protective effect of statins against breast cancer.

Last, Sprague and Wood point out that there is compelling laboratory evidence both in cell culture and animal models that statins have anticancer effects. In contrast, taking a closer look at the relevant literature, one may see that the issue remains controversial. In a review of rodent carcinogenicity tests, Newman and Hulley⁵ reported that lipid-lowering drugs, including statins, initiate or promote cancer in rats and mice. In some cases, the levels of exposure were similar to those prescribed to humans. Nevertheless, the results of laboratory and animal studies are difficult to extrapolate to humans.

We respect the enthusiasm of Drs Sprague and Wood regarding their ongoing randomized placebo controlled pilot trial in premenopausal women at high risk for breast cancer. Certainly, there is a long way to go toward the definite answer whether statins can reduce the risk of cancer. We look forward to seeing the outcome of this effort.

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[Abstract/Free Full Text]

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[Abstract/Free Full Text]

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. Newman TB, Hulley SB: Carcinogenicity of lipid-lowering drugs. JAMA 275:55-60, 1996[Abstract/Free Full Text]

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Related Correspondence

• Statins and Breast Cancer Prevention: Time for Randomized Controlled Trials
  Julian R. Sprague and Marie E. Wood
  JCO 2006 24: 2129-2130 [Full Text]

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