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Originally published as JCO Early Release 10.1200/JCO.2005.03.6202 on October 31 2005 © 2005 American Society of Clinical Oncology.
Can Statin Therapy Reduce the Risk of Breast Cancer?University of Pittsburgh School of Medicine, Magee-Womens Hospital, Pittsburgh, PA The statins are a class of cholesterol-lowering drugs first marketed in 1987.1 They are commonly used among persons aged 50 years and older, and atorvastatin is among the 10 most commonly prescribed drugs in the United States. A growing body of laboratory data suggests that the statins may have chemopreventive potential against cancer at various sites, including colon, lung, breast, and prostate.2-4 The statins inhibit the synthesis of cholesterol by inhibiting a key enzyme in the cholesterol pathway, 3-hydroxy-3-methylglutaryl–coenzyme A (HMG-CoA) reductase. The growth-suppressing properties of the statins may be a result of the inhibition of HMG-CoA reductase, but other mechanisms have also been suggested.5 Lovastatin and simvastatin suppress the growth of cancer cells in vitro by causing the cells to pause in the G1 phase of the mitotic cycle and by increasing cell death (apoptosis). Statins prevent the conversion of HMG-CoA into mevalonic acid. When mevalonate levels decrease with statin therapy, isoprenylation of key signal transduction proteins (such as Ras, Rap, and others) is prevented, their subcellular localization is disrupted, and they are inactivated as signal transducers. Administration of lovastatin to cells in culture impacts cell cycle progression. Lovastatin effectively synchronizes both tumor and normal cells and arrests cells in G1. The cell cycle pathways perturbed by lovastatin result in the induction of cyclin-dependent kinase inhibitors (CKIs) p21 and/or p27 independent of other standard G1-arresting agents or conditions such as serum starvation or double thymidine block. Additionally, the lovastatin-mediated G1 arrest and p21/p27 induction occur independently of the ras signaling pathway/function. Stabilization of p21 and p27 may be the result of a previously unknown function of the prodrug, beta-lactone ring form of lovastatin to inhibit the proteasome degradation of these CKIs. Mevalonate (which rescues cells from statin arrest) unexpectedly abrogates the lovastatin prodrug inhibition of the proteasome. Mevalonate increases the activity of the proteasome, which results in degradation of the CKIs, allowing lovastatin-arrested cells to resume cell division. The lovastatin-mediated inhibition of the proteasome suggests a unique mechanism for the putative chemopreventive effects of statins in human cancer. Two statins (atorvastatin and fluvastatin) are able to inhibit the proliferation of MCF-7 breast cancer cells in the absence of estradiol.6 This effect seems to depend on an apoptotic statin effect that may be mediated by the downregulation of the antiapoptotic protein Bcl-2, rather than upregulation of Fas-L or p53. However, in the presence of estradiol, the inhibitory effect of the statins is less pronounced. These mechanisms suggest that statins may have the ability to reduce the development of several human malignancies. Individual, mostly retrospective studies have found sometimes large reductions in the risk of breast cancer associated with the use of statin therapy. A recent study reported by Kochhar et al7 investigated the effect of statins on the development of breast cancer in a US female veterans population. Patients were considered to be statin users if they were taking statins before a diagnosis of breast cancer. However, dose, duration, and type of statin used were not factored into the analysis. Multiple logistic regression analysis was used to calculate the odds ratios (OR) and 95% CIs, and the data were adjusted for age, smoking, alcohol use, and diabetes. A total of 40,421 women were studied, and statin users were less likely to have developed breast cancer (OR = 0.49; 95% CI, 0.38 to 0.62; P < .0001) than women who were not statin users. Therefore, statin use was associated with a 51% risk reduction of breast cancer after controlling for age, smoking, alcohol use, and diabetes. Conversely, Newman and Hulley8 reviewed the findings on rodent carcinogenicity of lipid-lowering drugs and concluded that fibrates and HMG-CoA reductase inhibitors initiate or promote cancer in rodents. In some cases, the levels of exposure were similar to those prescribed to humans. All members of the two most popular classes of lipid-lowering drugs (the fibrates and the statins) cause cancer in rodents and, in some cases, at levels of animal exposure close to those prescribed to humans. One small trial showed a reduction of colon cancer among patients receiving statin therapy but an excess of breast cancer cases.9 However, the difference in breast cancer incidence between the treatment and placebo groups may have been caused by a deficit of breast cancers in the placebo group rather than an excess in the treatment group. Although a few cohort studies10,11 have demonstrated that low cholesterol levels are associated with more cancer deaths, the evidence for causality is weak because pre-existing cancer and other confounding variables might be responsible for the association.12 Evidence from clinical trials of lipid-modifying therapies is reassuring, but not conclusive. Law et al13 and Law and Thompson13,14 published a meta-analysis of randomized controlled trials, with an OR for cancer death of 1.07 (95% CI, 0.90 to 1.26). In an overview of randomized trials testing HMG-CoA reductase inhibitors, Hebert et al15 found no significant increase in the incidence of cancer (risk ratio = 1.03; 95% CI, 0.90 to 1.17). Some published studies have shown an increased risk of breast cancer with statin use. In one study, patients were defined as 1,132 women with breast cancer, and controls were 1,331 women admitted to hospital for conditions unrelated to statin use.1 The OR for breast cancer among statin users was estimated using multivariate unconditional logistic regression models to be 1.5 (95% CI, 1.0 to 2.3), which was largely accounted for by an OR of 1.8 (95% CI, 0.9 to 3.6) among patients with carcinoma-in-situ. Among patients with invasive cancer, the OR was 1.2 (95% CI, 0.7 to 2.0). These data do not support a protective effect of statins against breast cancer. Detection bias is a possible explanation for the higher ORs observed for carcinoma-in-situ or early-stage cancer compared with invasive breast cancer. Therefore, evidence of carcinogenicity or chemoprevention of lipid-lowering drugs from clinical trials in humans is inconclusive because of inconsistent results and insufficient duration of follow-up. In humans, the relationship between low cholesterol levels and cancer is the object of intense debate. In this issue, Bonovas et al16 report a meta-analysis of 16 published studies that have examined the relationship between statin use for cardiovascular disease prevention and the risk of breast cancer. There are a number of methodologic problems with using retrospective data, including the following: migration of patients in and out of the study cohort (case ascertainment); consistency of drug use (dose, schedule, and regularity; use of pill counts or other clinical trial compliance measures); and ascertainment of disease end points such as breast cancer. Each of these problems must be adequately addressed in the individual studies included in a meta-analysis because even rigorously conducted analyses of aggregated data cannot overcome flaws in the design and conduct of the individual trials. When we search for evidence for causality within an association, such as statin exposure and the risk of developing breast cancer, we should observe the following accepted tenets of clinical epidemiology17: (1) Is there a temporal relationship between the exposure and the outcome of interest? (2) What is the strength of the association? (3) Is there a dose-response relationship? (4) Has there been replication of the findings? (5) Is there biologic plausibility for the association? (6) Have we considered alternate explanations? (7) Does the relationship disappear on cessation of exposure? (8) Is there specificity of the association? (9) Are the observations consistent with other knowledge? On the basis of the careful work of Bonovas et al16 regarding the relationship between exposure to statins and a lowered risk of developing breast cancer, the answer to most of these criteria is no. Although there is both biologic plausibility and a temporal relationship between statin exposure and the diagnosis of breast cancer in many studies, the relationship is weak at best, and we have no evidence of a dose-response relationship. We have no data to address the question of a return to baseline breast cancer incidence rates on cessation of statin therapy if there is a small protective effect, and we are unlikely ever to obtain such information. The relationship, if any, between statin use and the risk of breast cancer is not specific to this tissue site, although many drugs have multiple sites of action. Consensus guidelines for reporting meta-analysis of observational studies have been published.18 Recommendations include (but are not limited to) defining the search strategy for the studies used; assessment of confounding and study quality; assessment of heterogeneity and description of the statistical methods used, including consideration of both fixed- and random-effects models; use of both graphical summaries and tables to report data; a quantitative assessment of bias and a justification for excluding any studies; and a generalization of the conclusions. Bonovas et al16 have followed these guidelines well. Guides for reading meta-analyses have also been published.19 The questions we should all ask when reviewing these findings include the following: (1) Were the questions and methods clearly stated? (2) Were the search methods used to locate relevant studies comprehensive? (3) Were explicit methods used to determine which articles to include in the review? (4) Was the methodologic quality of the primary studies assessed? (5) Were the selection and assessment of the primary studies reproducible and free from bias? (6) Were differences in individual study results adequately explained? (7) Were the results of the primary studies combined appropriately? (8) Were the reviewers' conclusions supported by the data cited? It seems that Bonovas et al16 have satisfied these requirements with some caveats. The randomized controlled trials included three different statins (simvastatin, pravastatin, and lovastatin), so we cannot conclude decisively that a single drug would not have a larger, more positive effect. Control for potential confounders was highly variable across the observational studies, and two studies controlled only for age. Only one study each controlled for smoking and body weight or size; both of these factors can affect the risk of developing breast cancer. In addition, the case-control studies varied in their method of control selection.20 Some investigators performed a case-control study of all lipid-lowering agents within a cohort, and this design maximizes comparability between the patients and controls. Other investigators used hospital controls who may have been sicker than population control participants. Many of the studies do not provide information on the characteristics of patients and controls with regard to important covariates. Another major limitation is the manner by which drug exposure is defined, and studies that obtained drug exposure information through interviews may be subject to recall bias. Statins may be well remembered because they are taken once daily, but other observational studies in real clinical settings have shown that adherence to prescribed drugs is highly variable. These are the realities of both meta-analysis and working with data as they are available in the published literature. Given these few concerns, we nevertheless have no evidence based on the published data to suggest that women who are at increased risk of breast cancer should take statins to reduce their risk. As a class, the statins have proven to have good safety profiles over nearly two decades of clinical use.21 The reported rates of serious adverse events with statins have been low (< 1%) and include a slight risk for elevation of liver enzymes and myopathy. Nevertheless, despite their tolerability, until a prospective, randomized clinical trial firmly establishes a certain role for statins in reducing the risk of incident breast cancer, the use of statins should be confined to the management of the risk of cardiovascular disease. Given the careful meta-analysis by Bonovas et al,16 there are few data to support conducting such a randomized trial. Author's Disclosures of Potential Conflicts of Interest The author indicated no potential conflicts of interest. REFERENCES 1. Coogan PF, Rosenberg L, Palmer JR, et al: Statin use and risk of breast and prostate cancer. Epidemiology 13: 262-267, 2002[CrossRef][Medline]
2. Keyomarsi K, Sandoval L, Band V, et al: Synchronization of tumor and normal cells from G1 to multiple cell cycles by lovastatin. Cancer Res 51: 3602-3609, 1991 3. 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]
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5. Rao S, Porter DC, Chen X, et al: Lovastatin-mediated G1 arrest is through inhibition of the proteasome, independent of hydroxymethyl glutaryl-CoA reductase. Proc Natl Acad Sci U S A 96: 7797-7802, 1999 6. Muck AO, Seeger H, Wallwiener D: Inhibitory effect of statins on the proliferation of human breast cancer cells. Int J Clin Pharmacol Ther 42: 695-700, 2004[Medline] 7. Kochhar R, Khurana V, Bejjanki H, et al: Statins reduce breast cancer risk: A case control study in US female veterans. J Clin Oncol 23: 7S, 2005 (suppl, abstr 514) 8. Newman TB, Hulley SB: Carcinogenicity of lipid-lowering drugs. JAMA 275: 55-60, 1996[Abstract]
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18. 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 19. Sackett DL, Haynes RB, Guyatt GH, et al: Clinical Epidemiology: A Basic Science for Clinical Medicine. Boston, MA, Little, Brown, 1991 20. Etminan M, Coogan PF, Rosenberg L: Statins and cancer: Will we ever know the answer? Epidemiology 13: 607, 2002[Medline] 21. Corsini A, Jacobson TA, Ballantyne CM: Fluvastatin: Clinical and safety profile. Drugs 64: 1305-1323, 2004[CrossRef][Medline] Related Article
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Copyright © 2005 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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