Issues and Insights

Statins: Assessing their Effects on Cancer Risk

There is considerable interest in the possibility that cholesterol-lowering HMG-CoA reductase inhibitors (commonly known as statins), which have been proven to significantly reduce the risk of cardiovascular events, may also have preventive effects against cancer. This concept was premised on observations made in the 1960s that some cancer cells are preferentially able to synthesize significant amounts of cholesterol, and on subsequent data demonstrating that statins can prevent colon tumorigenesis in a carcinogen-driven rodent model (1,2). On the other hand, there has also been concern that statins may increase the risk of cancer because of certain preclinical studies and the secondary findings of some cardiovascular prevention trials, such as the Simvastatin and Ezetimibe in Aortic Stenosis (SEAS) study (3,4). In that study, there was a 50% increase in cancer and a 70% increase in cancer-associated mortality in patients taking the simvastatin/ezetimibe combination compared to those taking placebo (4). Despite a growing compendium of scholarly articles from laboratory, clinical, and population studies, definitive answers to the question of statins' risks and benefits for cancer prevention still remain.

How They Work
Currently there are seven FDA-approved statins on the market in the US – atorvastatin (Lipitor), fluvastatin (Lescol), lovastatin (Mevacor), pravastatin (Pravachol), rosuvastatin (Crestor), simvastatin (Zocor), and most recently, pitavastatin (Livalo) – and all act by blocking the rate-imiting enzyme in cholesterol metabolism known as HMG Co-A reductase. Statins are functionally distinguished by their relative “lipophilic” or “hydrophilic” nature. Lipophilic statins, such as atorvastatin, fluvastatin, lovastatin, and simvastatin, readily dissolve in lipids (fatty molecules) and can therefore cross lipid layers in cell membranes in both liver and nonliver tissues, while hydrophilic statins, such as pravastatin and rosuvastatin, are unable to cross cell membrane lipid layers and therefore require molecules called anion transporters to enter liver cells (5). Preclinical studies have shown that statins have a wide variety of effects on cells and tissues that are relevant to cancer prevention beyond simply blunting cholesterol biosynthesis. These include blocking the development of new blood vessels that feed tumor growth; inhibiting cell growth, invasion, and spread; altering the connections between cells; and promoting the death of precancerous cells (6).

A Look at the Data
Statins have been investigated for their efficacy in cardiovascular risk reduction for almost two decades, leading to their widespread use in Western populations including over-the-counter sales in the United Kingdom. This body of data has provided the foundation for numerous observational studies, systematic reviews, and meta-analyses of statins and their possible association with cancer risks or benefits.

To date, there have been at least eight published systematic reviews and/or meta-analyses compiling data from clinical trials and observational studies. Although each has included different studies and applied different methods, all are in general agreement that available data show neither significant harms nor preventive benefits associated with statin use and cancer. As one example, the most recent meta-analysis by Kuoppala, et al. analyzed 42 studies that included 17 randomized controlled trials, 10 cohort studies, and 15 casecontrol studies (7). They concluded that statins had no effect on the overall risk of cancer (median RR = 0.96; range = 0.72-1.2), nor on the specific risks of lung, prostate, or breast cancer.

However, statin use may be associated with ~30-40% reductions in the risk of stomach cancer, liver cancer, and lymphoma; and with up to a 50-60% increased risk of melanoma or nonmelanoma skin cancer (7). The available meta-analyses - as well as many of the studies on which they're based - note several limitations, including: restricted statistical power due to the relatively small sample size, short duration of follow-up (typically less than 5 years), and youth of the studied population resulting in a small number of cancer events; the frequent reliance on selfreported exposures and/or outcome data; the heterogeneity of the involved populations; as well as the lack of detailed information regarding the specific statin(s) or the details of the regimen (e.g., dose, frequency, duration) used.

Clearly, early phase clinical trials are needed to further explore the actions of statins and tumor progression in patients at risk for cancer, thereby building or diminishing the case for definitive trials of statins in cancer prevention. Two such early phase trials are currently underway. A phase I/II study of atorvastatin in women at increased risk for breast cancer is exploring its effects against a panel of tissue and bloodbased biomarkers, and a second phase II trial is evaluating lovastatin in patients with colorectal aberrant crypt foci. Recently, a phase III adjuvant study of rosuvastatin ± aspirin versus placebo in patients who have undergone definitive surgical or endoscopic treatment for colorectal cancer has been planned as well, although the premise for such a trial is controversial.

Important issues to be addressed in future studies of statins and cancer risk include the role of specific classes of statins (e.g., lipophilic vs. hydrophilic), therapeutic regimens (e.g., dose, frequency, duration), genetic variation in HMG-CoA reductase (e.g., some pharmacogenetic studies have reported greater cardiovascular benefits of statins in population subsets based on genetic differences in HMG-CoA reductase) (8, 9) and types of cancer (e.g., some data suggest greater effects in colorectal cancer prevention) (10).

Possibilities, Promise
The possibility that statins might offer preventive efficacy against cancer is intriguing given their relative safety and usefulness in cardiovascular risk reduction. A large array of data regarding their potential in cancer prevention has been generated over the last 15 years.

However to date, the data offer no clear or compelling consensus. Mechanistic and animal studies often suggest chemopreventive efficacy against cancer, although clinical data compiled from approximately 50 observational, experimental, and meta-analytic studies have been fairly null. This situation suggests the importance of Phase II biomarker-driven studies of statins in people at risk for cancer as the best near-term strategy, as well as the continued development and validation of biomarkers of cancer risk and chemopreventive response nested within phase III trials.

References

1. Fumagalli R, Grossi E, Paoletti P, et al: Studies on lipids in brain tumours - I. Occurrence and significance of sterol precursors of cholesterol in human brain tumours. J Neurochem 11:561-565, 1964


2. Narisawa T, Fukaura Y, Terada K, et al: Prevention of 1,2-dimethylhydrazine-induced colon tumorigenesis by HNG-CoA reductase inhibitors, pravastatin and simvastatin, in ICR mice. Carcinogenesis 15:2045-2048, 1994


3. Newman TB, Hulley SB: Carcinogenicity of lipid-lowering drugs. JAMA 275:55-60, 1996


4. Rossebø AB, Pedersen TR, Boman K, et al: Intensive lipid lowering with simvastatin and ezetimibe in aortic stenosis. N Engl J Med 359:1343-1356, 2008


5. Campbell M, Esserman L, Zhou Y, et al: Breast cancer growth prevention by statins. Cancer Res 66:8707-8714, 2006.


6. Demierre M-F, Higgins PDR, Gruber SB, et al: Statins and cancer prevention. Nat Rev Cancer 5:930-942, 2005


7. Kuoppala J, Lamminpää A, Pukkala E: Statins and cancer: a systematic review and meta-analysis. Eur J Cancer 44:2122-2132, 2008


8. Chasman DI, Posada D, Subrahmanyan L, et al: Pharmacogenetic study of statin therapy and cholesterol reduction. JAMA 291:2821-2827, 2004


9. Iakoubova J, Sabatine MS, Rowland CM, et al: Polymorphism in KIF6 gene and benefit from statins after acute coronary syndromes: results from the PROVE IT-TIMI 22 study. Am J Coll Cardiol 51:449-455, 2008


10. Poynter JN, Gruber SB, Higgins PDR, et al: Statins and the risk of colorectal cancer. N Engl J Med 352:2184-2192, 2005