Evidence Grows for Statins and Cancer Prevention
A case-control study of nearly 4,000 patients recently found that those who received statins for at least 5 years had a lower risk of developing colorectal cancer compared with those who did not. The findings, published in the May 26, 2005
New England Journal of Medicine(NEJM), come on the heels of several analyses of another study presented at the 2005 American Society of Clinical Oncology (ASCO) annual meeting, which suggested that statins also may help prevent breast, prostate, and lung cancers.
These results hint at potentially large public health benefits of statins, but come at a time when the prospect for conclusive research on the drugs may be disappearing. Researchers are concerned that statins, some of which are available in nonprescription form in the United Kingdom, may become similarly available in the US. Food and Drug Administration (FDA) advisory committees thus far have recommended against proposals to sell statins over the counter in the US. When drugs are in widespread use among the public, it becomes more difficult to gather useful information about their effects in placebo-controlled trials.
The recently published statin case-control study in the NEJM, led by researchers at the University of Michigan Cancer Center and the CHS National Cancer Control Center in Haifa, Israel, found that patients who took statins for at least 5 years had a 47% reduction in the risk of colorectal cancer. Approximately half of the study participants had colorectal cancer. The most widely used statins were simvastatin and pravastatin.
"Researchers are generally finding consistent results and are encouraged," noted Stephen Gruber, MD, PhD, MPH, of the University of Michigan, who co-led the colon cancer study with Gadi Rennert, MD, of the CHS National Cancer Control Center in Israel. "We are now trying to identify which patients are likely to benefit most from the drugs."
In the accompanying NEJM editorial, Ernest Hawk, MD, MPH, director of the Office of Centers, Training and Resources at the National Cancer Institute (NCI), and Jaye Viner, MD, MPH, head of the Gastrointestinal and Other Cancers Research Group in NCI's Division of Cancer Prevention, review prior statin studies and suggest that the case for statins in cancer prevention is promising, but far from certain. According to the editorial, what distinguishes this study from previous ones is its exclusive focus on colorectal cancer and the large number of cases studied.
Even so, the evidence that statins prevent cancer remains largely circumstantial. By exploring the effects of statins on the process of cancer at the molecular level, researchers have found that statins work against critical cellular functions that may help control tumor initiation, tumor growth, and metastasis. Specifically, statins reduce or block the activity of HMG-CoA (3-hydroxy-3-methylglutaryl COA) reductase, and thereby reduce the levels of mevalonate and its associated products, such as cholesterol. The mevalonate pathway plays a role in cell membrane integrity, cell signaling, protein synthesis, and cell cycle progression, all of which are potential targets of interventions against carcinogenesis.
"Now is not the time to start taking these drugs for cancer prevention," emphasized Dr. Gruber. "Now is the time to study them as agents for cancer prevention." Noted Dr Viner, "What's interesting here is that you have a broadly used class of agents with the potential to treat multiple diseases associated with aging, such as cardiovascular disease and cancer."
Statins, which also include atorvastatin, lovastatin, and rosuvastatin, make up the largest segment of the prescription drug market in the US, and their safety profiles have been determined in large, long-term cardiovascular disease studies. Although generally well-tolerated, statins have been associated with both muscle damage and liver toxicity.
But the only way to understand the unique public health potential of these drugs is to undertake carefully controlled clinical trials, Drs. Hawk and Viner maintain. "Our best hope for answering certain questions about these drugs is through placebo-controlled studies, and the window of opportunity to test statins against placebos may be closing," according to Dr. Viner.
In the meantime, several phase II, randomized, placebo-controlled studies of statins and cancer are being designed. By early 2006 or sooner, two clinical trials sponsored by NCI will begin to explore whether statins can prevent colorectal cancer and melanoma.
NCI's Cancer Prevention Clinical Trials Consortium are developing a trial for individuals at increased risk for colorectal cancer who also have been found to have aberrant crypt foci (ACF). ACF are clusters of abnormal cells in the lining of the colon and rectum that have been associated with the development of colorectal tumors and ACF may represent the earliest stage of detectable risk for colorectal cancer as observed by existing technology.
In addition, NCI is developing a phase II placebo-controlled trial to evaluate whether lovastatin can reverse precancerous changes in dysplastic nevi, a precursor to melanoma skin cancer.
