Following Positive Epidemiologic Studies, Statins to Enter Clinical Trials for Cancer Prevention

NEWS - Statins grabbed the headlines earlier this year when several epidemiologic studies produced promising results that the cholesterol-lowering drugs might be associated with reduced risks of several cancers, including breast, colorectal, lung, and prostate cancers. Although some researchers have called for large randomized trials to assess statins anticancer effects, the drugs will receive their first tests in two smaller phase II trials set to begin later this year. The first study to receive attention was presented at the annual meeting of the American Association for Cancer Research in April. Using data from the Health Professionals Follow-up Study, Elizabeth Platz, Sc.D., from the Johns Hopkins Bloomberg School of Public Health in Baltimore, and colleagues found that the use of cholesterol-lowering drugs, mostly statins, was associated with a 46% relative reduction in the risk of advanced prostate cancer and a 66% reduction in the risk of metastatic or fatal disease, although there was no association with total risk of the cancer. The following month, at the American Society of Clinical Oncology annual meeting, three studies presented that were based on prescription records from the Veterans Administration found that statin use was associated with a 51% relative reduction in the risk of breast cancer, a 54% reduction in the risk of prostate cancer, and a 48% reduction in the risk of lung cancer. The same group presented two more studies based on the VA database at the 2005 Digestive Disease Week the same month that found statin use to be associated with reductions in the risk of esophageal and pancreatic cancers (56% and 59% relative reductions, respectively). The most recent study came in the May 26 issue of the New England Journal of Medicine. Stephen B. Gruber, M.D., Ph.D., an associate professor at the A second phase II trial, led by Ken Linden, M.D., Ph.D., of the University of California, Irvine, will evaluate whether lovastatin (Mevacor) can reverse precancerous changes in atypical nevi, which are a precursor for melanoma. Patient enrollment will begin late this year or early next. In addition, Ruby Kochhar, M.D., a hematologist/oncologist at the Naval Medical Center in Portsmouth, Va., president of the Kochhar Research Foundation, and lead researcher on one of the recent VA studies that was presented at ASCO, is planning to propose a prospective trial that will look at statins for the prevention of breast cancer. Some of the NCI cooperative groups have recommended starting a large randomized trial, particularly since statins may also have activity against other diseases, including multiple sclerosis and Alzheimer disease. However, theres just not enough evidence for this yet, according to Hawk. You dont want to jump into something so terribly costly, he said. A phase III trial would require a great amount of time, money, and participants, and there really isnt a compelling scientific basis for such a trial, Hawk said. Conducting a large randomized trial also might be very difficult because so many people already take the drugs, said Gad Rennert, M.D., Ph.D., director of the Clalit Health Services National Cancer Control Center in Haifa, Israel, and co-author on the recent NEJM study. First, because so many people are on the drugs and would have to be excluded from the trial, the study wouldnt necessarily represent the population. Second, contamination in the control arm would be another problem. What are the chances that, for the 5 to 7 years of the trial, theyll not take statins? he asked. It is possible that many participants could develop high cholesterol over the time of the trial and be given statins. Its so very difficult to get these into a clinical trial, he said. Another difficulty is that little is known about how exactly statins work against cancer. Theres really not a lot out there, said Limburg. Statins lower cholesterol by inhibiting the enzyme HMG-CoA reductase and preventing the conversion of HMG-CoA to mevalonate, a key step in the production of cholesterol in the liver. The leading hypothesis is that by inhibiting [HMG-CoA reductase], these drugs inhibit prenylation, said Gruber. Prenylation is the post-transcriptional modification that allows proteins, such as Ras and Rho, to move to the cell membranes. Disruption of this step in protein synthesis may lead to down Paul Limburg stream effects in a variety of cancer-related pathways, including tumor invasion, angiogenesis, apoptosis, and cell differentiation. Statins also have anti-inflammatory action, according to Gruber, which could play a role in their anticancer action. (See News, Vol. 95, No. 12, p. 844, Of Cancer and Cholesterol: Studies Elucidate Anticancer Mechanisms of Statins.) Furthermore, we do not know the effect [of statins] in normal people, those without high cholesterol or high triglycerides, said Kochhar. Conducting a large randomized trial brings the dangers that come with giving drugs to otherwise healthy people. But whether or not a large randomized trial of statins for chemoprevention is conducted may become a moot point. It may not be such an issue, said Rennert. If 25% of the population is already using them, we are already doing cancer prevention on 25% of the population. There is a potential that these agents would have a really large impact, said Hawk, particularly if they are shown to have effects in other diseases. However, its time for phase II studies, but probably nothing beyond that, he said. (...truncated)