Cover Story

Despite headlines, role of statins in cancer prevention far from proven

The potential role of statins in cancer prevention has received tremendous attention from the medical research community and the media.

Results from several recent studies suggested that statins may reduce risk for and mortality from many types of malignancies. Bold headlines — such as “Super statins beat cancer” and “Statins: The next miracle drug?” — have appeared on websites and front pages around the world.

When it comes to complex scientific investigations, however, headlines do not always tell the entire story. Members of the cardiology and oncology communities acknowledge the positive findings, but are in no rush to join in the media frenzy.

Mukesh K. Jain, MD, discussed the actions of statins independent of their lipid-lowering effects.

Mukesh K. Jain, MD, discussed the actions of
statins independent of their lipid-lowering effects.

Source: UH Case Medical Center;
reprinted with permission.

“It shows up on the news that statins are protective of cancer,” Dale R. Shepard, MD, PhD, staff physician in the department of solid tumor oncology at Cleveland Clinic’s Taussig Cancer Institute, said in an interview. “This might be a disservice because it has not been studied properly. A number of trials are investigating how statins may prevent cancer or recurrence. For the most part, though, these tend to be observational studies, which obviously do not carry the weight that prospective trials do. The general public does not get this message.”

In observational studies, researchers may ask questions related to lifestyle choices and medication use, but inquiries are not specific to statin use and cancer.

“These studies are not necessarily investigating or demonstrating cause and effect,” Shepard said.

Frank de Vries, PhD, PharmD, assistant professor at Maastricht University Medical Centre and Utrecht University in the Netherlands, remains unconvinced.

“There have been various meta-analyses of randomized clinical trials that compared statin use with placebo,” de Vries said in an interview. “The risk of cancer was not increased or decreased. Statins do not impact cancer risk.”

Roger S. Blumenthal

Roger S.

Roger S. Blumenthal, MD, professor of medicine and director of the Johns Hopkins Ciccarone Center for the Prevention of Heart Disease, agreed. “Overall, the effect of statin therapy on cancer incidence is probably modest since there was not a significant effect on cancer risk in the large Cholesterol Treatment Trialist collaboration,” said the Cardiology Today Section Editor.

Although Shepard and others believe that potential associations are far from proven, they acknowledge that some data sets culled from large sample sizes contain encouraging findings that may provide clues to statins’ mechanisms of action or the downstream benefits they may offer.

Those results have revitalized a debate Shepard called “a roller-coaster ride.”

“If you look in the literature in the late 1990s and early 2000s, you will see a great deal of information on statins being like chemotherapy and having direct antitumor effects,” he said. “That excitement has died, but recent research has put the argument in the forefront again.”

Joseph S. Alpert

Joseph S. Alpert

Further, there was once publicity surrounding the issue of whether statins put patients at greater risk for cancer.

“Early in the history of statin drug treatment, we feared that statins might increase the risk for cancer,” Joseph S. Alpert, MD, MACP, professor of medicine at the University of Arizona College of Medicine and Cardiology Today Editorial Board member, said in an interview. “That fear has been resolved and it is possible that the anti-inflammatory component of statins decreases the risks for certain cancers, just as nonsteroidal anti-inflammatory drugs reduce the risk for colon cancer, presumably through anti-inflammatory pathways.”

Downstream effects

Nearly one in four Americans aged older than 45 years take a statin, according to the National Center for Health Statistics.

Statins help treat and prevent CVD by blocking the enzyme HMG-CoA reductase, which the body requires to make cholesterol.

Additional downstream benefits could possibly be beneficial in the prevention of first cancers or recurrence, according to Marco Mielcarek, MD, associate member of the clinical research division at Fred Hutchinson Cancer Research Center and associate professor of medicine at the University of Washington.

“There is strong experimental evidence that some of the actions of statins may occur independent of their lipid-lowering effects,” Mukesh K. Jain, MD, professor of medicine and director of the Case Cardiovascular Research Institute at Case Western Reserve University, Cleveland, told Cardiology Today.

“A few years ago, it was found that statins can increase cellular levels of a class of proteins termed Kruppel-like factors (KLFs), which maintain healthy blood vessels and reduce atherosclerosis,” Jain said. “Intriguingly, this same class of proteins can regulate certain cancers by inhibiting cell proliferation, inducing apoptosis and dampening of inflammation. Thus, if one can design statins with a more robust ability to induce KLFs, the effect seen clinically in the treatment of cancers may be more robust.”

Some reports from observational studies correlate decrements in cholesterol levels in statin-treated patients with increments in cancer risk, Mielcarek said.

“Some investigators suggested that the reported inverse relationship between cancer risk and cholesterol reduction may be related to statin-induced increases of regulatory T-cell numbers in the blood,” Mielcarek said in an interview. “Some investigators believe that regulatory T cells play a role in reducing our immune system’s ability to eradicate early cancerous cells.”

Stephen J. Freedland

Stephen J.

Investigations in animal models have shown that when cholesterol is lowered, testosterone levels in tumors are lowered, said Stephen J. Freedland, MD, of the departments of surgery and urology at Duke University.

“Blood serum testosterone levels do not change on a statin, but tumor testosterone does,” Freedland said. “Hormonally sensitive tumors, like prostate and breast tumors, might be impacted.”