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.

“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, 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.”

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.”

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.”

Reduced mortality

In November, Nielsen and colleagues published a population-based study in The New England Journal of Medicine that showed a reduction in cancer-related mortality among statin users in Denmark.

The study involved 18,721 statin users and 277,204 never-users aged younger than 40 years who were diagnosed with cancer between 1995 and 2007. Statin use was associated with reduced all-cause mortality (HR=0.85; 95% CI, 0.83-0.87) and cancer-related mortality (HR=0.85; 95% CI, 0.82-0.87). The association was observed across all 13 cancer subtypes studied.

This paper had the “greatest impact” of any of the recent studies related to statins and cancer, Mielcarek said. “Even the smallest dose had a protective effect.”

Mielcarek noted a concern with the Nielsen findings.

“Population studies tend to have a healthy user bias,” he said. “The patients who fared better may have been more conscious of health anyway. It is difficult to avoid this in this kind of study.”

The challenge in studying these two cohorts is fairly straightforward, Freedland said.

“Is it the statin that is impacting the cancer risk, or is it everything else that being on a statin tells us about a person?” he asked.

JUPITER was the largest randomized, double blind, placebo-controlled trial conducted on a statin. In the study of more than 17,600 patients, those assigned rosuvastatin (Crestor, AstraZeneca) showed reduced cancer mortality compared with placebo (35 vs. 58 deaths; P=.02). Results also demonstrated no increase in cancer occurrence after rosuvastatin treatment.

In a 2009 article on the implications of the JUPITER data, investigator Paul M. Ridker, MD, MPH, said, “Although the total exposure time in JUPITER is too short to exclude long-term effects, it is reassuring that a nominally significant reduction in cancer mortality was observed.”

Today, Ridker cautioned against reading too much into the trial’s cancer-related results.

“I do not believe there is reliable evidence showing that statin therapy increases or decreases the risk of cancer,” Ridker, director of the Center for Cardiovascular Disease Prevention at Brigham and Women’s Hospital, wrote in an email to Cardiology Today. “However, these agents are highly effective at reducing the risks for heart attack, stroke and CV death in both primary and secondary prevention.”

The Cholesterol Treatment Trialists’ Collaboration, a meta-analysis of 27 randomized trials of 174,149 people, yielded similar results. Statin use for 5 years had no effect on newly diagnosed cancer or cancer-related mortality. This held true in trials of statin vs. control (cancer incidence: 1.4% vs. 1.4% per year; RR=1; 95% CI, 0.96-1.05; cancer mortality: 0.5% vs. 0.5% per year; RR=1; 95% CI, 0.93-1.08) and trials of higher-dose vs. lower-dose statins (cancer incidence: 1.6% vs. 1.6% per year; RR=1; 95% CI, 0.93-1.07; cancer mortality: 0.5% vs. 0.5% per year; RR=0.93; 95% CI, 0.82-1.06).

Effects on hepatocellular carcinoma

Singh and colleagues conducted a systematic review and meta-analysis to determine the effect of statins on hepatocellular carcinoma (HCC) risk that was published earlier this year in Gastroenterology. The study included 4,298 cases of HCC among 1,459,417 patients eligible for review. The adjusted OR for developing HCC among statin users was 0.63 (95% CI, 0.52-0.76).

Studies like this have shown there is benefit to statin therapy in this population, said William Sanchez, MD, of the departments of gastroenterology and hepatology at Mayo Clinic in Rochester, Minn.

“There are a lot of potential mechanisms, but the data are inconclusive,” he said.

Still, because statins are taken up by and enriched in the liver, it may be “a good organ to start with when you look at cancer chemo-prevention,” Mielcarek said.

Study location may have caused heterogeneity within the results, according to Singh and colleagues. The OR in the four studies conducted in Asia was 0.52 (95% CI, 0.42-0.64) compared with an OR of 0.67 (95% CI, 0.53-0.85) among patients included in six studies conducted in Western countries. Study design also may have been a factor, as the adjusted OR for the seven observational studies was 0.6 (95% CI, 0.49-0.73) and the adjusted OR for three clinical trials was 0.95 (95% CI, 0.62-1.45).

Role in breast cancer

Brewer and colleagues presented a retrospective cohort study at the 2012 San Antonio Breast Cancer Symposium. Results of the analysis, which included 724 patients with primary breast cancer, showed hydrophilic and lipophilic statin use were associated with improved disease-free survival and overall survival times across the entire cohort.

Results of a multivariate analysis adjusting for radiation therapy, as well as estrogen-receptor, progesterone-receptor and HER-2 expression, indicated that hydrophilic statin use was associated with improved disease-free survival compared with no statin use (HR=0.49; 95% CI, 0.28-0.84). Researchers also observed a nonsignificant link between hydrophilic statin use and time to mortality.

The data contain no statistical significance, and there may be larger issues to contend with in patients with a poor prognosis, Shepard said.

“Again, the problem is that there is a little bit of bias in terms of why people may have been taking statins,” he said. “We are not trying to prevent heart disease in 5 years in patients with poor-prognosis cancer, so it is not likely that they will be put on statins.”

Other randomized trials

Several studies presented at the American Association for Cancer Research Annual Meeting in April further propelled the argument that statins may offer a protective benefit against cancer.

Murtola and colleagues conducted a population-based study of 31,236 patients with newly diagnosed breast cancer in Finland between 1995 and 2003. Statin use after diagnosis was associated with a 67% reduction in breast cancer mortality among women with localized disease and a 48% decrease for women with metastatic disease.

Amsler and colleagues reported an 83% reduction in recurrence among 60 women with ovarian cancer who were taking statins to control diabetes.

McGlynn and colleagues conducted a study that included 75 patients with liver cancer and 373 controls. Univariate analysis indicated statins were associated with a 40% reduction in liver cancer risk, and a nonsignificant 52% reduction was observed in multivariate analysis.

Targeted investigations

Despite the conclusions of recent studies, Mielcarek said he is not convinced that statins are linked to improved prognosis.

“Statins have known effects on cell-cycling and signaling and may therefore slow down the growth of certain tumors, but the mechanisms need to be investigated more thoroughly,” Mielcarek said. “Therefore, randomized controlled trials in selected high-risk populations would be most informative.

“We may get some answers if we look at Asians at high risk for liver cancer, for example, or more in general at secondary prevention in patients in remission who have a high relapse risk,” he said.

Shepard said there has not been enough evidence of antitumor effects to show statins as a primary antitumor agent, adding that an adjuvant trial would be a better option.

“It will require a long time to get the data,” Shepard said. “We will need two arms — one with statins and one without — and we should look at which one has recurrence faster [and] which one has better overall survival.”

An investigation of patients with tumors that have been resected may be helpful, Sanchez said.

“Those patients are already at a high risk,” he said. “This type of secondary prevention might be easier to study than primary prevention.”

Shepard said a trial designed to minimize risk for recurrence in patients who have had cancer or resection may be feasible. Also, he said, a study in the metastatic setting may be effective.

“As the tumor metastasizes, we could observe how quickly — or if — the tumor responds,” he said. “But this will present clinical challenges because you will be simultaneously trying to treat the tumor, prevent progression and study the drug.”

Statins work at several different checkpoints of cell proliferation and dampen inflammatory response, which may make research difficult, Sanchez said.

De Vries said he was less optimistic. “It is probably a waste of resources and — given the current evidence — possibly not even ethical to conduct,” he said.

Statin prescription, restriction

The research is inconclusive to consider factoring in cancer prevention when prescribing statins, and physicians need to keep in mind the associated risks, Rita F. Redberg, MD, MSc, editor of JAMA Internal Medicine and director of women’s cardiovascular services at University of California, San Francisco, said in an interview.

“I think the data clearly show that we are not going to make the decision on statin prescription based on its risks and benefits for cancer prevention,” said Redberg, a member of the Cardiology Today Editorial Board. “The data available are mostly observational and are likely confounded by healthy user bias.

“The important question is whether their benefits outweigh the risks in primary prevention — the main indication — and, unfortunately, those data are sorely lacking. While some high-risk groups, mainly men, have seen a reduction in MI with statin use, there are no convincing data of a mortality benefit for statin use and there are accumulating data on many risks, including memory loss, diabetes, weakness, fatigue and muscle problems.”

Blumenthal said it is important to “continue to support clinical research trials that are looking at the effects of statins on certain types of cancers in subjects who would not otherwise qualify for statin therapy. We need more data before widely prescribing statin therapy in oncology patients.”

Overall, the debate itself may be doing a disservice to caregivers and the health care system, said Udho Thadani, MD, MRCP, FRCPC, FACC, FAHA, emeritus professor of medicine at University of Oklahoma and Cardiology Today Editorial Board member.

“These reports lead to increased inquiry by individuals to use a statin to prevent the occurrence of cancer and may unnecessarily burden the already-stretched health care providers and cost,” Thadani said. “It is imperative that society and physicians are made to realize that these observational and case-controlled studies are merely hypothesis-generating and must be confirmed or refuted by carrying out proper placebo-controlled, adequately powered, randomized trials in the target population in question.

“Until such studies are performed and reported, the use of statins should be limited to their current FDA-approved labeling.”

The right message

Reporting complex trial results to the general public is difficult, and regardless of how future trials are designed, increased efforts must be made to ensure the results are kept in perspective, Shepard said.

Shepard used the study by Singh and colleagues — an observational study in which patients on statins had less likelihood of developing liver cancer — as an example.

“The headline reads, ‘Statins linked to reduced liver cancer,’” Shepard said. “If you look at the study, it could be true — there are fewer liver cancers in those patients — but it is a big jump to make. The nuances are lost. ‘If you use statins, you get less cancer’ becomes the final message, even if it is not the right message.”

The FDA can also play a role in managing communication to physicians and the public. When a meta-analysis of approximately 62,000 patients reporting a small but relevant association between angiotensin-receptor blockers and cancer was published in 2010, the FDA launched its own larger meta-analysis of approximately 156,000 patients to study the link. In June 2011, the agency released a drug safety communication concluding that angiotensin-receptor blocker use did not increase risk for cancer, and encouraged physicians and patients to report associated adverse events to its MedWatch program.

Whether the FDA will weigh in on the publicity surrounding statins and cancer remains to be seen. In February 2012, the agency mandated a warning on statin labels about the risk for diabetes and memory loss.

“Every day, we get an overload of observational trials,” Shepard said. “After a while, you start either believing them all or believing none of them. Patients come into clinic confused about what they should or shouldn’t eat, what they should or shouldn’t do, what causes prevention or what doesn’t. We have to be more careful about how we present this information.”

Disclosure: Ridker reports financial ties with Abbott, AstraZeneca, Dade-Behring, Isis Pharmaceuticals, Merck, Merck-Schering Plough, Novartis, Roche, Sanofi-Aventis and Vascular Biogenics. Sanchez reports grant support from Esai Pharmaceuticals and Phillips. Thadani is a consultant for Arbor Pharmaceuticals, Gilead Science and Servier. Alpert, Blumenthal, de Vries, Freedland, Jain, Mielcarek, Redberg and Shepard report no relevant financial disclosures.