Statins may be more than a smoking gun, but level one data still lacking

In this edition of HemOnc Today, there is a detailed discussion about the cancer therapy effects of statins, a series of cholesterol lowering agents also known affectionately as 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors.

Over the past decade, there has been increasing circumstantial evidence to suggest that these agents have anti-cancer effects and may even have an impact on cancer prevention. That said, this is extraordinarily controversial, with no clear consensus among the experts.

One key factor, from my perspective, is that the experts tend to make broad statements about “statins and cancer” rather than focusing on specific cancers, defined histologically or at a molecular level. I wish to add my 10 cents, but I will focus on a disease that I know quite well — prostate cancer.

Provocative data

In 2005, Mark A. Moyad, MD, MPH, and colleagues published a provocative paper suggesting that atorvastatin may influence progression and biochemical PFS after brachytherapy for clinically localized prostate cancer. They described 512 patients with clinical stage T1c-T3aNxMo disease who were followed for at least 3 years after treatment, and who were stratified based on statin use.

Notwithstanding the risk for case acquisition bias and inadvertent selection for lifestyle differences, it was interesting to note that the statin group had lower post-treatment PSA values and percentage of positive biopsies, as well as a nonsignificant improvement in biochemical PFS. The study was under-powered and retrospective, but it was interesting as a hypothesis-generating exercise.

Several quite powerful studies have since supported the contention that statins influence the biology of prostate cancer favorably. In the largest published study — a meta-analysis of 39 cohort studies and two case-control studies that involved more than 990,000 patients — Zhong and colleagues concluded that the HR for all-cause mortality was 0.81 when comparing statin users with nonusers, and that the prostate cancer-specific mortality had an HR of 0.77. Of course, having included so many previously published sets of data, the phenomenon of data dredging and recycling clearly comes into play here.

Yu and colleagues studied statin use in more than 11,000 men with newly diagnosed prostate cancer — followed for a mean of 4.4 years (standard deviation, 2.9 years). Results showed an all-cause mortality HR of 0.86 associated with statin use and an HR of 0.76 for prostate cancer mortality. These figures were more pronounced if the subjects had commenced statins prior to cancer diagnosis.

Similarly, Platz and colleagues followed more than 30,000 health professionals from 1990 to 2002 and noted a 49% reduction in the risk for advanced prostate cancer and a 61% reduction in the risk for metastatic prostate cancer among statin users, trends that were more substantial with increased duration of use.

Postulated mechanisms for this association, such as those reported by Hindler and colleagues, include the impact of statins on cholesterol levels and lipid metabolism, a potentially anti-inflammatory impact of lowered lipids or of the drugs themselves, induction of apoptosis, or a direct impact on cell metabolism and/or steroidogenesis previously demonstrated preclinically.

In one of the more intriguing data sets, Harshman and colleagues from Dana-Farber Cancer Institute completed a preclinical modeling study and a translational trial in which they demonstrated that statins compete with androgens for access to a transporter protein, SLCO2B1, which facilitates entry into prostate cancer cells. Among more than 900 study patients, those taking statins demonstrated longer median time to progression on androgen deprivation therapy than nonusers (27.5 months vs. 17.4 months; adjusted HR = 0.83; 95% CI, 0.69-0.99).

Jespersen and colleagues reported an additional quantum of support for this hypothesis.

In this study, investigators compared 42,800 patients with prostate cancer with more than 200,000 age-matched controls. They used the Danish National Prescription Registry to record statin use. The researchers noted a 6% reduced incidence of prostate cancer among men taking statins compared with nonusers, an impact that increased for those on statins longer than 10 years.

High degree of controversy

However, not all studies have shown this effect.

In particular, other studies of radiotherapy for localized prostate cancer — such as those by Soto and colleagues, and Cuaron and colleagues — have failed to show any improvement in outcomes. In addition, a study that involved a post-hoc, retrospective analysis of the REDUCE trial conducted by Freedland and colleagues — which tested the impact of dutasteride vs. placebo on the development of prostate cancer — showed no difference in presence of prostate cancer between statin users and nonusers. However, it may well be that this study had a negative case selection bias for this purpose because a key entry criterion was a negative set of prostate biopsies for men aged 50 to 75 years, thus selecting against the potential for prostate cancer to be subsequently influenced by statin use.

One must also consider potential confounding factors that might explain the putative statin effect on cancer progression or genesis — for example, patients who are taking statins could exhibit a healthier medical behavior pattern and, thus, have the potential for cancer avoidance, earlier diagnosis or better adherence to treatment regimens. It is theoretically possible that there is nonrandom misrecording of death statistics, which may be affected by the concurrence with a cardiovascular or cholesterol-based diagnosis (eg, patients presenting for follow-up to their local practitioners more often, and perhaps being misallocated the diagnosis of “vascular” rather than “cancer” as cause of death).

The material in this edition of HemOnc Today indicates the high degree of controversy on this vexed topic. At present, the evidence seems pretty strong that statins may reduce death from cancers of the prostate, and/or may influence the biology of the disease in favor of less aggressive natural history.

The NCI is sponsoring five trials that are focused on phase 2 assessment of various statins in the management or prevention of prostate cancer. However, to my knowledge, there has not been a prospective randomized trial to address the compelling preclinical studies, clinical association data and overview analyses listed above.

I generally believe that level one data should influence most quantum changes in clinical practice. Our nation seems to throw a great deal of money toward the cancer prevention lobby with variable results from large studies asking some quite unusual questions based sometimes on pretty weak data. This seems an important topic for them to address on a large scale ... now!

• References:
• Cuaron J, et al. Brachytherapy. 2015;doi:10.1016/j.brachy.2014.05.019.
• Freedland SJ, et al. Prostate Cancer Prostatic Dis. 2013;doi:10.1038/pcan.2013.10.
• Harshman LC, et al. JAMA Oncol. 2015;doi:10.1001/jamaoncol.2015.0829.
• Hindler K, et al. Oncologist. 2006;11:306-315.
• Jespersen CG, et al. Cancer Epidemiol. 2014;doi:10.1016/j.canep.2013.10.010.
• Moyad MA, et al. Urology. 2005;66:1150-1154.
• Platz EA, et al. J Natl Cancer Inst. 2006;98:1819-1825.
• Soto DE, et al. Urology. 2009;doi:10.1016/j.urology.2008.02.055.
• Yu O, et al. J Clin Oncol. 2014,doi:10.1200/JCO.2013.49.4757.
• Zhong S, et al. Cancer Treat Rev. 2015;doi:10.1016/j.ctrv.2015.04.005.

• For more information:
• Derek Raghavan, MD, PhD, FACP, FRACP, FASCO, is HemOnc Today’s Chief Medical Editor for Oncology. He also is president of Levine Cancer Institute at Carolinas HealthCare System. He can be reached at derek.raghavan@carolinashealthcare.org.

Disclosure: Raghavan reports no relevant financial disclosures.