BERKELEY, CA (UroToday.com) - In our recent article in the Journal of Urology, we explored the association between statin use and progression after surgery for renal cell carcinoma. We have been studying statins as a possible anti-neoplastic agent for some time, particularly in prostate cancer. As one of the most plausible mechanisms of statins preventing cancer development or progression involves inhibition of the mTOR pathway, it became logical to explore the influence of statins in a disease where mTOR pathway signaling is commonly aberrant: kidney cancer.
When exploring a new epidemiological association, it is often easier to start with a group that already has the disease as it can help eliminate any biases inherent in disease detection. Thus, we chose to first look at a cohort treated surgically for renal cell carcinoma and see if statin use was associated with improved outcomes. Indeed, we did observe statin use was associated with a 20-30% reduction in the risk of progression and a 10-30% improvement in overall survival. These estimates varied based on how statin use was modeled: as a binary yes/no at time of surgery or as a time-dependent covariate which captures time on and off a statin more elegantly.
Statin users are a very different group than nonusers. This has been observed in many cohort studies in other diseases. As our Table 1 depicts, our study showed important differences in many of the typical ways statin users differ from nonusers. Statin users were older, heavier, had more comorbidities, and worse kidney function. Another common phenomenon in observational studies is that statin users represent a more recent cohort than nonusers. This is typically because statins were approved in the mid 1990s and only really became prevalently used in the early 2000s. This cohort effect can bias results if diagnosis, treatment or monitoring practices changed significantly over the last 20 years.
Using multivariate modeling we controlled for as much of the potential bias introduced by a statin cohort as possible. We also controlled for year of surgery to account for the more recent statin-using cohort. As was alluded to by Dr. Teemu J. Murtola in his accompanying editorial of our paper, there will always linger a possibility of bias confounding the relationship between statin use and the outcome of interest. Only a randomized controlled trial could potentially eliminate these sources of bias. Until a randomized trial is completed, analysis of other kidney cancer databases may help confirm or refute our observations, and further studies of the mechanisms of statin inhibition of progression will also aid our understanding.
We do think the role of statins inhibiting the mTOR pathway is an important mechanism in prevention of cancer and cancer progression. In the case of kidney cancer, there is potential synergy between statins and already approved drugs that target mTOR such as temsirolimus or everolimus. By combining statins with other therapies for advanced renal cell carcinoma, like tyrosine kinase inhibitors (e.g., sunitinib or sorafenib), there could be benefits to dual pathway blockade. This is an area ripe for research. Potential synergies between statins and metformin should also be explored, as metformin is known to inhibit mTOR signaling.
Robert J. Hamilton, MD, MPH, FRCSC as part of Beyond the Abstract on UroToday.com. This initiative offers a method of publishing for the professional urology community. Authors are given an opportunity to expand on the circumstances, limitations etc... of their research by referencing the published abstract.
Urology Service, Department of Surgery, Memorial Sloan-Kettering Cancer Center, New York, New York; Division of Urology, Department of Surgery, University of Toronto, Toronto, Ontario, Canada