In order to evaluate a potential effect on statin use and outcome in patients with kidney cancer Hamilton and colleagues1 recently reported on 2608 patients with localized renal cell carcinoma who were treated surgically between 1995 and 2010. Approximately 700 (27%) of the patients in this cohort were statin users at the time of surgery. At a median follow-up of 36 months, there were 247 progression events. Statin use was associated with a 33% reduction in the risk of progression after surgery, but overall mortality was not significantly reduced (11%).
Many uncontrolled variables were included in this interesting study of patients with clear cell (68%), papillary (14%), chromophobe (12%), and unclassified (6%) renal cell carcinoma, as there would be in any retrospective analysis.
While the potential effect of statin use to decrease progression of renal cell carcinoma would need to be evaluated in a controlled, randomized trial, an approach such as this does make mechanistic sense. It has recently been shown, in a study from The Cancer Genome Atlas, that high-grade, high-stage, low-survival clear cell kidney cancer undergoes a metabolic shift that is consistent with a remodeling of cellular energetics toward decreased mitochondrial function and an increase in fatty acid synthesis.2 A similar metabolic shift involving decreased mitochondrial function and increased fatty acid synthesis was recently described in an aggressive, genetically defined form of type 2 papillary kidney cancer.3
Targeting the increased production of fatty acids and lipids that are needed to build new membranes and cellular structures critical for rapidly growing cancer cells has long been considered to be a potentially important target for cancer therapy. Clear cell kidney cancer is characterized by mutation of the VHL gene,4 and, to date, the development of therapies for this disease has primarily been centered around targeting the VHL gene pathway.
While this approach has led to the remarkable development of seven FDA-approved targeted therapeutic agents for this malignancy, most patients experience progressive disease, and many will eventually die from this disease. Targeting lipid and fatty acid synthesis pathways with statins and/or with more specific targeted agents could potentially provide an additional or complementary therapeutic approach for patients with advanced or high-risk renal cell carcinoma.
- Hamilton RJ, Morilla D, Cabrera F, et al. The Association between Statin Medication and Progression after Surgery for Localized Renal Cell Carcinoma. J Urol. 2014;191(4):914-919.
- Cancer Genome Atlas Research Network. Comprehensive molecular characterization of clear cell renal cell carcinoma. Nature. 2013;499 (7456):43-49.
- Mullen AR, Wheaton WW, Jin ES, et al. Reductive carboxylation supports growth in tumour cells with defective mitochondria. Nature. 2011;481(7381):385-388.
- Latif F, Tory K, Gnarra J, et al. Identification of the von Hippel-Lindau disease tumor suppressor gene. Science. 1993;260(5112):1317-1320.
W Marston Linehan MD
Evidence suggests that statins may influence pathways of renal cell carcinoma proliferation, although to our knowledge no study has examined the influence of statin medications on the progression of renal cell carcinoma in humans.
MATERIALS AND METHODS
We identified 2,608 patients with localized renal cell carcinoma who were treated surgically between 1995 and 2010 at our tertiary referral center. Competing risks Cox proportional hazards models were used to evaluate the relationship between statin use and time to local recurrence or progression (metastases or death from renal cell carcinoma) and overall survival. Statin use was modeled as a time dependent covariate as a sensitivity analysis. Models were adjusted for clinical and demographic features.
Of 2,608 patients 699 (27%) were statin users at surgery. Statin users had similar pathological characteristics compared to nonusers. At a median followup of 36 months there were 247 progression events. Statin use was associated with a 33% reduction in the risk of progression after surgery (HR 0.67, 95% CI 0.47-0.96, p = 0.028) and an 11% reduction in overall mortality that was not significant (HR 0.89, 95% CI 0.71-1.13, p = 0.3). Modeling statin use as a time dependent covariate attenuated the risk reduction in progression to 23% (HR 0.77, p = 0.12) and augmented the risk reduction in overall survival (HR 0.71, p = 0.002).
In our cohort statin use was associated with a reduced risk of progression and overall mortality, although this effect was sensitive to the method of analysis. If validated in other cohorts, this finding warrants consideration of prospective research on statins in the adjuvant setting.
RJ Hamilton, D Morilla, F Cabrera, M Leapman, LY Chen, M Bernstein, AA Hakimi, VE Reuter, P Russo.
The Association Between Statin Medication and Progression After Surgery for Localized Renal Cell Carcinoma.
J Urol. 2014;191(4):914-919.