Increase in Cholesterol Predicts Survival Advantage in Renal Cell Carcinoma Patients Treated with Temsirolimus

Abstract

Purpose: Temsirolimus is an effective treatment for renal cell carcinoma. It is associated with increases in serum cholesterol, triglyceride, and glucose. We investigated whether changes of these biomarkers could predict its efficacy.Experimental Design: We examined serial measurements of cholesterol, triglycerides, and glucose from patients randomized to IFN or temsirolimus in the Global Advanced Renal Cell Carcinoma Trial. Using time-dependent proportional hazards models, we quantified the association between changes in these biomarkers from baseline with overall survival (OS) and progression-free survival (PFS). We also assess the extent to which changes of these biomarkers predict the effects of temsirolimus on survival.Results: Temsirolimus was associated with larger mean increases in cholesterol (1.02 mmol/L; P < 0.0001), triglycerides (0.32 mmol/L; P ¼ 0.0008), and glucose (1.28 mmol/L; P < 0.0001) compared with IFN and improved survival rate (OS: HR ¼ 0.76, P ¼ 0.02; PFS: HR ¼ 0.70, P ¼ 0.001). Cholesterol increase during study was associated with longer survival (OS: HR ¼ 0.77 per mmol/L, P < 0.0001; PFS: HR ¼ 0.81 per mmol/L; P < 0.0001). Temsirolimus effect on cholesterol predicted its effect on survival with no additional survival advantage observed after adjusting for cholesterol change during study (OS: HR ¼ 1.14, P ¼ 0.37; PFS: HR ¼ 0.88, P ¼ 0.35). Temsirolimus effect on triglycerides or glucose did not predict its effect on survival, with survival advantage in favor of temsirolimus still observed after adjusting for these factors (P ¼ 0.003 and P ¼ 0.002).Conclusion: Cholesterol increase is a potential predictor for temsirolimus efficacy. Longer survival in patients treated with temsirolimus was observed in those with larger increases in cholesterol. Prospectively designed biomarker studies of temsirolimus or other mTOR inhibitors are recommended.

Temsirolimus for advanced renal cell carcinoma

“…However, an increase in the cholesterol level is a potential predictor for temsirolimus efficacy and therefore remains a significant predictor for OS in multivariate analyses. Longer survival in patients treated with temsirolimus was observed in those with larger increases in cholesterol [45]. In a univariate analysis, Lee et al showed that a 1 mmol/l (39 mg/dl) increase in cholesterol was associated with an 18% reduction of the risk of death (hazard ratio [HR]: 0.82; 95% CI: 0.74-0.91; p < 0.001) [45] and was associated with a 10% reduction of the risk of disease progression (HR: 0.90; 95% CI: 0.83-0.99; p = 0.03) [45].…”

“…Longer survival in patients treated with temsirolimus was observed in those with larger increases in cholesterol [45]. In a univariate analysis, Lee et al showed that a 1 mmol/l (39 mg/dl) increase in cholesterol was associated with an 18% reduction of the risk of death (hazard ratio [HR]: 0.82; 95% CI: 0.74-0.91; p < 0.001) [45] and was associated with a 10% reduction of the risk of disease progression (HR: 0.90; 95% CI: 0.83-0.99; p = 0.03) [45]. In a Phase II trial of temsirolimus in the treatment of patients with glioblastoma multiforme, elevated serum lipids during the first two cycles of treatment were also significantly associated with radiographic response [46].…”

“…In a Phase II trial of temsirolimus in the treatment of patients with glioblastoma multiforme, elevated serum lipids during the first two cycles of treatment were also significantly associated with radiographic response [46]. A remarkable number of temsirolimus-treated patients were additionally treated with a statin [45]. In the study of Lee et al, statin treatment does not impact on temsirolimus treatment efficacy [45].…”

Pharmacotherapy options for advanced renal cell carcinoma

“…Hypothyroidism has been associated with response to sunitinib and sorafenib. Increase in cholesterol predicts survival advantage in patients treated with temsirolimus [40][41][42][43].…”

Serum Cholesterol and mTOR Inhibitors: Surrogate Biomarker or Epiphenomenon?

“…In this issue, Lee and colleagues present the results of a retrospective analysis of the correlation between changes in fasting serum cholesterol, triglycerides, and glucose during treatment and clinical outcome measures in patients treated with temsirolimus and IFN-a as part of the Global Advanced RCC Trial (1). In their analysis, the authors show that larger increases in serum cholesterol from baseline in patients treated with temsirolimus were associated with both reduced risk of disease progression and prolonged overall survival.…”