Analysis of PTEN and HIF-1alpha and correlation with efficacy in patients with advanced renal cell carcinoma treated with temsirolimus versus interferon-alpha.

Abstract

BACKGROUND:

Exploratory subgroup analyses from the phase 3 global advanced renal cell carcinoma (ARCC) trial were conducted to determine if baseline levels of the tumor molecular markers PTEN and HIF1 alpha correlated with efficacy in patients treated with temsirolimus (Torisel) versus interferon-alpha (IFN).

METHODS:

Patients in the IFN group received 3 million U (MU) subcutaneously 3x weekly, escalating to 18 MU. Patients in the temsirolimus group received 25 mg intravenously weekly. PTEN and HIF1 alpha baseline levels were measured in archived tumor specimens by immunohistochemistry.

RESULTS:

There was no correlation between baseline PTEN and HIF1 alpha levels and treatment effect with respect to overall survival (OS), progression-free survival, or objective response rate (ORR) in patients with advanced renal cell carcinoma with poor-risk prognostic factors.

CONCLUSIONS:

The baseline status of the molecular markers PTEN and HIF1 alpha did not correlate with efficacy in renal cell carcinoma patients treated with temsirolimus versus IFN. Patients demonstrated OS and progression-free survival benefit when treated with temsirolimus regardless of PTEN and HIF1 alpha status. Thus, baseline PTEN and HIF-1 levels may not predict response to temsirolimus. Alternatively, the lack of correlation may be due to the variability in tumor specimens that occurred because of the global nature of the clinical trial. Other markers in the phosphoinositide 3-kinase (PI3K)/Akt pathway may be of utility as predictors of response to temsirolimus in patients with advanced renal cell carcinoma.

• Authors: Robert A Figlin, Paul de Souza, David McDermott, Janice P Dutcher, Anna Berkenblit, Alexandra Thiele, Mizue Krygowski, Andrew Strahs, Jay Feingold, Joseph Boni, Gary Hudes
• Journal: Cancer (Cancer) Vol. 115 Issue 16 Pg. 3651-60 (Aug 15 2009) ISSN: 0008-543X [Print] United States
• PMID: 19526589 (Publication Type: Clinical Trial, Phase III, Comparative Study, Journal Article, Randomized Controlled Trial, Research Support, Non-U.S. Gov't)

Chemical References

• Biomarkers, Tumor
• Hypoxia-Inducible Factor 1, alpha Subunit
• Interferon-alpha
• temsirolimus
• PTEN Phosphohydrolase
• PTEN protein, human
• Sirolimus

Topics

• Antineoplastic Combined Chemotherapy Protocols (therapeutic use)
• Biomarkers, Tumor (analysis)
• Carcinoma, Renal Cell (drug therapy, metabolism, mortality)
• Female
• Humans
• Hypoxia-Inducible Factor 1, alpha Subunit (metabolism)
• Interferon-alpha (administration & dosage, therapeutic use)
• Kidney Neoplasms (drug therapy, metabolism, mortality)
• Male
• Middle Aged
• PTEN Phosphohydrolase (metabolism)
• Signal Transduction
• Sirolimus (administration & dosage, analogs & derivatives, therapeutic use)