von Hippel-Lindau Gene Status and Response to Vascular Endothelial Growth Factor Targeted Therapy for Metastatic Clear Cell Renal Cell Carcinoma
- 30 September 2008
- journal article
- Published by Ovid Technologies (Wolters Kluwer Health) in Journal of Urology
- Vol. 180 (3), 860-866
- https://doi.org/10.1016/j.juro.2008.05.015
Abstract
The von Hippel-Lindau (VHL) gene is often inactivated (by mutation or promoter hypermethylation) in renal cell carcinoma but the relation to therapeutic outcome is unclear. Patients with metastatic clear cell renal cell carcinoma with available baseline tumor samples who received vascular endothelial growth factor targeted therapy were included in analysis. Patient characteristics, VHL gene status and clinical outcome were documented. Our primary end point was to test for response rate in relation to VHL inactivation. Progression-free survival and overall survival in relation to VHL status were investigated as secondary end points. A total of 123 patients were evaluable. Response rate, median progression-free survival and median overall survival were 37% (95% CI 28–46), 10.8 (95% CI 7.7–14.8) and 29.8 (CI not estimable) months, respectively. Patients with VHL inactivation had a response rate of 41% vs 31% for those with wild-type VHL (p = 0.34). Patients with loss of function mutations (frameshift, nonsense, splice and in-frame deletions/insertions) had a 52% response rate vs 31% with wild-type VHL (p = 0.04). On multivariate analysis the presence of a loss of function mutation remained an independent prognostic factor associated with improved response. Progression-free survival and overall survival were not significantly different based on VHL status. To our knowledge this is the largest analysis investigating the impact of VHL inactivation on the outcome of vascular endothelial growth factor targeted agents in metastatic renal cell carcinoma. We did not find a statistically significant increase in response to vascular endothelial growth factor targeted agents in patients with VHL inactivation. Loss of function mutations identified a population of patients with a greater response. Investigation of downstream markers is under way.Keywords
This publication has 17 references indexed in Scilit:
- Sunitinib versus Interferon Alfa in Metastatic Renal-Cell CarcinomaThe New England Journal of Medicine, 2007
- Sorafenib in Advanced Clear-Cell Renal-Cell CarcinomaThe New England Journal of Medicine, 2007
- The Current Role of Angiogenesis Inhibitors in the Treatment of Renal Cell CarcinomaSeminars in Oncology, 2006
- Prognostic factors associated with long-term survival in previously untreated metastatic renal cell carcinomaAnnals of Oncology, 2006
- Clinical response to therapy targeted at vascular endothelial growth factor in metastatic renal cell carcinoma: impact of patient characteristics and Von Hippel‐Lindau gene statusBJU International, 2006
- Sunitinib in Patients With Metastatic Renal Cell CarcinomaJama-Journal Of The American Medical Association, 2006
- Bladder Cancer Outcome and Subtype Classification by Gene ExpressionClinical Cancer Research, 2005
- Evolving role of pegylated interferons in metastatic renal cell carcinomaExpert Review of Anticancer Therapy, 2003
- A Randomized Trial of Bevacizumab, an Anti–Vascular Endothelial Growth Factor Antibody, for Metastatic Renal CancerThe New England Journal of Medicine, 2003
- Mutations of the VHL tumour suppressor gene in renal carcinomaNature Genetics, 1994