von Hippel-Lindau Gene Status and Response to Vascular Endothelial Growth Factor Targeted Therapy for Metastatic Clear Cell Renal Cell Carcinoma

Toni K. Choueiri; Susan A.J. Vaziri; Erich Jaeger; Paul Elson; Laura Wood; Ish Prasad Bhalla; Eric J. Small; Vivian Weinberg; Nancy Sein; Jeff Simko; Ali Reza Golshayan; Linda Sercia; Ming Zhou; Frederic M. Waldman; Brian I. Rini; Ronald M. Bukowski; Ram Ganapathi

doi:10.1016/j.juro.2008.05.015

von Hippel-Lindau Gene Status and Response to Vascular Endothelial Growth Factor Targeted Therapy for Metastatic Clear Cell Renal Cell Carcinoma

Toni K. Choueiri, Susan A.J. Vaziri, Erich Jaeger, Paul Elson, Laura Wood, Ish Prasad Bhalla, Eric J. Small, Vivian Weinberg, Nancy Sein, Jeff Simko, Ali Reza Golshayan, Linda Sercia, Ming Zhou, Frederic M. Waldman, Brian I. Rini, Ronald M. Bukowski, Ram Ganapathi

Research output: Contribution to journal › Article › peer-review

179 Scopus citations

Abstract

Purpose: 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. Materials and Methods: 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. Results: 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. Conclusions: 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.

Original language	English (US)
Pages (from-to)	860-866
Number of pages	7
Journal	Journal of Urology
Volume	180
Issue number	3
DOIs	https://doi.org/10.1016/j.juro.2008.05.015
State	Published - Sep 2008

Keywords

carcinoma
prognosis
renal cell
vascular endothelial growth factors
von Hippel-Lindau disease

ASJC Scopus subject areas

Urology

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10.1016/j.juro.2008.05.015

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Choueiri, T. K., Vaziri, S. A. J., Jaeger, E., Elson, P., Wood, L., Bhalla, I. P., Small, E. J., Weinberg, V., Sein, N., Simko, J., Golshayan, A. R., Sercia, L., Zhou, M., Waldman, F. M., Rini, B. I., Bukowski, R. M., & Ganapathi, R. (2008). von Hippel-Lindau Gene Status and Response to Vascular Endothelial Growth Factor Targeted Therapy for Metastatic Clear Cell Renal Cell Carcinoma. Journal of Urology, 180(3), 860-866. https://doi.org/10.1016/j.juro.2008.05.015

Choueiri, TK, Vaziri, SAJ, Jaeger, E, Elson, P, Wood, L, Bhalla, IP, Small, EJ, Weinberg, V, Sein, N, Simko, J, Golshayan, AR, Sercia, L, Zhou, M, Waldman, FM, Rini, BI, Bukowski, RM & Ganapathi, R 2008, 'von Hippel-Lindau Gene Status and Response to Vascular Endothelial Growth Factor Targeted Therapy for Metastatic Clear Cell Renal Cell Carcinoma', Journal of Urology, vol. 180, no. 3, pp. 860-866. https://doi.org/10.1016/j.juro.2008.05.015

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title = "von Hippel-Lindau Gene Status and Response to Vascular Endothelial Growth Factor Targeted Therapy for Metastatic Clear Cell Renal Cell Carcinoma",

abstract = "Purpose: 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. Materials and Methods: 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. Results: 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. Conclusions: 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 = "carcinoma, prognosis, renal cell, vascular endothelial growth factors, von Hippel-Lindau disease",

author = "Choueiri, {Toni K.} and Vaziri, {Susan A.J.} and Erich Jaeger and Paul Elson and Laura Wood and Bhalla, {Ish Prasad} and Small, {Eric J.} and Vivian Weinberg and Nancy Sein and Jeff Simko and Golshayan, {Ali Reza} and Linda Sercia and Ming Zhou and Waldman, {Frederic M.} and Rini, {Brian I.} and Bukowski, {Ronald M.} and Ram Ganapathi",

year = "2008",

month = sep,

doi = "10.1016/j.juro.2008.05.015",

language = "English (US)",

volume = "180",

pages = "860--866",

journal = "Journal of Urology",

issn = "0022-5347",

publisher = "Elsevier Inc.",

number = "3",

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TY - JOUR

T1 - von Hippel-Lindau Gene Status and Response to Vascular Endothelial Growth Factor Targeted Therapy for Metastatic Clear Cell Renal Cell Carcinoma

AU - Choueiri, Toni K.

AU - Vaziri, Susan A.J.

AU - Jaeger, Erich

AU - Elson, Paul

AU - Wood, Laura

AU - Bhalla, Ish Prasad

AU - Small, Eric J.

AU - Weinberg, Vivian

AU - Sein, Nancy

AU - Simko, Jeff

AU - Golshayan, Ali Reza

AU - Sercia, Linda

AU - Zhou, Ming

AU - Waldman, Frederic M.

AU - Rini, Brian I.

AU - Bukowski, Ronald M.

AU - Ganapathi, Ram

PY - 2008/9

Y1 - 2008/9

N2 - Purpose: 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. Materials and Methods: 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. Results: 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. Conclusions: 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.

AB - Purpose: 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. Materials and Methods: 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. Results: 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. Conclusions: 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.

KW - carcinoma

KW - prognosis

KW - renal cell

KW - vascular endothelial growth factors

KW - von Hippel-Lindau disease

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U2 - 10.1016/j.juro.2008.05.015

DO - 10.1016/j.juro.2008.05.015

M3 - Article

C2 - 18635227

AN - SCOPUS:48649098245

SN - 0022-5347

VL - 180

SP - 860

EP - 866

JO - Journal of Urology

JF - Journal of Urology

IS - 3

ER -

von Hippel-Lindau Gene Status and Response to Vascular Endothelial Growth Factor Targeted Therapy for Metastatic Clear Cell Renal Cell Carcinoma

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