von Hippel-Lindau gene status and response to vascular endothelial growth factor targeted therapy for metastatic clear cell renal cell carcinoma
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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DOI：
10.1016/j.juro.2008.05.015
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发表时间：
2008-09-01
影响因子：
6.6
通讯作者：
Ganapathi, Ram
中科院分区：
文献类型：
--
作者：
Choueiri, Toni K.;Vaziri, Susan A. J.;Ganapathi, Ram
目的：von Hippel-Lindau（VHL）基因在肾细胞癌中经常失活（突变或启动子高甲基化），但与治疗结局的关系尚不清楚。材料和方法：接受血管内皮生长因子靶向治疗的转移性透明细胞肾细胞癌患者的基线肿瘤样本包括在分析中。记录患者特征、VHL基因状态和临床结果。我们的主要终点是测试相关的反应率。VHL失活。无进展生存率和总生存率与VHL状态的关系作为次要终点进行了研究。缓解率、中位无进展生存期和中位总生存期分别为37%（95% CI 28-46）、10.8（95% CI 7.7-14.8）和29.8（CI不可估计）个月。VHL失活患者的缓解率为41%，野生型VHL患者的缓解率为31%（p = 0.34）。功能缺失突变（移码、无义、剪接和框内缺失/插入）患者的缓解率为52%，野生型VHL患者为31%（p = 0.04）。在多变量分析中，功能丧失突变的存在仍然是与改善反应相关的独立预后因素。无进展生存期和总生存期没有显着差异的基础上VHL status.Conclusions：据我们所知，这是最大的分析调查的影响VHL失活的血管内皮生长因子靶向药物在转移性肾细胞癌的结果。我们没有发现VHL失活患者对血管内皮生长因子靶向药物的反应有统计学意义的增加。功能缺失突变确定了具有更大应答的患者人群。正在对下游标记物进行调查。
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.