1283

VHL mutation and response to VEGF pathway-targeted therapy. Purpose: To describe the relationship between the mutation status of the von Hippel-Lindau gene (VHL) and clinical outcome in metastatic conventional (clear cell) renal cell carcinoma (cRCC) patients receiving vascular endothelial growth factor (VEGF) pathway-targeted therapy. Experimental Design: All patients with metastatic cRCC who received therapy with either SU11248, AG013736, or IFNA and bevacizumab at The UCSF Comprehensive Cancer Center were considered for evaluation. DNA from pre-treatment formalin-fixed, paraffin-embedded (FFPE) tumor samples was sequenced and analyzed for mutations in VHL. Outcome following VEGF pathway-targeted therapy was recorded. Results: Fifty-three total patients were considered for evaluation, of whom 43 had evaluable tumors. Twenty-five tumors (58%) had a VHL mutation. Insertions, deletions, missense, nonsense, and splice site mutations were all observed, and ranged from minor (1-2 amino acids affected) to severe (up to 75% of amino acids altered). Although the number of samples with either minor or extensive amino acid changes was too small to permit robust statistical analysis (n=10 and n=15, respectively), the median time to disease progression (TTP) for patients with more severe mutations was 17.5 months, compared to 7.4 months in patients with only minor VHL sequence alterations (p=0.16). The median TTP in patients with no VHL mutation was 5.4 months. The proportion of patients that progressed in each mutation class also reflects this difference in TTP: 15 of 18 patients without mutation, 8 of 10 patients with less severe mutations, and 7 of 15 patients with more severe mutations have had disease progression. The remaining 13 patients continue on study. Conclusions: Response to VEGF pathway-targeted therapy in metastatic cRCC may be associated with certain types of VHL mutations. Further analyses of VHL pathway components, including VHL promoter methylation analysis and IHC analysis of protein expression, are underway, and should help to understand the biology of response to VEGF pathway-targeted agents in metastatic cRCC.

[Proc Amer Assoc Cancer Res, Volume 47, 2006]