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Proffered Abstract (Plenary Session): Successes in Developing Tumor Determinants for Targeted Therapies: Lessons Learned

Biomarkers of response to VEGF pathway-targeted therapy for renal cell carcinoma.

University of California, San Francisco, San Francisco, CA and Cleveland Clinic, Cleveland, OH

Abstract

PR-2

Background: Therapies that target the vascular endothelial growth factor (VEGF) pathway are effective in a significant fraction of patients with metastatic clear cell renal cell carcinoma (cRCC). The identification of molecular markers that predict response to these therapies will greatly help physicians with treatment decisions.Methods: Primary tumor blocks were obtained from 52 patients prior to treatment for metastatic cRCC. Patients were treated with SU11248, AG013736 [GenBank] , or IFNA and bevacizumab at the UCSF Comprehensive Cancer Center. DNA and RNA were extracted from formalin-fixed, paraffin-embedded (FFPE) samples. DNA was sequenced for mutations in the VHL coding sequence. RNA was analyzed by quantitative PCR (QPCR) for differences in the relative expression levels of 26 candidate genes. SYBR Green and Taqman QPCR assays were validated initially using an independent tumor set with matched pairs of FFPE and frozen samples for each tumor. Protein expression levels for a subset of the candidate genes were also determined by immunohistochemical analysis (IHC) of FFPE sections.Results: Twenty-five of 43 evaluable tumors (58%) had a VHL mutation, including 15 with frameshift and 10 with non-frameshift mutations. The median time to disease progression (TTP) for patients with mutations resulting in frameshifts was 13.7 months, compared to 7.4 months in patients with non-frameshift mutations and 5.5 months in patients with no VHL mutation (p=0.06). The proportion of patients that progressed in each mutation class also reflects this difference in median TTP: 17 of 18 patients without mutation, 10 of 10 patients with non-frameshift mutations, and 10 of 15 patients with frameshift mutations have had disease progression.We compared QPCR for matched pairs of FFPE and frozen tumors using either SYBR Green or Taqman approaches. SYBR Green performed better than Taqman, with significantly higher Spearman rank correlations for frozen vs. FFPE. Expression of candidate genes was compared to protein expression by IHC, and tested for association with response to therapy. CAIX expression showed the strongest correlation between gene expression and IHC, while HIF2 and VEGFR-2 were moderately correlated.Conclusions: Response to VEGF pathway-targeted therapy in metastatic cRCC appears to be associated with VHL mutations that extensively alter the amino acid sequence of the VHL protein. Differences in the expression of angiogenesis-related genes and proteins may also be associated with response to these therapies. Such analyses of VHL pathway components help to understand the biology and clinical response to VEGF pathway-targeted agents.