Data from The Role of Aberrant VHL/HIF Pathway Elements in Predicting Clinical Outcome to Pazopanib Therapy in Patients with Metastatic Clear-Cell Renal Cell Carcinoma

Abstract

<div>Abstract<p><b>Purpose:</b> Inactivation of von Hippel-Lindau (<i>VHL</i>) gene in clear-cell renal cell carcinoma (RCC) leads to increased levels of hypoxia-inducible factors (HIF) and overexpression of HIF target genes, such as VEGF and others. VEGF-targeted agents are standard in advanced clear-cell RCC but biomarkers of activity are lacking.</p><p><b>Experimental Design:</b> We analyzed tumor tissue samples from metastatic clear-cell RCC patients who received pazopanib as part of clinical trial VEG102616. We evaluated several components of the VHL/HIF pathway: <i>VHL</i> gene inactivation (mutation and/or methylation), HIF-1α and HIF-2α immunohistochemistry staining, and HIF-1α transcriptional signature. We evaluated the association of these biomarkers with best overall response rate (ORR) and progression-free survival (PFS) to pazopanib, a standard first-line VEGF-targeted agent.</p><p><b>Results:</b> The VEG102616 trial enrolled 225 patients, from whom 78 samples were available for tumor DNA extraction. Of these, 70 patients had <i>VHL</i> mutation or methylation. <i>VHL</i> gene status did not correlate with ORR or PFS. Similarly, HIF-1α (65 samples) and HIF-2α (66 samples) protein levels (high vs. low) did not correlate with ORR or PFS to pazopanib. The HIF-1α transcriptional signature (46 samples) was enriched in tumors expressing high HIF-1α levels. However, the HIF-1α gene expression signature was not associated with clinical outcome to pazopanib.</p><p><b>Conclusions:</b> In patients with advanced clear-cell RCC, several potential biomarkers along the VHL/HIF-1α/HIF-2α axis were not found to be predictive for pazopanib activity. Additional efforts must continue to identify biomarkers associated with clinical outcome to VEGF-targeted agents in metastatic RCC. <i>Clin Cancer Res; 19(18); 5218–26. ©2013 AACR</i>.</p></div>