title: 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: OBJECTIVE
  Inactivation of von Hippel-Lindau (VHL) 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.
  
  
  METHODS
  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: VHL 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.
  
  
  RESULTS
  The VEG102616 trial enrolled 225 patients, from whom 78 samples were available for tumor DNA extraction. Of these, 70 patients had VHL mutation or methylation. VHL 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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Authors' Affiliations: Dana-Farber Cancer Institute; Brigham and Women's Hospital; Harvard Medical School, Boston, Massachusetts; GlaxoSmithKline, Collegeville, Pennsylvania; Memorial Sloan-Kettering Cancer Center, New York, New York; and Texas Oncology-Baylor Charles A. Sammons Cancer Center, Dallas, Texas.
authors.forename: Toni K
authors.initials: TK
authors.lastname: Choueiri
authors.forename: André P
authors.initials: AP
authors.lastname: Fay
authors.forename: Robert
authors.initials: R
authors.lastname: Gagnon
authors.forename: Ying
authors.initials: Y
authors.lastname: Lin
authors.forename: Brittany
authors.initials: B
authors.lastname: Bahamon
authors.forename: Victoria
authors.initials: V
authors.lastname: Brown
authors.forename: Jonathan E
authors.initials: JE
authors.lastname: Rosenberg
authors.forename: Thomas E
authors.initials: TE
authors.lastname: Hutson
authors.forename: Katherine L
authors.initials: KL
authors.lastname: Baker-Neblett
authors.forename: Christopher
authors.initials: C
authors.lastname: Carpenter
authors.forename: Yuan
authors.initials: Y
authors.lastname: Liu
authors.forename: Lini
authors.initials: L
authors.lastname: Pandite
authors.forename: Sabina
authors.initials: S
authors.lastname: Signoretti
mesh_terms: D020533:Angiogenesis Inhibitors / Q000627:therapeutic use; D051792:Basic Helix-Loop-Helix Proteins / Q000378:metabolism*; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism; D002292:Carcinoma, Renal Cell / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000401:mortality; D004273:DNA, Neoplasm / Q000235:genetics; D005500:Follow-Up Studies; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism*; D007124:Immunoenzyme Techniques; D007191:Indazoles; D007680:Kidney Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000401:mortality; D009154:Mutation / Q000235:genetics*; D009367:Neoplasm Staging; D016133:Polymerase Chain Reaction; D011379:Prognosis; D011743:Pyrimidines / Q000627:therapeutic use*; D015398:Signal Transduction; D013449:Sulfonamides / Q000627:therapeutic use*; D015996:Survival Rate; D051794:Von Hippel-Lindau Tumor Suppressor Protein / Q000235:genetics*; D000099162:Endothelial PAS Domain-Containing Protein 1
chemical_list: D020533:Angiogenesis Inhibitors; D051792:Basic Helix-Loop-Helix Proteins; D014408:Biomarkers, Tumor; D004273:DNA, Neoplasm; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D007191:Indazoles; D011743:Pyrimidines; D013449:Sulfonamides; D051794:Von Hippel-Lindau Tumor Suppressor Protein; D000099162:Endothelial PAS Domain-Containing Protein 1; C497442:HIF1A protein, human; C516667:pazopanib; C497446:VHL protein, human