title: A systematic review of predictive and prognostic biomarkers for VEGF-targeted therapy in renal cell carcinoma.
abstract: BACKGROUND
  Vascular endothelial growth factor (VEGF)-targeted therapy is the currently standard treatment for advanced and metastatic renal cell carcinoma (RCC). Multiple candidate predictive and prognostic biomarkers have been evaluated. We performed a systematic review and graded the available evidence on the biomarkers for VEGF-targeted therapy in RCC.
  
  
  METHODS
  We conducted an independent review of PubMed and ASCO databases up to August 2013. Studies were included if biomarkers obtained from metastatic clear-cell RCC patients treated with the FDA-approved VEGF-targeted therapy were assessed for their correlation with clinical outcomes. We graded the studies and determined the Level-of-evidence for each biomarker using a previously published framework.
  
  
  RESULTS
  A total of 50 articles were selected for this review. Seven studies assessed the predictive value of biomarkers using the archived specimens from randomized controlled trials. Five predictive biomarkers, such as VEGF, interleukin (IL)-6, hepatocyte growth factor (HGF), osteopontin, single nucleotide polymorphisms in IL-8, satisfied Level II evidence. IL-6 is the most corroborated predictive biomarker based on its consistent predictive value in two different trials. The prognostic value of biomarkers was assessed in 48 studies using the archived specimens from clinical trials, prospective and retrospective observational registries. Three biomarkers, including IL-8, HGF and osteopontin, satisfied Level I evidence for PFS.
  
  
  CONCLUSIONS
  Though several promising predictive biomarkers for VEGF-targeted therapy have been found, none of them has satisfied the determination of Level I evidence. A more focused development of biomarkers with prospective assessment in clinical trials and clear intent of use in clinical practice is needed.
authors.affiliation: Department of Medicine, Beth Israel Medical Center, University Hospital and Manhattan Campus for the Albert Einstein College of Medicine, New York, NY, USA. Electronic address: tfunakoshi@chpnet.org.
authors.forename: Tomohiro
authors.initials: T
authors.lastname: Funakoshi
authors.affiliation: Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, NY, USA. Electronic address: leec4@mskcc.org.
authors.forename: Chung-Han
authors.initials: CH
authors.lastname: Lee
authors.affiliation: Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, NY, USA; Human Oncology and Pathogenesis Program, Memorial Sloan-Kettering Cancer Center, New York, NY, USA; Department of Medicine, Weill Medical College of Cornell University, New York, NY, USA. Electronic address: hsiehj@mskcc.org.
authors.forename: James J
authors.initials: JJ
authors.lastname: Hsieh
mesh_terms: D014408:Biomarkers, Tumor / Q000378:metabolism*; D002292:Carcinoma, Renal Cell / Q000188:drug therapy* / Q000378:metabolism*; D006801:Humans; D007680:Kidney Neoplasms / Q000188:drug therapy* / Q000378:metabolism*; D058990:Molecular Targeted Therapy / Q000379:methods; D015398:Signal Transduction / Q000187:drug effects; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors* / Q000378:metabolism*
chemical_list: D014408:Biomarkers, Tumor; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A
keywords: Biomarkers; Metastatic renal cell carcinoma; Systematic review; Vascular endothelial growth factor-targeted therapy