title: Predictive biomarkers in renal cell cancer: insights in drug resistance mechanisms.
abstract: BACKGROUND
  VEGF-targeted therapy is currently the first line treatment for patients with metastatic clear cell renal cell carcinoma (ccRCC), but most patients either display primary (intrinsic) resistance or acquire drug resistance. In recent years multiple mechanisms of resistance to VEGF-targeted therapy emerged from preclinical research, but it is currently unknown to what extent these drug resistance modalities play a role in the clinic. Here we reviewed the current literature on biomarkers that predict treatment outcome in patients with ccRCC to gain insight in clinical drug resistance mechanisms.
  
  
  METHODS
  A search syntax was compiled by combining different synonyms of "biomarker" AND "renal" AND "cancer". MEDLINE was accessed through PubMed, where this syntax was entered and used to search titles and abstracts of publications. Articles were selected based on three criteria: (1) description of patients with clear cell RCC, (2) treatment with VEGF targeted therapy and (3) discussion of biomarkers that were studied for potential association with treatment response.
  
  
  RESULTS
  The literature search was performed on March 4th 2014 and yielded 1882 articles. After carefully reading the titles and abstracts based on the three previously mentioned criteria, 103 publications were evaluated. Backward citation screening was performed on all eligible studies and revealed another 24 articles. This search revealed that (1) High glucose uptake and low contrast enhancement on PET- and CT-imaging before start of treatment may correlate with poor response to therapy, (2) Low dose intensity due to treatment intolerance is related to shorter progression free survival. (3) Acquired resistance appears to be associated with rebound vascularization based on both longitudinal monitoring of contrast enhancement by CT and blood vessel counts in tumor tissue, and (4) Based on plasma cytokine and single nucleotide polymorphism (SNP) studies, interleukin-8, VEGFR-3, FGFR2 and HGF/MET emerged as potential clinical markers for chemoresistance.
  
  
  CONCLUSIONS
  Low dose intensity, specific tumor-imaging techniques and potential biological biomarkers may be predictive for response to VEGF-targeted therapy in ccRCC. Some of these plausible biomarkers may also provide more insight into the underlying mechanisms of resistance such as altered glucose metabolism and rapid rebound vascularization.
authors.affiliation: Department of Medical Oncology, VU University Medical Center, Amsterdam, The Netherlands; Department of Hematology/Oncology, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA, USA.
authors.forename: Johannes C
authors.initials: JC
authors.lastname: van der Mijn
authors.affiliation: Department of Hematology/Oncology, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA, USA.
authors.forename: James W
authors.initials: JW
authors.lastname: Mier
authors.affiliation: Department of Medical Oncology, VU University Medical Center, Amsterdam, The Netherlands.
authors.forename: Henk J
authors.initials: HJ
authors.lastname: Broxterman
authors.affiliation: Department of Medical Oncology, VU University Medical Center, Amsterdam, The Netherlands. Electronic address: h.verheul@vumc.nl.
authors.forename: Henk M
authors.initials: HM
authors.lastname: Verheul
mesh_terms: D020533:Angiogenesis Inhibitors / Q000494:pharmacology*; D014408:Biomarkers, Tumor / Q000378:metabolism*; D002292:Carcinoma, Renal Cell / Q000098:blood supply / Q000188:drug therapy* / Q000378:metabolism* / Q000473:pathology; D018572:Disease-Free Survival; D019008:Drug Resistance, Neoplasm; D006801:Humans; D007680:Kidney Neoplasms / Q000098:blood supply / Q000188:drug therapy* / Q000378:metabolism* / Q000473:pathology; D058990:Molecular Targeted Therapy; D009389:Neovascularization, Pathologic / Q000378:metabolism / Q000473:pathology; D016896:Treatment Outcome; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
chemical_list: D020533:Angiogenesis Inhibitors; D014408:Biomarkers, Tumor; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A
keywords: Predictive biomarker; Renal cell carcinoma; VEGF targeted therapy