title: Prospective study assessing hypoxia-related proteins as markers for the outcome of treatment with sunitinib in advanced clear-cell renal cell carcinoma.
abstract: BACKGROUND
  Previous studies suggest that expression of hypoxia markers may be associated with response to antiangiogenic drugs. Thus, we aimed to identify predictors of sunitinib outcome in clear-cell renal cell carcinoma (ccRCC).
  
  
  METHODS
  The expression of eight key proteins related to hypoxia (CAIX, HIF1A, HIF2A, VEGFA, VEGFR1, VEGFR2, VEGFR3 and PDGFRB) and P-glycoprotein were assessed by immunohistochemistry in 67 primary ccRCC samples from prospectively recruited patients treated with first-line sunitinib. The proteins expression, VHL inactivation and EGLN3 mRNA content were compared with the patients' response to sunitinib.
  
  
  RESULTS
  High expression of HIF2A and PDGFRB was associated with better sunitinib RECIST objective response (P = 0.024 and P = 0.026; respectively) and increased VEGFR3 expression was associated with longer progression-free survival (P = 0.012). VEGFR3 overexpression showed a negative correlation with VEGFR3 polymorphism rs307826 (P = 0.002), a sunitinib resistance predictor. With respect to overall survival (OS), high VEGFA was associated with short (P = 0.009) and HIF2A with long (P = 0.048) survival times. High EGLN3 mRNA content was associated with shorter OS (P = 0.023).
  
  
  CONCLUSIONS
  We found an association between several proteins involved in hypoxia and sunitinib efficacy. In addition, low VEGFR3 expression was associated with worse outcome and with VEGFR3 rs307826 variant allele, reinforcing VEGFR3 as a marker of sunitinib resistance.
authors.affiliation: Genitourinary and Gynecological Tumors and Rare Cancer Programme, Centro Integral Oncológico Clara Campal, Madrid, Spain.
authors.forename: J
authors.initials: J
authors.lastname: Garcia-Donas
authors.forename: L J
authors.initials: LJ
authors.lastname: Leandro-García
authors.forename: A
authors.initials: A
authors.lastname: González Del Alba
authors.forename: M
authors.initials: M
authors.lastname: Morente
authors.forename: I
authors.initials: I
authors.lastname: Alemany
authors.forename: E
authors.initials: E
authors.lastname: Esteban
authors.forename: J A
authors.initials: JA
authors.lastname: Arranz
authors.forename: M A
authors.initials: MA
authors.lastname: Climent
authors.forename: E
authors.initials: E
authors.lastname: Gallardo
authors.forename: D E
authors.initials: DE
authors.lastname: Castellano
authors.forename: J
authors.initials: J
authors.lastname: Bellmunt
authors.forename: B
authors.initials: B
authors.lastname: Mellado
authors.forename: J
authors.initials: J
authors.lastname: Puente
authors.forename: F
authors.initials: F
authors.lastname: Moreno
authors.forename: A
authors.initials: A
authors.lastname: Font
authors.forename: S
authors.initials: S
authors.lastname: Hernando
authors.forename: M
authors.initials: M
authors.lastname: Robledo
authors.forename: C
authors.initials: C
authors.lastname: Rodríguez-Antona
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D020533:Angiogenesis Inhibitors / Q000009:adverse effects / Q000627:therapeutic use; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000627:therapeutic use; D051792:Basic Helix-Loop-Helix Proteins / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism; D014408:Biomarkers, Tumor / Q000378:metabolism; D002292:Carcinoma, Renal Cell / Q000188:drug therapy* / Q000235:genetics / Q000401:mortality; D015687:Cell Hypoxia / Q000187:drug effects; D018572:Disease-Free Survival; D019008:Drug Resistance, Neoplasm; D005260:Female; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D064799:Hypoxia-Inducible Factor-Proline Dioxygenases / Q000235:genetics*; D007150:Immunohistochemistry; D007211:Indoles / Q000009:adverse effects / Q000627:therapeutic use*; D007680:Kidney Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000401:mortality; D008297:Male; D008875:Middle Aged; D009362:Neoplasm Metastasis; D011446:Prospective Studies; D011758:Pyrroles / Q000009:adverse effects / Q000627:therapeutic use*; D012333:RNA, Messenger / Q000096:biosynthesis; D000077210:Sunitinib; D013534:Survival; D016896:Treatment Outcome; D040321:Vascular Endothelial Growth Factor Receptor-3 / Q000096:biosynthesis / Q000235:genetics* / Q000378:metabolism; D000099162:Endothelial PAS Domain-Containing Protein 1
chemical_list: D020533:Angiogenesis Inhibitors; D000970:Antineoplastic Agents; D051792:Basic Helix-Loop-Helix Proteins; D014408:Biomarkers, Tumor; D064799:Hypoxia-Inducible Factor-Proline Dioxygenases; D007211:Indoles; D011758:Pyrroles; D012333:RNA, Messenger; D000077210:Sunitinib; D040321:Vascular Endothelial Growth Factor Receptor-3; D000099162:Endothelial PAS Domain-Containing Protein 1; C488894:EGLN3 protein, human; C581309:FLT4 protein, human
keywords: EGLN3; hypoxia; immunohistochemistry; predictive marker; renal carcinoma; sunitinib