Prospective study assessing hypoxia-related proteins as markers for the outcome of treatment with sunitinib in advanced clear-cell renal cell carcinoma

Ann Oncol. 2013 Sep;24(9):2409-14. doi: 10.1093/annonc/mdt219. Epub 2013 Jun 20.


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).

Patients and 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.

Keywords: EGLN3; hypoxia; immunohistochemistry; predictive marker; renal carcinoma; sunitinib.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Aged, 80 and over
  • Angiogenesis Inhibitors / adverse effects
  • Angiogenesis Inhibitors / therapeutic use
  • Antineoplastic Agents / adverse effects
  • Antineoplastic Agents / therapeutic use
  • Basic Helix-Loop-Helix Transcription Factors / biosynthesis
  • Basic Helix-Loop-Helix Transcription Factors / genetics
  • Basic Helix-Loop-Helix Transcription Factors / metabolism
  • Biomarkers, Tumor / metabolism
  • Carcinoma, Renal Cell / drug therapy*
  • Carcinoma, Renal Cell / genetics
  • Carcinoma, Renal Cell / mortality
  • Cell Hypoxia / drug effects
  • Disease-Free Survival
  • Drug Resistance, Neoplasm
  • Female
  • Gene Expression / drug effects
  • Humans
  • Hypoxia-Inducible Factor-Proline Dioxygenases / genetics*
  • Immunohistochemistry
  • Indoles / adverse effects
  • Indoles / therapeutic use*
  • Kidney Neoplasms / drug therapy*
  • Kidney Neoplasms / genetics
  • Kidney Neoplasms / mortality
  • Male
  • Middle Aged
  • Neoplasm Metastasis
  • Prospective Studies
  • Pyrroles / adverse effects
  • Pyrroles / therapeutic use*
  • RNA, Messenger / biosynthesis
  • Sunitinib
  • Survival
  • Treatment Outcome
  • Vascular Endothelial Growth Factor Receptor-3 / biosynthesis
  • Vascular Endothelial Growth Factor Receptor-3 / genetics*
  • Vascular Endothelial Growth Factor Receptor-3 / metabolism


  • Angiogenesis Inhibitors
  • Antineoplastic Agents
  • Basic Helix-Loop-Helix Transcription Factors
  • Biomarkers, Tumor
  • Indoles
  • Pyrroles
  • RNA, Messenger
  • endothelial PAS domain-containing protein 1
  • EGLN3 protein, human
  • Hypoxia-Inducible Factor-Proline Dioxygenases
  • FLT4 protein, human
  • Vascular Endothelial Growth Factor Receptor-3
  • Sunitinib