Plasma Tie2 is a tumor vascular response biomarker for VEGF inhibitors in metastatic colorectal cancer

Nat Commun. 2018 Nov 7;9(1):4672. doi: 10.1038/s41467-018-07174-1.


Oncological use of anti-angiogenic VEGF inhibitors has been limited by the lack of informative biomarkers. Previously we reported circulating Tie2 as a vascular response biomarker for bevacizumab-treated ovarian cancer patients. Using advanced MRI and circulating biomarkers we have extended these findings in metastatic colorectal cancer (n = 70). Bevacizumab (10 mg/kg) was administered to elicit a biomarker response, followed by FOLFOX6-bevacizumab until disease progression. Bevacizumab induced a correlation between Tie2 and the tumor vascular imaging biomarker, Ktrans (R:-0.21 to 0.47) implying that Tie2 originated from the tumor vasculature. Tie2 trajectories were independently associated with pre-treatment tumor vascular characteristics, tumor response, progression free survival (HR for progression = 3.01, p = 0.00014; median PFS 248 vs. 348 days p = 0.0008) and the modeling of progressive disease (p < 0.0001), suggesting that Tie2 should be monitored clinically to optimize VEGF inhibitor use. A vascular response is defined as a 30% reduction in Tie2; vascular progression as a 40% increase in Tie2 above the nadir. Tie2 is the first, validated, tumor vascular response biomarker for VEGFi.

Publication types

  • Clinical Trial
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Angiogenesis Inhibitors / therapeutic use*
  • Angiopoietin-2 / metabolism
  • Bevacizumab / pharmacology
  • Bevacizumab / therapeutic use
  • Biomarkers, Tumor / blood*
  • Colorectal Neoplasms / blood supply
  • Colorectal Neoplasms / blood*
  • Colorectal Neoplasms / drug therapy
  • Colorectal Neoplasms / secondary*
  • Disease Progression
  • Disease-Free Survival
  • Female
  • Humans
  • Kaplan-Meier Estimate
  • Male
  • Middle Aged
  • Models, Biological
  • Neovascularization, Pathologic / blood
  • Prognosis
  • Receptor, TIE-2 / blood*
  • Vascular Endothelial Growth Factor A / antagonists & inhibitors*
  • Vascular Endothelial Growth Factor A / metabolism


  • Angiogenesis Inhibitors
  • Angiopoietin-2
  • Biomarkers, Tumor
  • Vascular Endothelial Growth Factor A
  • Bevacizumab
  • Receptor, TIE-2
  • TEK protein, human