Correlation of angiogenic biomarker signatures with clinical outcomes in metastatic colorectal cancer patients receiving capecitabine, oxaliplatin, and bevacizumab

Cancer Med. 2013 Apr;2(2):234-42. doi: 10.1002/cam4.71. Epub 2013 Mar 6.


A novel combination of capecitabine, oxaliplatin, and bevacizumab was evaluated in colorectal cancer patients enrolled in a phase II clinical trial. In this retrospective analysis, plasma samples from patients receiving capecitabine, oxaliplatin, and bevacizumab were analyzed to investigate biomarkers of clinical benefit. Forty-one protein biomarkers were tested in 38 patients at baseline and after two cycles of drug administration. Correlations among analytes were evaluated by Spearman analysis. Analyte levels at baseline and changes on-treatment were correlated with progression-free survival (PFS) and overall survival (OS) by univariate analysis. Multivariate analyses were determined using the Cox proportional hazard model. Time to event analyses were evaluated by Kaplan-Meier analysis and compared by log-rank test. Baseline levels of vWF and Ang-2 significantly correlated with PFS, while levels of VCAM-1, vWF, TSP-2, IL-8, MMP-2, and Ang-2 correlated with OS (P < 0.05). The fold change of IGF-1 levels from baseline to the end of cycle 2 was correlated with PFS, while fold changes of Ang-2, TSP-2, and TGF-β2 correlated with OS. A baseline signature of Ang-2, IGFBP-3, IL-6, and VCAM-1 identified a low-risk and high-risk group of patients (OS: 33.9 months vs. 18.1 months, respectively, P = 0.016). For treatment-related changes, a signature consisting of Ang-2, E-Cadherin, IL-6, MCP-1, OPN, and TGF-β1 was able to stratify patients into high- and low-risk groups (PFS: 7.7 months vs. 15.5 months, P = 0.004). Multiplex analysis of patient plasma in this trial identified several baseline- and treatment-related biomarkers associated with clinical outcome. These findings merit further exploration in larger, controlled clinical trials.

Trial registration: NCT00416494.

Keywords: Angiome; bevacizumab; biomarker; chemotherapy; colorectal cancer.

Publication types

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

MeSH terms

  • Adult
  • Aged
  • Aged, 80 and over
  • Angiogenesis Inhibitors / adverse effects
  • Angiogenesis Inhibitors / therapeutic use
  • Antibodies, Monoclonal, Humanized / adverse effects
  • Antibodies, Monoclonal, Humanized / therapeutic use
  • Antimetabolites, Antineoplastic / adverse effects
  • Antimetabolites, Antineoplastic / therapeutic use
  • Antineoplastic Agents / adverse effects
  • Antineoplastic Agents / therapeutic use
  • Antineoplastic Combined Chemotherapy Protocols / adverse effects
  • Antineoplastic Combined Chemotherapy Protocols / therapeutic use*
  • Bevacizumab
  • Biomarkers, Tumor / blood*
  • Capecitabine
  • Colorectal Neoplasms / drug therapy*
  • Colorectal Neoplasms / genetics
  • Colorectal Neoplasms / metabolism*
  • Deoxycytidine / adverse effects
  • Deoxycytidine / analogs & derivatives
  • Deoxycytidine / therapeutic use
  • Disease-Free Survival
  • Female
  • Fluorouracil / adverse effects
  • Fluorouracil / analogs & derivatives
  • Fluorouracil / therapeutic use
  • Humans
  • Male
  • Middle Aged
  • Neovascularization, Pathologic
  • Organoplatinum Compounds / adverse effects
  • Organoplatinum Compounds / therapeutic use
  • Oxaliplatin
  • Retrospective Studies
  • Treatment Outcome
  • Young Adult


  • Angiogenesis Inhibitors
  • Antibodies, Monoclonal, Humanized
  • Antimetabolites, Antineoplastic
  • Antineoplastic Agents
  • Biomarkers, Tumor
  • Organoplatinum Compounds
  • Oxaliplatin
  • Deoxycytidine
  • Bevacizumab
  • Capecitabine
  • Fluorouracil

Associated data