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

Yingmiao Liu, Mark D Starr, Anuradha Bulusu, Herbert Pang, Nan Soon Wong, Wanda Honeycutt, Anthony Amara, Herbert I Hurwitz, Andrew B Nixon, Yingmiao Liu, Mark D Starr, Anuradha Bulusu, Herbert Pang, Nan Soon Wong, Wanda Honeycutt, Anthony Amara, Herbert I Hurwitz, Andrew B Nixon

Abstract

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: ClinicalTrials.gov NCT00416494.

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

Figures

Figure 1
Figure 1
Change from baseline to the end of cycle 2 for biomarkers with statistical significance (P ≤ 0.0001). *Censored patients. Golden lines represent patients whose progression-free survival (PFS) ≥ median; black lines represent patients whose PFS < median.
Figure 2
Figure 2
Kaplan–Meier analysis of overall survival of patients stratified according to baseline biomarkers levels. The signature for the high-risk group is baseline level of IL-6 median.
Figure 3
Figure 3
Kaplan–Meier analysis of progression-free survival of patients stratified according to on-treatment biomarker changes. The L-ratio signature for the high-risk group is IL-6, OPN, TGF-β1, E-Cadherin, MCP-1 median.

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