Systematic analysis of circulating soluble angiogenesis-associated proteins in ICON7 identifies Tie2 as a biomarker of vascular progression on bevacizumab

Abstract

Background: There is a critical need for predictive/resistance biomarkers for VEGF inhibitors to optimise their use.

Methods: Blood samples were collected during and following treatment and, where appropriate, upon progression from ovarian cancer patients in ICON7, a randomised phase III trial of carboplatin and paclitaxel with or without bevacizumab. Plasma concentrations of 15 circulating angio-biomarkers were measured using a validated multiplex ELISA, analysed through a novel network analysis and their relevance to the PFS then determined.

Results: Samples (n=650) were analysed from 92 patients. Bevacizumab induced correlative relationships between Ang1 and Tie2 plasma concentrations, which reduced after initiation of treatment and remained decreased until progressive disease occurred. A 50% increase from the nadir in the concentration of circulating Tie2 (or the product of circulating Ang1 and Tie2) predicted tumour progression. Combining Tie2 with GCIG-defined Ca125 data yielded a significant improvement in the prediction of progressive disease in patients receiving bevacizumab in comparison with Ca125 alone (74.1% vs 47.3%, P<1 × 10(-9)).

Conclusions: Tie2 is a vascular progression marker for bevacizumab-treated ovarian cancer patients. Tie2 in combination with Ca125 provides superior information to clinicians on progressive disease in patients with VEGFi-treated ovarian cancers.

Figures

Figure 1

Analysis of correlation networks.(A) Pearson's correlation network for all patients pre-treatment. (B) Partial correlation network for all patients pre-treatment. (C) Pearson's correlation network for patients on the standard arm, during treatment. (D) Partial correlation network for patients on the standard arm, during treatment. (E) Pearson's correlation network for patients on the experimental arm, during treatment. (F) Partial correlation network for patients on the experimental arm, during treatment. Pearson's correlation networks were plotted on the left panel (A, C, E) and partial correlation networks were plotted on the right (B, D, F). Each row of plots, from top to bottom, demonstrated the correlation networks for patients at baseline, on standard arm during treatment and on experimental arm during treatment, respectively. Each node in the networks represents one angio-biomarker. The thickness of the edge between two nodes represents the strength of correlation. Positive correlations are red solid lines and negative correlations, green dashed lines. Correlations with absolute values smaller than 0.3 were not displayed. The thickest line represents a maximum correlation of 0.74 while the median correlation shown in the networks is 0.55. Angio-biomarkers are highlighted if they demonstrate significant changes in correlation.

Figure 2

Mean trajectory of Ang1, Tie2 and Ca125.The dynamics of Ang1, Tie2 and Ca125, measured as mean percentage change over baseline (log ratio), were plotted against percentage of PFS. The red solid line refers to the experimental arm, and the blue dashed line refers to the standard arm. The data points are presented as ±s.e. Mann–Whitney U tests were used to compare the two arms at each 10% time interval and the minimum P-value was listed. P-values smaller than 0.0003 can be considered as indicating significant difference between the two arms, in accordance with Bonferroni correction for multiple comparison. As Ca125 (2c) was not subject to multiple comparisons, it achieved statistical significance with P=0.01. The first time point represents the mean of the two pre-treatment samples.

Figure 3

Tie2 in combination with Ca125 provides better prediction on tumour progression.The performance of Tie2, Ang1 × Tie2 and Ca125 as biomarkers for predicting tumour progression is shown. 1–biomarker prediction rate is plotted against percentage of PFS time when a prediction is made. Data points close to the top left corner indicate superior performance. The red solid line represents the performance of using Ca125 and the GCIG criteria are shown as a red circle. The green dashed line and the blue dotted line represent the performance of Tie2 and Ang1 × Tie2 as resistance biomarkers, respectively. The highlighted dots on these lines correspond to using 50% elevation from nadir points as criteria for prediction. It demonstrated that if Tie2 was used in conjunction with Ca125, a better prediction can be made compared with using either one alone, as indicated by the black diamond. The combination of Tie2 and Ca125 predicted tumour progression in 74.1% of patients at an average of 62.8%±14.1 %PFS time.