The combination of circulating Ang1 and Tie2 levels predicts progression-free survival advantage in bevacizumab-treated patients with ovarian cancer.

Abstract

PURPOSE:

Randomized ovarian cancer trials, including ICON7, have reported improved progression-free survival (PFS) when bevacizumab was added to conventional cytotoxic therapy. The improvement was modest prompting the search for predictive biomarkers for bevacizumab.

EXPERIMENTAL DESIGN:

Pretreatment training (n=91) and validation (n=114) blood samples were provided by ICON7 patients. Plasma concentrations of 15 angio-associated factors were determined using validated multiplex ELISAs. Our statistical approach adopted PFS as the primary outcome measure and involved (i) searching for biomarkers with prognostic relevance or which related to between-individual variation in bevacizumab effect; (ii) unbiased determination of cutoffs for putative biomarker values; (iii) investigation of biologically meaningfully predictive combinations of putative biomarkers; and (iv) replicating the analysis on candidate biomarkers in the validation dataset.

RESULTS:

The combined values of circulating Ang1 (angiopoietin 1) and Tie2 (Tunica internal endothelial cell kinase 2) concentrations predicted improved PFS in bevacizumab-treated patients in the training set. Using median concentrations as cutoffs, high Ang1/low Tie2 values were associated with significantly improved PFS for bevacizumab-treated patients in both datasets (median, 23.0 months vs. 16.2; P=0.003) for the interaction of Ang1-Tie2 treatment in Cox regression analysis. The prognostic indices derived from the training set also distinguished high and low probability for progression in the validation set (P=0.008), generating similar values for HR (0.21 vs. 0.27) between treatment and control arms for patients with high Ang1 and low Tie2 values.

CONCLUSIONS:

The combined values of Ang1 and Tie2 are predictive biomarkers for improved PFS in bevacizumab-treated patients with ovarian cancer. These findings need to be validated in larger trials due to the limitation of sample size in this study.

• Authors: Alison Backen, Andrew G Renehan, Andrew R Clamp, Carlo Berzuini, Cong Zhou, Amit Oza, Selina Bannoo, Stefan J Scherer, Rosamonde E Banks, Caroline Dive, Gordon C Jayson
• Journal: Clinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 20 Issue 17 Pg. 4549-4558 (Sep 01 2014) ISSN: 1557-3265 [Electronic] United States
• PMID: 24947924 (Publication Type: Journal Article, Randomized Controlled Trial, Research Support, Non-U.S. Gov't)
• Copyright: ©2014 American Association for Cancer Research.

Chemical References

• ANGPT1 protein, human
• Angiopoietin-1
• Antibodies, Monoclonal, Humanized
• Biomarkers, Tumor
• VEGFA protein, human
• Vascular Endothelial Growth Factor A
• Bevacizumab
• Receptor, TIE-2

Topics

• Adult
• Aged
• Angiopoietin-1 (genetics)
• Antibodies, Monoclonal, Humanized (administration & dosage, genetics)
• Bevacizumab
• Biomarkers, Tumor
• Disease-Free Survival
• Female
• Humans
• Middle Aged
• Neoplastic Cells, Circulating
• Neovascularization, Pathologic (drug therapy, genetics)
• Ovarian Neoplasms (drug therapy, genetics, pathology)
• Prognosis
• Receptor, TIE-2 (genetics)
• Vascular Endothelial Growth Factor A (antagonists & inhibitors, genetics)