title: 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.
authors.affiliation: Institute of Cancer Sciences, University of Manchester, Manchester, UK.
authors.forename: Cong
authors.initials: C
authors.lastname: Zhou
authors.affiliation: Institute of Cancer Sciences, University of Manchester, Manchester, UK.|Department of Medical Oncology, The Christie NHS Foundation Trust, Manchester, UK.
authors.forename: Andrew
authors.initials: A
authors.lastname: Clamp
authors.affiliation: Institute of Cancer Sciences, University of Manchester, Manchester, UK.|Clinical and Experimental Pharmacology Group, CRUK Manchester Institute, University of Manchester, Manchester, UK.
authors.forename: Alison
authors.initials: A
authors.lastname: Backen
authors.affiliation: Centre for Biostatistics, University of Manchester, Manchester, UK.
authors.forename: Carlo
authors.initials: C
authors.lastname: Berzuini
authors.affiliation: Institute of Cancer Sciences, University of Manchester, Manchester, UK.
authors.forename: Andrew
authors.initials: A
authors.lastname: Renehan
authors.affiliation: Clinical and Biomedical Proteomics Group, St James's University Hospital, Cancer Research UK Clinical Centre, University of Leeds, Leeds, UK.
authors.forename: Rosamonde E
authors.initials: RE
authors.lastname: Banks
authors.affiliation: MRC Clinical Trials Unit, University College London, London, UK.
authors.forename: Richard
authors.initials: R
authors.lastname: Kaplan
authors.affiliation: Novartis/GSK Pharmaceutical Cooperation, East Hanover, NJ, USA.
authors.forename: Stefan J
authors.initials: SJ
authors.lastname: Scherer
authors.affiliation: Department of Gynecological Oncology, Oslo University Hospital, Oslo, Norway.
authors.forename: Gunnar B
authors.initials: GB
authors.lastname: Kristensen
authors.affiliation: Group d'Investigateurs Nationaux pour l'Etude des Cancers Ovariens (GINECO) and Université Paris Descartes, Assistance Publique-Hôpitaux de Paris, Paris, France.
authors.forename: Eric
authors.initials: E
authors.lastname: Pujade-Lauraine
authors.affiliation: Clinical and Experimental Pharmacology Group, CRUK Manchester Institute, University of Manchester, Manchester, UK.
authors.forename: Caroline
authors.initials: C
authors.lastname: Dive
authors.affiliation: Institute of Cancer Sciences, University of Manchester, Manchester, UK.|Department of Medical Oncology, The Christie NHS Foundation Trust, Manchester, UK.
authors.forename: Gordon C
authors.initials: GC
authors.lastname: Jayson
mesh_terms: D042501:Angiogenic Proteins / Q000097:blood*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D001499:Bayes Theorem; D000068258:Bevacizumab / Q000627:therapeutic use*; D014408:Biomarkers, Tumor / Q000378:metabolism*; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D006801:Humans; D009389:Neovascularization, Pathologic; D010051:Ovarian Neoplasms / Q000188:drug therapy; D017239:Paclitaxel / Q000008:administration & dosage; D042787:Receptor, TIE-2 / Q000378:metabolism*
chemical_list: D042501:Angiogenic Proteins; D014408:Biomarkers, Tumor; D000068258:Bevacizumab; D042787:Receptor, TIE-2; D017239:Paclitaxel