title: The combination of circulating Ang1 and Tie2 levels predicts progression-free survival advantage in bevacizumab-treated patients with ovarian cancer.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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.affiliation: Clinical and Experimental Pharmacology, Paterson Institute for Cancer Research, University of Manchester, Wilmslow Road, Withington, Manchester M20 4BX, United Kingdom.
authors.forename: Alison
authors.initials: A
authors.lastname: Backen
authors.affiliation: Institute of Cancer Sciences, University of Manchester, Manchester Academic Health Science Center, The Christie NHS Foundation Trust, Wilmslow Road, Withington, Manchester, M20 4BX, UK.
authors.forename: Andrew G
authors.initials: AG
authors.lastname: Renehan
authors.affiliation: Dept Medical Oncology, University of Manchester and Christie Hospital, Wilmslow Road, Withington, Manchester M20 4BX, UK.
authors.forename: Andrew R
authors.initials: AR
authors.lastname: Clamp
authors.affiliation: Center for Biostatistics, Institute of Population Health, University of Manchester, Oxford Road, Manchester, M13 9PL, UK.
authors.forename: Carlo
authors.initials: C
authors.lastname: Berzuini
authors.affiliation: Clinical and Experimental Pharmacology, Paterson Institute for Cancer Research, University of Manchester, Wilmslow Road, Withington, Manchester M20 4BX, United Kingdom.
authors.forename: Cong
authors.initials: C
authors.lastname: Zhou
authors.affiliation: Bras Family Drug Development Program, Princess Margaret Hospital, 610 University Avenue, Toronto M5G 2M9.
authors.forename: Amit
authors.initials: A
authors.lastname: Oza
authors.affiliation: MRC Clinical Trials Unit, Aviation House, 125 Kingsway, London WC2B 6NH.
authors.forename: Selina
authors.initials: S
authors.lastname: Bannoo
authors.affiliation: Biocartis SA, EPFL-Quartier de l'Innovation, Bâtimont G, CH-1015 Lausanne.
authors.forename: Stefan J
authors.initials: SJ
authors.lastname: Scherer
authors.affiliation: Leeds Institute of Cancer and Pathology, St James University Hospital, Leeds LS9 7TF, UK.
authors.forename: Rosamonde E
authors.initials: RE
authors.lastname: Banks
authors.affiliation: Clinical and Experimental Pharmacology, Paterson Institute for Cancer Research, University of Manchester, Wilmslow Road, Withington, Manchester M20 4BX, United Kingdom.
authors.forename: Caroline
authors.initials: C
authors.lastname: Dive
authors.affiliation: Translational Angiogenesis Group, University of Manchester and Christie Hospital, Wilmslow Road, Withington, Manchester, M20 4BX, UK.
authors.forename: Gordon C
authors.initials: GC
authors.lastname: Jayson
mesh_terms: D000328:Adult; D000368:Aged; D042683:Angiopoietin-1 / Q000235:genetics*; D061067:Antibodies, Monoclonal, Humanized / Q000008:administration & dosage* / Q000235:genetics; D000068258:Bevacizumab; D014408:Biomarkers, Tumor; D018572:Disease-Free Survival; D005260:Female; D006801:Humans; D008875:Middle Aged; D009360:Neoplastic Cells, Circulating; D009389:Neovascularization, Pathologic / Q000188:drug therapy / Q000235:genetics; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000235:genetics* / Q000473:pathology; D011379:Prognosis; D042787:Receptor, TIE-2 / Q000235:genetics*; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors / Q000235:genetics
chemical_list: C467630:ANGPT1 protein, human; D042683:Angiopoietin-1; D061067:Antibodies, Monoclonal, Humanized; D014408:Biomarkers, Tumor; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D000068258:Bevacizumab; D042787:Receptor, TIE-2