title: Analysis of serum protein levels of angiogenic factors and their soluble receptors as markers of response to cediranib in the NCIC CTG BR.24 clinical trial.
abstract: OBJECTIVE
  Prognostic and predictive ability of circulating vascular endothelial growth factor (VEGF), stromal derived factor (SDF)-1α and soluble VEGF receptors (sVEGFR) 2 and 3, were evaluated in non-small cell lung cancer (NSCLC) patients enrolled in NCIC Clinical Trials Group BR. 24 comparing chemotherapy with or without cediranib.
  
  
  METHODS
  Biomarker levels were assessed by ELISA in serum from 149/296 enrolled patients at baseline and 146/149 patients after one treatment cycle. Experimental cut-offs for baseline measures determined using a graphic method were:
  < or ≥1 ng/ml, SDF-1α: ≤ or >3.5 ng/ml, sVEGFR2: < or ≥11 ng/ml and sVEGFR3: < or ≥35.5 ng/ml. Changes in markers from baseline to on-treatment were predefined as increased ≥10%, stable within 10% or decreased ≥10%. Cox regression models were used to correlate biomarkers with patient characteristics and outcomes including progression-free survival (PFS) and overall survival (OS).
  
  
  RESULTS
  No baseline biomarker was prognostic for OS, however, high baseline sVEGFR2 was prognostic for better PFS (p=0.0008) in the chemotherapy alone arm. Low baseline sVEGFR2 or sVEGFR3 were predictive of PFS benefit from cediranib (interaction p=0.06 and p=0.05, respectively). While on treatment, VEGF-A increases were associated with better PFS (p=0.02) and OS (p=0.01) for cediranib treated patients. Decreases in sVEGFR2 (p=0.01) or sVEGFR3 (p=0.02) were also predictive of better OS in cediranib treated patients.
  
  
  CONCLUSIONS
  Low baseline sVEGFR2 and sVEGFR3 were predictive for PFS benefit from cediranib, whereas increases in VEGF-A and decreases in sVEGFR2 or sVEGFR3 levels from baseline to on-treatment were predictive of an OS benefit from cediranib in chemotherapy treated NSCLC patients. Validation of these results is warranted.
authors.affiliation: Cancer Therapeutics Program, Ottawa Hospital Research Institute, 501 Smyth Road, Ottawa, Ontario K1H 8L6, Canada; Division of Medical Oncology Department of Medicine, University of Ottawa and the Ottawa Hospital Cancer Centre, 501 Smyth Road, Ottawa, Ontario K1H 8L6, Canada. Electronic address: caddison@ohri.ca.
authors.forename: Christina L
authors.initials: CL
authors.lastname: Addison
authors.affiliation: NCIC Clinical Trials Group and Queen's University, 10 Stuart Street, Kingston, Ontario K7L 3N6, Canada. Electronic address: kding@ctg.queensu.ca.
authors.forename: Keyue
authors.initials: K
authors.lastname: Ding
authors.affiliation: NCIC Clinical Trials Group and Queen's University, 10 Stuart Street, Kingston, Ontario K7L 3N6, Canada. Electronic address: LSeymour@ctg.queensu.ca.
authors.forename: Lesley
authors.initials: L
authors.lastname: Seymour
authors.affiliation: Cancer Therapeutics Program, Ottawa Hospital Research Institute, 501 Smyth Road, Ottawa, Ontario K1H 8L6, Canada. Electronic address: hzhao@ohri.ca.
authors.forename: Huijun
authors.initials: H
authors.lastname: Zhao
authors.affiliation: Cancer Therapeutics Program, Ottawa Hospital Research Institute, 501 Smyth Road, Ottawa, Ontario K1H 8L6, Canada; Division of Medical Oncology Department of Medicine, University of Ottawa and the Ottawa Hospital Cancer Centre, 501 Smyth Road, Ottawa, Ontario K1H 8L6, Canada. Electronic address: slaurie@toh.on.ca.
authors.forename: Scott A
authors.initials: SA
authors.lastname: Laurie
authors.affiliation: Department of Medical Oncology and Hematology, Princess Margaret Cancer Centre University Health Network, and the University of Toronto, 610 University Avenue, Toronto, Ontario M5G 2M9, Canada. Electronic address: Frances.Shepherd@uhn.ca.
authors.forename: Frances A
authors.initials: FA
authors.lastname: Shepherd
authors.affiliation: Cancer Therapeutics Program, Ottawa Hospital Research Institute, 501 Smyth Road, Ottawa, Ontario K1H 8L6, Canada; Division of Medical Oncology Department of Medicine, University of Ottawa and the Ottawa Hospital Cancer Centre, 501 Smyth Road, Ottawa, Ontario K1H 8L6, Canada. Electronic address: ggoss@toh.on.ca.
authors.forename: Glenwood D
authors.initials: GD
authors.lastname: Goss
authors.affiliation: Department of Medical Oncology and Hematology, Princess Margaret Cancer Centre University Health Network, and the University of Toronto, 610 University Avenue, Toronto, Ontario M5G 2M9, Canada. Electronic address: Penelope.Bradbury@uhn.ca.
authors.forename: Penelope A
authors.initials: PA
authors.lastname: Bradbury
mesh_terms: D043925:Angiogenesis Inducing Agents / Q000097:blood*; D000970:Antineoplastic Agents / Q000627:therapeutic use; D014408:Biomarkers, Tumor / Q000097:blood*; D001798:Blood Proteins / Q000378:metabolism*; D002289:Carcinoma, Non-Small-Cell Lung / Q000097:blood / Q000188:drug therapy* / Q000378:metabolism; D018572:Disease-Free Survival; D005260:Female; D006801:Humans; D008175:Lung Neoplasms / Q000097:blood / Q000188:drug therapy* / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D011379:Prognosis; D011799:Quinazolines / Q000627:therapeutic use*; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000378:metabolism; D040321:Vascular Endothelial Growth Factor Receptor-3 / Q000378:metabolism; D007211:Indoles
chemical_list: D043925:Angiogenesis Inducing Agents; D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; D001798:Blood Proteins; D011799:Quinazolines; D042461:Vascular Endothelial Growth Factor A; D040301:Vascular Endothelial Growth Factor Receptor-2; D040321:Vascular Endothelial Growth Factor Receptor-3; C467484:VEGFA protein, human; C581309:FLT4 protein, human; C000588866:KDR protein, human; C500926:cediranib; D007211:Indoles
keywords: Biomarker; Cediranib; Non-small cell lung cancer; Predictive; Prognostic; Survival; VEGF; sVEGFR