title: Mechanism-related circulating proteins as biomarkers for clinical outcome in patients with unresectable hepatocellular carcinoma receiving sunitinib.
abstract: BACKGROUND
  Several proteins that promote angiogenesis are overexpressed in hepatocellular carcinoma (HCC) and have been implicated in disease pathogenesis. Sunitinib has antiangiogenic activity and is an oral multitargeted inhibitor of vascular endothelial growth factor receptors (VEGFRs)-1, -2, and -3, platelet-derived growth factor receptors (PDGFRs)-α and -β, stem-cell factor receptor (KIT), and other tyrosine kinases. In a phase II study of sunitinib in advanced HCC, we evaluated the plasma pharmacodynamics of five proteins related to the mechanism of action of sunitinib and explored potential correlations with clinical outcome.
  
  
  METHODS
  Patients with advanced HCC received a starting dose of sunitinib 50 mg/day administered orally for 4 weeks on treatment, followed by 2 weeks off treatment. Plasma samples from 37 patients were obtained at baseline and during treatment and were analyzed for vascular endothelial growth factor (VEGF)-A, VEGF-C, soluble VEGFR-2 (sVEGFR-2), soluble VEGFR-3 (sVEGFR-3), and soluble KIT (sKIT).
  
  
  RESULTS
  At the end of the first sunitinib treatment cycle, plasma VEGF-A levels were significantly increased relative to baseline, while levels of plasma VEGF-C, sVEGFR-2, sVEGFR-3, and sKIT were significantly decreased. Changes from baseline in VEGF-A, sVEGFR-2, and sVEGFR-3, but not VEGF-C or sKIT, were partially or completely reversed during the first 2-week off-treatment period. High levels of VEGF-C at baseline were significantly associated with Response Evaluation Criteria in Solid Tumors (RECIST)-defined disease control, prolonged time to tumor progression (TTP), and prolonged overall survival (OS). Baseline VEGF-C levels were an independent predictor of TTP by multivariate analysis. Changes from baseline in VEGF-A and sKIT at cycle 1 day 14 or cycle 2 day 28, and change in VEGF-C at the end of the first off-treatment period, were significantly associated with both TTP and OS, while change in sVEGFR-2 at cycle 1 day 28 was an independent predictor of OS.
  
  
  CONCLUSIONS
  Baseline plasma VEGF-C levels predicted disease control (based on RECIST) and were positively associated with both TTP and OS in this exploratory analysis, suggesting that this VEGF family member may have utility in predicting clinical outcome in patients with HCC who receive sunitinib.
  
  
  BACKGROUND
  ClinicalTrials.gov: NCT00247676.
authors.affiliation: Pfizer Oncology, La Jolla, CA, USA. charles.harmon@pfizer.com
authors.forename: Charles S
authors.initials: CS
authors.lastname: Harmon
authors.forename: Samuel E
authors.initials: SE
authors.lastname: DePrimo
authors.forename: Eric
authors.initials: E
authors.lastname: Raymond
authors.forename: Ann-Lii
authors.initials: AL
authors.lastname: Cheng
authors.forename: Eveline
authors.initials: E
authors.lastname: Boucher
authors.forename: Jean-Yves
authors.initials: JY
authors.lastname: Douillard
authors.forename: Ho Y
authors.initials: HY
authors.lastname: Lim
authors.forename: Jun S
authors.initials: JS
authors.lastname: Kim
authors.forename: Maria José
authors.initials: MJ
authors.lastname: Lechuga
authors.forename: Silvana
authors.initials: S
authors.lastname: Lanzalone
authors.forename: Xun
authors.initials: X
authors.lastname: Lin
authors.forename: Sandrine
authors.initials: S
authors.lastname: Faivre
mesh_terms: D020533:Angiogenesis Inhibitors / Q000627:therapeutic use; D014408:Biomarkers, Tumor / Q000097:blood*; D006528:Carcinoma, Hepatocellular / Q000097:blood* / Q000188:drug therapy* / Q000601:surgery; D018450:Disease Progression; D005260:Female; D006801:Humans; D007211:Indoles / Q000627:therapeutic use*; D053208:Kaplan-Meier Estimate; D008113:Liver Neoplasms / Q000097:blood* / Q000188:drug therapy* / Q000601:surgery; D008297:Male; D015999:Multivariate Analysis; D009363:Neoplasm Proteins / Q000097:blood*; D011758:Pyrroles / Q000627:therapeutic use*; D012372:ROC Curve; D000077210:Sunitinib; D013997:Time Factors; D016896:Treatment Outcome; D042582:Vascular Endothelial Growth Factor C / Q000097:blood
chemical_list: D020533:Angiogenesis Inhibitors; D014408:Biomarkers, Tumor; D007211:Indoles; D009363:Neoplasm Proteins; D011758:Pyrroles; C467486:VEGFC protein, human; D042582:Vascular Endothelial Growth Factor C; D000077210:Sunitinib