title: Ligands of epidermal growth factor receptor and the insulin-like growth factor family as serum biomarkers for response to epidermal growth factor receptor inhibitors in patients with advanced non-small cell lung cancer.
abstract: BACKGROUND
  The selection of patients with non-small cell lung cancer (NSCLC) for epidermal growth factor receptor (EGFR) inhibitor (EGFR-tyrosine kinase inhibitors [TKIs]) therapy is suboptimal as tumor tissue is often unavailable. Ligands of EGFR, transforming growth factor-alpha (TGFa) and amphiregulin (ARG), and the insulin-like growth factor (IGF) family have been associated with resistance to EGFR-TKIs. The aim of our study was to explore whether concentrations of these factors measured in serum were predictive of response to EGFR-TKIs.
  
  
  METHODS
  We assessed serum levels of marker candidates using enzyme-linked immunosorbent (TGFa and ARG) and chemiluminescent (IGF1 and IGF-binding protein-3) assays in 61 patients with advanced NSCLC treated with EGFR-TKIs and 63 matched advanced NSCLC control patients without EGFR-TKIs treatment. We dichotomized marker levels at the 20th, 50th, or 80th percentile and evaluated whether the effect of EGFR-TKIs treatment on disease-specific survival (DSS) differed by marker level based on multivariate proportional hazards regression with an interaction term.
  
  
  RESULTS
  The effect of EGFR-TKIs treatment on DSS showed a significant difference by TGFa and ARG (interaction p = 0.046 and p = 0.004, respectively). Low concentrations of TGFa and high concentrations of ARG were associated with a better DSS in EGFR-TKIs patients compared with control patients. Patients with high concentrations of IGF-binding protein-3 had significantly longer DSS, independent of treatment (hazard ratio: 0.60 per 1 mg/liter, 95% confidence interval: 0.46-0.79).
  
  
  CONCLUSIONS
  Our results suggest that concentrations of TGFa and ARG measured in serum are predictive of EGFR-TKI response. The combination of these two biomarkers could be of value in the process of selecting patients for treatment with EGFR-TKIs.
authors.affiliation: Division of Molecular Biology, Netherlands Cancer Institute-Antoni van Leeuwenhoek Hospital, Amsterdam, The Netherlands.
authors.forename: Marieke A
authors.initials: MA
authors.lastname: Vollebergh
authors.forename: Ingrid
authors.initials: I
authors.lastname: Kappers
authors.forename: Houke M
authors.initials: HM
authors.lastname: Klomp
authors.forename: Johanna C
authors.initials: JC
authors.lastname: Buning-Kager
authors.forename: Catharina M
authors.initials: CM
authors.lastname: Korse
authors.forename: Michael
authors.initials: M
authors.lastname: Hauptmann
authors.forename: Karin E
authors.initials: KE
authors.lastname: de Visser
authors.forename: Michel M
authors.initials: MM
authors.lastname: van den Heuvel
authors.forename: Sabine C
authors.initials: SC
authors.lastname: Linn
mesh_terms: D000328:Adult; D000368:Aged; D066258:Amphiregulin; D015415:Biomarkers; D002289:Carcinoma, Non-Small-Cell Lung / Q000097:blood / Q000188:drug therapy*; D066255:EGF Family of Proteins; D066246:ErbB Receptors / Q000037:antagonists & inhibitors*; D005260:Female; D006023:Glycoproteins / Q000097:blood*; D006801:Humans; D018972:Insulin-Like Growth Factor Binding Protein 3; D018969:Insulin-Like Growth Factor Binding Proteins / Q000097:blood*; D007334:Insulin-Like Growth Factor I / Q000032:analysis*; D036341:Intercellular Signaling Peptides and Proteins / Q000097:blood*; D008175:Lung Neoplasms / Q000097:blood / Q000188:drug therapy*; D008297:Male; D008875:Middle Aged; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use*; D012189:Retrospective Studies; D016211:Transforming Growth Factor alpha / Q000097:blood*
chemical_list: C587848:AREG protein, human; D066258:Amphiregulin; D015415:Biomarkers; D066255:EGF Family of Proteins; D006023:Glycoproteins; C515497:IGFBP3 protein, human; D018972:Insulin-Like Growth Factor Binding Protein 3; D018969:Insulin-Like Growth Factor Binding Proteins; D036341:Intercellular Signaling Peptides and Proteins; D047428:Protein Kinase Inhibitors; D016211:Transforming Growth Factor alpha; D007334:Insulin-Like Growth Factor I; D066246:ErbB Receptors