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

J Thorac Oncol. 2010 Dec;5(12):1939-48. doi: 10.1097/JTO.0b013e3181f77a39.


Introduction: 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).

Conclusion: 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.

MeSH terms

  • Adult
  • Aged
  • Amphiregulin
  • Biomarkers
  • Carcinoma, Non-Small-Cell Lung / blood
  • Carcinoma, Non-Small-Cell Lung / drug therapy*
  • EGF Family of Proteins
  • ErbB Receptors / antagonists & inhibitors*
  • Female
  • Glycoproteins / blood*
  • Humans
  • Insulin-Like Growth Factor Binding Protein 3
  • Insulin-Like Growth Factor Binding Proteins / blood*
  • Insulin-Like Growth Factor I / analysis*
  • Intercellular Signaling Peptides and Proteins / blood*
  • Lung Neoplasms / blood
  • Lung Neoplasms / drug therapy*
  • Male
  • Middle Aged
  • Protein Kinase Inhibitors / therapeutic use*
  • Retrospective Studies
  • Transforming Growth Factor alpha / blood*


  • AREG protein, human
  • Amphiregulin
  • Biomarkers
  • EGF Family of Proteins
  • Glycoproteins
  • IGFBP3 protein, human
  • Insulin-Like Growth Factor Binding Protein 3
  • Insulin-Like Growth Factor Binding Proteins
  • Intercellular Signaling Peptides and Proteins
  • Protein Kinase Inhibitors
  • Transforming Growth Factor alpha
  • Insulin-Like Growth Factor I
  • ErbB Receptors