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
Vollebergh, M.A.; Kappers, I.; Klomp, H.M.; Buning-Kager, J.C.; Korse, C.M.; Hauptmann, M.; de Visser, K.E.; van den Heuvel, M.M.; Linn, S.C.
Journal of Thoracic Oncology: Official Publication of the International Association for the Study of Lung Cancer 5(12): 1939-1948
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. 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. 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). 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.