Impact of Serum HGF on Treatment Response to EGFR Tyrosine Kinase Inhibitors in Patients with Non-Small-Cell Lung Adenocarcinoma

Purpose: The EGFR mutation status has emerged as a validated biomarker for predicting the response to treatment with EGFR-tyrosine kinase inhibitors (EGFR-TKIs) in patients with non-small-cell lung cancer. However, the responses to EGFR-TKIs vary even among patients with EGFR mutations. We studied several other independently active biomarkers for EGFR-TKIs treatment. Experimental Design: We retrospectively analyzed the serum concentrations of 13 molecules in a cohort of 95 patients with non-small-cell lung adenocarcinoma who received EGFR-TKIs treatment at three centers. The pre-treatment serum concentrations of amphiregulin, beta-cellulin, EGF, sEGFR, epiregulin, FGF-basic, HB-EGF, HGF, PDGF-BB, PIGF, tenascin C, TGF-alpha, and VEGF were measured using ELISA and a multiplex immunoassay system. The associations between clinical outcomes and these molecules were evaluated. Results: The concentrations of HGF and VEGF were significantly higher among patients with progressive disease (PD) than among those without PD ( P <0.0001). HGF and VEGF were strongly associated with progression-free survival (PFS) and overall survival (OS) in a univariate Cox analysis (all tests for hazard ratio showed P <0.0001). A stratified multivariate Cox model according to EGFR mutation status (mutant, n =20; wild-type, n =23; unknown, n =52) showed that higher HGF levels were significantly associated with a shorter PFS and OS ( P <0.0001 for both PFS and OS). These observations were also consistent in the subset analyses. Conclusions: Serum HGF was strongly related to the outcome of EGFR-TKIs treatment. Our results suggest that the serum HGF level could be used to refine the selection of patients expected to respond to EGFR-TKIs treatment, warranting further prospective study. contribute to the further individualization of treatment for NSCLC. In this report, we retrospectively studied the serum concentrations of several molecules in patients with non-small-cell lung adenocarcinoma who underwent treatment with EGFR-TKIs. (wild-type/mutant/unknown) was treated as a stratified variable. We applied the above analyses to all the cases, to the cases in which the EGFR status was evaluated, and to the cases with wild-type EGFR to check the robustness of the conclusions. The survival curves for PFS and OS were estimated using the Kaplan-Meier (KM) method. The KM curves were shown just to visualize the trends of the association between the molecules and PFS/OS, as any determination of the optimal cut-off point for the molecules relative to the PFS/OS was beyond the scope of the present study. All the statistical analyses were performed using SAS for Windows (ver. 9.1.3) and Medcalc for Windows (ver. 11.1.1). patients with wild-type EGFR are to be less sensitive to EGFR-TKIs, our results might allow the identification of a selective subgroup of these patients who might benefit from this treatment. used in with the EGFR mutation status, the serum HGF level might increase the clinical benefit of EGFR-TKIs by allowing the further individualization of this treatment. We plan to conduct a prospective study to validate the ability of the serum HGF level to predict the response to EGFR-TKIs treatment. Univariate analysis was performed for all the patients and in a subset of patients with a known EGFR mutation status. Log-transformed values are used for all the molecules.