Impact of serum hepatocyte growth factor on treatment response to epidermal growth factor receptor tyrosine kinase inhibitors in patients with non-small cell lung adenocarcinoma.
OBJECTIVE
The epidermal growth factor receptor (EGFR) mutation status has emerged as a validated biomarker for predicting the response to treatment with EGFR-tyrosine kinase inhibitors (EGFR-TKI) 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-TKI treatment.


METHODS
We retrospectively analyzed the serum concentrations of 13 molecules in a cohort of 95 patients with non-small cell lung adenocarcinoma who received EGFR-TKI treatment at three centers. The pretreatment serum concentrations of amphiregulin, β-cellulin, EGF, EGFR, epiregulin, fibroblast growth factor-basic, heparin-binding EGF-like growth factor, hepatocyte growth factor (HGF), platelet-derived growth factor β polypeptide, placental growth factor, tenascin C, transforming growth factor-α, and vascular endothelial growth factor (VEGF) were measured using enzyme-linked immunosorbent assay 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 than among those without progressive disease (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-TKI treatment. Our results suggest that the serum HGF level could be used to refine the selection of patients expected to respond to EGFR-TKI treatment, warranting further prospective study.
Kasahara
Kazuo
K
Respiratory Medicine, School of Medicine, Kanazawa University, Kanazawa, Ishikawa, Japan.
Arao
Tokuzo
T
Sakai
Kazuko
K
Matsumoto
Kazuko
K
Sakai
Asao
A
Kimura
Hideharu
H
Sone
Takashi
T
Horiike
Atsushi
A
Nishio
Makoto
M
Ohira
Tatsuo
T
Ikeda
Norihiko
N
Yamanaka
Takeharu
T
Saijo
Nagahiro
N
Nishio
Kazuto
K
D000230:Adenocarcinoma / Q000097:blood / Q000175:diagnosis / Q000188:drug therapy / Q000401:mortality; D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000627:therapeutic use; D054316:Biomarkers, Pharmacological / Q000097:blood; D014408:Biomarkers, Tumor / Q000097:blood / Q000502:physiology; D002289:Carcinoma, Non-Small-Cell Lung / Q000097:blood / Q000175:diagnosis* / Q000188:drug therapy* / Q000401:mortality; D015331:Cohort Studies; D066246:ErbB Receptors / Q000037:antagonists & inhibitors*; D005260:Female; D017228:Hepatocyte Growth Factor / Q000097:blood* / Q000502:physiology; D006801:Humans; D008175:Lung Neoplasms / Q000097:blood / Q000175:diagnosis* / Q000188:drug therapy* / Q000401:mortality; D008297:Male; D008875:Middle Aged; D011379:Prognosis; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use*; D012189:Retrospective Studies
D000970:Antineoplastic Agents; D054316:Biomarkers, Pharmacological; D014408:Biomarkers, Tumor; D047428:Protein Kinase Inhibitors; D017228:Hepatocyte Growth Factor; D066246:ErbB Receptors