Article Abstract

Expression of HGF, MET and mutated EGFR in EGFR mutated lung adenocarcinoma and their clinical significance

Authors: Shu-Ling Zhang, Xin Sun, Li Sun, Zhi-Cheng Xiong, Jie-Tao Ma, Le-Tian Huang, Cheng-Bo Han


Background: Patients with non-small cell lung cancer (NSCLC) harboring sensitive mutations in the epidermal growth factor receptor (EGFR) gene have high sensitivity to EGFR tyrosine kinase inhibitors (TKIs), but the efficacy is largely different among individuals. In this study, we analyzed the correlation between the expression of mesenchymal to epithelial transition factor (MET) receptor and its ligand hepatocyte growth factor (HGF) and different EGFR mutations, and their clinical significances.
Methods: One hundred thirty patients with pathologically confirmed lung adenocarcinoma were screened for EGFR mutations of exon 19 (E19) deletion (del) and exon 21 (E21) L858R using the amplification refractory mutation system (ARMS). Subsequently, in patients who harbored mutations, the proteins expression of EGFR E19 del or E21 L858R, MET, and HGF was quantitated by immunohistochemistry. Kaplan-Meier was used to draw the survival curve with different clinicopathological and molecular characteristics, and log-rank test was used to compare the difference. Multivariate analysis was performed by a Cox proportional hazard regression model to identify the statistically significant prognostic factors of survival.
Results: Fifty-five patients were finally detected as positive for EGFR E19 del or E21 L858R. The expression levels of HGF and MET proteins in patients with positive expression of EGFR-mutant protein was significantly higher than those in patients with negative expression (35.3% vs. 19.0%, P=0.038; and 29.4% vs. 14.3%, P=0.039, respectively). Fifty patients who underwent radical resection did not receive postoperative EGFR-TKI treatment, and a significantly increased median disease-free survival (DFS) (26 vs. 18 months, P=0.003) was found in patients with negative expression of HGF compared to patients with positive expression of HGF. Twenty-nine patients who either experienced recurrence after surgery or were initially diagnosed with advanced disease, received EGFR-TKI treatment. Patients with negative expression of HGF had a significantly increased overall response rate (ORR) (76% vs. 25%, P=0.035) compared with those with positive expression of HGF, though no statistical differences were found between them in progression-free survival (PFS) and overall survival (OS) (18 vs. 14 months, P=0.19; 48 vs. 28 months, P=0.10, respectively). Multivariate analysis showed that HGF expression was an independent prognostic factor of DFS in postoperative patients (P=0.004) and OS (P=0.048) in patients with advanced disease receiving EGFR-TKI treatment.
Conclusions: HGF could be used as a prognostic indicator of early recurrence in postoperative patients with EGFR-mutant NSCLC, and as a potential predictor of survival for patients with advanced disease given EGFR-TKIs.