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  • br Introduction Hepatocyte Growth Factor HGF and


    Introduction Hepatocyte Growth Factor (HGF) and its receptor cellular Mesenchymal Epithelial Transition factor (c-MET), a heterodimeric tyrosine kinase receptor, are frequently expressed in non-small cell lung cancer (NSCLC) and represents an oncogenic signaling pathway of major interest in NSCLC. c-MET protein overexpression, gene amplification and exon 14 splicing mutation (METex14) have been proposed as potential prognostic biomarkers as well as predictive biomarkers for targeted therapy, albeit their role in the clinical setting has not been firmly established yet [1,2]. c-MET protein is overexpressed in 13–36 % of primary lung cancer specimens and is often associated with poor prognosis [[3], [4], [5]]. Albeit, in the ETOP study by Bubendorf et al, neither c-MET overexpression nor MET gene amplification influenced prognosis in a large cohort of early stage NSCLC patients [6]. In the ITF2357 (Givinostat) metastatic setting, c-MET overexpression has been reported to be as high as 44.4% [7]. The immunohistochemistry (IHC) methods used to define c-MET overexpression have varied in different publications, and up to date no consensus exists [2,[6], [7], [8], [9], [10]]. The role of c-MET as a predictive biomarker is still unclear. A recent surgical cohort study in Asian NSCLC patients (n = 311, of whom 151 received adjuvant chemotherapy), showed that overall survival (OS) was significantly prolonged in the c-MET positive cases who received platinum-based adjuvant chemotherapy, but this finding needs to be verified in larger cohorts [2]. However, in a study by Cappuzzo et al. in early stage NSCLC, MET gene amplification was a negative prognostic biomarker for OS [11]. Another study done in 689 patients with early stage disease who were treated with surgery, failed to show any prognostic value of MET amplification or cMET overexpression. In this study the prevalence of MET overexpression and MET amplification was 17% and 2.4% respectively [10]. An Asian randomized phase 3 trial with erlotinib with or without the c-MET inhibitor tivantinib (ARQ197) in EGFR wild-type non-squamous NSLCL failed to show any survival benefit with the combination, and was terminated prematurely due to higher incidence of interstitial lung disease in the tivantinib arm [12]. Another phase 3 study with a similar design in Caucasian population was terminated early at the interim analysis due to futility [13]. Both of these studies were done in an unselected population regarding c-MET expression. Onartuzumab, a fully humanized recombinant monoclonal antibody binding to the extracellular domain of c-MET, failed to show any survival benefit when combined with erlotinib compared to single erlotinib in a phase 3 randomized trial in previously treated stage IIIB or IV NSCLC determined to be c-MET positive (≥ 50% of tumor cells with IHC scores of 2+ [moderate] or 3+ [strong] levels of MET) [14]. Furthermore, no effect of onartuzumab/erlotinib combo was shown in exploratory analyses using MET FISH and gene expression. Although the above mentioned trials failed to show any benefit, several smaller trials and case series have shown efficacy of c-MET tyrosine kinase inhibitors or monoclonal antibodies targeting c-MET, mainly in MET exon 14 mutated NSCLC, but these findings need verification in larger randomized trials [9,15].
    Discussion The role of c-MET protein overexpression as a prognostic and predictive biomarker in early stage NSCLC was the primary objective of our study. It is still unclear how c-MET protein expression, MET amplification and MET exon 14 mutation correlate with each other. The Cancer Genome Atlas study of lung adenocarcinoma and a Japanese study, both done in surgically resected tumors (early stage disease), showed that MET exon 14 mutation and MET amplification are mutually exclusive [19,20]. A recently published study with 28 MET exon 14 mutated cases showed a statistically significant co-existence of MET exon 14 skipping mutation and both MET gene amplification/c-MET protein overexpression in stage IV NSCLC [9]. In this study there was a significant association between MET amplification and stage IV disease, something which was not verified in a larger cohort with 298 MET exon 14 skipped patients [15]. Dziadziuszko et al showed that MET gene copy number determined by silver in situ hybridization (SISH) and protein expression evaluated by IHC correlated significantly in a cohort of 189 patients with surgically resected NSCLC [21]. This finding could not be confirmed in another surgical cohort (n = 222), where no significant association was observed between c-MET expression and gene copy number, but these two studies used different IHC scoring systems [8]. Bubendorf et al found a statistically significant correlation between MET gene amplification and c-MET protein overexpression in a large cohort of surgically resected NSCLC patients [6].