MET FISH-positive status predicts short progression-free survival and overall survival after gefitinib treatment in lung adenocarcinoma with EGFR mutation

Abstract

BackgroundLung adenocarcinoma patients with EGFR gene mutations have shown a dramatic response to gefitinib. However, drug resistance eventually emerges which limits the mean duration of response. With that in view, we examined the correlations between MET gene status as assessed by fluorescence in situ hybridization (FISH) with overall survival (OS) and progression-free survival (PFS) in adenocarcinoma patients with EGFR gene mutations who had received gefitinib therapy.MethodsWe evaluated 35 lung cancer samples with EGFR mutation from adenocarcinoma patients who had received gefitinib. Gene copy numbers (GCNs) and amplification of MET gene before gefitinib therapy was examined by FISH. MET protein expression was also evaluated by immunohistochemistry (IHC).ResultsFISH assessment showed that of the 35 adenocarcinoma samples, 10 patients (29%) exhibited high polysomy (5 copies≦mean MET per cell) and 1 patient (3%) exhibited amplification (2≦MET gene (red)/CEP7q (green) per cell). IHC evaluation of MET protein expression could not confirm MET high polysomy status. The Eleven patients with MET FISH positivity had significantly shorter progression-free survival (PFS) and overall survival (OS) than the 24 patients who were MET FISH-negative (PFS: p = 0.001 and OS: p = 0.03). Median PFS and OS with MET FISH-positivity were 7.6 months and 16.8 months, respectively, whereas PFS and OS with MET FISH-negativity were 15.9 months and 33.0 months, respectively. Univariate analysis revealed that MET FISH-positivity was the most significant independent factor associated with a high risk of progression and death (hazard ratio, 3.83 (p = 0.0008) and 2.25 (p = 0.03), respectively).ConclusionsUsing FISH analysis to detect high polysomy and amplification of MET gene may be useful in predicting shortened PFS and OS after Gefitinib treatment in lung adenocarcinoma. The correlation between MET gene status and clinical outcomes for EGFR-TKI should be further evaluated using large scale samples.

Phase II study of erlotinib plus tivantinib (ARQ 197) in patients with locally advanced or metastatic EGFR mutation-positive non-small-cell lung cancer just after progression on EGFR-TKI, gefitinib or erlotinib

“…This indicates that the tivantinib/erlotinib combination presents superior efficacy in EGFR-resistant patients with high expression of c-Met high or HGF high, both reported as poor prognostic factors. [8][9][10][11] Interestingly, similar superior efficacy in a poor prognosis population (ie, c-Met high and/or HGF high) was observed in previous phase III studies testing the tivantinib/erlotinib combination, even though those studies enrolled patients with NSCLC with backgrounds different from this study. The MARQUEE study enrolled EGFR-TKI-naive Caucasian patients including about 10% EGFR mutation-positive patients, and resulted in longer OS in c-Met high; HR was 0.70 (95% CI 0.49 to 1.01, vs placebo) in c-Met high, and 0.90 (95% CI 0.64 to 1.26, vs placebo) in c-Met low.…”

“…7 Activation of HGF/c-Met signalling due to overexpression of HGF/c-Met is reported to be involved in tumour infiltration and metastasis, and is identified as a poor prognosis factor in NSCLC. [8][9][10][11] Tivantinib (ARQ 197) is an oral, non-ATP-competitive, low-molecular weight selective c-Met inhibitor. The primary metabolic enzyme of tivantinib, CYP2C19, is known for the gene polymorphism associated with loss of function.…”

Inhibition of ABCB1 Overcomes Cancer Stem Cell–like Properties and Acquired Resistance to MET Inhibitors in Non–Small Cell Lung Cancer

“…In lung cancer, MET can be activated by HGF stimulation (11). Our recent study demonstrated that MET amplification and gene copy number gains showed a short response to gefitinib treatments in lung adenocarcinoma with EGFR mutation (12). Recently, MET inhibitors have been administered to NSCLC patients who are na€ ve or resistant to EGFR TKIs in a clinical trial (13).…”

Prognostic significance of ABCB1 in stage I lung adenocarcinoma

“…Evaluation of ABCB1, CD44 and ALDH1A1 protein expression. IHC scoring was performed using the Histoscore (H-score) (12,13). CD44 expression level was scored on a scale according to a previous study as follows: No expression, 0; low expression, 1+; and high expression, 2+ and 3+ (14).…”