The impact of MET, IGF-1, IGF1R expression and EGFR mutations on survival of patients with non-small-cell lung cancer

Abstract

IntroductionTo compare the efficacy of silver in situ hybridization (SISH) and immunohistochemistry (IHC) in detecting MET and IGF1R alterations and to investigate their prevalence and prognostic significance. A possible correlation between MET receptor expression, MET gene alterations and the two most frequent occurring EGFR gene mutations was also investigated.Materials and methodsStage I to IIIA tumors from 326 patients with NSCLC were immunohistochemically tested for protein expression of MET and IGF-1. Their cytoplasmic expression was compared with the gene copy number of the MET and IGF1Rgenes by SISH in paraffin-embedded, formalin-fixed material. Correlations were made with the immunohistochemical expression of two frequent EGFR mutations and clinicopathological variables. Univariate and multivariate survival analyses was used to evaluate the prognostic efficacy of the tested markers.ResultsIn univariate analyses, high cytoplasmic MET expression showed a significant negative prognostic effect in adenocarcinoma patients (p = 0.026). MET gene to chromosome 7 ratio was a significant positive prognostic marker (p = 0.005), probably only due to the highly negative prognostic significance of chromosome 7 polysomy (p = 0.002). High IGF1R gene copy number was a negative prognostic marker for all NSCLC patients (p = 0.037). In the multivariate analysis, polysomy of chromosome 7 in tumor cells correlated significantly and independently with a poor prognosis (p = 0.011). In patients with adenocarcinoma, a high cytoplasmic MET expression was an independent negative prognostic marker (p = 0.013). In males a high IGF1R gene copy number to chromosome 15 count ratio was significantly and independently correlated to a poor prognosis (p = 0.018).ConclusionMET protein expression provides superior prognostic information compared with SISH. Polysomy of chromosome 7 is an independent negative prognostic factor in NSCLC patients. This finding has an important implication while examining genes located on chromosome 7 by means of SISH. High IGF1R gene copy number to chromosome 15 count ratio is an independent predictor of inferior survival in male patients with primary NSCLC.

ALK and IGF-1R as independent targets in crizotinib resistant lung cancer

“…Early results have indicated that as a monotherapy AX1717 is as effective as existing chemotherapy and with less toxicity 22 – 24 . Moreover, the role of IGF-1R activation in non-small lung cancer prognosis has been very recently confirmed in a study of 326 NSCLC patients 25 .…”

Prognostic value of MET copy number gain in non-small-cell lung cancer: an updated meta-analysis

“…Of the remaining 35 potentially eligible studies, 14 were further excluded by the inclusion criteria. Finally, 21 studies were included in the meta-analysis 19 - 39 . Figure 1 shows the search flow diagram of this meta-analysis.…”

“…Except for two with a prospective cohort 26 , 32 , most were retrospective studies. The detection method and cut-off criteria for high MET CNG were variable across studies: FISH were most commonly used 20 , 21 , 23 , 24 , 26 , 27 , 32 - 37 , but various cut-off criteria were adopted 19 - 39 . Frequencies of high MET CNG in the included studies ranged from 1% to 38.9% depending on the technique used and the cut-point for positivity.…”

“…Some studies have reported that high MET expression is associated with a worse prognosis in patients with NSCLC 14 , 15 . The rate of MET amplification (true amplification or copy gain) in NSCLC has been reported to range from 1% to 39% 18 - 39 , depending on the histology and detection methods. Recently, MET amplification has been proposed as a potential mode of resistance to EGFR tyrosine kinase inhibitors in NSCLC 40 - 42 .…”

“…Recently, MET amplification has been proposed as a potential mode of resistance to EGFR tyrosine kinase inhibitors in NSCLC 40 - 42 . In addition, several studies reported a negative prognostic impact of high MET gene copy number gain (CNG) in patients with NSCLC 20 , 21 , 29 , 30 , 32 , 37 , 39 , 43 , 44 . However, the data are limited and other studies have failed to confirm this finding 17 , 19 , 22 - 28 , 31 , 33 - 36 , 38 .…”