MET IHC Is a Poor Screen for MET Amplification or MET Exon 14 Mutations in Lung Adenocarcinomas: Data from a Tri-Institutional Cohort of the Lung Cancer Mutation Consortium

Abstract

Introduction: MNNG HOS Transforming gene (MET) amplification and MET exon 14 (METex14) alterations in lung cancers affect sensitivity to MET proto-oncogene, receptor tyrosine kinase (MET [also known by the alias hepatocyte growth factor receptor]) inhibitors. Fluorescence in situ hybridization (FISH), next-generation sequencing (NGS), and immunohistochemistry (IHC) have been used to evaluate MET dependency. Here, we have determined the association of MET IHC with METex14 mutations and MET amplification. Methods: We collected data on a tri-institutional cohort from the Lung Cancer Mutation Consortium. All patients had metastatic lung adenocarcinomas and no prior targeted therapies. MET IHC positivity was defined by an H-score of 200 or higher using SP44 antibody. MET amplification was defined by copy number fold change of 1.8x or more with use of NGS or a MET-to-centromere of chromosome 7 ratio greater than 2.2 with use of FISH. Results: We tested tissue from 181 patients for MET IHC, MET amplification, and METex14 mutations. Overall, 71 of 181 patients (39%) were MET IHC-positive, three of 181 (2%) were MET-amplified, and two of 181 (1%) harbored METex14 mutations. Of the MET-amplified cases, two were FISH positive with MET-to-centromere of chromosome 7

MET immunochemistry: a reliable screening tool for MET exon 14 skipping mutations in non-small cell lung cancer?

“…They combined NGS with FLA, so probably no MET exon 14 skipping mutations were missed and indeed the prevalence of 2.2% is in accordance with current literature (7,14). While 2 patients is a small number to base firm conclusions on, Guo et al performed a similar study in 2019 and they came to the same conclusion as Baldacci et al: MET IHC is not suitable as a screening tool to detect MET exon 14 skipping mutations (15). In 2018, Lambros et al also described MET IHC as a very weak tool for screening purposes and they report that MET IHC might even decrease the probability of predicting MET exon 14 skipping mutations in a multiclass model (16).…”

Novel Therapies for Metastatic Non-Small Cell Lung Cancer with MET Exon 14 Alterations: A Spotlight on Capmatinib

“…24 Several studies have shown MET IHC overexpression poorly predicts for the presence of METex14 alterations. [25][26][27] Furthermore, there may be a high degree of inter-observer variability in the interpretation of IHC. 28 As such, most of the assays for METex14 involve molecular techniques ( Figure 2).…”

Extensive MET alterations confer clinical response to MET inhibitors in gliomas

“…Consequently, MET overexpression is expected to be strongly associated with MET alterations. However, MET overexpression does not always accompany MET amplification or METex14 in lung cancers [19]. Here, we investigated the association between MET overexpression and the MET alterations in sGBM.…”