Highly accurate DNA-based detection and treatment results of MET exon 14 skipping mutations in lung cancer

Melinda Pruis, Ina Geurts - Giele, Jan von der Thüsen, Isabelle Meijssen, Winand Dinjens, Joachim Aerts, AMA Dingemans, Martijn Lolkema, Marthe Paats, Erik jan Dubbink*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

40 Citations (Scopus)
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Abstract

Objectives: 

The oncogenic MET exon 14 skipping mutation (METex14del) is described to drive 1.3 %–5.7 % of non-small-cell lung cancer (NSCLC) and multiple studies with cMET inhibitors show promising clinical responses. RNA-based analysis seems most optimal for METex14del detection, however, acquiring sufficient RNA material is often problematic. An alternative is DNA-based analysis, but commercially available DNA-based panels only detect up to 63 % of known METex14del alterations. The goal of this study is to describe an optimized DNA-based diagnostic test for METex14del in NSCLC, including clinical features and follow-up of patients treated with cMET-targeted therapy and consequent resistance mechanisms. 

Material and methods: 

Routinely processed diagnostic pathology non-squamous NSCLC specimens were investigated by a custom-made DNA-based targeted amplicon-based next generation sequencing (NGS) panel, which includes 4 amplicons for METex14del detection. Retrospectively, histopathological characteristics and clinical follow up were investigated for advanced non-squamous NSCLC with METex14del. 

Results: 

In silico analysis showed that our NGS panel is able to detect 96 % of reported METex14 alterations. METex14del was found in 2 % of patients with non-squamous NSCLC tested for therapeutic purposes. In total, from May 2015 - Sep 2018, METex14del was found in 46 patients. Thirty-six of these patients had advanced non-squamous NSCLC, they were predominantly elderly (76.5 years [53–90]), male (25/36) and (ex)-smokers (23/36). Five patients received treatment with crizotinib (Pfizer Oncology), in a named patient based program, disease control was achieved for 4/5 patients (3 partial responses, 1 stable disease) and one patient had a mixed response. Two patients developed a MET D1228N mutation during crizotinib treatment, inducing a resistance mechanism to crizotinib. 

Conclusions: 

This study shows that METex14del can be reliably detected by routine DNA NGS analysis. Although a small cohort, patients responded well to targeted treatment, underlining the need for routine testing of METex14del in advanced non-squamous NSCLC to guarantee optimal personalized treatment.

Original languageEnglish
Pages (from-to)46-54
Number of pages9
JournalLung Cancer
Volume140
DOIs
Publication statusPublished - Feb 2020

Bibliographical note

Publisher Copyright:
© 2019 The Authors

Research programs

  • EMC MM-03-24-01
  • EMC MM-04-42-02

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