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

M.A. Pruis, W.R.R. Geurts-Giele, J.H. von der Thusen, I.C. Meijssen, W.N.M. Dinjens, J.G.J.V. Aerts, A.M.C. Dingemans, M.P. Lolkema, M.S. Paats, H.J. Dubbink*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

25 Citations (Web of Science)

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 [53-901), 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 - 1 Feb 2020

Keywords

  • amplification
  • crizotinib
  • diagnostics
  • driver mutation
  • inhibition
  • met exon 14 skipping
  • met inhibitor
  • next generation sequencing
  • non-small cell lung cancer
  • patient
  • resistance
  • resistance against cmet inhibition
  • sarcomatoid carcinoma
  • target
  • targeted therapy
  • Driver mutation
  • TARGET
  • Diagnostics
  • Targeted therapy
  • MET inhibitor
  • AMPLIFICATION
  • INHIBITION
  • MET exon 14 skipping
  • CRIZOTINIB
  • SARCOMATOID CARCINOMA
  • Next generation sequencing
  • Non-small cell lung cancer
  • Resistance against cMET inhibition
  • RESISTANCE
  • PATIENT

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