Highly accurate DNA-based detection and treatment results of MET exon 14 skipping mutations in lung cancer. (February 2020)

• Record Type: Journal Article
• Authors: Pruis, M.A.; Geurts-Giele, W.R.R.; von der, Thüsen J.H.; Meijssen, I.C.; Dinjens, W.N.M.; Aerts, J.G.J.V.; Dingemans, A.M.C.; Lolkema, M.P.; Paats, M.S.; Dubbink, H.J.
• Is Part Of: Lung cancer. Volume 140(2020)
• Page Start: 46
• Page End: 54
• Publication Date: 2020-02
• Subjects: METex14del MET exon 14 skipping mutation; MET exon 14 skipping -- Non-small cell lung cancer -- Next generation sequencing -- MET inhibitor -- Resistance against cMET inhibition -- Driver mutation -- Targeted therapy -- Diagnostics; Lungs -- Cancer -- Periodicals; Lung Neoplasms -- Abstracts; Lung Neoplasms -- Periodicals; Poumons -- Cancer -- Périodiques; Lungs -- Cancer; Periodicals; Electronic journals; Electronic journals; 616.99424
• DOI: 10.1016/j.lungcan.2019.11.010
• Languages: English
• ISSNs: 0169-5002

Abstract

Highlights: MET exon 14 skipping mutations in lung cancer can be reliably detected in DNA. 2 % of the non-squamous NSCLC is driven by a MET exon 14 skipping mutation. These patients represent an elderly population in relatively good condition. cMET targeted therapy shows promising response rates. Resistance mechanisms to cMET targeted therapy occur during treatment. 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.