MET Exon 14 Skipping Mutations in Lung Adenocarcinoma: Clinicopathologic Implications and Prognostic Values

Lee, Geun Dong; Lee, Seung Eun; Oh, Doo‐Yi; Yu, Dan-bi; Jeong, Han Mo; Kim, Joo-Seok; Hong, Sung Kyu; Jung, Hun Soon; Oh, Ensel; Song, Ji-Young; Lee, Mi-Sook; Kim, Mingi; Jung, Kyungsoo; Kim, Young Tae; Shin, Young Kee; Choi, Yoon‐La; Kim, Hyeong Ryul

doi:10.1016/j.jtho.2017.04.031

Cited by 68 publications

(65 citation statements)

References 30 publications

(44 reference statements)

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“…In this study, we show that with our custom-made DNA-based NGS approach, we prospectively find METex14del mutations in 2 % (32/ 1497) of non-squamous NSCLC, in line with previous studies [5,[8][9][10][11][12][13][14].…”

Section: Discussionsupporting

confidence: 91%

“…Some studies do suggest METex14del has a significant worse overall survival than METex14 wild-type [8][9][10][11][12]42]. Nevertheless, there is limited data available concerning prognosis.…”

Section: Discussionmentioning

confidence: 99%

“…The effect of exon 14 skipping is the expression of a constitutively active cMET receptor with impaired degradation and consequently induction of cell proliferation and tumor growth [6][7][8]. METex14del is shown in 1.3 %-5.7 % of NSCLC patients based on both RNA and DNA tests using RT-PCR or Next Generation Sequencing (NGS) [5,[8][9][10][11][12][13][14]. This alteration has been described as a potential oncogenic driver, showing mostly mutual exclusiveness with other oncogenic driver mutations [5,12,15].…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2020

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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 nonsquamous 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.

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Section: Discussionsupporting

confidence: 91%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

et al. 2020

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“…Of note, eligibility for treatment with dabrafenib/trametinib according to the current FDA and EMA regulations is limited to one third only (n = 50) of these cases, namely those featuring V600 mutations. [30][31][32] Collectively, these data suggest that a more comprehensive sequencing approach can expand therapeutic options in NSCLC. 29 For 12 additional cases, literature suggests that the third generation BRAF inhibitors avoiding paradoxical ERK pathway activation due to aberrant RAS activity, socalled paradox breakers or pan-RAF inhibitors, will be very useful for BRAF mutant NSCLC with non-V600E mutations.…”

Section: Discussionmentioning

confidence: 90%

“…Even though testing for these alterations is not required by the current guidelines, 5,7 it can facilitate selection of cases for experimental treatment with MET, HER, NRG1, FGFR and BET inhibitors, respectively, which could confer significant clinical benefit. [30][31][32] Collectively, these data suggest that a more comprehensive sequencing approach can expand therapeutic options in NSCLC.…”

Section: Discussionmentioning

confidence: 90%

Combined targeted DNA and RNA sequencing of advanced NSCLC in routine molecular diagnostics: Analysis of the first 3,000 Heidelberg cases

Volckmar

Leichsenring

Kirchner

et al. 2019

Intl Journal of Cancer

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Tyrosine kinase inhibitors currently confer the greatest survival gain for nonsmall cell lung cancer (NSCLC) patients with actionable genetic alterations. Simultaneously, the increasing number of targets and compounds poses the challenge of reliable, broad and timely molecular assays for the identification of patients likely to benefit from novel treatments. Here, we demonstrate the feasibility and clinical utility of comprehensive, NGS‐based genetic profiling for routine workup of advanced NSCLC based on the first 3,000 patients analyzed in our department. Following automated extraction of DNA and RNA from formalin‐fixed, paraffin‐embedded tissue samples, parallel sequencing of DNA and RNA for detection of mutations and gene fusions, respectively, was performed using PCR‐based enrichment with an ion semiconductor sequencing platform. Overall, 807 patients (27%) were eligible for currently approved, EGFR‐/BRAF‐/ALK‐ and ROS1‐directed therapies, while 218 additional cases (7%) with MET, ERBB2 (HER2) and RET alterations could potentially benefit from experimental targeted compounds. In addition, routine capturing of comutations, e.g. TP53 (55%), KEAP1 (11%) and STK11 (11%), as well as the precise typing of fusion partners and involved exons in case of actionable translocations including ALK and ROS1, are prognostic and predictive tools currently gaining importance for further refinement of therapeutic and surveillance strategies. The reliability, low dropout rates (<5%), minimal tissue requirements, fast turnaround times (6 days on average) and lower costs of the diagnostic approach presented here compared to sequential single‐gene testing, highlight its practicability in order to support individualized decisions in routine patient care, enrollment in molecularly stratified clinical trials, as well as translational research.

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Predictive molecular pathology of lung cancer in Germany with focus on gene fusion testing: Methods and quality assurance

Siemanowski

Heydt

Merkelbach‐Bruse

2020

Cancer Cytopathology

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Predictive molecular testing has become an important part of the diagnosis of any patient with lung cancer. Using reliable methods to ensure timely and accurate results is inevitable for guiding treatment decisions. In the past few years, parallel sequencing has been established for mutation testing, and its use is currently broadened for the detection of other genetic alterations, such as gene fusion and copy number variations. In addition, conventional methods such as immunohistochemistry and in situ hybridization are still being used, either for formalin‐fixed, paraffin‐embedded tissue or for cytological specimens. For the development and broad implementation of such complex technologies, interdisciplinary and regional networks are needed. The Network Genomic Medicine (NGM) has served as a model of centralized testing and decentralized treatment of patients and incorporates all German comprehensive cancer centers. Internal quality control, laboratory accreditation, and participation in external quality assessment is mandatory for the delivery of reliable results. Here, we provide a summary of current technologies used to identify patients who have lung cancer with gene fusions, briefly describe the structures of NGM and the national NGM (nNGM), and provide recommendations for quality assurance.

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MET Exon 14 Skipping Mutations in Lung Adenocarcinoma: Clinicopathologic Implications and Prognostic Values

Cited by 68 publications

References 30 publications

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

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

Combined targeted DNA and RNA sequencing of advanced NSCLC in routine molecular diagnostics: Analysis of the first 3,000 Heidelberg cases

Predictive molecular pathology of lung cancer in Germany with focus on gene fusion testing: Methods and quality assurance

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