Molecular Diagnostic Assays and Clinicopathologic Implications of MET Exon 14 Skipping Mutation in Non–small-cell Lung Cancer

Kim, Min Jung; Kim, Kyung A; Lee, Chang Young; Kim, Sang Woo; Chang, Sunhee; Cho, Byoung Chul; Shim, Hyo Sup

doi:10.1016/j.cllc.2018.10.004

Cited by 55 publications

(45 citation statements)

References 48 publications

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“…Our pathological and clinical findings correspond mostly to the current literature; predominantly adenocarcinomas were seen, as well as a uniquely high percentage of sarcomatoid carcinomas, with a high PD-L1 expression, in an elderly population (78 % > 65 yr) of which the majority has a smoking history with over 20 pack years [29][30][31]. However, in contrast to previous studies, we describe a predominantly male population, which may reflect the uncertainty whether there is any sex predominance in the METex14del population.…”

Section: Discussionsupporting

confidence: 88%

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: 88%

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

et al. 2020

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“…This post translational dysregulation activates MET signaling in cancer cells and promotes oncogenesis [6,120]. Exon 14-skipping mutations have been amply reported in lung cancer, with a prevalence of approximately 3-5%, and in other tumor types, with probably lower frequencies [121][122][123]. These mutations are very likely to confer sensitivity to MET targeted therapies [65,124,125].…”

Section: Ii-c-exon 14 Skipping Mutationsmentioning

confidence: 99%

HGF/MET pathway aberrations as diagnostic, prognostic, and predictive biomarkers in human cancers

Moosavi

Giovannetti

Saso³

et al. 2019

Critical Reviews in Clinical Laboratory Sciences

129

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Cancer is a major cause of death worldwide. MET tyrosine kinase receptor [MET, c-MET, hepatocyte growth factor (HGF) receptor] pathway activation is associated with the appearance of several hallmarks of cancer. The HGF/MET pathway has emerged as an important actionable target across many solid tumors; therefore, biomarker discovery becomes essential in order to guide clinical intervention and patient stratification with the aim of moving towards personalized medicine. The focus of this review is on how the aberrant activation of the HGF/MET pathway in tumor tissue or the circulation can provide diagnostic and prognostic biomarkers and predictive biomarkers of drug response. Many meta-analyses have shown that aberrant activation of the MET pathway in tumor tissue, including MET gene overexpression, gene amplification, exon 14 skipping and other activating mutations, is almost invariably associated with shorter survival and poor prognosis. Most meta-analyses have been performed in non-small cell lung cancer (NSCLC), breast, head and neck cancers as well as colorectal, gastric, pancreatic and other gastrointestinal cancers. Furthermore, several studies have shown the predictive value of MET biomarkers in the identification of patients who gain the most benefit from HGF/MET targeted therapies administered as single or combination therapies. The highest predictive values have been observed for response to foretinib and savolitinib in renal cancer, as well as tivantinib in NSCLC and colorectal cancer. However, some studies, especially those based on MET expression, have failed to show much value in these stratifications. This may be rooted in lack of standardization of methodologies, in particular in scoring systems applied in immunohistochemistry determinations or absence of oncogenic addiction of cancer cells to the MET pathway, despite detection of overexpression. Measurements of amplification and mutation aberrations are less likely to suffer from these pitfalls. Increased levels of MET soluble ectodomain (sMET) in circulation have also been associated with poor prognosis; however, the evidence is not as strong as it is with tissue-based biomarkers. As a diagnostic biomarker, sMET has shown its value in distinguishing cancer patients from healthy individuals in prostate and bladder cancers and in melanoma. On the other hand, increased circulating HGF has also been presented as a valuable prognostic and diagnostic biomarker in many cancers; however, there is controversy on the predictive value of HGF as a biomarker. Other biomarkers such as circulating tumor DNA (ctDNA) and tumor HGF levels have also been briefly covered. In conclusion, HGF/MET aberrations can provide valuable diagnostic, prognostic and predictive biomarkers and represent vital assets for personalized cancer therapy.

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“…Despite the different characteristics of analyzed case series, MET exon 14 mutations seem to occur particularly in PSC, ranging from 3% to 31.8%. [81][82][83][87][88][89][90][91][92][93] The particular attention focused on MET exon 14 skipping mutations is then related to the relatively high frequency of this genetic alteration in PSC histology when compared with other conventional NSCLC, also predicting a good clinical response to MET inhibitors. The rate of MET exon 14 mutations is significantly higher in case series including PSC without common targetable mutations in EGFR, KRAS, ALK, ROS1, and RET.…”

Section: Recent Insights Into Psc Genetic and Transcriptional Featuresmentioning

confidence: 99%

“…92,93 Nevertheless, whenever possible all histological types of NSCLC should be investigated for this mutation. Activation of MET signaling is frequently associated and functionally supports the Epithelial to Mesenchymal Transition (EMT), 90,91 which is believed to be a driver mechanism in the progression of PSC from welldifferentiated lesions.…”

Section: Recent Insights Into Psc Genetic and Transcriptional Featuresmentioning

confidence: 99%

<p>Approaches to Tumor Classification in Pulmonary Sarcomatoid Carcinoma</p>

Baldovini¹,

Rossi²,

Ciarrocchi³

2019

LCTT

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Pulmonary sarcomatoid carcinoma (PSC) is a heterogeneous category of primary lung cancer accounting from 0.3% to 3% of all primary lung malignancies. According to the most recent 2015 World Health Organization (WHO) classification, PSC includes several different variants of malignant epithelial tumors (carcinomas) histologically mimicking sarcomas showing or entirely lacking a conventional component of non-small cell lung cancer (NSCLC). Thus, this rare subheading of lung neoplasms includes pleomorphic carcinoma, spindle cell carcinoma, giant cell carcinoma, pulmonary blastoma, and carcinosarcoma. A diagnosis of PSC may be suspected on small biopsy or cytology, but commonly requires a surgical resection to reach a conclusive definition. The majority of patients with PSC consists of elderly, smoking men with a large, peripheral mass characterized by well-defined margins. However, presentation with a central, polypoid endobronchial lesion is well-documented, particularly in pleomorphic carcinoma and carcinosarcoma showing a squamous cell carcinoma component. As expected, PSC may pose diagnostic problems and immunohistochemistry is largely used when pathologists deal these tumors in routine practice. Indeed, PSC tends to overexpress molecules associated with the epithelial-to-mesenchymal transition, such as vimentin, but the panel of immunostains also includes epithelial markers (cytokeratins, EMA), TTF-1, p40 and negative markers (e.g., melanocytic, mesothelial and sarcoma-related primary antibodies). Although rare, PSC has increased their interest among oncologist community for different reasons: a. identification of the epithelial-to-mesenchymal phenomenon as a major mechanism of secondary resistance to tyrosine kinase inhibitors; b. over-expression of PD-L1 and effective treatment with immunotherapy; c. identification of c-MET exon 14 skipping mutation representing an effective target to crizotinib and other specific inhibitors. In this review, the feasibility of the diagnosis of PSC, its differential diagnosis and novel molecular findings characterizing this group of lung tumor are discussed.

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Molecular Diagnostic Assays and Clinicopathologic Implications of MET Exon 14 Skipping Mutation in Non–small-cell Lung Cancer

Cited by 55 publications

References 48 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

HGF/MET pathway aberrations as diagnostic, prognostic, and predictive biomarkers in human cancers

<p>Approaches to Tumor Classification in Pulmonary Sarcomatoid Carcinoma</p>

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