Clinicopathological implications of MET exon 14 mutations in non-small cell lung cancer – A systematic review and meta-analysis

Vuong, Huy Gia; Ho, An Thi Nhat; Altibi, Ahmed; Nakazawa, Tadao; Katoh, Ryohei; Kondo, Tetsuo

doi:10.1016/j.lungcan.2018.07.006

Cited by 104 publications

(99 citation statements)

References 34 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: 87%

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: 87%

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, MET exon 14 skipping has been reported to be associated with PSCs. Therefore, c‐MET inhibitors may represent a viable treatment option . In our case, the tumor was positive for a rearrangement involving the ROS1 gene only.…”

Section: Discussion/conclusionmentioning

confidence: 99%

Sarcomatoid carcinoma in cytology: Report of a rare entity presenting in pleural and pericardial fluid preparations

Basu

Moreira

Simms

et al. 2019

Diagnostic Cytopathology

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Sarcomatoid carcinoma is rarely found in pleural or pericardial fluid, with very few cases published to date. Here, we describe a 59-year-old female who presented with cough persisting for 5 months.Chest CT scan revealed a 6.0 cm cavitary mass in the left lung base with bulky mediastinal and hilar lymphadenopathy. An additional 1.2 cm right adrenal mass was seen and was suspicious for metastatic disease. The patient developed dyspnea, tachycardia, pleuritic chest pain and generalized weakness and was admitted to the hospital. She was found to have pleural and pericardial effusions, which were drained and sent to cytology. The fluid revealed enlarged highly pleomorphic malignant cells, some displaying multinucleation with irregular nuclear borders, coarse chromatin and prominent nucleoli. Tumor cells were positive for CK7 and Vimentin and negative for MOC-31, Ber-EP4, B72.3, Sox10, Melan-A, TTF-1, Napsin-A and CK20. A concurrent surgical biopsy of the tumor mass displayed immunopositivity for AE1/AE3 and CAM5.2. The tumor was negative for p40, TTF-1, calretinin, D2-40 and STAT6. A diagnosis of sarcomatoid carcinoma with giant cells and spindle cells was rendered. Sarcomatoid carcinomas of the lung are very uncommon consisting of 1% of nonsmall-cell lung carcinomas and are even more unusual in cytology specimens. Despite its rarity, it is important to keep this entity in mind in the differential diagnosis of a fluid specimen with bizarre nuclear atypia and the above staining pattern. K E Y W O R D Scytology, pulmonary sarcomatoid carcinoma

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“…83,89 Noticeably, while MET exon 14 mutations occur in about 3% of NSCLCs (according to TCGA data), up to 32% of PSCs are reported to carry this alteration. Indeed, according to a recent systematic meta-analysis, 90 the incidence of MET exon 14 mutations in PSC is variable. Overall, its frequency in NSCLC is 2% in adenocarcinoma, 1% in squamous cell carcinoma, 6% in adenosquamous carcinoma and 13% in PSC.…”

Section: Recent Insights Into Psc Genetic and Transcriptional Featuresmentioning

confidence: 99%

“…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%

See 1 more Smart Citation

<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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Clinicopathological implications of MET exon 14 mutations in non-small cell lung cancer – A systematic review and meta-analysis

Cited by 104 publications

References 34 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

Sarcomatoid carcinoma in cytology: Report of a rare entity presenting in pleural and pericardial fluid preparations

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

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