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      Brief Report: Tepotinib as a Treatment Option in MET Exon 14 Skipping-Positive Lung Cancers—Investigating Discordance Between ArcherMET and the Oncomine Dx Target Test

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          Abstract

          Introduction

          NSCLC is a leading cause of cancer-related mortality worldwide. Specific genetic alterations, such as MET exon 14 ( METex14) skipping, have been identified in NSCLC, allowing targeted therapy. Tepotinib, a highly selective MET inhibitor, has displayed promise in patients with advanced NSCLC. Nevertheless, challenges arise when identifying treatment strategies for patients with discordant results regarding METex14 skipping detection between diagnostic tests.

          Methods

          We investigated patients with NSCLC and discordant results for METex14 skipping between the Oncomine Dx Target Test (ODxTT) and ArcherMET. Clinical response, adverse events, and the duration of tepotinib treatment were assessed, and statistical analysis was performed.

          Results

          Among the 19 patients deemed METex14 skipping positive by ODxTT, only 10 had concordant results with ArcherMET. The number of METex14 skipping reads detected by ODxTT was significantly lower in discordant cases. Of the 19 patients, 14 received tepotinib, and comparable response and disease control rates were observed in both concordant and discordant cases. The duration of treatment did not significantly differ between the two groups.

          Conclusions

          Our findings suggest that tepotinib has comparable therapeutic effects in patients with METex14 skipping-positive NSCLC irrespective of the concordance of results between ODxTT and ArcherMET. Tepotinib is a possible treatment option for patients with METex14 skipping, even in patients with discordant test results.

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          Most cited references16

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          Comprehensive molecular profiling of lung adenocarcinoma

          Adenocarcinoma of the lung is the leading cause of cancer death worldwide. Here we report molecular profiling of 230 resected lung adenocarcinomas using messenger RNA, microRNA and DNA sequencing integrated with copy number, methylation and proteomic analyses. High rates of somatic mutation were seen (mean 8.9 mutations per megabase). Eighteen genes were statistically significantly mutated, including RIT1 activating mutations and newly described loss-of-function MGA mutations which are mutually exclusive with focal MYC amplification. EGFR mutations were more frequent in female patients, whereas mutations in RBM10 were more common in males. Aberrations in NF1, MET, ERBB2 and RIT1 occurred in 13% of cases and were enriched in samples otherwise lacking an activated oncogene, suggesting a driver role for these events in certain tumours. DNA and mRNA sequence from the same tumour highlighted splicing alterations driven by somatic genomic changes, including exon 14 skipping in MET mRNA in 4% of cases. MAPK and PI(3)K pathway activity, when measured at the protein level, was explained by known mutations in only a fraction of cases, suggesting additional, unexplained mechanisms of pathway activation. These data establish a foundation for classification and further investigations of lung adenocarcinoma molecular pathogenesis.
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            Comprehensive genomic characterization of squamous cell lung cancers

            Summary Lung squamous cell carcinoma (lung SqCC) is a common type of lung cancer, causing approximately 400,000 deaths per year worldwide. Genomic alterations in lung SqCC have not been comprehensively characterized and no molecularly targeted agents have been developed specifically for its treatment. As part of The Cancer Genome Atlas (TCGA), we profiled 178 lung SqCCs to provide a comprehensive landscape of genomic and epigenomic alterations. Lung SqCC is characterized by complex genomic alterations, with a mean of 360 exonic mutations, 165 genomic rearrangements, and 323 segments of copy number alteration per tumor. We found statistically recurrent mutations in 18 genes in including mutation of TP53 in nearly all specimens. Previously unreported loss-of-function mutations were seen in the HLA-A class I major histocompatibility gene. Significantly altered pathways included NFE2L2/KEAP1 in 34%, squamous differentiation genes in 44%, PI3K/AKT in 47%, and CDKN2A/RB1 in 72% of tumors. We identified a potential therapeutic target in the majority of tumors, offering new avenues of investigation for lung SqCC treatment.
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              Distinct patterns of somatic genome alterations in lung adenocarcinomas and squamous cell carcinomas

              To compare lung adenocarcinoma (ADC) and lung squamous cell carcinoma (SqCC) and to identify new drivers of lung carcinogenesis, we examined exome sequences and copy number profiles of 660 lung ADC and 484 lung SqCC tumor/normal pairs. Recurrent alterations in lung SqCCs were more similar to other squamous carcinomas than to lung ADCs. Novel significantly mutated genes included PPP3CA, DOT1L, and FTSJD1 in lung ADC, RASA1 in lung SqCC, and KLF5, EP300, and CREBBP in both tumor types. Novel amplification peaks encompassed MIR21 in lung ADC, MIR205 in lung SqCC, and MAPK1 in both. Lung ADCs lacking receptor tyrosine kinase/Ras/Raf alterations revealed mutations in SOS1, VAV1, RASA1, and ARHGAP35. Regarding neoantigens, 47% of the lung ADC and 53% of the lung SqCC tumors had at least 5 predicted neoepitopes. While targeted therapies for lung ADC and lung SqCC are largely distinct, immunotherapies may aid in treatment for both subtypes.
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                Author and article information

                Contributors
                Journal
                JTO Clin Res Rep
                JTO Clin Res Rep
                JTO Clinical and Research Reports
                Elsevier
                2666-3643
                29 April 2024
                June 2024
                29 April 2024
                : 5
                : 6
                : 100679
                Affiliations
                [a ]Lung Cancer and Respiratory Disease Center, Yamanashi Central Hospital, Yamanashi, Japan
                [b ]Genome Analysis Center, Yamanashi Central Hospital, Yamanashi, Japan
                [c ]Division of Genetics and Clinical Laboratory, Yamanashi Central Hospital, Yamanashi, Japan
                [d ]Pathology Division, Laboratory Department, Yamanashi Central Hospital, Yamanashi, Japan
                [e ]Department of Gastroenterology, Yamanashi Central Hospital, Yamanashi, Japan
                [f ]The University of Tokyo, Tokyo, Japan
                Author notes
                []Corresponding author. Address for correspondence: Yosuke Hirotsu, PhD, Genome Analysis Center, Yamanashi Central Hospital, 1-1-1 Fujimi, Kofu, Yamanashi, 400-8506, Japan. hirotsu-bdyu@ 123456ych.pref.yamanashi.jp
                Article
                S2666-3643(24)00049-3 100679
                10.1016/j.jtocrr.2024.100679
                11150947
                38841537
                b7aea27c-4af7-43b8-a87b-44b34eb89a30
                © 2024 The Authors

                This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

                History
                : 16 June 2023
                : 15 April 2024
                : 18 April 2024
                Categories
                Brief Report

                lung cancer,met,tepotinib,oncomine,archer
                lung cancer, met, tepotinib, oncomine, archer

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