BACKGROUND: Mesenchymal-to-epithelial transition (MET) exon 14 skipping mutations and MET gene amplification occur in 3-5% of non-small cell lung cancer (NSCLC) patients. Tyrosine kinase inhibitors (TKIs) targeting MET alterations have shown promising results in these patients. OBJECTIVE: The aim of this study was to describe the genomic profile, PD-L1 expression and clinicopathological features of MET dysregulated NSCLC. PATIENTS AND METHODS: We identified 188 patients with advanced-stage NSCLC with data on MET expression by immunohistochemistry (IHC). IHC for PD-L1 expression was performed in 131 patient samples, and next-generation sequencing (NGS) analysis was performed in 109 patient samples. RESULTS: MET exon 14 skipping alterations were identified in 16 (14.7%) samples, MET amplifications with cut-off ≥4 copy number variations were identified in 11 (10.1%) samples, and an oncogenic MET mutation (MET p.D1228N) was identified in 1 (0.9%) sample. 12/15 tumors (80.0%) harboring MET exon 14 alterations and 7/11 (63.6%) MET-amplified tumors expressed PD-L1 in ≥1% of tumor cells. Tumors harboring MET exon 14 skipping alterations expressed PD-L1 more frequently than MET wild-type IHC-positive tumors (p = 0.045). Twenty-five percent of MET exon 14-altered cases and 33% of MET-amplified cases harbored potentially targetable oncogenic co-mutations in KRAS, BRAF, and EGFR. The most frequent co-occurring mutations in all MET-altered tumors were TP53, KRAS, BRAF, and CDK4. CONCLUSIONS: We demonstrated that MET exon 14 skipping alterations and MET amplification are not mutually exclusive to other oncogenic co-mutations, and report the association of genomic MET alterations with PD-L1 expression. Since genomic MET alterations are emerging targets requiring upfront treatment, optimal understanding of the co-mutational landscape for this patient population is needed.
BACKGROUND: Mesenchymal-to-epithelial transition (MET) exon 14 skipping mutations and MET gene amplification occur in 3-5% of non-small cell lung cancer (NSCLC) patients. Tyrosine kinase inhibitors (TKIs) targeting MET alterations have shown promising results in these patients. OBJECTIVE: The aim of this study was to describe the genomic profile, PD-L1 expression and clinicopathological features of MET dysregulated NSCLC. PATIENTS AND METHODS: We identified 188 patients with advanced-stage NSCLC with data on MET expression by immunohistochemistry (IHC). IHC for PD-L1 expression was performed in 131 patient samples, and next-generation sequencing (NGS) analysis was performed in 109 patient samples. RESULTS: MET exon 14 skipping alterations were identified in 16 (14.7%) samples, MET amplifications with cut-off ≥4 copy number variations were identified in 11 (10.1%) samples, and an oncogenic MET mutation (MET p.D1228N) was identified in 1 (0.9%) sample. 12/15 tumors (80.0%) harboring MET exon 14 alterations and 7/11 (63.6%) MET-amplified tumors expressed PD-L1 in ≥1% of tumor cells. Tumors harboring MET exon 14 skipping alterations expressed PD-L1 more frequently than MET wild-type IHC-positive tumors (p = 0.045). Twenty-five percent of MET exon 14-altered cases and 33% of MET-amplified cases harbored potentially targetable oncogenic co-mutations in KRAS, BRAF, and EGFR. The most frequent co-occurring mutations in all MET-altered tumors were TP53, KRAS, BRAF, and CDK4. CONCLUSIONS: We demonstrated that MET exon 14 skipping alterations and MET amplification are not mutually exclusive to other oncogenic co-mutations, and report the association of genomic MET alterations with PD-L1 expression. Since genomic MET alterations are emerging targets requiring upfront treatment, optimal understanding of the co-mutational landscape for this patient population is needed.
Authors: Ermanno Gherardi; Mark E Youles; Ricardo N Miguel; Tom L Blundell; Luisa Iamele; Julian Gough; Abhishek Bandyopadhyay; Guido Hartmann; P Jonathan G Butler Journal: Proc Natl Acad Sci U S A Date: 2003-10-03 Impact factor: 11.205
Authors: Mark M Awad; Geoffrey R Oxnard; David M Jackman; Daniel O Savukoski; Dimity Hall; Priyanka Shivdasani; Jennifer C Heng; Suzanne E Dahlberg; Pasi A Jänne; Suman Verma; James Christensen; Peter S Hammerman; Lynette M Sholl Journal: J Clin Oncol Date: 2016-01-04 Impact factor: 44.544
Authors: Sumanta K Pal; Siraj M Ali; Evgeny Yakirevich; Daniel M Geynisman; Jose A Karam; Julia A Elvin; Garrett M Frampton; Xuan Huang; Douglas I Lin; Mark Rosenzweig; Doron Lipson; Philip J Stephens; Jeffrey S Ross; Vincent A Miller; Neeraj Agarwal; Brian Shuch; Toni K Choueiri; Jon H Chung Journal: Eur Urol Date: 2017-06-04 Impact factor: 20.096
Authors: D P Bottaro; J S Rubin; D L Faletto; A M Chan; T E Kmiecik; G F Vande Woude; S A Aaronson Journal: Science Date: 1991-02-15 Impact factor: 47.728
Authors: Jeffrey A Engelman; Kreshnik Zejnullahu; Tetsuya Mitsudomi; Youngchul Song; Courtney Hyland; Joon Oh Park; Neal Lindeman; Christopher-Michael Gale; Xiaojun Zhao; James Christensen; Takayuki Kosaka; Alison J Holmes; Andrew M Rogers; Federico Cappuzzo; Tony Mok; Charles Lee; Bruce E Johnson; Lewis C Cantley; Pasi A Jänne Journal: Science Date: 2007-04-26 Impact factor: 47.728