Henning Reis1, Martin Metzenmacher2, Moritz Goetz1, Nikoleta Savvidou2, Kaid Darwiche3, Clemens Aigner4, Thomas Herold1, Wilfried E Eberhardt5, Charlotte Skiba2, Jörg Hense2, Isabel Virchow2, Daniela Westerwick1, Simon Bogner2, Saskia Ting1, Stefan Kasper2, Martin Stuschke6, Felix Nensa7, Ken Herrmann8, Thomas Hager1, Kurt W Schmid9, Martin Schuler10, Marcel Wiesweg2. 1. Institute of Pathology, West German Cancer Centre, University Hospital Essen, University of Duisburg-Essen, Essen, Germany. 2. Department of Medical Oncology, West German Cancer Centre, University Hospital Essen, University of Duisburg-Essen, Essen, Germany. 3. Department of Pulmonary Medicine, Section of Interventional Pneumology, Ruhrlandklinik - University Hospital Essen, University of Duisburg-Essen, Essen, Germany. 4. Department of Thoracic Surgery and Endoscopy, Ruhrlandklinik - University Hospital Essen, University of Duisburg-Essen, Essen, Germany. 5. Department of Medical Oncology, West German Cancer Centre, University Hospital Essen, University of Duisburg-Essen, Essen, Germany; Division of Thoracic Oncology, Ruhrlandklinik - University Hospital Essen, University of Duisburg-Essen, Essen, Germany. 6. Department of Radiotherapy, West German Cancer Centre, University Hospital Essen, University of Duisburg-Essen, Essen, Germany; German Cancer Consortium (DKTK), Partner Site University Hospital Essen, Essen, Germany. 7. Institute of Diagnostic and Interventional Radiology and Neuroradiology, West German Cancer Centre, University Hospital Essen, University of Duisburg-Essen, Essen, Germany. 8. German Cancer Consortium (DKTK), Partner Site University Hospital Essen, Essen, Germany; Department of Nuclear Medicine, University Hospital Essen, University of Duisburg-Essen, Essen, Germany. 9. Institute of Pathology, West German Cancer Centre, University Hospital Essen, University of Duisburg-Essen, Essen, Germany; German Cancer Consortium (DKTK), Partner Site University Hospital Essen, Essen, Germany. 10. Department of Medical Oncology, West German Cancer Centre, University Hospital Essen, University of Duisburg-Essen, Essen, Germany; Division of Thoracic Oncology, Ruhrlandklinik - University Hospital Essen, University of Duisburg-Essen, Essen, Germany; German Cancer Consortium (DKTK), Partner Site University Hospital Essen, Essen, Germany. Electronic address: martin.schuler@uk-essen.de.
Abstract
BACKGROUND: The receptor tyrosine kinase MET is implicated in malignant transformation, tumor progression, metastasis, and acquired treatment resistance. We conducted an analysis of the effect of MET expression and MET genomic aberrations on the outcome of patients with advanced or metastatic pulmonary adenocarcinomas prospectively enrolled in an institutional precision oncology program. PATIENTS AND METHODS: Standardized immunohistochemistry (IHC) analyses of MET and markers of pathway activation were available in 384 patients, and next-generation sequencing-based MET hotspot mutation analyses were available from 892 patients. Clinical data were retrieved with a median follow-up from initial diagnosis of 37 months. RESULTS: High MET expression, defined as MET IHC 3+ or MET H-Score in the upper quartile, was observed in 102 of 384 patients (26.6%). MET exon 14 mutations were only detected in 7 of 892 patients (0.78%). High MET expression correlated with activation markers of the mitogen-activated protein kinase (MAPK) and phosphatidylinositol 3-kinase/protein kinase B (PI3K/AKT) pathways only in cases without Kirsten rat sarcoma viral oncogene homolog (KRAS), epidermal growth factor receptor (EGFR), v-Raf murine sarcoma viral oncogene homolog B (BRAF), anaplastic lymphoma kinase (ALK) and proto-oncogene tyrosine-protein kinase ROS (ROS1) aberrations. There was no association of MET expression with outcome during chemotherapy. High MET expression negatively affected the outcome during EGFR-targeting therapy but was associated with more favorable results with programmed death 1/programmed death ligand 1 (PD-L1)-directed therapy, independent of smoking history, PD-L1 expression or KRAS mutation. Two patients with MET exon 14 mutation and high PD-L1 expression failed to respond to pembrolizumab. CONCLUSION: MET expression affects the outcomes of targeted therapies in non-small-cell lung cancer, thus supporting the development of biomarker-informed combination strategies. The interaction of MET expression and MET mutation with immune checkpoint inhibitor therapy is novel and merits further investigation.
BACKGROUND: The receptor tyrosine kinase MET is implicated in malignant transformation, tumor progression, metastasis, and acquired treatment resistance. We conducted an analysis of the effect of MET expression and MET genomic aberrations on the outcome of patients with advanced or metastatic pulmonary adenocarcinomas prospectively enrolled in an institutional precision oncology program. PATIENTS AND METHODS: Standardized immunohistochemistry (IHC) analyses of MET and markers of pathway activation were available in 384 patients, and next-generation sequencing-based MET hotspot mutation analyses were available from 892 patients. Clinical data were retrieved with a median follow-up from initial diagnosis of 37 months. RESULTS: High MET expression, defined as MET IHC 3+ or MET H-Score in the upper quartile, was observed in 102 of 384 patients (26.6%). MET exon 14 mutations were only detected in 7 of 892 patients (0.78%). High MET expression correlated with activation markers of the mitogen-activated protein kinase (MAPK) and phosphatidylinositol 3-kinase/protein kinase B (PI3K/AKT) pathways only in cases without Kirsten ratsarcoma viral oncogene homolog (KRAS), epidermal growth factor receptor (EGFR), v-Raf murine sarcoma viral oncogene homolog B (BRAF), anaplastic lymphoma kinase (ALK) and proto-oncogene tyrosine-protein kinase ROS (ROS1) aberrations. There was no association of MET expression with outcome during chemotherapy. High MET expression negatively affected the outcome during EGFR-targeting therapy but was associated with more favorable results with programmed death 1/programmed death ligand 1 (PD-L1)-directed therapy, independent of smoking history, PD-L1 expression or KRAS mutation. Two patients with MET exon 14 mutation and high PD-L1 expression failed to respond to pembrolizumab. CONCLUSION: MET expression affects the outcomes of targeted therapies in non-small-cell lung cancer, thus supporting the development of biomarker-informed combination strategies. The interaction of MET expression and MET mutation with immune checkpoint inhibitor therapy is novel and merits further investigation.
Authors: Alessa Fischer; Lorenz Bankel; Stefanie Hiltbrunner; Markus Rechsteiner; Jan H Rüschoff; Elisabeth Jane Rushing; Christian Britschgi; Alessandra Curioni-Fontecedro Journal: Target Oncol Date: 2022-09-22 Impact factor: 4.864
Authors: Anna Michelotti; Marco de Scordilli; Elisa Bertoli; Elisa De Carlo; Alessandro Del Conte; Alessandra Bearz Journal: Int J Mol Sci Date: 2022-06-17 Impact factor: 6.208
Authors: H S Abboud; D Camuzi; D C Rapozo; P V Fernandes; P Nicolau-Neto; S Guaraldi; T A Simão; L F Ribeiro Pinto; I M Gonzaga; S C Soares-Lima Journal: Braz J Med Biol Res Date: 2021-05-24 Impact factor: 2.590
Authors: Theresa A Boyle; Farah K Khalil; Mari Mino-Kenudson; Gabriel L Sica; Andre L Moreira; Lynette M Sholl; Mirna Z Knight; Liping Zhang; James Saller; Marileila Varella-Garcia; Lynne D Berry; Heidi Chen; Kim E Ellison; Christopher J Rivard; Kelly Kugler; Ignacio I Wistuba; Junya Fujimoto; David J Kwiatkowski; Paul A Bunn; Mark G Kris; Eric B Haura; Fred R Hirsch Journal: Appl Immunohistochem Mol Morphol Date: 2020-10