Anna Kron1, Matthias Scheffler1, Carina Heydt2, Lea Ruge1, Carsten Schaepers1, Anna-Kristina Eisert1, Sabine Merkelbach-Bruse2, Richard Riedel1, Lucia Nogova1, Rieke Nila Fischer1, Sebastian Michels1, Diana S Y Abdulla1, Sophia Koleczko1, Jana Fassunke2, Anne M Schultheis2, Florian Kron3, Frank Ueckeroth2, Gabriele Wessling2, Juliane Sueptitz1, Frank Beckers4, Jan Braess5, Jens Panse6, Christian Grohé7, Michael Hamm8, Hans-Joachim Kabitz9, Kato Kambartel10, Britta Kaminsky11, Stefan Krueger12, Clemens Schulte13, Joachim Lorenz14, Johann Lorenzen15, Wolfram Meister16, Andreas Meyer17, Jutta Kappes18, Niels Reinmuth19, Bernhard Schaaf20, Wolfgang Schulte21, Monika Serke22, Reinhard Buettner2, Jürgen Wolf23. 1. Network Genomic Medicine, Cologne, Germany; Department I of Internal Medicine, Center for Integrated Oncology Aachen Bonn Cologne Duesseldorf, University Hospital of Cologne, Cologne, Germany. 2. Network Genomic Medicine, Cologne, Germany; Institute of Pathology, Center for Integrated Oncology Aachen Bonn Cologne Duesseldorf, University Hospital of Cologne, Cologne, Germany. 3. Network Genomic Medicine, Cologne, Germany; Department I of Internal Medicine, Center for Integrated Oncology Aachen Bonn Cologne Duesseldorf, University Hospital of Cologne, Cologne, Germany; FOM University of Applied Sciences, Essen, Germany. 4. Network Genomic Medicine, Cologne, Germany; Department of Thoracic Surgery, St. Vinzenz-Hospital Cologne, Cologne, Germany. 5. Network Genomic Medicine, Cologne, Germany; Department of Hematology and Oncology, Hospital Barmherzige Brueder Regensburg, Regensburg, Germany. 6. Network Genomic Medicine, Cologne, Germany; Department of Internal Medicine IV, Center for Integrated Oncology Aachen Bonn Cologne Duesseldorf, University Hospital RWTH Aachen, Aachen, Germany. 7. Network Genomic Medicine, Cologne, Germany; Department of Pneumology, Evangelische Lungenklinik Berlin, Berlin, Germany. 8. Network Genomic Medicine, Cologne, Germany; Department of Pneumology and Respiratory Medicine, Helios Medical Center of Hildesheim, Hildesheim, Germany. 9. Network Genomic Medicine, Cologne, Germany; Department of Internal Medicine II, Clinic of Konstanz, Konstanz, Germany. 10. Network Genomic Medicine, Cologne, Germany; Department of Thoracic Oncology and Interventional Bronchology, Hospital Bethanien Moers, Moers, Germany. 11. Network Genomic Medicine, Cologne, Germany; Department of Pneumonology and Allergology, Hospital Bethanien Solingen, Solingen, Germany. 12. Network Genomic Medicine, Cologne, Germany; Department of Pneumonology, Florence-Nightingale Hospital Düsseldorf, Düsseldorf, Germany. 13. Network Genomic Medicine, Cologne, Germany; Joint Private Practice for Hematology/Oncology, Dortmund, Germany. 14. Network Genomic Medicine, Cologne, Germany; Department of Pneumology, Hospital Luedenscheid, Luedenscheid, Germany. 15. Network Genomic Medicine, Cologne, Germany; Department of Pathology, Hospital Dortmund, Dortmund, Germany. 16. Network Genomic Medicine, Cologne, Germany; Department of Thoracic Oncology and Interventional Bronchology, Helios Medical Center of Hildesheim, Hildesheim, Germany. 17. Network Genomic Medicine, Cologne, Germany; Department of Pulmonary Medicine, Maria Hilf Hospital GmbH, Moenchengladbach, Germany. 18. Network Genomic Medicine, Cologne, Germany; Department of Internal Medicine and Pneumology, Catholic Hospital Koblenz, Koblenz, Germany. 19. Network Genomic Medicine, Cologne, Germany; Department of Oncology, Asklepios Clinic Munich-Gauting, Munich-Gauting, Germany. 20. Network Genomic Medicine, Cologne, Germany; Department of Respiratory Medicine and Infectious Diseases, Medical Center North of Dortmund, Dortmund, Germany. 21. Network Genomic Medicine, Cologne, Germany; Department of Pneumology and Allergology, GFO Clinic Bonn, Bonn, Germany. 22. Network Genomic Medicine, Cologne, Germany; Department of Pneumology and Oncology, Evangelic Hospital Hamm, Hamm, Germany. 23. Network Genomic Medicine, Cologne, Germany; Department I of Internal Medicine, Center for Integrated Oncology Aachen Bonn Cologne Duesseldorf, University Hospital of Cologne, Cologne, Germany. Electronic address: juergen.wolf@uk-koeln.de.
Abstract
INTRODUCTION: Robust data on the outcome of MET-aberrant NSCLC with nontargeted therapies are limited, especially in consideration of the heterogeneity of MET-amplified tumors (METamp). METHODS: A total of 337 tumor specimens of patients with MET-altered Union for International Cancer Control stage IIIB/IV NSCLC were analyzed using next-generation sequencing, fluorescence in situ hybridization, and immunohistochemistry. The evaluation focused on the type of MET aberration, co-occurring mutations, programmed death-ligand 1 expression, and overall survival (OS). RESULTS: METamp tumors (n = 278) had a high frequency of co-occurring mutations (>80% for all amplification levels), whereas 57.6% of the 59 patients with MET gene and exon 14 (METex14) tumors had no additional mutations. In the METamp tumors, with increasing gene copy number (GCN), the frequency of inactivating TP53 mutations increased (GCN < 4: 58.2%; GCN ≥ 10: 76.5%), whereas the frequency of KRAS mutations decreased (GCN < 4: 43.2%; GCN ≥ 10: 11.8%). A total of 10.1% of all the METamp tumors with a GCN ≥ 10 had a significant worse OS (4.0 mo; 95% CI: 1.9-6.0) compared with the tumors with GCN < 10 (12.0 mo; 95% confidence interval [CI]: 9.4-14.6). In the METamp NSCLC, OS with immune checkpoint inhibitor (ICI) therapy was significantly better compared with chemotherapy with 19.0 months (95% CI: 15.8-22.2) versus 8.0 months (95% CI: 5.8-10.2, p < 0.0001). No significant difference in median OS was found between ICI therapy and chemotherapy in the patients with METex14 (p = 0.147). CONCLUSIONS: METex14, METamp GCN ≥ 10, and METamp GCN < 10 represent the subgroups of MET-dysregulated NSCLC with distinct molecular and clinical features. The patients with METex14 do not seem to benefit from immunotherapy in contrast to the patients with METamp, which is of particular relevance for the prognostically poor METamp GCN ≥ 10 subgroup.
INTRODUCTION: Robust data on the outcome of MET-aberrant NSCLC with nontargeted therapies are limited, especially in consideration of the heterogeneity of MET-amplified tumors (METamp). METHODS: A total of 337 tumor specimens of patients with MET-altered Union for International Cancer Control stage IIIB/IV NSCLC were analyzed using next-generation sequencing, fluorescence in situ hybridization, and immunohistochemistry. The evaluation focused on the type of MET aberration, co-occurring mutations, programmed death-ligand 1 expression, and overall survival (OS). RESULTS: METamp tumors (n = 278) had a high frequency of co-occurring mutations (>80% for all amplification levels), whereas 57.6% of the 59 patients with MET gene and exon 14 (METex14) tumors had no additional mutations. In the METamp tumors, with increasing gene copy number (GCN), the frequency of inactivating TP53 mutations increased (GCN < 4: 58.2%; GCN ≥ 10: 76.5%), whereas the frequency of KRAS mutations decreased (GCN < 4: 43.2%; GCN ≥ 10: 11.8%). A total of 10.1% of all the METamp tumors with a GCN ≥ 10 had a significant worse OS (4.0 mo; 95% CI: 1.9-6.0) compared with the tumors with GCN < 10 (12.0 mo; 95% confidence interval [CI]: 9.4-14.6). In the METamp NSCLC, OS with immune checkpoint inhibitor (ICI) therapy was significantly better compared with chemotherapy with 19.0 months (95% CI: 15.8-22.2) versus 8.0 months (95% CI: 5.8-10.2, p < 0.0001). No significant difference in median OS was found between ICI therapy and chemotherapy in the patients with METex14 (p = 0.147). CONCLUSIONS:METex14, METamp GCN ≥ 10, and METamp GCN < 10 represent the subgroups of MET-dysregulated NSCLC with distinct molecular and clinical features. The patients with METex14 do not seem to benefit from immunotherapy in contrast to the patients with METamp, which is of particular relevance for the prognostically poor METamp GCN ≥ 10 subgroup.
Authors: Maximilian Boesch; Florent Baty; Werner C Albrich; Lukas Flatz; Regulo Rodriguez; Sacha I Rothschild; Markus Joerger; Martin Früh; Martin H Brutsche Journal: Oncoimmunology Date: 2021-12-10 Impact factor: 8.110
Authors: Parneet K Cheema; Shantanu O Banerji; Normand Blais; Quincy S-C Chu; Patrice Desmeules; Rosalyn A Juergens; Natasha B Leighl; Brandon S Sheffield; Paul F Wheatley-Price; Barbara L Melosky Journal: Curr Oncol Date: 2021-11-09 Impact factor: 3.677