Kron, Anna, Scheffler, Matthias, Heydt, Carina, Ruge, Lea, Schaepers, Carsten, Eisert, Anna-Kristina, Merkelbach-Bruse, Sabine, Riedel, Richard, Nogova, Lucia, Fischer, Rieke Nila, Michels, Sebastian, Abdulla, Diana S. Y., Koleczko, Sophia, Fassunke, Jana, Schultheis, Anne M., Kron, Florian, Ueckeroth, Frank, Wessling, Gabriele, Sueptitz, Juliane, Beckers, Frank, Braess, Jan, Panse, Jens, Grohe, Christian, Hamm, Michael, Kabitz, Hans-Joachim, Kambartel, Kato, Kaminsky, Britta, Krueger, Stefan, Schulte, Clemens, Lorenz, Joachim, Lorenzen, Johann, Meister, Wolfram, Meyer, Andreas, Kappes, Jutta, Reinmuth, Niels, Schaaf, Bernhard, Schulte, Wolfgang, Serke, Monika, Buettner, Reinhard and Wolf, Juergen (2021). Genetic Heterogeneity of MET-Aberrant NSCLC and Its Impact on the Outcome of Immunotherapy. J. Thorac. Oncol., 16 (4). S. 572 - 583. NEW YORK: ELSEVIER SCIENCE INC. ISSN 1556-1380

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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. (c) 2020 Published by Elsevier Inc. on behalf of International Association for the Study of Lung Cancer.

Item Type: Journal Article
Creators:
CreatorsEmailORCIDORCID Put Code
Kron, AnnaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Scheffler, MatthiasUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Heydt, CarinaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Ruge, LeaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Schaepers, CarstenUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Eisert, Anna-KristinaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Merkelbach-Bruse, SabineUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Riedel, RichardUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Nogova, LuciaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Fischer, Rieke NilaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Michels, SebastianUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Abdulla, Diana S. Y.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Koleczko, SophiaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Fassunke, JanaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Schultheis, Anne M.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kron, FlorianUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Ueckeroth, FrankUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Wessling, GabrieleUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Sueptitz, JulianeUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Beckers, FrankUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Braess, JanUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Panse, JensUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Grohe, ChristianUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hamm, MichaelUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kabitz, Hans-JoachimUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kambartel, KatoUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kaminsky, BrittaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Krueger, StefanUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Schulte, ClemensUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Lorenz, JoachimUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Lorenzen, JohannUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Meister, WolframUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Meyer, AndreasUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kappes, JuttaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Reinmuth, NielsUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Schaaf, BernhardUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Schulte, WolfgangUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Serke, MonikaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Buettner, ReinhardUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Wolf, JuergenUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
URN: urn:nbn:de:hbz:38-601856
DOI: 10.1016/j.jtho.2020.11.017
Journal or Publication Title: J. Thorac. Oncol.
Volume: 16
Number: 4
Page Range: S. 572 - 583
Date: 2021
Publisher: ELSEVIER SCIENCE INC
Place of Publication: NEW YORK
ISSN: 1556-1380
Language: English
Faculty: Unspecified
Divisions: Unspecified
Subjects: no entry
Uncontrolled Keywords:
KeywordsLanguage
CELL LUNG-CANCER; MUTATIONS; AMPLIFICATION; TP53Multiple languages
Oncology; Respiratory SystemMultiple languages
URI: http://kups.ub.uni-koeln.de/id/eprint/60185

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