Genetic Heterogeneity of MET-Aberrant NSCLC and Its Impact on the Outcome of Immunotherapy
| Autor: | Jan Braess, Frank Ueckeroth, Diana S.Y. Abdulla, Carina Heydt, Anna-Kristina Eisert, Frank Beckers, Wolfram Meister, Hans-Joachim Kabitz, Johann Lorenzen, Monika Serke, Sabine Merkelbach-Bruse, Sebastian Michels, Jana Fassunke, Florian Kron, A. Meyer, Gabriele Wessling, Lucia Nogova, Bernhard Schaaf, Juliane Sueptitz, Matthias Scheffler, Carsten Schaepers, Sophia Koleczko, Reinhard Buettner, Clemens Schulte, Britta Kaminsky, Richard F. Riedel, Anna Kron, Stefan Krueger, Wolfgang Schulte, Joachim Lorenz, Michael Hamm, Kato Kambartel, Anne M. Schultheis, Christian Grohé, Jürgen Wolf, Lea Ruge, Jutta Kappes, Jens Panse, Niels Reinmuth, Rieke Fischer |
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| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
Pulmonary and Respiratory Medicine Lung Neoplasms medicine.medical_treatment MET Exon 14 Mutation 03 medical and health sciences Exon Genetic Heterogeneity 0302 clinical medicine medicine Humans Copy-number variation Gene In Situ Hybridization Fluorescence medicine.diagnostic_test business.industry Genetic heterogeneity Immunotherapy Proto-Oncogene Proteins c-met 030104 developmental biology Oncology 030220 oncology & carcinogenesis Mutation Cancer research Immunohistochemistry business Fluorescence in situ hybridization |
| Zdroj: | Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer. 16(4) |
| ISSN: | 1556-1380 |
| Popis: | 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).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).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 (GCN4: 58.2%; GCN ≥ 10: 76.5%), whereas the frequency of KRAS mutations decreased (GCN4: 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 GCN10 (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, p0.0001). No significant difference in median OS was found between ICI therapy and chemotherapy in the patients with METex14 (p = 0.147).METex14, METamp GCN ≥ 10, and METamp GCN10 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. |
| Databáze: | OpenAIRE |
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