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Genomic Profiling Identifies Outcome-Relevant Mechanisms of Innate and Acquired Resistance to Third-Generation Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor Therapy in Lung Cancer

PURPOSE: Third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) are effective in acquired resistance (AR) to early-generation EGFR TKIs in EGFR-mutant lung cancer. However, efficacy is marked by interindividual heterogeneity. We present the molecular profiles of p...

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Detalles Bibliográficos
Autores principales: Michels, Sebastian, Heydt, Carina, van Veggel, Bianca, Deschler-Baier, Barbara, Pardo, Nuria, Monkhorst, Kim, Rüsseler, Vanessa, Stratmann, Jan, Griesinger, Frank, Steinhauser, Susanne, Kostenko, Anna, Diebold, Joachim, Fassunke, Jana, Fischer, Rieke, Engel-Riedel, Walburga, Gautschi, Oliver, Geissinger, Eva, Haneder, Stefan, Ihle, Michaela A., Kopp, Hans-Georg, de Langen, Adrianus J., Martinez-Marti, Alex, Nogova, Lucia, Persigehl, Thorsten, Plenker, Dennis, Puesken, Michael, Rodermann, Ernst, Rosenwald, Andreas, Scheel, Andreas H., Scheffler, Matthias, Spengler, Werner, Seggewiss-Bernhardt, Ruth, Brägelmann, Johannes, Sebastian, Martin, Vrugt, Bart, Hellmich, Martin, Sos, Martin L., Heukamp, Lukas C., Felip, Enriqueta, Merkelbach-Bruse, Sabine, Smit, Egbert F., Büttner, Reinhard, Wolf, Jürgen
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Society of Clinical Oncology 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7446436/
https://www.ncbi.nlm.nih.gov/pubmed/32914023
http://dx.doi.org/10.1200/PO.18.00210
Descripción
Sumario:PURPOSE: Third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) are effective in acquired resistance (AR) to early-generation EGFR TKIs in EGFR-mutant lung cancer. However, efficacy is marked by interindividual heterogeneity. We present the molecular profiles of pretreatment and post-treatment samples from patients treated with third-generation EGFR TKIs and their impact on treatment outcomes. METHODS: Using the databases of two lung cancer networks and two lung cancer centers, we molecularly characterized 124 patients with EGFR p.T790M-positive AR to early-generation EGFR TKIs. In 56 patients, correlative analyses of third-generation EGFR TKI treatment outcomes and molecular characteristics were feasible. In addition, matched post-treatment biopsy samples were collected for 29 patients with progression to third-generation EGFR TKIs. RESULTS: Co-occurring genetic aberrations were found in 74.4% of EGFR p.T790-positive samples (n = 124). Mutations in TP53 were the most frequent aberrations detected (44.5%; n = 53) and had no significant impact on third-generation EGFR TKI treatment. Mesenchymal-epithelial transition factor (MET) amplifications were found in 5% of samples (n = 6) and reduced efficacy of third-generation EGFR TKIs significantly (eg, median progression-free survival, 1.0 months; 95% CI, 0.37 to 1.72 v 8.2 months; 95% CI, 1.69 to 14.77 months; P ≤ .001). Genetic changes in the 29 samples with AR to third-generation EGFR TKIs were found in EGFR (eg, p.T790M loss, acquisition of p.C797S or p.G724S) or in other genes (eg, MET amplification, KRAS mutations). CONCLUSION: Additional genetic aberrations are frequent in EGFR-mutant lung cancer and may mediate innate and AR to third-generation EGFR TKIs. MET amplification was strongly associated with primary treatment failure and was a common mechanism of AR to third-generation EGFR TKIs. Thus, combining EGFR inhibitors with TKIs targeting common mechanisms of resistance may delay AR.