1. 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
- Author
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Anna Kostenko, Enriqueta Felip, Bianca van Veggel, Ruth Seggewiss-Bernhardt, Jürgen Wolf, Stefan Haneder, Reinhard Büttner, Vanessa Rüsseler, Eva Geissinger, Johannes Brägelmann, Andreas Rosenwald, Jan Stratmann, Michael Puesken, Matthias Scheffler, Michaela Angelika Ihle, Rieke Fischer, Egbert F. Smit, Martin L. Sos, N. Pardo, Frank Griesinger, Sabine Merkelbach-Bruse, Sebastian Michels, Andreas H. Scheel, Susanne Steinhauser, Hans-Georg Kopp, Lucia Nogova, Ernst Rodermann, Barbara Deschler-Baier, Alex Martinez-Marti, Jana Fassunke, Martin Hellmich, Thorsten Persigehl, Martin Sebastian, Adrianus J. de Langen, Werner Spengler, Carina Heydt, Kim Monkhorst, Walburga Engel-Riedel, Dennis Plenker, Joachim Diebold, Lukas C. Heukamp, Bart Vrugt, and Oliver Gautschi
- Subjects
0301 basic medicine ,Cancer Research ,Genomic profiling ,biology ,business.industry ,medicine.disease ,Third generation ,respiratory tract diseases ,03 medical and health sciences ,Egfr tki ,030104 developmental biology ,0302 clinical medicine ,Acquired resistance ,Oncology ,030220 oncology & carcinogenesis ,Cancer research ,biology.protein ,Original Report ,Medicine ,Epidermal growth factor receptor ,business ,Lung cancer ,Tyrosine kinase ,Epidermal growth factor receptor tyrosine kinase - Abstract
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.
- Published
- 2019