Michels, Sebastian, Heydt, Carina, van Veggel, Bianca, Deschler-Baier, Barbara, Pardo, Nuria, Monkhorst, Kim, Ruesseler, 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, Braegelmann, Johannes, Sebastian, Martin, Vrugt, Bart, Hellmich, Martin, Sos, Martin L., Heukamp, Lukas C., Felip, Enriqueta, Merkelbach-Bruse, Sabine, Smit, Egbert F., Buettner, Reinhard and Wolf, Juergen (2019). 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. JCO Precis. Oncol., 3. ALEXANDRIA: AMER SOC CLINICAL ONCOLOGY. ISSN 2473-4284

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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. (C) 2019 by American Society of Clinical Oncology

Item Type: Journal Article
Creators:
CreatorsEmailORCIDORCID Put Code
Michels, SebastianUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Heydt, CarinaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
van Veggel, BiancaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Deschler-Baier, BarbaraUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Pardo, NuriaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Monkhorst, KimUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Ruesseler, VanessaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Stratmann, JanUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Griesinger, FrankUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Steinhauser, SusanneUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kostenko, AnnaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Diebold, JoachimUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Fassunke, JanaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Fischer, RiekeUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Engel-Riedel, WalburgaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Gautschi, OliverUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Geissinger, EvaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Haneder, StefanUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Ihle, Michaela A.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kopp, Hans-GeorgUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
de Langen, Adrianus J.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Martinez-Marti, AlexUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Nogova, LuciaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Persigehl, ThorstenUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Plenker, DennisUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Puesken, MichaelUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Rodermann, ErnstUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Rosenwald, AndreasUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Scheel, Andreas H.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Scheffler, MatthiasUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Spengler, WernerUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Seggewiss-Bernhardt, RuthUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Braegelmann, JohannesUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Sebastian, MartinUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Vrugt, BartUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hellmich, MartinUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Sos, Martin L.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Heukamp, Lukas C.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Felip, EnriquetaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Merkelbach-Bruse, SabineUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Smit, Egbert F.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Buettner, ReinhardUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Wolf, JuergenUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
URN: urn:nbn:de:hbz:38-153358
DOI: 10.1200/PO.18.00210
Journal or Publication Title: JCO Precis. Oncol.
Volume: 3
Date: 2019
Publisher: AMER SOC CLINICAL ONCOLOGY
Place of Publication: ALEXANDRIA
ISSN: 2473-4284
Language: English
Faculty: Unspecified
Divisions: Unspecified
Subjects: no entry
Uncontrolled Keywords:
KeywordsLanguage
EGFR MUTATION; 1ST-LINE TREATMENT; OPEN-LABEL; AZD9291; ADENOCARCINOMA; TP53; CHEMOTHERAPY; GEFITINIB; EMERGENCE; HETEROGENEITYMultiple languages
OncologyMultiple languages
Refereed: Yes
URI: http://kups.ub.uni-koeln.de/id/eprint/15335

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