Wagener-Ryczek, Svenja, Heydt, Carina, Sueptitz, Juliane, Michels, Sebastian, Falk, Markus, Alidousty, Christina, Fassunke, Jana, Ihle, Michaela Angelika, Tiemann, Markus, Heukamp, Lukas, Wolf, Juergen, Buettner, Reinhard and Merkelbach-Bruse, Sabine (2020). Mutational spectrum of acquired resistance to reversible versus irreversible EGFR tyrosine kinase inhibitors. BMC Cancer, 20 (1). LONDON: BMC. ISSN 1471-2407

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Abstract

BackgroundOver the past years, EGFR tyrosine kinase inhibitors (TKI) revolutionized treatment response. 1st-generation (reversible) EGFR TKI and later the 2nd -generation irreversible EGFR TKI Afatinib were aimed to improve treatment response. Nevertheless, diverse resistance mechanisms develop within the first year of therapy. Here, we evaluate the prevalence of acquired resistance mechanisms towards reversible and irreversible EGFR TKI.MethodsRebiopsies of patients after progression to EGFR TKI therapy (>6months) were targeted to histological and molecular analysis. Multiplexed targeted sequencing (NGS) was conducted to identify acquired resistance mutations (e.g. EGFR p.T790M). Further, Fluorescence in situ hybridisation (FISH) was applied to investigate the status of bypass mechanisms like, MET or HER2 amplification.ResultsOne hundred twenty-three rebiopsy samples of patients that underwent first-line EGFR TKI therapy (PFS >= 6months) were histologically and molecularly profiled upon clinical progression. The EGFR p.T790M mutation is the major mechanism of acquired resistance in patients treated with reversible as well as irreversible EGFR TKI. Nevertheless a statistically significant difference for the acquisition of T790M mutation has been identified: 45% of afatinib- vs 65% of reversible EGFR TKI treated patients developed a T790M mutation (p-value 0.02). Progression free survival (PFS) was comparable in patients treated with irreversible EGFR irrespective of the sensitising primary mutation or the acquisition of p.T790M.ConclusionsThe EGFR p.T790M mutation is the most prominent mechanism of resistance to reversible and irreversible EGFR TKI therapy. Nevertheless there is a statistically significant difference of p.T790M acquisition between the two types of TKI, which might be of importance for clinical therapy decision.

Item Type: Journal Article
Creators:
CreatorsEmailORCIDORCID Put Code
Wagener-Ryczek, SvenjaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Heydt, CarinaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Sueptitz, JulianeUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Michels, SebastianUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Falk, MarkusUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Alidousty, ChristinaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Fassunke, JanaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Ihle, Michaela AngelikaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Tiemann, MarkusUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Heukamp, LukasUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Wolf, JuergenUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Buettner, ReinhardUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Merkelbach-Bruse, SabineUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
URN: urn:nbn:de:hbz:38-333938
DOI: 10.1186/s12885-020-06920-3
Journal or Publication Title: BMC Cancer
Volume: 20
Number: 1
Date: 2020
Publisher: BMC
Place of Publication: LONDON
ISSN: 1471-2407
Language: English
Faculty: Unspecified
Divisions: Unspecified
Subjects: no entry
Uncontrolled Keywords:
KeywordsLanguage
CELL LUNG-CANCER; TKI THERAPY; AFATINIB; ADENOCARCINOMA; MECHANISMS; GEFITINIB; AMPLIFICATION; OSIMERTINIB; STRATEGIES; ERLOTINIBMultiple languages
OncologyMultiple languages
URI: http://kups.ub.uni-koeln.de/id/eprint/33393

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