Mutational spectrum of acquired resistance to reversible versus irreversible EGFR tyrosine kinase inhibitors
| Autor: | Markus Falk, Christina Alidousty, Jürgen Wolf, Markus Tiemann, Sabine Merkelbach-Bruse, Sebastian Michels, Carina Heydt, Svenja Wagener-Ryczek, Lukas C. Heukamp, Juliane Süptitz, Reinhard Büttner, Michaela Angelika Ihle, Jana Fassunke |
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| Jazyk: | angličtina |
| Rok vydání: | 2020 |
| Předmět: |
Male
0301 basic medicine Cancer Research Lung Neoplasms Afatinib medicine.disease_cause NSCLC T790M 0302 clinical medicine Surgical oncology Carcinoma Non-Small-Cell Lung Medicine Molecular Targeted Therapy Aged 80 and over Mutation Gefitinib Middle Aged Prognosis lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens TKI ErbB Receptors Survival Rate Oncology Erlotinib 030220 oncology & carcinogenesis Female Research Article medicine.drug Adult EGFR lcsh:RC254-282 03 medical and health sciences Acquired resistance Biomarkers Tumor Genetics Humans Progression-free survival Protein Kinase Inhibitors Aged Retrospective Studies business.industry respiratory tract diseases 030104 developmental biology Drug Resistance Neoplasm Cancer research business Follow-Up Studies |
| Zdroj: | BMC Cancer, Vol 20, Iss 1, Pp 1-11 (2020) BMC Cancer |
| ISSN: | 1471-2407 |
| DOI: | 10.1186/s12885-020-06920-3 |
| Popis: | 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 (> 6 months) 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 ≥6 months) were histologically and molecularly profiled upon clinical progression. TheEGFRp.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 irreversibleEGFRirrespective of the sensitising primary mutation or the acquisition of p.T790M.ConclusionsTheEGFRp.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. |
| Databáze: | OpenAIRE |
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