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Mechanisms of acquired resistance to afatinib clarified with liquid biopsy

Although mechanisms of acquired resistance to 1(st) and 3(rd) generation EGFR-TKI continue to be elucidated, there have been few clinical investigations into the mechanisms of acquired resistance to the 2(nd) generation EGFR-TKI afatinib. We analyzed data from 20 patients with advanced lung adenocar...

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Autores principales: Nakamura, Tomomi, Nakashima, Chiho, Komiya, Kazutoshi, Kitera, Kazuki, Hirai, Mitsuharu, Kimura, Shinya, Aragane, Naoko
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6294373/
https://www.ncbi.nlm.nih.gov/pubmed/30550608
http://dx.doi.org/10.1371/journal.pone.0209384
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author Nakamura, Tomomi
Nakashima, Chiho
Komiya, Kazutoshi
Kitera, Kazuki
Hirai, Mitsuharu
Kimura, Shinya
Aragane, Naoko
author_facet Nakamura, Tomomi
Nakashima, Chiho
Komiya, Kazutoshi
Kitera, Kazuki
Hirai, Mitsuharu
Kimura, Shinya
Aragane, Naoko
author_sort Nakamura, Tomomi
collection PubMed
description Although mechanisms of acquired resistance to 1(st) and 3(rd) generation EGFR-TKI continue to be elucidated, there have been few clinical investigations into the mechanisms of acquired resistance to the 2(nd) generation EGFR-TKI afatinib. We analyzed data from 20 patients with advanced lung adenocarcinoma who acquired resistance to afatinib, including resistance during EGFR-TKI re-challenge. We examined EGFR T790M and C797S mutations, BRAF V600E mutation, and MET amplification with the MBP-QP method and with droplet digital PCR using ctDNA and re-biopsy samples obtained before and after afatinib treatment. Just before afatinib treatment, 15 of the 20 patients were T790M negative and five were positive. Among the T790M negative patients, 40.0% (6/15) became positive at the time of PD under afatinib. In patients positive for T790M, changes in T790M allele frequency were correlated with afatinib treatment efficacy. C797S was not detected in any patients just before afatinib treatment, but it appeared after treatment in three patients, although with very low allele frequency. Two of these three patients, although positive for both C797S and T790M, achieved PR to osimertinib. However, PFS of these patients was somewhat shorter than that of patients positive for T790M only. BRAF V600E was detected in one patient at PD under afatinib. MET amplification was not detected in this study. T790M is associated with acquired resistance to afatinib, as with 1(st) generation EGFR-TKI, but with somewhat lower frequency. The influence of C797S on resistance to afatinib is less than that of T790M, but C797S might cause shorter PFS under osimertinib.
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spelling pubmed-62943732018-12-28 Mechanisms of acquired resistance to afatinib clarified with liquid biopsy Nakamura, Tomomi Nakashima, Chiho Komiya, Kazutoshi Kitera, Kazuki Hirai, Mitsuharu Kimura, Shinya Aragane, Naoko PLoS One Research Article Although mechanisms of acquired resistance to 1(st) and 3(rd) generation EGFR-TKI continue to be elucidated, there have been few clinical investigations into the mechanisms of acquired resistance to the 2(nd) generation EGFR-TKI afatinib. We analyzed data from 20 patients with advanced lung adenocarcinoma who acquired resistance to afatinib, including resistance during EGFR-TKI re-challenge. We examined EGFR T790M and C797S mutations, BRAF V600E mutation, and MET amplification with the MBP-QP method and with droplet digital PCR using ctDNA and re-biopsy samples obtained before and after afatinib treatment. Just before afatinib treatment, 15 of the 20 patients were T790M negative and five were positive. Among the T790M negative patients, 40.0% (6/15) became positive at the time of PD under afatinib. In patients positive for T790M, changes in T790M allele frequency were correlated with afatinib treatment efficacy. C797S was not detected in any patients just before afatinib treatment, but it appeared after treatment in three patients, although with very low allele frequency. Two of these three patients, although positive for both C797S and T790M, achieved PR to osimertinib. However, PFS of these patients was somewhat shorter than that of patients positive for T790M only. BRAF V600E was detected in one patient at PD under afatinib. MET amplification was not detected in this study. T790M is associated with acquired resistance to afatinib, as with 1(st) generation EGFR-TKI, but with somewhat lower frequency. The influence of C797S on resistance to afatinib is less than that of T790M, but C797S might cause shorter PFS under osimertinib. Public Library of Science 2018-12-14 /pmc/articles/PMC6294373/ /pubmed/30550608 http://dx.doi.org/10.1371/journal.pone.0209384 Text en © 2018 Nakamura et al http://creativecommons.org/licenses/by/4.0/ This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
spellingShingle Research Article
Nakamura, Tomomi
Nakashima, Chiho
Komiya, Kazutoshi
Kitera, Kazuki
Hirai, Mitsuharu
Kimura, Shinya
Aragane, Naoko
Mechanisms of acquired resistance to afatinib clarified with liquid biopsy
title Mechanisms of acquired resistance to afatinib clarified with liquid biopsy
title_full Mechanisms of acquired resistance to afatinib clarified with liquid biopsy
title_fullStr Mechanisms of acquired resistance to afatinib clarified with liquid biopsy
title_full_unstemmed Mechanisms of acquired resistance to afatinib clarified with liquid biopsy
title_short Mechanisms of acquired resistance to afatinib clarified with liquid biopsy
title_sort mechanisms of acquired resistance to afatinib clarified with liquid biopsy
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6294373/
https://www.ncbi.nlm.nih.gov/pubmed/30550608
http://dx.doi.org/10.1371/journal.pone.0209384
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