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Concomitant driver mutations in advanced EGFR-mutated non-small-cell lung cancer and their impact on erlotinib treatment
BACKGROUND: Patients with EGFR-mutated non-small-cell lung cancer benefit from EGFR tyrosine kinase inhibitors (TKIs) like erlotinib. However, the efficacy may be impaired by driver mutations in other genes. METHODS: Five hundred and fourteen consecutive patients with NSCLC of all stages were tested...
Autores principales: | , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Impact Journals LLC
2018
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5995236/ https://www.ncbi.nlm.nih.gov/pubmed/29899852 http://dx.doi.org/10.18632/oncotarget.25490 |
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author | Jakobsen, Jan Nyrop Santoni-Rugiu, Eric Grauslund, Morten Melchior, Linea Sørensen, Jens Benn |
author_facet | Jakobsen, Jan Nyrop Santoni-Rugiu, Eric Grauslund, Morten Melchior, Linea Sørensen, Jens Benn |
author_sort | Jakobsen, Jan Nyrop |
collection | PubMed |
description | BACKGROUND: Patients with EGFR-mutated non-small-cell lung cancer benefit from EGFR tyrosine kinase inhibitors (TKIs) like erlotinib. However, the efficacy may be impaired by driver mutations in other genes. METHODS: Five hundred and fourteen consecutive patients with NSCLC of all stages were tested for EGFR-mutations by cobas® EGFR Mutation Test. Fluorescent in situ hybridization (FISH) for MET-amplification, immunohistochemistry (IHC) for MET- and ALK-expression, and Next Generation Sequencing (NGS) for concomitant driver mutations were performed on EGFR-mutated tumor samples from erlotinib-treated patients. RESULTS: Thirty-six patients (7%) had EGFR-mutations, including 2 with intrinsic resistance mutation p.T790M together with the p.L858R sensitizing mutation and 1 harboring the p.G719C/S768I double-mutation. Twenty-three patients had either locally advanced or advanced disease and received first-line erlotinib-treatment. Concomitant driver mutations were found in 15/21 (71%) of NGS-analyzed TKI-treated NSCLCs, involving in 67% of cases TP53, in 13% CTNNB1, and in 7% KRAS, MET, SMAD4, PIK3CA, FGFR1, FGFR3, NRAS, DDR2, and ERBB4. No ALK-expression was found, whereas MET-overexpression and MET-amplification were observed in 5 and 4 patients, respectively. Objective responses occurred in 17/23 patients (74%), 4 did not respond (17%), and 2 harboring a SMAD4-mutation (p.R135(*)(stop)) and a FGFR3-mutation (p.D785fs(*)31), respectively, displayed mixed response with simultaneously progressing and responding tumors (8.7%). Thus, EGFR-mutated tumors harboring co-mutations were not less likely to respond. CONCLUSION: Co-mutations in other cancer-driver genes (oncogenes or tumor suppressor genes) were frequent in EGFR-mutated NSCLCs and few cases harbored concomitant activating and resistance EGFR-mutations before TKI-treatment. Most co-mutations did not impact the response to first-line erlotinib-treatment, but may represent potential additional therapeutic targets. |
format | Online Article Text |
id | pubmed-5995236 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2018 |
publisher | Impact Journals LLC |
record_format | MEDLINE/PubMed |
spelling | pubmed-59952362018-06-13 Concomitant driver mutations in advanced EGFR-mutated non-small-cell lung cancer and their impact on erlotinib treatment Jakobsen, Jan Nyrop Santoni-Rugiu, Eric Grauslund, Morten Melchior, Linea Sørensen, Jens Benn Oncotarget Research Paper BACKGROUND: Patients with EGFR-mutated non-small-cell lung cancer benefit from EGFR tyrosine kinase inhibitors (TKIs) like erlotinib. However, the efficacy may be impaired by driver mutations in other genes. METHODS: Five hundred and fourteen consecutive patients with NSCLC of all stages were tested for EGFR-mutations by cobas® EGFR Mutation Test. Fluorescent in situ hybridization (FISH) for MET-amplification, immunohistochemistry (IHC) for MET- and ALK-expression, and Next Generation Sequencing (NGS) for concomitant driver mutations were performed on EGFR-mutated tumor samples from erlotinib-treated patients. RESULTS: Thirty-six patients (7%) had EGFR-mutations, including 2 with intrinsic resistance mutation p.T790M together with the p.L858R sensitizing mutation and 1 harboring the p.G719C/S768I double-mutation. Twenty-three patients had either locally advanced or advanced disease and received first-line erlotinib-treatment. Concomitant driver mutations were found in 15/21 (71%) of NGS-analyzed TKI-treated NSCLCs, involving in 67% of cases TP53, in 13% CTNNB1, and in 7% KRAS, MET, SMAD4, PIK3CA, FGFR1, FGFR3, NRAS, DDR2, and ERBB4. No ALK-expression was found, whereas MET-overexpression and MET-amplification were observed in 5 and 4 patients, respectively. Objective responses occurred in 17/23 patients (74%), 4 did not respond (17%), and 2 harboring a SMAD4-mutation (p.R135(*)(stop)) and a FGFR3-mutation (p.D785fs(*)31), respectively, displayed mixed response with simultaneously progressing and responding tumors (8.7%). Thus, EGFR-mutated tumors harboring co-mutations were not less likely to respond. CONCLUSION: Co-mutations in other cancer-driver genes (oncogenes or tumor suppressor genes) were frequent in EGFR-mutated NSCLCs and few cases harbored concomitant activating and resistance EGFR-mutations before TKI-treatment. Most co-mutations did not impact the response to first-line erlotinib-treatment, but may represent potential additional therapeutic targets. Impact Journals LLC 2018-05-25 /pmc/articles/PMC5995236/ /pubmed/29899852 http://dx.doi.org/10.18632/oncotarget.25490 Text en Copyright: © 2018 Jakobsen et al. http://creativecommons.org/licenses/by/3.0/ This article is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0/) (CC-BY), which permits unrestricted use and redistribution provided that the original author and source are credited. |
spellingShingle | Research Paper Jakobsen, Jan Nyrop Santoni-Rugiu, Eric Grauslund, Morten Melchior, Linea Sørensen, Jens Benn Concomitant driver mutations in advanced EGFR-mutated non-small-cell lung cancer and their impact on erlotinib treatment |
title | Concomitant driver mutations in advanced EGFR-mutated non-small-cell lung cancer and their impact on erlotinib treatment |
title_full | Concomitant driver mutations in advanced EGFR-mutated non-small-cell lung cancer and their impact on erlotinib treatment |
title_fullStr | Concomitant driver mutations in advanced EGFR-mutated non-small-cell lung cancer and their impact on erlotinib treatment |
title_full_unstemmed | Concomitant driver mutations in advanced EGFR-mutated non-small-cell lung cancer and their impact on erlotinib treatment |
title_short | Concomitant driver mutations in advanced EGFR-mutated non-small-cell lung cancer and their impact on erlotinib treatment |
title_sort | concomitant driver mutations in advanced egfr-mutated non-small-cell lung cancer and their impact on erlotinib treatment |
topic | Research Paper |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5995236/ https://www.ncbi.nlm.nih.gov/pubmed/29899852 http://dx.doi.org/10.18632/oncotarget.25490 |
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