Cis-oriented solvent-front EGFR G796S mutation in tissue and ctDNA in a patient progressing on osimertinib: a case report and review of the literature

Samuel J Klempner,1,2 Pareen Mehta,3 Alexa B Schrock,4 Siraj M Ali,4 Sai-Hong Ignatius Ou5 1The Angeles Clinic and Research Institute, Los Angeles, CA, USA; 2Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA; 3Department of Radiology, The Angeles Clinic...

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Autores principales:	Klempner SJ, Mehta P, Schrock AB, Ali SM, Ou SI
Formato:	article
Lenguaje:	EN
Publicado:	Dove Medical Press 2017
Materias:	EGFR G796 lung cancer ctDNA resistance osimertinib T790M Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282
Acceso en línea:	https://doaj.org/article/36b860e18699493189bad32c17e2e68f
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spelling	oai:doaj.org-article:36b860e18699493189bad32c17e2e68f2021-12-02T01:33:04ZCis-oriented solvent-front EGFR G796S mutation in tissue and ctDNA in a patient progressing on osimertinib: a case report and review of the literature1179-2728https://doaj.org/article/36b860e18699493189bad32c17e2e68f2017-12-01T00:00:00Zhttps://www.dovepress.com/cis-oriented-solvent-front-egfr-g796s-mutation-in-tissue-and-ctdna-in--peer-reviewed-article-LCTThttps://doaj.org/toc/1179-2728Samuel J Klempner,1,2 Pareen Mehta,3 Alexa B Schrock,4 Siraj M Ali,4 Sai-Hong Ignatius Ou5 1The Angeles Clinic and Research Institute, Los Angeles, CA, USA; 2Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA; 3Department of Radiology, The Angeles Clinic and Research Institute, Los Angeles, CA, USA; 4Clinical Development, Foundation Medicine, Inc., Cambridge, MA, USA; 5Department of Medicine-Hematology/Oncology, Chao Family Comprehensive Cancer Center, University of California Irvine School of Medicine, Orange, CA, USA Abstract: Acquired resistance to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKI) is a universal event and limits clinical efficacy. The third-generation EGFR inhibitor osimertinib is active in EGFR-mutant/T790M positive non-small-cell lung cancer. Mechanisms of acquired resistance are emerging, and here we describe a cis-oriented solvent-front EGFR G796S mutation as the resistance mechanism observed in a progression biopsy and circulating tumor DNA (ctDNA) from a patient with initial response followed by progression on osimertinib. This is one of the earliest reports of a sole solvent-front tertiary EGFR mutation as a resistance mechanism to osimertinib. Our case suggests a monoclonal resistance mechanism. We review the importance of the solvent-front residues across TKIs and describe known osimertinib resistance mechanisms. We observe that nearly all clinical osimertinib-resistant tertiary EGFR mutations are oriented in cis with EGFR T790M. This case highlights the importance of mutations affecting EGFR kinase domains and supports the feasibility of broad panel ctDNA assays for detection of novel acquired resistance and tumor heterogeneity in routine clinical care. Keywords: EGFR G796, lung cancer, ctDNA, resistance, osimertinib, T790MKlempner SJMehta PSchrock ABAli SMOu SIDove Medical PressarticleEGFR G796lung cancerctDNAresistanceosimertinibT790MNeoplasms. Tumors. Oncology. Including cancer and carcinogensRC254-282ENLung Cancer: Targets and Therapy, Vol Volume 8, Pp 241-247 (2017)
institution	DOAJ
collection	DOAJ
language	EN
topic	EGFR G796 lung cancer ctDNA resistance osimertinib T790M Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282
spellingShingle	EGFR G796 lung cancer ctDNA resistance osimertinib T790M Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282 Klempner SJ Mehta P Schrock AB Ali SM Ou SI Cis-oriented solvent-front EGFR G796S mutation in tissue and ctDNA in a patient progressing on osimertinib: a case report and review of the literature
description	Samuel J Klempner,1,2 Pareen Mehta,3 Alexa B Schrock,4 Siraj M Ali,4 Sai-Hong Ignatius Ou5 1The Angeles Clinic and Research Institute, Los Angeles, CA, USA; 2Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA; 3Department of Radiology, The Angeles Clinic and Research Institute, Los Angeles, CA, USA; 4Clinical Development, Foundation Medicine, Inc., Cambridge, MA, USA; 5Department of Medicine-Hematology/Oncology, Chao Family Comprehensive Cancer Center, University of California Irvine School of Medicine, Orange, CA, USA Abstract: Acquired resistance to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKI) is a universal event and limits clinical efficacy. The third-generation EGFR inhibitor osimertinib is active in EGFR-mutant/T790M positive non-small-cell lung cancer. Mechanisms of acquired resistance are emerging, and here we describe a cis-oriented solvent-front EGFR G796S mutation as the resistance mechanism observed in a progression biopsy and circulating tumor DNA (ctDNA) from a patient with initial response followed by progression on osimertinib. This is one of the earliest reports of a sole solvent-front tertiary EGFR mutation as a resistance mechanism to osimertinib. Our case suggests a monoclonal resistance mechanism. We review the importance of the solvent-front residues across TKIs and describe known osimertinib resistance mechanisms. We observe that nearly all clinical osimertinib-resistant tertiary EGFR mutations are oriented in cis with EGFR T790M. This case highlights the importance of mutations affecting EGFR kinase domains and supports the feasibility of broad panel ctDNA assays for detection of novel acquired resistance and tumor heterogeneity in routine clinical care. Keywords: EGFR G796, lung cancer, ctDNA, resistance, osimertinib, T790M
format	article
author	Klempner SJ Mehta P Schrock AB Ali SM Ou SI
author_facet	Klempner SJ Mehta P Schrock AB Ali SM Ou SI
author_sort	Klempner SJ
title	Cis-oriented solvent-front EGFR G796S mutation in tissue and ctDNA in a patient progressing on osimertinib: a case report and review of the literature
title_short	Cis-oriented solvent-front EGFR G796S mutation in tissue and ctDNA in a patient progressing on osimertinib: a case report and review of the literature
title_full	Cis-oriented solvent-front EGFR G796S mutation in tissue and ctDNA in a patient progressing on osimertinib: a case report and review of the literature
title_fullStr	Cis-oriented solvent-front EGFR G796S mutation in tissue and ctDNA in a patient progressing on osimertinib: a case report and review of the literature
title_full_unstemmed	Cis-oriented solvent-front EGFR G796S mutation in tissue and ctDNA in a patient progressing on osimertinib: a case report and review of the literature
title_sort	cis-oriented solvent-front egfr g796s mutation in tissue and ctdna in a patient progressing on osimertinib: a case report and review of the literature
publisher	Dove Medical Press
publishDate	2017
url	https://doaj.org/article/36b860e18699493189bad32c17e2e68f
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Cis-oriented solvent-front EGFR G796S mutation in tissue and ctDNA in a patient progressing on osimertinib: a case report and review of the literature

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