Real-World Approach for Molecular Analysis of Acquired EGFR Tyrosine Kinase Inhibitor Resistance Mechanisms in NSCLC

Introduction: With the approval of first-line osimertinib treatment in stage IV EGFR-mutated NSCLC, detection of resistance mechanisms will become increasingly important—and complex. Clear guidelines for analyses of these resistance mechanisms are currently lacking. Here, we provide our recommendati...

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Autores principales:	Liesbeth M. Hondelink, MD, Merel Jebbink, MD, Jan H. von der Thüsen, MD, PhD, Danielle Cohen, MD, PhD, Hendrikus J. Dubbink, PhD, Marthe S. Paats, MD, PhD, Anne-Marie C. Dingemans, MD, PhD, Adrianus J. de Langen, MD, PhD, Mirjam C. Boelens, PhD, Egbert F. Smit, MD, PhD, Pieter E. Postmus, MD, PhD, Tom van Wezel, PhD, Kim Monkhorst, MD, PhD
Formato:	article
Lenguaje:	EN
Publicado:	Elsevier 2021
Materias:	Non–small cell lung cancer Molecular diagnostics Tyrosine kinase inhibitors Acquired resistance Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282
Acceso en línea:	https://doaj.org/article/15653a46b49e44dca1398d582c62eabe
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spelling	oai:doaj.org-article:15653a46b49e44dca1398d582c62eabe2021-11-22T04:31:13ZReal-World Approach for Molecular Analysis of Acquired EGFR Tyrosine Kinase Inhibitor Resistance Mechanisms in NSCLC2666-364310.1016/j.jtocrr.2021.100252https://doaj.org/article/15653a46b49e44dca1398d582c62eabe2021-12-01T00:00:00Zhttp://www.sciencedirect.com/science/article/pii/S2666364321001119https://doaj.org/toc/2666-3643Introduction: With the approval of first-line osimertinib treatment in stage IV EGFR-mutated NSCLC, detection of resistance mechanisms will become increasingly important—and complex. Clear guidelines for analyses of these resistance mechanisms are currently lacking. Here, we provide our recommendations for optimal molecular diagnostics in the post-EGFR tyrosine kinase inhibitor (TKI) resistance setting. Methods: We compared molecular workup strategies from three hospitals of 161 first- or second-generation EGFR TKI–treated cases and 159 osimertinib-treated cases. Laboratories used combinations of DNA next-generation sequencing (NGS), RNA NGS, in situ hybridization (ISH), and immunohistochemistry (IHC). Results: Resistance mechanisms were identified in 72 first-generation TKI cases (51%) and 85 osimertinib cases (57%). RNA NGS, when performed, revealed fusions or exon-skipping events in 4% of early TKI cases and 10% of osimertinib cases. Of the 30 MET and HER2 amplifications, 10 were exclusively detected by ISH or IHC, and not detected by DNA NGS, mostly owing to low tumor cell percentage (<30%) and possibly tumor heterogeneity. Conclusions: Our real-world data support a method for molecular diagnostics, consisting of a parallel combination of DNA NGS, RNA NGS, MET ISH, and either HER2 ISH or IHC. Combining RNA and DNA isolation into one step limits dropout rates. In case of financial or tissue limitations, a sequential approach is justifiable, in which RNA NGS is only performed in case no resistance mechanisms are identified. Yet, this is suboptimal as—although rare—multiple acquired resistance mechanisms may occur.Liesbeth M. Hondelink, MDMerel Jebbink, MDJan H. von der Thüsen, MD, PhDDanielle Cohen, MD, PhDHendrikus J. Dubbink, PhDMarthe S. Paats, MD, PhDAnne-Marie C. Dingemans, MD, PhDAdrianus J. de Langen, MD, PhDMirjam C. Boelens, PhDEgbert F. Smit, MD, PhDPieter E. Postmus, MD, PhDTom van Wezel, PhDKim Monkhorst, MD, PhDElsevierarticleNon–small cell lung cancerMolecular diagnosticsTyrosine kinase inhibitorsAcquired resistanceNeoplasms. Tumors. Oncology. Including cancer and carcinogensRC254-282ENJTO Clinical and Research Reports, Vol 2, Iss 12, Pp 100252- (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Non–small cell lung cancer Molecular diagnostics Tyrosine kinase inhibitors Acquired resistance Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282
spellingShingle	Non–small cell lung cancer Molecular diagnostics Tyrosine kinase inhibitors Acquired resistance Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282 Liesbeth M. Hondelink, MD Merel Jebbink, MD Jan H. von der Thüsen, MD, PhD Danielle Cohen, MD, PhD Hendrikus J. Dubbink, PhD Marthe S. Paats, MD, PhD Anne-Marie C. Dingemans, MD, PhD Adrianus J. de Langen, MD, PhD Mirjam C. Boelens, PhD Egbert F. Smit, MD, PhD Pieter E. Postmus, MD, PhD Tom van Wezel, PhD Kim Monkhorst, MD, PhD Real-World Approach for Molecular Analysis of Acquired EGFR Tyrosine Kinase Inhibitor Resistance Mechanisms in NSCLC
description	Introduction: With the approval of first-line osimertinib treatment in stage IV EGFR-mutated NSCLC, detection of resistance mechanisms will become increasingly important—and complex. Clear guidelines for analyses of these resistance mechanisms are currently lacking. Here, we provide our recommendations for optimal molecular diagnostics in the post-EGFR tyrosine kinase inhibitor (TKI) resistance setting. Methods: We compared molecular workup strategies from three hospitals of 161 first- or second-generation EGFR TKI–treated cases and 159 osimertinib-treated cases. Laboratories used combinations of DNA next-generation sequencing (NGS), RNA NGS, in situ hybridization (ISH), and immunohistochemistry (IHC). Results: Resistance mechanisms were identified in 72 first-generation TKI cases (51%) and 85 osimertinib cases (57%). RNA NGS, when performed, revealed fusions or exon-skipping events in 4% of early TKI cases and 10% of osimertinib cases. Of the 30 MET and HER2 amplifications, 10 were exclusively detected by ISH or IHC, and not detected by DNA NGS, mostly owing to low tumor cell percentage (<30%) and possibly tumor heterogeneity. Conclusions: Our real-world data support a method for molecular diagnostics, consisting of a parallel combination of DNA NGS, RNA NGS, MET ISH, and either HER2 ISH or IHC. Combining RNA and DNA isolation into one step limits dropout rates. In case of financial or tissue limitations, a sequential approach is justifiable, in which RNA NGS is only performed in case no resistance mechanisms are identified. Yet, this is suboptimal as—although rare—multiple acquired resistance mechanisms may occur.
format	article
author	Liesbeth M. Hondelink, MD Merel Jebbink, MD Jan H. von der Thüsen, MD, PhD Danielle Cohen, MD, PhD Hendrikus J. Dubbink, PhD Marthe S. Paats, MD, PhD Anne-Marie C. Dingemans, MD, PhD Adrianus J. de Langen, MD, PhD Mirjam C. Boelens, PhD Egbert F. Smit, MD, PhD Pieter E. Postmus, MD, PhD Tom van Wezel, PhD Kim Monkhorst, MD, PhD
author_facet	Liesbeth M. Hondelink, MD Merel Jebbink, MD Jan H. von der Thüsen, MD, PhD Danielle Cohen, MD, PhD Hendrikus J. Dubbink, PhD Marthe S. Paats, MD, PhD Anne-Marie C. Dingemans, MD, PhD Adrianus J. de Langen, MD, PhD Mirjam C. Boelens, PhD Egbert F. Smit, MD, PhD Pieter E. Postmus, MD, PhD Tom van Wezel, PhD Kim Monkhorst, MD, PhD
author_sort	Liesbeth M. Hondelink, MD
title	Real-World Approach for Molecular Analysis of Acquired EGFR Tyrosine Kinase Inhibitor Resistance Mechanisms in NSCLC
title_short	Real-World Approach for Molecular Analysis of Acquired EGFR Tyrosine Kinase Inhibitor Resistance Mechanisms in NSCLC
title_full	Real-World Approach for Molecular Analysis of Acquired EGFR Tyrosine Kinase Inhibitor Resistance Mechanisms in NSCLC
title_fullStr	Real-World Approach for Molecular Analysis of Acquired EGFR Tyrosine Kinase Inhibitor Resistance Mechanisms in NSCLC
title_full_unstemmed	Real-World Approach for Molecular Analysis of Acquired EGFR Tyrosine Kinase Inhibitor Resistance Mechanisms in NSCLC
title_sort	real-world approach for molecular analysis of acquired egfr tyrosine kinase inhibitor resistance mechanisms in nsclc
publisher	Elsevier
publishDate	2021
url	https://doaj.org/article/15653a46b49e44dca1398d582c62eabe
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Real-World Approach for Molecular Analysis of Acquired EGFR Tyrosine Kinase Inhibitor Resistance Mechanisms in NSCLC

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