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

Liesbeth M. Hondelink; Merel Jebbink; Jan H. von der Thüsen; Danielle Cohen; Hendrikus J. Dubbink; Marthe S. Paats; Anne Marie C. Dingemans; Adrianus J. de Langen; Mirjam C. Boelens; Egbert F. Smit; Pieter E. Postmus; Tom van Wezel; Kim Monkhorst

doi:10.1016/j.jtocrr.2021.100252

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

Liesbeth M. Hondelink, Merel Jebbink, Jan H. von der Thüsen, Danielle Cohen^*, Hendrikus J. Dubbink, Marthe S. Paats, Anne Marie C. Dingemans, Adrianus J. de Langen, Mirjam C. Boelens, Egbert F. Smit, Pieter E. Postmus, Tom van Wezel, Kim Monkhorst

^*Corresponding author for this work

Research output: Contribution to journal › Article › Academic › peer-review

7 Citations (Scopus)

56 Downloads (Pure)

Abstract

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.

Original language	English
Article number	100252
Journal	JTO Clinical and Research Reports
Volume	2
Issue number	12
DOIs	https://doi.org/10.1016/j.jtocrr.2021.100252
Publication status	Published - 1 Dec 2021

Bibliographical note

Funding Information:
Disclosure: Dr. von der Thüsen reports receiving grants from AstraZeneca , Bristol-Myers Squibb , and Pfizer ; nonfinancial support from Roche; and personal fees from Merck Sharp & Dohme and Roche, outside of the submitted work. Dr. Dubbink reports receiving personal fees from AbbVie , AstraZeneca , Bayer, Janssen, and Eli Lilly and grants from AstraZeneca , Illumina, Merck Sharp & Dohme, and Pfizer, outside of the submitted work. Prof. Dingemans reports receiving personal fees from Roche, Eli Lilly, Pfizer, PharmaMar, Takeda, Boehringer Ingelheim, AstraZeneca, Jansen, Chiesi, Amgen, and Bayer and grants from AstraZeneca and Amgen, outside of the submitted work. Dr. de Langen reports receiving grants from Bristol-Myers Squibb, Merck Sharp & Dohme, Boehringer, and AstraZeneca and nonfinancial support from Merck Serono and Roche, outside of the submitted work. Prof. Smit reports receiving grants and other fees from AstraZeneca, during the conduct of the study. Prof. Postmus reports receiving personal fees from Boehringer Ingelheim, Merck Sharp & Dohme, and Bristol-Myers Squibb, outside of the submitted work. Dr. Monkhorst reports receiving grants from AstraZeneca; personal fees from Roche , Eli Lilly , Bayer, Boehringer Ingelheim, AstraZeneca , AbbVie, Merck Sharp & Dohme , and Bristol-Myers Squibb; and nonfinancial support from Takeda, Personal Genome Diagnostics, and Delfi, outside of the submitted work. The remaining authors declare no conflict of interest.

Publisher Copyright:
© 2021 THE AUTHORS

Access to Document

10.1016/j.jtocrr.2021.100252

PIIS2666364321001119Final published version, 836 KBLicence: CC BY

Cite this

Hondelink, L. M., Jebbink, M., von der Thüsen, J. H., Cohen, D., Dubbink, H. J., Paats, M. S., Dingemans, A. M. C., de Langen, A. J., Boelens, M. C., Smit, E. F., Postmus, P. E., van Wezel, T., & Monkhorst, K. (2021). Real-World Approach for Molecular Analysis of Acquired EGFR Tyrosine Kinase Inhibitor Resistance Mechanisms in NSCLC. JTO Clinical and Research Reports, 2(12), Article 100252. https://doi.org/10.1016/j.jtocrr.2021.100252

@article{65b5a066add54b13952f0893848edc3e,

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

abstract = "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.",

author = "Hondelink, {Liesbeth M.} and Merel Jebbink and {von der Th{\"u}sen}, {Jan H.} and Danielle Cohen and Dubbink, {Hendrikus J.} and Paats, {Marthe S.} and Dingemans, {Anne Marie C.} and {de Langen}, {Adrianus J.} and Boelens, {Mirjam C.} and Smit, {Egbert F.} and Postmus, {Pieter E.} and {van Wezel}, Tom and Kim Monkhorst",

note = "Funding Information: Disclosure: Dr. von der Th{\"u}sen reports receiving grants from AstraZeneca , Bristol-Myers Squibb , and Pfizer ; nonfinancial support from Roche; and personal fees from Merck Sharp & Dohme and Roche, outside of the submitted work. Dr. Dubbink reports receiving personal fees from AbbVie , AstraZeneca , Bayer, Janssen, and Eli Lilly and grants from AstraZeneca , Illumina, Merck Sharp & Dohme, and Pfizer, outside of the submitted work. Prof. Dingemans reports receiving personal fees from Roche, Eli Lilly, Pfizer, PharmaMar, Takeda, Boehringer Ingelheim, AstraZeneca, Jansen, Chiesi, Amgen, and Bayer and grants from AstraZeneca and Amgen, outside of the submitted work. Dr. de Langen reports receiving grants from Bristol-Myers Squibb, Merck Sharp & Dohme, Boehringer, and AstraZeneca and nonfinancial support from Merck Serono and Roche, outside of the submitted work. Prof. Smit reports receiving grants and other fees from AstraZeneca, during the conduct of the study. Prof. Postmus reports receiving personal fees from Boehringer Ingelheim, Merck Sharp & Dohme, and Bristol-Myers Squibb, outside of the submitted work. Dr. Monkhorst reports receiving grants from AstraZeneca; personal fees from Roche , Eli Lilly , Bayer, Boehringer Ingelheim, AstraZeneca , AbbVie, Merck Sharp & Dohme , and Bristol-Myers Squibb; and nonfinancial support from Takeda, Personal Genome Diagnostics, and Delfi, outside of the submitted work. The remaining authors declare no conflict of interest. Publisher Copyright: {\textcopyright} 2021 THE AUTHORS",

year = "2021",

month = dec,

day = "1",

doi = "10.1016/j.jtocrr.2021.100252",

language = "English",

volume = "2",

journal = "JTO Clinical and Research Reports",

issn = "2666-3643",

publisher = "Elsevier Inc.",

number = "12",

}

Hondelink, LM, Jebbink, M, von der Thüsen, JH, Cohen, D, Dubbink, HJ , Paats, MS , Dingemans, AMC, de Langen, AJ, Boelens, MC, Smit, EF, Postmus, PE, van Wezel, T & Monkhorst, K 2021, 'Real-World Approach for Molecular Analysis of Acquired EGFR Tyrosine Kinase Inhibitor Resistance Mechanisms in NSCLC', JTO Clinical and Research Reports, vol. 2, no. 12, 100252. https://doi.org/10.1016/j.jtocrr.2021.100252

TY - JOUR

T1 - Real-World Approach for Molecular Analysis of Acquired EGFR Tyrosine Kinase Inhibitor Resistance Mechanisms in NSCLC

AU - Hondelink, Liesbeth M.

AU - Jebbink, Merel

AU - von der Thüsen, Jan H.

AU - Cohen, Danielle

AU - Dubbink, Hendrikus J.

AU - Paats, Marthe S.

AU - Dingemans, Anne Marie C.

AU - de Langen, Adrianus J.

AU - Boelens, Mirjam C.

AU - Smit, Egbert F.

AU - Postmus, Pieter E.

AU - van Wezel, Tom

AU - Monkhorst, Kim

N1 - Funding Information: Disclosure: Dr. von der Thüsen reports receiving grants from AstraZeneca , Bristol-Myers Squibb , and Pfizer ; nonfinancial support from Roche; and personal fees from Merck Sharp & Dohme and Roche, outside of the submitted work. Dr. Dubbink reports receiving personal fees from AbbVie , AstraZeneca , Bayer, Janssen, and Eli Lilly and grants from AstraZeneca , Illumina, Merck Sharp & Dohme, and Pfizer, outside of the submitted work. Prof. Dingemans reports receiving personal fees from Roche, Eli Lilly, Pfizer, PharmaMar, Takeda, Boehringer Ingelheim, AstraZeneca, Jansen, Chiesi, Amgen, and Bayer and grants from AstraZeneca and Amgen, outside of the submitted work. Dr. de Langen reports receiving grants from Bristol-Myers Squibb, Merck Sharp & Dohme, Boehringer, and AstraZeneca and nonfinancial support from Merck Serono and Roche, outside of the submitted work. Prof. Smit reports receiving grants and other fees from AstraZeneca, during the conduct of the study. Prof. Postmus reports receiving personal fees from Boehringer Ingelheim, Merck Sharp & Dohme, and Bristol-Myers Squibb, outside of the submitted work. Dr. Monkhorst reports receiving grants from AstraZeneca; personal fees from Roche , Eli Lilly , Bayer, Boehringer Ingelheim, AstraZeneca , AbbVie, Merck Sharp & Dohme , and Bristol-Myers Squibb; and nonfinancial support from Takeda, Personal Genome Diagnostics, and Delfi, outside of the submitted work. The remaining authors declare no conflict of interest. Publisher Copyright: © 2021 THE AUTHORS

PY - 2021/12/1

Y1 - 2021/12/1

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=85119377644&partnerID=8YFLogxK

U2 - 10.1016/j.jtocrr.2021.100252

DO - 10.1016/j.jtocrr.2021.100252

M3 - Article

C2 - 34849493

AN - SCOPUS:85119377644

SN - 2666-3643

VL - 2

JO - JTO Clinical and Research Reports

JF - JTO Clinical and Research Reports

IS - 12

M1 - 100252

ER -

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

Abstract

Bibliographical note

Access to Document

Other files and links

Fingerprint

Cite this