MET Amplification in Non-Small Cell Lung Cancer (NSCLC)-A Consecutive Evaluation Using Next-Generation Sequencing (NGS) in a Real-World Setting

Christoph Schubart; Robert Stöhr; Lars Tögel; Florian Fuchs; Horia Sirbu; Gerhard Seitz; Ruth Seggewiss-Bernhardt; Rumo Leistner; William Sterlacci; Michael Vieth; Christoph Seidl; Michael Mugler; Markus Kapp; Wolfgang Hohenforst-Schmidt; Arndt Hartmann; Florian Haller; Ramona Erber

doi:10.3390/cancers13195023

MET Amplification in Non-Small Cell Lung Cancer (NSCLC)-A Consecutive Evaluation Using Next-Generation Sequencing (NGS) in a Real-World Setting

Cancers (Basel). 2021 Oct 7;13(19):5023. doi: 10.3390/cancers13195023.

Authors

Christoph Schubart^{1

2}, Robert Stöhr^{1

2}, Lars Tögel^{1

2}, Florian Fuchs^{2

3}, Horia Sirbu^{2

4}, Gerhard Seitz⁵, Ruth Seggewiss-Bernhardt⁶, Rumo Leistner⁷, William Sterlacci⁸, Michael Vieth⁸, Christoph Seidl^{9

10}, Michael Mugler^{9

10}, Markus Kapp¹¹, Wolfgang Hohenforst-Schmidt¹², Arndt Hartmann^{1

2}, Florian Haller^{1

2}, Ramona Erber^{1

2}

Affiliations

¹ Institute of Pathology, University Hospital Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), 91054 Erlangen, Germany.
² Comprehensive Cancer Center Erlangen-EMN (CCC ER-EMN), 91054 Erlangen, Germany.
³ Department of Medicine 1, University Hospital Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), 91054 Erlangen, Germany.
⁴ Department of Thoracic Surgery, University Hospital Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), 91054 Erlangen, Germany.
⁵ Institute of Pathology, Neuropathology, Molecular Diagnostics and Cytology, Klinikum Bamberg, Sozialstiftung Bamberg, 96049 Bamberg, Germany.
⁶ Department of Medicine 5, Klinikum Bamberg, Sozialstiftung Bamberg, 96049 Bamberg, Germany.
⁷ Department of Medicine 4, Klinikum Bamberg, Sozialstiftung Bamberg, 96049 Bamberg, Germany.
⁸ Institute of Pathology, Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), Klinikum Bayreuth, 95445 Bayreuth, Germany.
⁹ Diagnosticum, Pathology and Cytology, 95032 Hof, Germany.
¹⁰ Diagnosticum, Laboratory Medicine, Microbiology, Pathology, Human Genetics, 09221 Neukirchen, Germany.
¹¹ Department of Gastroenterology, Hepatology and Infectiology, Section Hematology & Oncology, Sana Klinikum Hof, 95032 Hof, Germany.
¹² Department of Cardiology, Sana Klinikum Hof, 95032 Hof, Germany.

Abstract

In non-small cell lung cancer (NSCLC), approximately 1-3% of cases harbor an increased gene copy number (GCN) of the MET gene. This alteration can be due to de novo amplification of the MET gene or can represent a secondary resistance mechanism in response to targeted therapies. To date, the gold standard method to evaluate the GCN of MET is fluorescence in situ hybridization (FISH). However, next-generation sequencing (NGS) is becoming more relevant to optimize therapy by revealing the mutational profile of each NSCLC. Using evaluable n = 205 NSCLC cases of a consecutive cohort, this study addressed the question of whether an amplicon based NGS assay can completely replace the FISH method regarding the classification of MET GCN status. Out of the 205 evaluable cases, only n = 9 cases (43.7%) of n = 16 high-level MET amplified cases assessed by FISH were classified as amplified by NGS. Cases harboring a MET GCN > 10 showed the best concordance when comparing FISH versus NGS (80%). This study confirms that an amplicon-based NGS assessment of the MET GCN detects high-level MET amplified cases harboring a MET GCN > 10 but fails to detect the various facets of MET gene amplification in the context of a therapy-induced resistance mechanism.

Keywords: MET; MET inhibitor; NSCLC; amplification; fluorescence in situ hybridization; next-generation sequencing; precision medicine; resistance mechanism.