Prevalence and Therapeutic Targeting of High Level ERBB2 Amplification in Non-Small Cell Lung Cancer.
ERBB2
HER2
HER2 antibody-drug conjugate
biomarker
lung cancer
molecular pathology
pulmonary pathology
tyrosine kinase inhibitor
Journal
Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer
ISSN: 1556-1380
Titre abrégé: J Thorac Oncol
Pays: United States
ID NLM: 101274235
Informations de publication
Date de publication:
26 Dec 2023
26 Dec 2023
Historique:
received:
21
10
2023
revised:
12
12
2023
accepted:
16
12
2023
medline:
29
12
2023
pubmed:
29
12
2023
entrez:
28
12
2023
Statut:
aheadofprint
Résumé
ERBB2 amplification in lung cancer remains poorly characterized. HER2 (encoded by ERBB2) is a transmembrane tyrosine kinase capable of ligand-independent dimerization and signaling when overexpressed, and a common cause of HER2 overexpression is ERBB2 amplification. Here we evaluated the clinicopathologic and genomic characteristics of ERBB2-amplified NSCLC and explored a HER2 ADC therapeutic strategy. Our institutional next-generation DNA sequencing data (OncoPanel) from 5,769 NSCLC samples (5,075 patients) were queried for cases showing high level ERBB2 amplification (≥ 6 copies). Clinical and demographic characteristics were extracted from the electronic medical records. Efficacy of the pan-ERBB inhibitor afatinib, or HER2 ADCs [trastuzumab deruxtecan (T-DXd) and trastuzumab emtansine (T-DM1)] were evaluated in NSCLC preclinical models and patients with ERBB2 amplification. High-level ERBB2 amplification was identified in 0.9% of lung adenocarcinomas (LUAD) and reliably predicted overexpression of HER2. ERBB2 amplification events are detected in two distinct clinicopathological and genomic subsets of NSCLC: as the sole mitogenic driver in tumors arising in patients with a smoking history, or as a concomitant alteration with other mitogenic drivers in patients with a light or never smoking history. We further show that T-DXd is effective therapy in in vitro and in vivo preclinical models of NSCLC harboring ERBB2 amplification, and report two cases of clinical activity of an anti-HER2 ADC in patients who acquired ERBB2 amplification after previous targeted therapy. High level ERBB2 amplification reliably predicts HER2 amplification in NSCLC patients and HER2 ADC is effective therapy in this population.
Sections du résumé
BACKGROUND
BACKGROUND
ERBB2 amplification in lung cancer remains poorly characterized. HER2 (encoded by ERBB2) is a transmembrane tyrosine kinase capable of ligand-independent dimerization and signaling when overexpressed, and a common cause of HER2 overexpression is ERBB2 amplification. Here we evaluated the clinicopathologic and genomic characteristics of ERBB2-amplified NSCLC and explored a HER2 ADC therapeutic strategy.
METHODS
METHODS
Our institutional next-generation DNA sequencing data (OncoPanel) from 5,769 NSCLC samples (5,075 patients) were queried for cases showing high level ERBB2 amplification (≥ 6 copies). Clinical and demographic characteristics were extracted from the electronic medical records. Efficacy of the pan-ERBB inhibitor afatinib, or HER2 ADCs [trastuzumab deruxtecan (T-DXd) and trastuzumab emtansine (T-DM1)] were evaluated in NSCLC preclinical models and patients with ERBB2 amplification.
RESULTS
RESULTS
High-level ERBB2 amplification was identified in 0.9% of lung adenocarcinomas (LUAD) and reliably predicted overexpression of HER2. ERBB2 amplification events are detected in two distinct clinicopathological and genomic subsets of NSCLC: as the sole mitogenic driver in tumors arising in patients with a smoking history, or as a concomitant alteration with other mitogenic drivers in patients with a light or never smoking history. We further show that T-DXd is effective therapy in in vitro and in vivo preclinical models of NSCLC harboring ERBB2 amplification, and report two cases of clinical activity of an anti-HER2 ADC in patients who acquired ERBB2 amplification after previous targeted therapy.
CONCLUSIONS
CONCLUSIONS
High level ERBB2 amplification reliably predicts HER2 amplification in NSCLC patients and HER2 ADC is effective therapy in this population.
Identifiants
pubmed: 38154514
pii: S1556-0864(23)02428-0
doi: 10.1016/j.jtho.2023.12.019
pii:
doi:
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Informations de copyright
Copyright © 2023 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.