Prevalence and therapeutic targeting of high-level ERBB2 amplification in NSCLC Journal Article
| Authors: | Odintsov, I.; Makarem, M.; Nishino, M.; Bachert, S. E.; Zhang, T.; LoPiccolo, J.; Paweletz, C. P.; Gokhale, P. C.; Ivanova, E.; Saldanha, A.; Rudin, C. M.; Lockwood, W. W.; Ladanyi, M.; Somwar, R.; Jänne, P. A.; Sholl, L. M. |
| Article Title: | Prevalence and therapeutic targeting of high-level ERBB2 amplification in NSCLC |
| Abstract: | Introduction: 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 antibody–drug conjugate (ADC) therapeutic strategy. Methods: Our institutional next-generation DNA sequencing data (OncoPanel) from 5769 NSCLC samples (5075 patients) were queried for cases having 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 and trastuzumab emtansine) was evaluated in NSCLC preclinical models and patients with ERBB2 amplification. Results: High-level ERBB2 amplification was identified in 0.9% of lung adenocarcinomas and reliably predicted overexpression of HER2. ERBB2 amplification events are detected in two distinct clinicopathologic 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 reveal that trastuzumab deruxtecan 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: High-level ERBB2 amplification reliably predicts HER2 overexpression in patients with NSCLC, and HER2 ADC is effective therapy in this population. © 2023 International Association for the Study of Lung Cancer |
| Keywords: | adult; controlled study; treatment outcome; aged; human cell; major clinical study; clinical feature; dose response; drug efficacy; nonhuman; mouse; animal tissue; gene; gene targeting; gene overexpression; gene amplification; prevalence; animal experiment; animal model; genetic association; lung cancer; smoking; in vivo study; in vitro study; drug effect; drug mechanism; biomarker; gene identification; genomics; clinical effectiveness; trastuzumab; tyrosine kinase inhibitor; erbb2; her2; non small cell lung cancer; high throughput sequencing; afatinib; erbb2 gene; dna sequencing; human; male; female; article; trastuzumab deruxtecan; her2 antibody–drug conjugate |
| Journal Title: | Journal of Thoracic Oncology |
| Volume: | 19 |
| Issue: | 5 |
| ISSN: | 1556-0864 |
| Publisher: | Elsevier Inc. |
| Date Published: | 2024-05-01 |
| Start Page: | 732 |
| End Page: | 748 |
| Language: | English |
| DOI: | 10.1016/j.jtho.2023.12.019 |
| PUBMED: | 38154514 |
| PROVIDER: | scopus |
| PMCID: | PMC11957432 |
| DOI/URL: | |
| Notes: | Article -- MSK Cancer Center Support Grant (P30 CA008748) acknowledged in PDF -- Source: Scopus |
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