Prevalence and Therapeutic Targeting of High Level ERBB2 Amplification in Non-Small Cell Lung Cancer
医学
肺癌
癌症研究
肿瘤科
内科学
癌症
作者
Igor Odintsov,Maisam Makarem,Mizuki Nishino,Sara E Bachert,Tom Zhang,Jaclyn LoPiccolo,Cloud P. Paweletz,Prafulla C. Gokhale,Elena Ivanova,Aisha L. Saldanha,Charles M. Rudin,William W. Lockwood,Marc Ladanyi,Romel Somwar,Pasi A. Jänne,Lynette M. Sholl
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 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 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 High level ERBB2 amplification reliably predicts HER2 amplification in NSCLC patients and HER2 ADC is effective therapy in this population.