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.
Subject(s)
Camptothecin/analogs & derivatives , Carcinoma, Non-Small-Cell Lung , Gene Amplification , Lung Neoplasms , Receptor, ErbB-2 , Humans , Lung Neoplasms/drug therapy , Lung Neoplasms/genetics , Lung Neoplasms/pathology , Receptor, ErbB-2/metabolism , Receptor, ErbB-2/genetics , Carcinoma, Non-Small-Cell Lung/genetics , Carcinoma, Non-Small-Cell Lung/drug therapy , Carcinoma, Non-Small-Cell Lung/pathology , Female , Male , Middle Aged , Animals , Immunoconjugates/therapeutic use , Immunoconjugates/pharmacology , Aged , Mice , Trastuzumab/therapeutic use , Trastuzumab/pharmacology , Prevalence , Afatinib/therapeutic use , Afatinib/pharmacology , Ado-Trastuzumab Emtansine/therapeutic use , Ado-Trastuzumab Emtansine/pharmacologyABSTRACT
OBJECTIVES: We discuss two main categories of blood substitutes: perfluorocarbons and hemoglobin-based oxygen carriers. METHODS: We provide a review of the notable products developed in both categories and include their attributes as well as their setbacks. RESULTS: We contribute a case report tothe growing literature of the successful use of Sanguinate. CONCLUSIONS: We find that artificial oxygen carriers are an attractive field of research because of the practical limitations and the multitude of potential complications that surround human blood transfusions.
