PMID- 26723242 OWN - NLM STAT- MEDLINE DCOM- 20170104 LR - 20220330 IS - 1556-1380 (Electronic) IS - 1556-0864 (Print) IS - 1556-0864 (Linking) VI - 11 IP - 3 DP - 2016 Mar TI - HER2 Amplification and HER2 Mutation Are Distinct Molecular Targets in Lung Cancers. PG - 414-9 LID - S1556-0864(15)00048-9 [pii] LID - 10.1016/j.jtho.2015.10.025 [doi] AB - INTRODUCTION: Human epidermal growth factor receptor 2 gene (HER2 [also known as ERBB2]) alterations have been identified as oncogenic drivers and potential therapeutic targets in lung cancers. The molecular associations of HER2 gene amplification, mutation, and HER2 protein overexpression in lung cancers have not been distinctly defined. To explore these associations, Memorial Sloan Kettering Cancer Center and the University of Colorado combined their data on HER2 alterations in lung cancers. METHODS: Tumor specimens from 175 patients with lung adenocarcinomas and no prior targeted therapy were evaluated for the presence of HER2 amplification and mutation and HER2 protein overexpression. Amplification was assessed by fluorescence in situ hybridization (FISH) and defined as an HER2-to-chromosome enumeration probe 17 ratio of at least 2.0. Mutation was assessed by fragment analysis, mass spectrometry genotyping, and Sanger sequencing. Overexpression was assessed by immunohistochemical (IHC) staining. The frequencies of HER2 amplification and mutation and HER2 overexpression were calculated and their overlap examined. RESULTS: HER2 amplification was detected by FISH in 5 of 175 cases (3%). HER2 mutation was detected in 4 of 148 specimens (3%), including three identical 12-base pair insertions (p.A775_G776insYVMA) and a 9-base pair insertion, all in exon 20. None of the HER2-mutant cases was amplified. HER2 overexpression (2+ or 3+) on IHC staining was not detected in the 25 specimens available for testing, and negative IHC staining correlated with the negative results according to FISH. CONCLUSIONS: HER2 mutations are not associated with HER2 amplification, thus suggesting a distinct entity and therapeutic target. HER2-positive lung cancer may not be an adequate term, and patient cohorts for the study of HER2-targeted agents should be defined by the specific HER2 alteration present. CI - Copyright (c) 2015 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved. FAU - Li, Bob T AU - Li BT AD - Thoracic Oncology Service, Division of Solid Tumor Oncology, Department of Medicine, Memorial Sloan Kettering Cancer Center, Weill Cornell Medical College, New York, NY, USA; Sydney Medical School, University of Sydney, Sydney, NSW, Australia. Electronic address: lib1@mskcc.org. FAU - Ross, Dara S AU - Ross DS AD - Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, USA. FAU - Aisner, Dara L AU - Aisner DL AD - Department of Pathology, University of Colorado School of Medicine, Aurora, CO, USA. FAU - Chaft, Jamie E AU - Chaft JE AD - Thoracic Oncology Service, Division of Solid Tumor Oncology, Department of Medicine, Memorial Sloan Kettering Cancer Center, Weill Cornell Medical College, New York, NY, USA. FAU - Hsu, Meier AU - Hsu M AD - Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY, USA. FAU - Kako, Severine L AU - Kako SL AD - Department of Pathology, University of Colorado School of Medicine, Aurora, CO, USA. FAU - Kris, Mark G AU - Kris MG AD - Thoracic Oncology Service, Division of Solid Tumor Oncology, Department of Medicine, Memorial Sloan Kettering Cancer Center, Weill Cornell Medical College, New York, NY, USA. FAU - Varella-Garcia, Marileila AU - Varella-Garcia M AD - Department of Pathology, University of Colorado School of Medicine, Aurora, CO, USA. FAU - Arcila, Maria E AU - Arcila ME AD - Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, USA; Molecular Diagnostics Service, Department of Pathology, Memorial Sloan Kettering Cancer Center, Weill Cornell Medical College, New York, NY, USA. LA - eng GR - P50 CA058187/CA/NCI NIH HHS/United States GR - P30 CA008748/CA/NCI NIH HHS/United States GR - P30 CA046934/CA/NCI NIH HHS/United States GR - P50CA058187/CA/NCI NIH HHS/United States GR - RC2 CA148394/CA/NCI NIH HHS/United States GR - 1RC2 CA148394/CA/NCI NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't DEP - 20151224 PL - United States TA - J Thorac Oncol JT - Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer JID - 101274235 RN - EC 2.7.10.1 (ERBB2 protein, human) RN - EC 2.7.10.1 (Receptor, ErbB-2) SB - IM MH - Adenocarcinoma/enzymology/*genetics MH - Adenocarcinoma of Lung MH - Aged MH - Female MH - Gene Amplification MH - *Genes, erbB-2 MH - Humans MH - In Situ Hybridization, Fluorescence MH - Lung Neoplasms/enzymology/*genetics MH - Male MH - Middle Aged MH - Molecular Targeted Therapy MH - *Mutation MH - Receptor, ErbB-2/genetics PMC - PMC4698879 MID - NIHMS736624 OTO - NOTNLM OT - Amplification OT - HER2 OT - Lung cancer OT - Mutation OT - Overexpression EDAT- 2016/01/03 06:00 MHDA- 2017/01/05 06:00 PMCR- 2017/03/01 CRDT- 2016/01/03 06:00 PHST- 2015/08/30 00:00 [received] PHST- 2015/10/12 00:00 [revised] PHST- 2015/10/30 00:00 [accepted] PHST- 2017/03/01 00:00 [pmc-release] PHST- 2016/01/03 06:00 [entrez] PHST- 2016/01/03 06:00 [pubmed] PHST- 2017/01/05 06:00 [medline] AID - S1556-0864(15)00048-9 [pii] AID - 10.1016/j.jtho.2015.10.025 [doi] PST - ppublish SO - J Thorac Oncol. 2016 Mar;11(3):414-9. doi: 10.1016/j.jtho.2015.10.025. Epub 2015 Dec 24.