HER2 expression and markers of phosphoinositide-3-kinase pathway activation define a favorable subgroup of metastatic pulmonary adenocarcinomas. Issue 1 (April 2015)

• Record Type: Journal Article
• Authors: Reis, H.; Herold, T.; Ting, S.; Worm, K.; Huber, U.; Christoph, D.C.; Eberhardt, W.E.; Kostbade, K.; Kasper, S.; Stamatis, G.; Welter, S.; Darwiche, K.; Karpf-Wissel, R.; Theegarten, D.; Schmid, K.W.; Schuler, M.; Wiesweg, M.
• Is Part Of: Lung cancer. Volume 88:Issue 1(2015:Apr.)
• Page Start: 34
• Page End: 41
• Publication Date: 2015-04
• Subjects: ADCa denocarcinoma of the lung -- ALKa naplastic lymphoma kinase -- (p)AKT (phospho-)protein kinase B -- bpb ase pair -- BRAF V-Raf murine sarcoma viral oncogene homolog B -- (C/F/D)ISH (chromogenic/fluorescence/dual color) in-situ hybridization -- cMETh epatocyte growth factor receptor -- EGFRe pidermal growth factor receptor -- (p)ERK (phospho-)extracellular-signal-regulated kinase -- FDA Food and Drug Administration -- FFPEf ormalin fixed, paraffin embedded -- HER2h uman epidermal growth factor receptor 2 -- HER4r eceptor tyrosine–protein kinase erbB-4 -- HRh azard ratio -- IHCi mmunohistochemistry -- KRAS V-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog -- MAPKm itogen-activated protein kinase -- mTORm echanistic target of rapamycin -- NGSn ext generation sequencing -- NSCLCn on-small cell lung cancer -- OSo verall survival -- PCRp olymerase chain reaction -- PFSp rogression-free survival -- PI3K (CA)p hosphoinositide-3 kinase (catalytic subunit alpha) -- PTENp hosphatase and tensin homolog -- RECISTr esponse evaluation criteria in solid tumors -- TKIt yrosine kinase inhibitor -- TTFt ime to treatment failure after first treatment line -- UICC Union internationale contre le cancer -- WHO World Health Organization; HER2 -- PI3K -- NSCLC -- Lung adenocarcinoma -- Biomarker -- Prospective study; Lungs -- Cancer -- Periodicals; Lung Neoplasms -- Abstracts; Lung Neoplasms -- Periodicals; Poumons -- Cancer -- Périodiques; Lungs -- Cancer; Periodicals; Electronic journals; Electronic journals; 616.99424
• DOI: 10.1016/j.lungcan.2015.02.002
• Languages: English
• ISSNs: 0169-5002

Abstract

Highlights: Prospective HER2-analysis in 193 patients with stage III/IV pulmonary adenocarcinoma. HER2- and pAKT-expression correlate with favorable prognosis in stage IV disease. HER2 IHC is not predictive of HER2 amplification or mutation. Abstract: Objectives: Pulmonary adenocarcinomas (ADC) can be sub-grouped based on dominant oncogenic drivers. EGFR mutations define an entity of metastatic ADC with favorable prognosis and high susceptibility to EGFR tyrosine kinase inhibition. In contrast, the clinical impact of additional ERBB family members in ADC is less defined. To this end we prospectively studied HER2 expression, gene amplification, and mutation in relation to outcome of patients with advanced or metastatic ADC. Materials and methods: Diagnostic tumor biopsies from 193 sequential patients with stage III/IV ADC were prospectively studied for HER2 expression by immunohistochemistry (IHC). Cases with IHC scores 2+ or 3+ were analyzed by HER2 chromogenic in situ hybridization (CISH), and sequencing of HER2 exons 20 and 23. Additional prospectively determined biomarkers included PTEN, cMET, pAKT, and pERK expression, KRAS, EGFR, BRAF and PIK3CA mutations, and ALK fluorescence ISH (FISH) . Results and conclusion: HER2–IHC was feasible in 176 (91.2%) cases. Of 53 (30%) cases with IHC scores 2+/3+, 45 (85%) could be studied by CISH and 34 (64%) by sequencing. The lower number of HER2 -mutational analyses resulted from exhaustion of tumor tissue and DNA following mutational analysis of KRAS, EGFR, BRAF and PIK3CA . HER2 amplification was detected in 4 cases (2.3%), while no mutation was found. HER2 expression correlated with expression of pAKT and cMET. Expression of HER2 and pAKT was associated with favorable overall survival in stage IV disease. HER2-expressing ADC more frequently harbored KRAS mutations, while HER2 expression was absent in all 4 cases with BRAF mutation. HER2–IHC was not predictive of HER2 gene amplification or mutation, which both were rare events in prospectively studied patients with advanced or metastatic ADC. Expression of HER2 and pAKT define a population of patients with stage IV ADC with a distinct disease course, who could benefit from specifically tailored pharmacotherapies.