Biomarker analysis of cetuximab plus oxaliplatin/leucovorin/5-fluorouracil in first-line metastatic gastric and oesophago-gastric junction cancer: results from a phase II trial of the Arbeitsgemeinschaft Internistische Onkologie (AIO)

BMC Cancer

Research Article

Esther Endlicher¹  Gunnar Folprecht²  Gisela Keller³  Joëlle Deplazes³  Rupert Langer³  Birgit Luber³  Heinz Höfler⁴  Falko Fend⁵  Axel Walch⁶  Sandra Rauser⁶  Martin Eichmann⁷  Christian Peschel⁸  Florian Lordick⁹  Ewald Wöll^1,10  Sylvie Lorenzen^1,11  Susanna Hegewisch-Becker^1,12  Thomas Decker^1,13 

[1] 1st Medical Department, Klinikum der Universität, Franz-Josef-Strauß-Allee 11, 93053, Regensburg, Germany;1st Medical Department, Universitätsklinik Carl Gustav Carus, Fetscherstraße 74, 01307, Dresden, Germany;Institut für Allgemeine Pathologie und Pathologische Anatomie, Technische Universität München, Trogerstraße 18, 81675, München, Germany;Institut für Allgemeine Pathologie und Pathologische Anatomie, Technische Universität München, Trogerstraße 18, 81675, München, Germany;Institute of Pathology, Helmholtz Zentrum München, Ingolstädter Landstraße 1, 85764, Neuherberg, Germany;Institute of Pathology, Eberhard-Karls-Universität, Liebermeisterstraße 8, 72076, Tübingen, Germany;Institute of Pathology, Helmholtz Zentrum München, Ingolstädter Landstraße 1, 85764, Neuherberg, Germany;Institute of Pathology, Helmholtz Zentrum München, Ingolstädter Landstraße 1, 85764, Neuherberg, Germany;Department of Immunobiology, King's College London, London, UK;Klinikum rechts der Isar, 3rd Medical Department, Technische Universität München, Ismaninger Straße 22, 81675, München, Germany;Klinikum rechts der Isar, 3rd Medical Department, Technische Universität München, Ismaninger Straße 22, 81675, München, Germany;3rd Medical Department, Klinikum Braunschweig, Celler Straße 38, 38114, Braunschweig, Germany;Medical Department, Krankenhaus St. Vinzenz, Sanatoriumstraße 43, 6511, Zams, Austria;National Center of Tumor Diseases, University of Heidelberg, Im Neuenheimer Feld 460, 69120, Heidelberg, Germany;Onkologische Schwerpunktpraxis Eppendorf, Eppendorfer Landstraße 42, 20249, Hamburg, Germany;Onkologische Schwerpunktpraxis, Wilhelm-Hauff-Straße 41, 88214, Ravensburg, Germany;

关键词: Overall Survival;    Epidermal Growth Factor Receptor;    Cetuximab;    Overall Response Rate;    Epidermal Growth Factor Receptor Expression;   

DOI  :  10.1186/1471-2407-11-509

 received in 2011-11-01, accepted in 2011-12-07,  发布年份 2011

来源: Springer

【 摘 要 】

BackgroundThe activity of the epidermal growth factor receptor (EGFR)-directed monoclonal antibody cetuximab combined with oxaliplatin/leucovorin/5-fluorouracil (FUFOX) was assessed in first-line metastatic gastric and oesophago-gastric junction (OGJ) cancer in a prospective phase II study showing a promising objective tumour response rate of 65% and a low mutation frequency of KRAS (3%). The aim of the correlative tumour tissue studies was to investigate the relationship between EGFR gene copy numbers, activation of the EGFR pathway, expression and mutation of E-cadherin, V600E BRAF mutation and clinical outcome of patients with gastric and OGJ cancer treated with cetuximab combined with FUFOX.MethodsPatients included in this correlative study (n = 39) were a subset of patients from the clinical phase II study. The association between EGFR gene copy number, activation of the EGFR pathway, abundance and mutation of E-cadherin which plays an important role in these disorders, BRAF mutation and clinical outcome of patients was studied. EGFR gene copy number was assessed by FISH. Expression of the phosphorylated forms of EGFR and its downstream effectors Akt and MAPK, in addition to E-cadherin was analysed by immunohistochemistry. The frequency of mutant V600E BRAF was evaluated by allele-specific PCR and the mutation profile of the E-cadherin gene CDH1 was examined by DHPLC followed by direct sequence analysis. Correlations with overall survival (OS), time to progression (TTP) and overall response rate (ORR) were assessed.ResultsOur study showed a significant association between increased EGFR gene copy number (≥ 4.0) and OS in gastric and OGJ cancer, indicating the possibility that patients may be selected for treatment on a genetic basis. Furthermore, a significant correlation was shown between activated EGFR and shorter TTP and ORR, but not between activated EGFR and OS. No V600E BRAF mutations were identified. On the other hand, an interesting trend between high E-cadherin expression levels and better OS was observed and two CDH1 exon 9 missense mutations (A408V and D402H) were detected.ConclusionOur finding that increased EGFR gene copy numbers, activated EGFR and the E-cadherin status are potentially interesting biomarkers needs to be confirmed in larger randomized clinical trials.Trial registrationMulticentre clinical study with the European Clinical Trials Database number 2004-004024-12.

【 授权许可】

CC BY   
© Luber et al.; licensee BioMed Central Ltd. 2011