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)
1 Institut für Allgemeine Pathologie und Pathologische Anatomie, Technische Universität München, Trogerstraße 18, 81675 München, Germany
2 Institute of Pathology, Helmholtz Zentrum München, Ingolstädter Landstraße 1, 85764 Neuherberg, Germany
3 Onkologische Schwerpunktpraxis Eppendorf, Eppendorfer Landstraße 42, 20249 Hamburg, Germany
4 1st Medical Department, Universitätsklinik Carl Gustav Carus, Fetscherstraße 74, 01307 Dresden, Germany
5 Medical Department, Krankenhaus St. Vinzenz, Sanatoriumstraße 43, 6511 Zams, Austria
6 Onkologische Schwerpunktpraxis, Wilhelm-Hauff-Straße 41, 88214 Ravensburg, Germany
7 1st Medical Department, Klinikum der Universität, Franz-Josef-Strauß-Allee 11, 93053 Regensburg, Germany
8 National Center of Tumor Diseases, University of Heidelberg, Im Neuenheimer Feld 460, 69120 Heidelberg, Germany
9 Institute of Pathology, Eberhard-Karls-Universität, Liebermeisterstraße 8, 72076 Tübingen, Germany
10 Klinikum rechts der Isar, 3rd Medical Department, Technische Universität München, Ismaninger Straße 22, 81675 München, Germany
11 3rd Medical Department, Klinikum Braunschweig, Celler Straße 38, 38114 Braunschweig, Germany
12 Department of Immunobiology, King's College London, London, UK
BMC Cancer 2011, 11:509 doi:10.1186/1471-2407-11-509Published: 7 December 2011
The 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.
Patients 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.
Our 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.
Our 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.
Multicentre clinical study with the European Clinical Trials Database number 2004-004024-12.