TY - JOUR
T1 - Biomarker analysis of cetuximab plus oxaliplatin/leucovorin/5-fluorouracil in first-line metastatic gastric and oesophago-gastric junction cancer
T2 - results from a phase II trial of the Arbeitsgemeinschaft Internistische Onkologie (AIO)
AU - Luber, Birgit
AU - Deplazes, Joëlle
AU - Keller, Gisela
AU - Walch, Axel
AU - Rauser, Sandra
AU - Eichmann, Martin
AU - Langer, Rupert
AU - Höfler, Heinz
AU - Hegewisch-Becker, Susanna
AU - Folprecht, Gunnar
AU - Wöll, Ewald
AU - Decker, Thomas
AU - Endlicher, Esther
AU - Lorenzen, Sylvie
AU - Fend, Falko
AU - Peschel, Christian
AU - Lordick, Florian
N1 - Funding Information:
We thank Christine Hermannstädter, Susanne Plaschke, Birgit Geist, Ulrike Buchholz and Claudia-Mareike Pflüger from the Institutes of Pathology of the Technische Universität München and the Helmholtz Zentrum München for their excellent technical assistance, Tibor Schuster from the Institute of Medical Statistics and Epidemiology of the Technische Universität München for counselling in statistical data analysis and Nadine Röthling from the Munich Center for Clinical Studies for her support in conducting the clinical study and obtaining the clinical data. This correlative research project was supported by Merck Darmstadt KGaA Germany by an unrestricted grant. Merck KGaA has reviewed the publication and the views and opinions in the publication do not necessarily reflect those of Merck KGaA.
PY - 2011/12/7
Y1 - 2011/12/7
N2 - Background: 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.Methods: 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.Results: 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.Conclusion: 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.Trial registration: Multicentre clinical study with the European Clinical Trials Database number 2004-004024-12.
AB - Background: 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.Methods: 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.Results: 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.Conclusion: 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.Trial registration: Multicentre clinical study with the European Clinical Trials Database number 2004-004024-12.
UR - http://www.scopus.com/inward/record.url?scp=82755167862&partnerID=8YFLogxK
U2 - 10.1186/1471-2407-11-509
DO - 10.1186/1471-2407-11-509
M3 - Article
C2 - 22152101
AN - SCOPUS:82755167862
SN - 1471-2407
VL - 11
JO - BMC Cancer
JF - BMC Cancer
M1 - 509
ER -