title: 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).
abstract: 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.
  
  
  CONCLUSIONS
  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.
  
  
  BACKGROUND
  Multicentre clinical study with the European Clinical Trials Database number 2004-004024-12.
authors.affiliation: Institut für Allgemeine Pathologie und Pathologische Anatomie, Technische Universität München, Trogerstraße 18, 81675 München, Germany. luber@lrz.tu-muenchen.de
authors.forename: Birgit
authors.initials: B
authors.lastname: Luber
authors.forename: Joëlle
authors.initials: J
authors.lastname: Deplazes
authors.forename: Gisela
authors.initials: G
authors.lastname: Keller
authors.forename: Axel
authors.initials: A
authors.lastname: Walch
authors.forename: Sandra
authors.initials: S
authors.lastname: Rauser
authors.forename: Martin
authors.initials: M
authors.lastname: Eichmann
authors.forename: Rupert
authors.initials: R
authors.lastname: Langer
authors.forename: Heinz
authors.initials: H
authors.lastname: Höfler
authors.forename: Susanna
authors.initials: S
authors.lastname: Hegewisch-Becker
authors.forename: Gunnar
authors.initials: G
authors.lastname: Folprecht
authors.forename: Ewald
authors.initials: E
authors.lastname: Wöll
authors.forename: Thomas
authors.initials: T
authors.lastname: Decker
authors.forename: Esther
authors.initials: E
authors.lastname: Endlicher
authors.forename: Sylvie
authors.initials: S
authors.lastname: Lorenzen
authors.forename: Falko
authors.initials: F
authors.lastname: Fend
authors.forename: Christian
authors.initials: C
authors.lastname: Peschel
authors.forename: Florian
authors.initials: F
authors.lastname: Lordick
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000911:Antibodies, Monoclonal / Q000008:administration & dosage; D061067:Antibodies, Monoclonal, Humanized; D015703:Antigens, CD; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D014408:Biomarkers, Tumor / Q000378:metabolism; D015820:Cadherins / Q000235:genetics / Q000378:metabolism; D000068818:Cetuximab; D066246:ErbB Receptors / Q000235:genetics / Q000378:metabolism; D004938:Esophageal Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000556:secondary; D004943:Esophagogastric Junction; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage; D006801:Humans; D007150:Immunohistochemistry; D002955:Leucovorin / Q000008:administration & dosage; D008297:Male; D008875:Middle Aged; D009944:Organoplatinum Compounds / Q000008:administration & dosage; D000077150:Oxaliplatin; D011446:Prospective Studies; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics; D013274:Stomach Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000556:secondary; D016019:Survival Analysis; D014803:Vitamin B Complex / Q000627:therapeutic use*
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D015703:Antigens, CD; D014408:Biomarkers, Tumor; C513384:CDH1 protein, human; D015820:Cadherins; D009944:Organoplatinum Compounds; D000077150:Oxaliplatin; D014803:Vitamin B Complex; D066246:ErbB Receptors; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; D000068818:Cetuximab; D002955:Leucovorin; D005472:Fluorouracil