title: Homogeneous EGFR amplification defines a subset of aggressive Barrett's adenocarcinomas with poor prognosis.
abstract: OBJECTIVE
  The epidermal growth factor receptor (EGFR) is a tyrosine kinase (TK) involved in the tumour progression of many cancer types and may serve as an important therapeutic target (erlotinib, cetuximab). Heterogeneity of EGFR amplification and expression could represent a major drawback for anti-EGFR therapy. The aim of this study was performed to determine the potential impact of tumour heterogeneity on anti-EGFR therapy in Barrett's adenocarcinoma (BAC).
  
  
  RESULTS
  Tissue microarray (TMA) sections of 112 BAC and 45 lymph node metastases were analysed for EGFR amplification and expression using fluorescence in situ hybridization (FISH) and immunohistochemistry (IHC). A subset of 20 samples was also sequenced for EGFR exons 18-21 and Kirsten rat sarcoma viral oncogene homologue (KRAS) exons 2-3 mutations. EGFR amplification was seen in seven (6.25%) of 112 interpretable BAC and typically high-level with more than 10-20 EGFR copies per tumour cell (EGFR/centromere 7 ratio >3). EGFR amplification was associated with high pT, pN and poor prognosis (P = 0.0004). Identical EGFR amplification status was found in 29 primary tumours and 29 matched lymph node metastases. Moreover, FISH analysis of three to 16 large sections from all amplified BAC and corresponding lymph node metastases did not reveal any heterogeneity of EGFR amplification. No EGFR mutation but one KRAS mutation was found.
  
  
  CONCLUSIONS
  The high level and homogeneity of EGFR amplification in primary tumours and metastases suggests the potential therapeutic utility of anti-EGFR drugs in BAC.
authors.affiliation: Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany. a.marx@uke.de
authors.forename: Andreas H
authors.initials: AH
authors.lastname: Marx
authors.forename: Margarete
authors.initials: M
authors.lastname: Zielinski
authors.forename: Charlotte-Marie
authors.initials: CM
authors.lastname: Kowitz
authors.forename: Ana-Maria
authors.initials: AM
authors.lastname: Dancau
authors.forename: Sabrina
authors.initials: S
authors.lastname: Thieltges
authors.forename: Ronald
authors.initials: R
authors.lastname: Simon
authors.forename: Matthias
authors.initials: M
authors.lastname: Choschzick
authors.forename: Emre
authors.initials: E
authors.lastname: Yekebas
authors.forename: Jussuf T
authors.initials: JT
authors.lastname: Kaifi
authors.forename: Martina
authors.initials: M
authors.lastname: Mirlacher
authors.forename: Djordje
authors.initials: D
authors.lastname: Atanackovic
authors.forename: Tim H
authors.initials: TH
authors.lastname: Brümmendorf
authors.forename: Walter
authors.initials: W
authors.lastname: Fiedler
authors.forename: Carsten
authors.initials: C
authors.lastname: Bokemeyer
authors.forename: Jakob R
authors.initials: JR
authors.lastname: Izbicki
authors.forename: Guido
authors.initials: G
authors.lastname: Sauter
mesh_terms: D000230:Adenocarcinoma / Q000473:pathology*; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001471:Barrett Esophagus / Q000378:metabolism / Q000473:pathology*; D066246:ErbB Receptors / Q000235:genetics* / Q000378:metabolism; D004938:Esophageal Neoplasms / Q000473:pathology*; D005260:Female; D005784:Gene Amplification; D006801:Humans; D007150:Immunohistochemistry; D017404:In Situ Hybridization, Fluorescence; D008198:Lymph Nodes / Q000473:pathology; D008297:Male; D008875:Middle Aged; D011379:Prognosis
chemical_list: D066246:ErbB Receptors