Homogeneous EGFR amplification defines a subset of aggressive Barrett's adenocarcinomas with poor prognosis.
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.
Marx
Andreas H
AH
Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany. a.marx@uke.de
Zielinski
Margarete
M
Kowitz
Charlotte-Marie
CM
Dancau
Ana-Maria
AM
Thieltges
Sabrina
S
Simon
Ronald
R
Choschzick
Matthias
M
Yekebas
Emre
E
Kaifi
Jussuf T
JT
Mirlacher
Martina
M
Atanackovic
Djordje
D
Brümmendorf
Tim H
TH
Fiedler
Walter
W
Bokemeyer
Carsten
C
Izbicki
Jakob R
JR
Sauter
Guido
G
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
D066246:ErbB Receptors