Amplification of HER-2 in gastric carcinoma: association with Topoisomerase IIalpha gene amplification, intestinal type, poor prognosis and sensitivity to trastuzumab.
BACKGROUND
HER-2/neu gene amplification has predictive value in breast cancer patients responding to trastuzumab. We wanted to investigate the frequency and clinical significance of HER-2/neu amplification in gastric carcinoma.


METHODS
The frequency of HER-2/neu and Topoisomerase IIalpha gene amplification was studied in adenocarcinomas of the stomach (n=131) and the gastroesophageal junction (n=100) by chromogenic in situ hybridization (CISH). Sensitivity of a gastric cancer cell line N87 with HER-2/neu amplification to trastuzumab was studied by a cell viability assay and compared with that of a HER-2 amplified breast cancer cell line SKBR-3. Growth inhibition of N87 cells was also verified in vivo in N87 xenograft tumors.


RESULTS
HER-2/neu amplification was present in 16 (12.2%) of the 131 gastric and in 24 (24.0%) of the 100 gastroesophageal adenocarcinomas. Co-amplification of Topoisomerase IIalpha was present in the majority of gastric (63%) and esophagogastric junction cancers (68%) with HER-2/neu amplification. HER-2/neu amplification was more common in the intestinal histologic type of gastric cancer (21.5%) than in the diffuse (2%) or the mixed/anaplastic type (5%, P=0.0051), but it was not associated with gender, age at diagnosis or clinical stage. Presence of HER-2/neu amplification was associated with poor carcinoma-specific survival (P=0.0089). HER-2/neu targeting antibody trastuzumab inhibited the growth of a p185(HER-2/neu) overexpressing gastric and breast carcinoma cell lines (N87 and SKBR-3) with equal efficacy.


CONCLUSIONS
HER-2/neu amplification is common in the intestinal type of gastric carcinoma, and it is associated with a poor outcome. HER-2 might be a useful target in this disease, and this hypothesis deserves to be investigated in clinical trials.
Tanner
M
M
Laboratory of Cancer Biology, Institute of Medical Technology, University of Tampere and Tampere University Hospital, FIN-33101 Tampere, Finland.
Hollmén
M
M
Junttila
T T
TT
Kapanen
A I
AI
Tommola
S
S
Soini
Y
Y
Helin
H
H
Salo
J
J
Joensuu
H
H
Sihvo
E
E
Elenius
K
K
Isola
J
J
D000230:Adenocarcinoma / Q000235:genetics* / Q000473:pathology*; D000368:Aged; D000951:Antigens, Neoplasm / Q000235:genetics*; D001943:Breast Neoplasms / Q000473:pathology; D004250:DNA Topoisomerases, Type II / Q000235:genetics*; D004268:DNA-Binding Proteins / Q000235:genetics*; D019008:Drug Resistance, Neoplasm; D004938:Esophageal Neoplasms / Q000235:genetics* / Q000473:pathology*; D004943:Esophagogastric Junction / Q000473:pathology*; D005260:Female; D005784:Gene Amplification; D018734:Genes, erbB-2; D006801:Humans; D007527:Isoenzymes; D008297:Male; D011237:Predictive Value of Tests; D011379:Prognosis; D013274:Stomach Neoplasms / Q000235:genetics* / Q000473:pathology*; D014407:Tumor Cells, Cultured
D000951:Antigens, Neoplasm; D004268:DNA-Binding Proteins; D007527:Isoenzymes; D004250:DNA Topoisomerases, Type II