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Annals of Oncology 2005 16(2):273-278; doi:10.1093/annonc/mdi064
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© 2005 European Society for Medical Oncology

Original article

Amplification of HER-2 in gastric carcinoma: association with Topoisomerase II{alpha} gene amplification, intestinal type, poor prognosis and sensitivity to trastuzumab

M. Tanner1,2, M. Hollmén3,4, T. T. Junttila3,4, A. I. Kapanen1, S. Tommola5, Y. Soini6, H. Helin5, J. Salo7, H. Joensuu8, E. Sihvo7, K. Elenius3,9 and J. Isola1,*

1Laboratory of Cancer Biology, Institute of Medical Technology, University of Tampere and Tampere University Hospital, Tampere; Departments of 2 Oncology and 5Pathology, Tampere University Hospital, Tampere; 3Medicity Research Laboratories, and Department of Medical Biochemistry and Molecular Biology, University of Turku; 4Turku Graduate School of Biomedical Sciences, University of Turku, Turku; 9Department of Oncology, Turku University Hospital, Turku, Finland; 6Department of Pathology, University of Oulu and Oulu University Hospital, Oulu; Departments of 7 Cardiothoracic Surgery and 8 Oncology, Helsinki University Central Hospital, Helsinki, Finland

* Correspondence to: Professor J. Isola, Laboratory of Cancer Biology, Institute of Medical Technology, University of Tampere & Tampere University Hospital, P.O. Box 607, FIN-33101 Tampere, Finland. Tel: +358-3-2156729; Fax: +358-3-2158923; Email: jorma.isola{at}uta.fi

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.

Patients and methods: The frequency of HER-2/neu and Topoisomerase II{alpha} 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 II{alpha} 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 p185HER-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.

Key words: CISH, gastric carcinoma, HER-2, Lauren's classification, trastuzumab


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C. Gravalos and A. Jimeno
HER2 in gastric cancer: a new prognostic factor and a novel therapeutic target
Ann. Onc., September 1, 2008; 19(9): 1523 - 1529.
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