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

• Published in: Annals of oncology Vol. 16; no. 2; pp. 273 - 278
• Main Authors: Tanner, M, Hollmén, M, Junttila, T T, Kapanen, A I, Tommola, S, Soini, Y, Helin, H, Salo, J, Joensuu, H, Sihvo, E, Elenius, K, Isola, J
• Format: Journal Article
• Language: English
• Published: England 01.02.2005
• Subjects: Adenocarcinoma - genetics; Adenocarcinoma - pathology; Aged; Antigens, Neoplasm - genetics; Breast Neoplasms - pathology; DNA Topoisomerases, Type II - genetics; DNA-Binding Proteins - genetics; Drug Resistance, Neoplasm; Esophageal Neoplasms - genetics; Esophageal Neoplasms - pathology; Esophagogastric Junction - pathology; Female; Gene Amplification; Genes, erbB-2; Humans; Isoenzymes; Male; Predictive Value of Tests; Prognosis; Stomach Neoplasms - genetics; Stomach Neoplasms - pathology; Tumor Cells, Cultured
• ISSN: 0923-7534

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. 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. 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. 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.