title: Comparison of intratumoral heterogeneity of HER2 expression between primary tumor and multiple organ metastases in gastric cancer: Clinicopathological study of three autopsy cases and one resected case.
abstract: Intratumoral heterogeneity of HER2 expression in the metastatic foci of HER2-positive advanced gastric cancer remains unclear. In this study, we compared HER2 expression between primary and metastatic tumors in HER2-positive three autopsied cases and one resected case with multiple organ metastases by immunohistochemistry (IHC) and dual color in situ hybridization (DISH). All four cases judged positive (IHC3+) at the primary tumor tissues showed varying HER2 gene amplification (GA) status. One homogeneously HER2-positive autopsied case (Case 1) and one intratumorally heterogeneous positive resected case (Case 2) with high GA showed a homogeneous positive staining pattern in all the metastatic foci. One heterogeneously HER2-positive autopsied case (Case 3) with low GA showed a partially heterogeneous HER2 staining pattern in all the metastatic foci. In contrast, one heterogeneously HER2-positive autopsied case (Case 4) with equivocal GA showed a completely heterogeneous HER2 staining pattern in the metastatic foci. These results indicate that HER2-positive gastric cancers with low to high GA at the primary tumor show substantially homogeneous HER2 overexpression in the metastatic foci, whereas HER2-positive gastric cancers with equivocal GA expressed HER2 heterogeneously within the metastatic tumor, suggesting that metastatic foci of the latter HER2-positive cases would be potentially resistant to trastuzumab.
authors.affiliation: Department of Epidemiology, Program in Health and Community Medicine, Nagoya University Graduate School of Medicine, Nagoya, Japan.
authors.forename: Takuya
authors.initials: T
authors.lastname: Saito
authors.affiliation: Department of Clinical Oncology, Japanese Red Cross Nagoya Daiichi Hospital, Nagoya, Japan.
authors.forename: Chihiro
authors.initials: C
authors.lastname: Kondo
authors.affiliation: Department of Gastrointestinal Oncology, National Cancer Center Hospital East, Chiba, Japan.
authors.forename: Kohei
authors.initials: K
authors.lastname: Shitara
authors.affiliation: Department of Gastroenterological Surgery, Aichi Cancer Center Central Hospital, Nagoya, Japan.
authors.forename: Yuichi
authors.initials: Y
authors.lastname: Ito
authors.affiliation: Division of Oncological Pathology, Aichi Cancer Center Research Institute, Nagoya, Japan.
authors.forename: Noriko
authors.initials: N
authors.lastname: Saito
authors.affiliation: Molecular Medicine Team, Research Centre for Medical Glycoscience, National Institute of Advanced Industrial Science and Technology, Ibaraki, Japan.
authors.forename: Yuzuru
authors.initials: Y
authors.lastname: Ikehara
authors.affiliation: Department of Pathology and Molecular Diagnostics, Aichi Cancer Center Central Hospital, Nagoya, Japan.
authors.forename: Yasushi
authors.initials: Y
authors.lastname: Yatabe
authors.affiliation: Department of Surgery, Osaka Saiseikai Izuo Hospital, Osaka, Japan.
authors.forename: Keigo
authors.initials: K
authors.lastname: Yamamichi
authors.affiliation: Department of Epidemiology, Program in Health and Community Medicine, Nagoya University Graduate School of Medicine, Nagoya, Japan.
authors.forename: Hideo
authors.initials: H
authors.lastname: Tanaka
authors.affiliation: Laboratory of Pathology and Clinical Research, Aichi Cancer Center, Aichi Hospital, Okazaki, Japan.
authors.forename: Hayao
authors.initials: H
authors.lastname: Nakanishi
mesh_terms: D000230:Adenocarcinoma / Q000378:metabolism / Q000473:pathology* / Q000556:secondary; D000328:Adult; D000368:Aged; D001344:Autopsy; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism*; D005784:Gene Amplification; D006801:Humans; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D008113:Liver Neoplasms / Q000556:secondary*; D008297:Male; D008875:Middle Aged; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics / Q000378:metabolism*; D013274:Stomach Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*
chemical_list: D014408:Biomarkers, Tumor; D018719:Erb-b2 Receptor Tyrosine Kinases; C508053:ERBB2 protein, human
keywords: HER2 gene amplification; drug resistance; gastric cancer; intratumoral heterogeneity; metastases; trastuzumab