title: Fc-Gamma receptor polymorphism and gene expression of peripheral blood mononuclear cells in patients with HER2-positive metastatic breast cancer receiving single-agent trastuzumab.
abstract: OBJECTIVE
  The aim of this study was to investigate gene expression in the peripheral blood mononuclear cells (PBMCs) of patients with HER2-positive breast cancer receiving trastuzumab. We also evaluated the effect of Fc-gamma receptor genotype on trastuzumab-driven gene expression.
  
  
  METHODS
  Gene expression was assessed by microarray analyses before and after administration of single-agent trastuzumab in 34 patients with metastatic HER2-positive breast cancer who were genotyped for Fc-gamma receptor (FcGR) IIA H131R and FcGRIIIA V158F. Gene set enrichment analysis (GSEA) was used to identify the gene sets that were significantly enriched after administration of trastuzumab in patient cohorts categorized by FcGR variant.
  
  
  RESULTS
  At baseline three non-immune-related gene sets were identified only in patient cohort of FcGRIIA non-H/H variant. Thirty gene sets were identified in the cohort of FcGRIIIA V/V variants, while no gene set was identified in FcGRIIIA non-V/V variants one week after starting trastuzumab. Eleven gene sets were identified in FcGRIIA H/H variants 8 week after starting trastuzumab, but none in non-H/H variants. Immune-related gene sets were significantly down-regulated after administration of trastuzumab.
  
  
  CONCLUSIONS
  The response of PBMCs to trastuzumab markedly varied with polymorphisms in FcGRIIA and FcGRIIIA. These results indicate that FcGR polymorphisms contribute to the systemic immune reaction triggered by trastuzumab. Further investigations are needed to clarify the biological effects of FcGR variation on the mechanism of trastuzumab activity.
authors.affiliation: Department of Breast and Medical Oncology, National Cancer Center Hospital, 5-1-1 Tsukiji, Chuo-ku, Tokyo, 104-0045, Japan. cshimizu@ncc.go.jp.|Department of Bioinformatics, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo, 113-0034, Japan. cshimizu@ncc.go.jp.
authors.forename: Chikako
authors.initials: C
authors.lastname: Shimizu
authors.affiliation: Department of Bioinformatics, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo, 113-0034, Japan.
authors.forename: Kaoru
authors.initials: K
authors.lastname: Mogushi
authors.affiliation: Department of Bioinformatics, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo, 113-0034, Japan. msmorioka-tky@umin.ac.jp.
authors.forename: Masaki Suimye
authors.initials: MS
authors.lastname: Morioka
authors.affiliation: Department of Breast and Medical Oncology, National Cancer Center Hospital, 5-1-1 Tsukiji, Chuo-ku, Tokyo, 104-0045, Japan.
authors.forename: Harukaze
authors.initials: H
authors.lastname: Yamamoto
authors.affiliation: Department of Breast and Medical Oncology, National Cancer Center Hospital, 5-1-1 Tsukiji, Chuo-ku, Tokyo, 104-0045, Japan.
authors.forename: Kenji
authors.initials: K
authors.lastname: Tamura
authors.affiliation: Department of Breast and Medical Oncology, National Cancer Center Hospital, 5-1-1 Tsukiji, Chuo-ku, Tokyo, 104-0045, Japan.
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Fujiwara
authors.affiliation: Department of Bioinformatics, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo, 113-0034, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Tanaka
mesh_terms: D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000627:therapeutic use; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000502:physiology; D008875:Middle Aged; D011110:Polymorphism, Genetic; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism; D017452:Receptors, IgG / Q000235:genetics*; D000068878:Trastuzumab / Q000627:therapeutic use*; D016896:Treatment Outcome
chemical_list: D000970:Antineoplastic Agents; D018719:Erb-b2 Receptor Tyrosine Kinases; D017452:Receptors, IgG; D000068878:Trastuzumab; C496124:FCGR3A protein, human; C080568:Fc gamma receptor IIA; C508053:ERBB2 protein, human
keywords: Fc-gamma receptor polymorphism; Gene set enrichment analysis; HER2-positive breast cancer; Peripheral blood mononuclear cell; Trastuzumab