title: Clinical significance of intratumoral HER2 heterogeneity in gastric cancer.
abstract: OBJECTIVE
  To evaluate the clinical significance of intratumoral HER2 heterogeneity in gastric cancer (GC).
  
  
  METHODS
  A total of 322 GC tissues were evaluated by HER2 immunohistochemistry (IHC), of which 73 with IHC 2+ or 3+ were subjected to fluorescence in situ hybridisation (FISH). Also, 3-5 distinct spots in each case showing different HER2 staining intensities were evaluated individually by comparing IHC staining intensity with gene copy number (GCN). Minimum, average and maximum FISH scores were generated for each case.
  
  
  RESULTS
  Intratumoral heterogeneity of HER2 overexpression and gene amplification were 54 and 30 of 73 cases with IHC 2+ or 3+, respectively. These cases were characterised by diffuse or mixed Lauren type, HER2 IHC 2+, and low-level amplification. Kaplan-Meier survival analysis revealed that the heterogeneous overexpression was significantly associated with longer disease-free survival times than the homogeneous, and the high average GCN was most associated with poor outcome. Also, there was a strong correlation between the IHC and FISH results for each spot. Quantitative polymerase chain reaction (PCR) analysis of the cancer tissues and the cell-free plasma showed that HER2 gene copy by quantitative PCR on tissue correlated well with those by FISH, but plasma HER2 level was not.
  
  
  CONCLUSIONS
  Considering the high incidence of intratumoral HER2 heterogeneity in GC, accurate HER2 assessment would require larger tissues and more detailed guidelines. The guidelines should include the recommendation that FISH-scoring areas be selected with reference to a corresponding IHC slide. Also, the definition of HER2-positive tumours should be reassessed considering the intratumoral heterogeneity.
authors.affiliation: Department of Pathology, Seoul National University Hospital, Seoul, South Korea.
authors.forename: Hee Eun
authors.initials: HE
authors.lastname: Lee
authors.forename: Kyoung Un
authors.initials: KU
authors.lastname: Park
authors.forename: Seol Bong
authors.initials: SB
authors.lastname: Yoo
authors.forename: Soo Kyung
authors.initials: SK
authors.lastname: Nam
authors.forename: Do Joong
authors.initials: DJ
authors.lastname: Park
authors.forename: Hyung-Ho
authors.initials: HH
authors.lastname: Kim
authors.forename: Hye Seung
authors.initials: HS
authors.lastname: Lee
mesh_terms: D000368:Aged; D056915:DNA Copy Number Variations; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007150:Immunohistochemistry; D017404:In Situ Hybridization, Fluorescence; D053208:Kaplan-Meier Estimate; D008297:Male; D008875:Middle Aged; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000097:blood / Q000235:genetics* / Q000378:metabolism; D012189:Retrospective Studies; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013274:Stomach Neoplasms / Q000097:blood / Q000235:genetics* / Q000378:metabolism
chemical_list: D018719:Erb-b2 Receptor Tyrosine Kinases