title: Her2 amplification is significantly more frequent in lymph node metastases from urothelial bladder cancer than in the primary tumours.
abstract: BACKGROUND
  Her2, an alias for the protein of v-erb-b2 erythroblastic leukemia viral oncogene homolog 2, neuro/glioblastoma derived oncogene homolog (avian), might be an attractive therapeutic target in metastasising bladder cancer. Genotype and phenotype of primary tumours and their metastases may differ.
  
  
  OBJECTIVE
  Determine Her2 status in both tumour components to better assess the potential of anti-Her2 therapies.
  
  
  METHODS
  Histologic examination revealed lymph node metastases in 150 patients with urothelial bladder cancer clinically staged as N0M0. A tissue microarray was constructed with four tumour samples per patient: two from the primary tumour and two from nodal metastases. Her2 status was determined at the gene level by fluorescence in situ hybridisation (FISH) and at the protein level by immunohistochemistry (IHC).
  
  
  METHODS
  All patients underwent cystectomy and standardised extended lymphadenectomy.
  
  
  METHODS
  Overall survival was assessed according to HER2 gene status and protein expression in primary bladder cancers and lymph node metastases.
  
  
  CONCLUSIONS
  Her2 amplification was significantly more frequent in lymph node metastases (15.3%) than in matched primary bladder cancers (8.7%; p = 0.003). Her2 amplification in primary tumours was highly preserved in the corresponding metastases as indicated by only one amplified primary tumour without amplification of the metastasis. There was a high concordance in HER2 FISH results between both samples from the primary tumour (κ = 0.853) and from the metastases (κ = 0.930). IHC results were less concordant (κ=0.539 and 0.830). FISH and IHC results were poorly correlated in primary tumours (κ = 0.566) and metastases (κ = 0.673). While Her2 amplification in the primary tumour significantly predicted poor outcome (p = 0.044), IHC-based survival prediction was unsuccessful.
  
  
  CONCLUSIONS
  Her2 amplification in metastasising bladder cancer is relatively frequent, is homogeneous in each tumour component, and predicts early death. This suggests a high potential for anti-Her2 therapies. For patient selection, FISH might be more accurate than IHC.
authors.affiliation: Institute of Pathology, University of Bern, Bern, Switzerland. achim.fleischmann@pathology.unibe.ch
authors.forename: Achim
authors.initials: A
authors.lastname: Fleischmann
authors.forename: Diana
authors.initials: D
authors.lastname: Rotzer
authors.forename: Roland
authors.initials: R
authors.lastname: Seiler
authors.forename: Urs E
authors.initials: UE
authors.lastname: Studer
authors.forename: George N
authors.initials: GN
authors.lastname: Thalmann
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor / Q000032:analysis / Q000235:genetics*; D015653:Cystectomy; D005260:Female; D005784:Gene Amplification; D006801:Humans; D007150:Immunohistochemistry; D017404:In Situ Hybridization, Fluorescence; D053208:Kaplan-Meier Estimate; D008197:Lymph Node Excision; D008198:Lymph Nodes / Q000737:chemistry* / Q000473:pathology / Q000601:surgery; D008207:Lymphatic Metastasis; D008297:Male; D008875:Middle Aged; D009367:Neoplasm Staging; D011237:Predictive Value of Tests; D016016:Proportional Hazards Models; D011446:Prospective Studies; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000032:analysis / Q000235:genetics*; D018570:Risk Assessment; D012307:Risk Factors; D015996:Survival Rate; D013557:Switzerland; D013997:Time Factors; D046888:Tissue Array Analysis; D016896:Treatment Outcome; D001749:Urinary Bladder Neoplasms / Q000737:chemistry / Q000235:genetics* / Q000401:mortality / Q000556:secondary / Q000601:surgery; D019459:Urothelium / Q000737:chemistry* / Q000473:pathology / Q000601:surgery
chemical_list: D014408:Biomarkers, Tumor; D018719:Erb-b2 Receptor Tyrosine Kinases; C508053:ERBB2 protein, human