title: Clinicopathological significance of HER2/neu genetic heterogeneity in HER2/neu non-amplified invasive breast carcinomas and its concurrent axillary metastasis.
abstract: BACKGROUND
  HER2/neu (HER2) is a significant prognostic marker for breast carcinomas. Recently, new guidelines defining HER2 genetic heterogeneity (GH) were published by the College of American Pathologists.
  
  
  OBJECTIVE
  To determine the prevalence of HER2 GH as defined in primary invasive breast carcinoma, to determine its relationship with prognostic variables and to investigate its impact on concurrent axillary metastasis.
  
  
  METHODS
  235 consecutive infiltrating breast carcinomas were evaluated for GH (defined as presence of 5-50% of neoplastic cells with HER2/CEP17 ratio >2.2) using fluorescence in situ hybridisation. Pathological features of carcinomas with GH were compared with those lacking GH. GH was also evaluated in a subset of 37 paired primary carcinomas and its concurrent axillary nodal metastases using dual in situ hybridisation.
  
  
  RESULTS
  HER2 GH was noted in 27% of HER2 negative breast carcinomas. These carcinomas demonstrated aggressive characteristics (larger size, higher grade and greater incidence of lymph node metastasis) in comparison with HER2 negative cases without GH. Higher levels of GH were associated with the equivocal HER2 status. GH was maintained in the concurrent lymph node metastases with some variations; however, two cases with clusters of HER2 amplified cells in the primary carcinoma showed HER2 amplification in the nodal metastasis.
  
  
  CONCLUSIONS
  HER2 GH is present in 27% of breast carcinomas, portends an aggressive phenotype and contributes to the equivocal HER2 status. Evaluation of the HER2 status in nodal metastasis of select primary carcinomas with GH may be beneficial before treatment selection.
authors.affiliation: Department of Pathology and Laboratory Medicine, Cedars-Sinai Medical Center, Los Angeles, California 90048, USA. hedyeh.shafi@cshs.org
authors.forename: Hedyeh
authors.initials: H
authors.lastname: Shafi
authors.forename: Kristine
authors.initials: K
authors.lastname: Astvatsaturyan
authors.forename: Fai
authors.initials: F
authors.lastname: Chung
authors.forename: James
authors.initials: J
authors.lastname: Mirocha
authors.forename: Michael
authors.initials: M
authors.lastname: Schmidt
authors.forename: Shikha
authors.initials: S
authors.lastname: Bose
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001943:Breast Neoplasms / Q000378:metabolism / Q000473:pathology*; D018270:Carcinoma, Ductal, Breast / Q000378:metabolism / Q000473:pathology*; D018275:Carcinoma, Lobular / Q000378:metabolism / Q000473:pathology*; D005260:Female; D018740:Genetic Heterogeneity; D006801:Humans; D008207:Lymphatic Metastasis; D008875:Middle Aged; D018198:Mixed Tumor, Malignant / Q000378:metabolism / Q000473:pathology; D009361:Neoplasm Invasiveness; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics* / Q000378:metabolism
chemical_list: D018719:Erb-b2 Receptor Tyrosine Kinases; C508053:ERBB2 protein, human
keywords: BREAST CANCER; CANCER GENETICS; GENE AMPLIFICATION