title: Activation (tyrosine phosphorylation) of ErbB-2 (HER-2/neu): a study of incidence and correlation with outcome in breast cancer.
abstract: OBJECTIVE
  We hypothesize that phosphorylated ErbB-2 (P-ErbB-2, identified by a novel antibody PN2A) may provide either more significant or additional prognostic marker data for breast cancer patients. This study was designed to compare the incidence and prognostic value of ErbB-2 (HER-2/neu) and P-ErbB-2 immunoexpression in archival breast cancer samples.
  
  
  METHODS
  Eight hundred sixteen invasive breast cancers with a median of 16.3 years of follow-up were immunostained for ErbB-2 (using antibody CB11) and P-ErbB-2 (using antibody PN2A). ErbB-2 and P-ErbB-2 data were compared with clinical, histologic, immunohistochemical, and outcome variables.
  
  
  RESULTS
  Of 816 primary breast cancers, 307 (38%) were positive for ErbB-2 and 37 (12% of ErbB-2 positive and 5% of the study population) expressed P-ErbB-2. P-ErbB-2 was not detected in ErbB-2-negative cases (n = 509). ErbB-2 immunohistochemical data were bimodal; patients with > or = 80% cellular expression had the shortest disease-free and disease-specific survival. P-ErbB-2 was associated with a higher percentage of ErbB-2-positive cells, a higher number of positive lymph nodes, and cellular proliferation. ErbB-2 and P-ErbB-2 were indicators of poor prognosis in node-positive patients in both univariate and multivariate analyses. We found that either P-ErbB-2 expression or high (> or = 80%) ErbB-2 expression provided the most significant prognostic value in node-positive cases by multivariate analyses. There were too few P-ErbB-2-positive cases and events in the node-negative patient group to allow statistical analysis of P-ErbB-2 in that subgroup.
  
  
  CONCLUSIONS
  PN2A immunostaining identified a subset (approximately 12% of ErbB-2-positive breast cancers) with activation (phosphorylation) of the receptor ErbB-2. P-ErbB-2 expression was strongly associated with higher levels of ErbB-2 expression (> or = 80%), although it was not a surrogate. Identification of cases with a high percentage of invasive breast cancer cells expressing ErbB-2 or determination of receptor activation via P-ErbB-2 may provide additional prognostic value in node-positive breast cancers.
authors.affiliation: Department of Pathology, Evanston Hospital/Northwestern University, Evanston, IL 60201, USA. a-thor@nwu.edu.
authors.forename: A D
authors.initials: AD
authors.lastname: Thor
authors.forename: S
authors.initials: S
authors.lastname: Liu
authors.forename: S
authors.initials: S
authors.lastname: Edgerton
authors.forename: D
authors.initials: D
authors.lastname: Moore
authors.forename: K M
authors.initials: KM
authors.lastname: Kasowitz
authors.forename: C C
authors.initials: CC
authors.lastname: Benz
authors.forename: D F
authors.initials: DF
authors.lastname: Stern
authors.forename: M P
authors.initials: MP
authors.lastname: DiGiovanna
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000906:Antibodies; D014408:Biomarkers, Tumor / Q000276:immunology / Q000378:metabolism*; D001943:Breast Neoplasms / Q000378:metabolism* / Q000473:pathology / Q000628:therapy; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D007150:Immunohistochemistry; D008875:Middle Aged; D015999:Multivariate Analysis; D010766:Phosphorylation; D011379:Prognosis; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000276:immunology / Q000378:metabolism*; D012189:Retrospective Studies; D016019:Survival Analysis; D016896:Treatment Outcome; D014443:Tyrosine / Q000378:metabolism*
chemical_list: D000906:Antibodies; D014408:Biomarkers, Tumor; D018719:Erb-b2 Receptor Tyrosine Kinases; D014443:Tyrosine