title: Invasion factors uPA/PAI-1 and HER2 status provide independent and complementary information on patient outcome in node-negative breast cancer.
abstract: OBJECTIVE
  The independent clinical relevance of invasion factors urokinase-type plasminogen activator (uPA)/PAI-1 and HER2 status was evaluated in lymph node-negative breast cancer patients (N = 118) without adjuvant systemic therapy after long-term follow-up of more than 10 years (median, 126 months).
  
  
  METHODS
  Levels of uPA and its inhibitor PAI-1 were prospectively measured by enzyme-linked immunosorbent assay in primary tumor tissue extracts. HER2 gene amplification (HER2_AMP) was evaluated by fluorescence in situ hybridization (FISH; Ventana Medical Systems HER-2/neu probe; Tucson, AZ), and HER2 protein overexpression (HER2_EXP) was evaluated by immunohistochemistry (IHC; Oncogene Science antibody Ab-3; Cambridge, MA) on parallel-cut formalin-fixed paraffin-embedded tissue sections.
  
  
  RESULTS
  uPA/PAI-1 was high (either one or both factors were high) in 44% of the tumors. HER2_AMP was detected by FISH in 33% of the patients, and HER2_EXP was found by IHC in 44% of the patients. In a multivariate analysis of established and tumor-biologic prognostic factors, uPA/PAI-1 was the only independent prognostic factor for disease-free survival ([DFS]; P <.001; relative risk [RR], 8.3; 95% confidence interval [CI], 3.4 to 20.4). Although HER2_AMP and HER2_EXP did not reach significance for DFS, they were significant for overall survival (OS), even in multivariate analysis (HER2_AMP: P =.004; RR, 3.7; 95% CI, 1.5 to 9.2; HER2_EXP: P =.009; RR, 3.4; 95% CI, 1.4 to 8.7).
  
  
  CONCLUSIONS
  After long-term follow-up, uPA/PAI-1 levels in primary tumor tissue reliably and strongly indicate an aggressive course of disease in lymph node-negative breast cancer independent of HER2 status. The particular prognostic effect of HER2 status on OS may reflect its ability to predict resistance to systemic therapy.
authors.affiliation: Frauenklinik and Institut für Allgemeine Pathologie und Pathologische Anatomie, Technische Universität, and Gemeinschaftspraxis Lachnerstrasse 2 für Pathologie und Zytologie, München, Germany.
authors.forename: Iris
authors.initials: I
authors.lastname: Zemzoum
authors.forename: Ronald E
authors.initials: RE
authors.lastname: Kates
authors.forename: Jeffrey S
authors.initials: JS
authors.lastname: Ross
authors.forename: Peer
authors.initials: P
authors.lastname: Dettmar
authors.forename: Moshumi
authors.initials: M
authors.lastname: Dutta
authors.forename: Cordula
authors.initials: C
authors.lastname: Henrichs
authors.forename: Suna
authors.initials: S
authors.lastname: Yurdseven
authors.forename: Heinz
authors.initials: H
authors.lastname: Höfler
authors.forename: Marion
authors.initials: M
authors.lastname: Kiechle
authors.forename: Manfred
authors.initials: M
authors.lastname: Schmitt
authors.forename: Nadia
authors.initials: N
authors.lastname: Harbeck
mesh_terms: D000328:Adult; D000368:Aged; D000704:Analysis of Variance; D014408:Biomarkers, Tumor / Q000032:analysis* / Q000276:immunology; D001943:Breast Neoplasms / Q000737:chemistry* / Q000401:mortality / Q000473:pathology; D018572:Disease-Free Survival; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D007150:Immunohistochemistry; D017404:In Situ Hybridization, Fluorescence; D008875:Middle Aged; D009361:Neoplasm Invasiveness; D009367:Neoplasm Staging; D017395:Plasminogen Activator Inhibitor 1 / Q000032:analysis* / Q000276:immunology; D011237:Predictive Value of Tests; D011379:Prognosis; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000032:analysis*; D012680:Sensitivity and Specificity; D016019:Survival Analysis; D015854:Up-Regulation; D014568:Urokinase-Type Plasminogen Activator / Q000032:analysis* / Q000276:immunology
chemical_list: D014408:Biomarkers, Tumor; D017395:Plasminogen Activator Inhibitor 1; D018719:Erb-b2 Receptor Tyrosine Kinases; D014568:Urokinase-Type Plasminogen Activator