title: HER-2 and topo-isomerase IIalpha as predictive markers in a population of node-positive breast cancer patients randomly treated with adjuvant CMF or epirubicin plus cyclophosphamide.
abstract: BACKGROUND
  The predictive role of HER-2 in node-positive breast cancer patients receiving CMF or an anthracycline-based adjuvant therapy remains unclear. In addition, topo-isomerase II alpha (topo IIalpha), as the cellular target of anthracyclines, might have value as a predictive marker.
  
  
  METHODS
  Four hundred eighty-one archival primary tumor samples were collected among 777 patients entered into a multicenter phase III trial comparing classical CMF with epirubicin cyclophosphamide (HEC) as adjuvant therapy of node-positive breast cancer. HER-2 was evaluated by immunohistochemistry (IHC) using different antibodies (Abs). Topo IIalpha was evaluated by IHC using the Ab KiS 1. In each subgroup of patients identified by HER-2 and topo IIalpha, adjusted hazard ratios for event-free survival (EFS) and the corresponding 95% confidence intervals have been calculated for the different study comparisons. An interaction test has been performed to investigate the role of HER-2 and topo IIalpha as predictive markers.
  
  
  RESULTS
  When HER-2 was evaluated by CB-11 and 4D5 mAbs, the EFS adjusted hazard ratios (HR) for the main study comparison HEC vs. CMF were: HER-2 positive: 0.33 (95% confidence interval (95% CI): 0.09 1.27, P = 0.08), HER-2 negative: 1.16 (95%, CI: 0.71-1.90, P = 0.56); the P-value for the interaction test was 0.10. When HER-2 was evaluated by TAB-250 + pAbl Abs, the adjusted HR for the same comparison were: HER-2 positive: 1.06 (95% CI: 0.45-2.52, P = 0.90), HER-2 negative: 0.99 (95% CI: 0.58-1.68, P = 0.97); the P-value for the interaction test was 0.84. With regard to topo IIalpha, the adjusted HR for the EFS comparison HEC vs. CMF were: topo IIalpha positive: 0.66 (95% CI: 0.32-1.36, P = 0.25), topo IIalpha negative: 1.26 (95% CI: 0.63-2.50, P = 0.51); the P-value for the interaction test was 0.13.
  
  
  CONCLUSIONS
  This study suggests that in node-positive breast cancer patients randomly treated with CMF or an epirubicin-based regimen, the predictive value of HER-2 may vary according to the Abs used in the immunohistochemistry assay. In addition, the study supports the concept that topo IIalpha might be involved in the determination of tumor responsiveness to an anthracycline-based adjuvant therapy.
authors.affiliation: Department of Chemotherapy, Jules Bordet Institute, Brussels, Belgium. Angelo.Dileo@bordet.be
authors.forename: A
authors.initials: A
authors.lastname: Di Leo
authors.forename: D
authors.initials: D
authors.lastname: Larsimont
authors.forename: D
authors.initials: D
authors.lastname: Gancberg
authors.forename: T
authors.initials: T
authors.lastname: Jarvinen
authors.forename: M
authors.initials: M
authors.lastname: Beauduin
authors.forename: A
authors.initials: A
authors.lastname: Vindevoghel
authors.forename: J
authors.initials: J
authors.lastname: Michel
authors.forename: C H
authors.initials: CH
authors.lastname: Focan
authors.forename: F
authors.initials: F
authors.lastname: Ries
authors.forename: P H
authors.initials: PH
authors.lastname: Gobert
authors.forename: M T
authors.initials: MT
authors.lastname: Closon-Dejardin
authors.forename: S
authors.initials: S
authors.lastname: Dolci
authors.forename: G
authors.initials: G
authors.lastname: Rouas
authors.forename: M
authors.initials: M
authors.lastname: Paesmans
authors.forename: J P
authors.initials: JP
authors.lastname: Lobelle
authors.forename: J
authors.initials: J
authors.lastname: Isola
authors.forename: M J
authors.initials: MJ
authors.lastname: Piccart
mesh_terms: D000328:Adult; D000368:Aged; D000951:Antigens, Neoplasm; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage / Q000627:therapeutic use*; D014408:Biomarkers, Tumor / Q000032:analysis*; D001943:Breast Neoplasms / Q000737:chemistry* / Q000188:drug therapy* / Q000601:surgery; D017024:Chemotherapy, Adjuvant; D016001:Confidence Intervals; D003520:Cyclophosphamide / Q000008:administration & dosage; D004250:DNA Topoisomerases, Type II / Q000032:analysis*; D004268:DNA-Binding Proteins; D015251:Epirubicin / Q000008:administration & dosage; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage; D018734:Genes, erbB-2 / Q000235:genetics*; D006801:Humans; D008727:Methotrexate / Q000008:administration & dosage; D008875:Middle Aged; D011237:Predictive Value of Tests; D011379:Prognosis; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000032:analysis*; D012189:Retrospective Studies; D016896:Treatment Outcome
chemical_list: D000951:Antigens, Neoplasm; D014408:Biomarkers, Tumor; D003520:Cyclophosphamide; D004250:DNA Topoisomerases, Type II; D004268:DNA-Binding Proteins; D015251:Epirubicin; D005472:Fluorouracil; D008727:Methotrexate; D018719:Erb-b2 Receptor Tyrosine Kinases