title: Topoisomerase II alpha and responsiveness of breast cancer to adjuvant chemotherapy.
abstract: BACKGROUND
  Amplification or deletion of the topoisomerase II alpha (TOP2A) gene in breast cancers has been postulated to be more closely associated with responsiveness to anthracycline-containing chemotherapy than amplification of the human epidermal growth factor receptor type 2 (HER2) gene.
  
  
  METHODS
  We studied 438 tumors from 710 premenopausal women with node-positive breast cancer who received cyclophosphamide, epirubicin, and 5-fluorouracil (CEF) or cyclophosphamide, methotrexate, and 5-fluorouracil (CMF) as adjuvant chemotherapy in the randomized National Cancer Institute of Canada Clinical Trials Group Mammary 5 (MA.5) trial. TOP2A alterations and HER2 amplification were quantified by fluorescence in situ hybridization. The association of TOP2A and HER2 status with recurrence-free survival (RFS) and overall survival (OS) in the two treatment groups was analyzed using Kaplan-Meier curves, the log-rank test, and Cox proportional hazard models. All statistical tests were two-sided.
  
  
  RESULTS
  In patients whose tumors showed TOP2A alterations (either amplifications or deletions), treatment with CEF was statistically significantly superior to treatment with CMF in terms of RFS (adjusted hazard ratio [HR] = 0.35, 95% confidence interval [CI] = 0.17 to 0.73, P = .005) and OS (adjusted HR = 0.33, 95% CI = 0.15 to 0.75, P = .008). In patients without TOP2A amplification or deletion, the corresponding adjusted hazard ratios for RFS and OS were 0.90 (95% CI = 0.66 to 1.23, P = .49) and 1.09 (95% CI = 0.77 to 1.56, P = .62). Adjusted tests of interaction between treatment and TOP2A status were P = .09 for RFS and P = .02 for OS. Adjusted tests of interaction between treatment and HER2 status were P = .008 for RFS and P = .02 for OS.
  
  
  CONCLUSIONS
  TOP2A gene alterations (amplifications or deletions) are associated with an increase in responsiveness to anthracycline-containing chemotherapy regimens relative to non-anthracycline regimens that is similar to that seen in patients with HER2 amplification.
authors.affiliation: Sunnybrook Odette Cancer Centre, University of Toronto, 2075 Bayview Ave, Toronto, Ontario, Canada.
authors.forename: F P
authors.initials: FP
authors.lastname: O'Malley
authors.forename: S
authors.initials: S
authors.lastname: Chia
authors.forename: D
authors.initials: D
authors.lastname: Tu
authors.forename: L E
authors.initials: LE
authors.lastname: Shepherd
authors.forename: M N
authors.initials: MN
authors.lastname: Levine
authors.forename: V H
authors.initials: VH
authors.lastname: Bramwell
authors.forename: I L
authors.initials: IL
authors.lastname: Andrulis
authors.forename: K I
authors.initials: KI
authors.lastname: Pritchard
mesh_terms: D000328:Adult; D018943:Anthracyclines / Q000008:administration & dosage; D000951:Antigens, Neoplasm / Q000235:genetics*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000201:enzymology* / Q000235:genetics / Q000473:pathology / Q000601:surgery; D017024:Chemotherapy, Adjuvant; D004250:DNA Topoisomerases, Type II / Q000235:genetics*; D004268:DNA-Binding Proteins / Q000235:genetics*; D018572:Disease-Free Survival; D005260:Female; D005784:Gene Amplification; D015971:Gene Expression Regulation, Enzymologic; D015972:Gene Expression Regulation, Neoplastic; D018734:Genes, erbB-2; D006801:Humans; D053208:Kaplan-Meier Estimate; D008207:Lymphatic Metastasis; D008408:Mastectomy / Q000379:methods; D008875:Middle Aged; D020411:Oligonucleotide Array Sequence Analysis; D000075223:Poly-ADP-Ribose Binding Proteins; D017697:Premenopause
chemical_list: D018943:Anthracyclines; D000951:Antigens, Neoplasm; D004268:DNA-Binding Proteins; D000075223:Poly-ADP-Ribose Binding Proteins; D004250:DNA Topoisomerases, Type II; C000618811:TOP2A protein, human