title: Alteration of topoisomerase II-alpha gene in human breast cancer: association with responsiveness to anthracycline-based chemotherapy.
abstract: OBJECTIVE
  Approximately 35% of HER2-amplified breast cancers have coamplification of the topoisomerase II-alpha (TOP2A) gene encoding an enzyme that is a major target of anthracyclines. This study was designed to evaluate whether TOP2A gene alterations may predict incremental responsiveness to anthracyclines in some breast cancers.
  
  
  METHODS
  A total of 4,943 breast cancers were analyzed for alterations in TOP2A and HER2. Primary tumor tissues from patients with metastatic breast cancer treated in a trial of chemotherapy plus/minus trastuzumab were studied for amplification/deletion of TOP2A and HER2 as a test set followed by evaluation of malignancies from two separate, large trials for changes in these same genes as a validation set. Association between these alterations and clinical outcomes was determined.
  
  
  RESULTS
  Test set cases containing HER2 amplification treated with doxorubicin and cyclophosphamide (AC) plus trastuzumab, demonstrated longer progression-free survival compared to those treated with AC alone (P = .0002). However, patients treated with AC alone whose tumors contain HER2/TOP2A coamplification experienced a similar improvement in survival (P = .004). Conversely, for patients treated with paclitaxel, HER2/TOP2A coamplification was not associated with improved outcomes. These observations were confirmed in a larger validation set, where HER2/TOP2A coamplification was again associated with longer survival when only anthracycline-containing chemotherapy was used for treatment compared with outcome in HER2-positive cancers lacking TOP2A coamplification.
  
  
  CONCLUSIONS
  In a study involving nearly 5,000 breast malignancies, both test set and validation set demonstrate that TOP2A coamplification, not HER2 amplification, is the clinically useful predictive marker of an incremental response to anthracycline-based chemotherapy. Absence of HER2/TOP2A coamplification may indicate a more restricted efficacy advantage for breast cancers than previously thought.
authors.affiliation: Norris Comprehensive Cancer Center, University of Southern California, CA, USA. press@usc.edu
authors.forename: Michael F
authors.initials: MF
authors.lastname: Press
authors.forename: Guido
authors.initials: G
authors.lastname: Sauter
authors.forename: Marc
authors.initials: M
authors.lastname: Buyse
authors.forename: Leslie
authors.initials: L
authors.lastname: Bernstein
authors.forename: Roberta
authors.initials: R
authors.lastname: Guzman
authors.forename: Angela
authors.initials: A
authors.lastname: Santiago
authors.forename: Ivonne E
authors.initials: IE
authors.lastname: Villalobos
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Eiermann
authors.forename: Tadeusz
authors.initials: T
authors.lastname: Pienkowski
authors.forename: Miguel
authors.initials: M
authors.lastname: Martin
authors.forename: Nicholas
authors.initials: N
authors.lastname: Robert
authors.forename: John
authors.initials: J
authors.lastname: Crown
authors.forename: Valerie
authors.initials: V
authors.lastname: Bee
authors.forename: Henry
authors.initials: H
authors.lastname: Taupin
authors.forename: Kerry J
authors.initials: KJ
authors.lastname: Flom
authors.forename: Isabelle
authors.initials: I
authors.lastname: Tabah-Fisch
authors.forename: Giovanni
authors.initials: G
authors.lastname: Pauletti
authors.forename: Mary-Ann
authors.initials: MA
authors.lastname: Lindsay
authors.forename: Alessandro
authors.initials: A
authors.lastname: Riva
authors.forename: Dennis J
authors.initials: DJ
authors.lastname: Slamon
mesh_terms: D000328:Adult; D000368:Aged; D018943:Anthracyclines / Q000008:administration & dosage*; D000951:Antigens, Neoplasm / Q000187:drug effects / Q000235:genetics*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics* / Q000401:mortality; D004250:DNA Topoisomerases, Type II / Q000187:drug effects / Q000235:genetics*; D004268:DNA-Binding Proteins / Q000187:drug effects / Q000235:genetics*; D018572:Disease-Free Survival; D005260:Female; D005784:Gene Amplification / Q000187:drug effects*; D015972:Gene Expression Regulation, Neoplastic; D018734:Genes, erbB-2 / Q000187:drug effects*; D020022:Genetic Predisposition to Disease; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D008875:Middle Aged; D000075223:Poly-ADP-Ribose Binding Proteins; D011379:Prognosis; D016016:Proportional Hazards Models; D018570:Risk Assessment; D018709:Statistics, Nonparametric; D016019:Survival Analysis; D016896:Treatment Outcome
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