title: Multifactorial approach to predicting resistance to anthracyclines.
abstract: OBJECTIVE
  Validated biomarkers predictive of response/resistance to anthracyclines in breast cancer are currently lacking. The neoadjuvant Trial of Principle (TOP) study, in which patients with estrogen receptor (ER) -negative tumors were treated with anthracycline (epirubicin) monotherapy, was specifically designed to evaluate the predictive value of topoisomerase II-α (TOP2A) and develop a gene expression signature to identify those patients who do not benefit from anthracyclines.
  
  
  METHODS
  The TOP trial included 149 patients, 139 of whom were evaluable for response prediction analyses. The primary end point was pathologic complete response (pCR). TOP2A and gene expression profiles were evaluated using pre-epirubicin biopsies. Gene expression data from ER-negative samples of the EORTC (European Organisation for Research and Treatment of Cancer) 10994/BIG (Breast International Group) 00-01 and MDACC (MD Anderson Cancer Center) 2003-0321 neoadjuvant trials were used for validation purposes.
  
  
  RESULTS
  A pCR was obtained in 14% of the evaluable patients in the TOP trial. TOP2A amplification, but not protein overexpression, was significantly associated with pCR (P ≤ .001 v P ≤ .33). We developed an anthracycline-based score (A-Score) combining three signatures: a TOP2A gene signature and two previously published signatures related to tumor invasion and immune response. The A-Score was characterized by a high negative predictive value ([NPV]; NPV, 0.98; 95% CI, 0.90 to 1.00) overall and in the human epidermal growth factor receptor 2 (HER2) -negative and HER2-positive subpopulations. Its performance was independently confirmed in the anthracycline-based arms of the two validation trials (BIG 00-01: NPV, 0.83; 95% CI, 0.64 to 0.94 and MDACC 2003-0321: NPV, 1.00; 95% CI, 0.80 to 1.00).
  
  
  CONCLUSIONS
  Given its high NPV, the A-Score could become, if further validated, a useful clinical tool to identify those patients who do not benefit from anthracyclines and could therefore be spared the non-negligible adverse effects.
authors.affiliation: Breast Cancer Translational Research Laboratory JC Heuson, Université Libre de Bruxelles, Institut Jules Bordet, 125 Bld de Waterloo, 1000 Brussels, Belgium. christine.desmedt@bordet.be
authors.forename: Christine
authors.initials: C
authors.lastname: Desmedt
authors.forename: Angelo
authors.initials: A
authors.lastname: Di Leo
authors.forename: Evandro
authors.initials: E
authors.lastname: de Azambuja
authors.forename: Denis
authors.initials: D
authors.lastname: Larsimont
authors.forename: Benjamin
authors.initials: B
authors.lastname: Haibe-Kains
authors.forename: Jean
authors.initials: J
authors.lastname: Selleslags
authors.forename: Suzette
authors.initials: S
authors.lastname: Delaloge
authors.forename: Caroline
authors.initials: C
authors.lastname: Duhem
authors.forename: Jean-Pierre
authors.initials: JP
authors.lastname: Kains
authors.forename: Birgit
authors.initials: B
authors.lastname: Carly
authors.forename: Marie
authors.initials: M
authors.lastname: Maerevoet
authors.forename: Anita
authors.initials: A
authors.lastname: Vindevoghel
authors.forename: Ghislane
authors.initials: G
authors.lastname: Rouas
authors.forename: Françoise
authors.initials: F
authors.lastname: Lallemand
authors.forename: Virginie
authors.initials: V
authors.lastname: Durbecq
authors.forename: Fatima
authors.initials: F
authors.lastname: Cardoso
authors.forename: Roberto
authors.initials: R
authors.lastname: Salgado
authors.forename: Rodrigo
authors.initials: R
authors.lastname: Rovere
authors.forename: Gianluca
authors.initials: G
authors.lastname: Bontempi
authors.forename: Stefan
authors.initials: S
authors.lastname: Michiels
authors.forename: Marc
authors.initials: M
authors.lastname: Buyse
authors.forename: Jean-Marie
authors.initials: JM
authors.lastname: Nogaret
authors.forename: Yuan
authors.initials: Y
authors.lastname: Qi
authors.forename: Fraser
authors.initials: F
authors.lastname: Symmans
authors.forename: Lajos
authors.initials: L
authors.lastname: Pusztai
authors.forename: Véronique
authors.initials: V
authors.lastname: D'Hondt
authors.forename: Martine
authors.initials: M
authors.lastname: Piccart-Gebhart
authors.forename: Christos
authors.initials: C
authors.lastname: Sotiriou
mesh_terms: D000903:Antibiotics, Antineoplastic / Q000009:adverse effects / Q000627:therapeutic use*; D000951:Antigens, Neoplasm / Q000032:analysis / Q000235:genetics; D014408:Biomarkers, Tumor / Q000032:analysis; D001706:Biopsy; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D017024:Chemotherapy, Adjuvant; D004250:DNA Topoisomerases, Type II / Q000032:analysis / Q000235:genetics; D004268:DNA-Binding Proteins / Q000032:analysis / Q000037:antagonists & inhibitors / Q000235:genetics; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D015251:Epirubicin / Q000009:adverse effects / Q000627:therapeutic use*; D005060:Europe; D005260:Female; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008875:Middle Aged; D020360:Neoadjuvant Therapy; D016017:Odds Ratio; D018579:Patient Selection; D000075223:Poly-ADP-Ribose Binding Proteins; D011237:Predictive Value of Tests; D011446:Prospective Studies; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000032:analysis; D011960:Receptors, Estrogen / Q000032:analysis; D015203:Reproducibility of Results; D018570:Risk Assessment; D012307:Risk Factors; D013781:Texas; D017211:Treatment Failure
chemical_list: D000903:Antibiotics, Antineoplastic; D000951:Antigens, Neoplasm; D014408:Biomarkers, Tumor; D004250:DNA Topoisomerases, Type II; D004268:DNA-Binding Proteins; D015251:Epirubicin; D000075223:Poly-ADP-Ribose Binding Proteins; D018719:Erb-b2 Receptor Tyrosine Kinases; D011960:Receptors, Estrogen; C508053:ERBB2 protein, human; C000618811:TOP2A protein, human