title: TP53 status for prediction of sensitivity to taxane versus non-taxane neoadjuvant chemotherapy in breast cancer (EORTC 10994/BIG 1-00): a randomised phase 3 trial.
abstract: BACKGROUND
  TP53 has a crucial role in the DNA damage response. We therefore tested the hypothesis that taxanes confer a greater advantage than do anthracyclines on breast cancers with mutated TP53 than in those with wild-type TP53.
  
  
  METHODS
  In an open-label, phase 3 study, women (age <71 years) with locally advanced, inflammatory, or large operable breast cancers were randomly assigned in a 1:1 ratio to either a standard anthracycline regimen (six cycles of intravenous fluorouracil 500 mg/m², epirubicin 100 mg/m², and cyclophosphamide 500 mg/m² every 21 days [FEC100], or fluorouracil 600 mg/m², epirubicin 75 mg/m², cyclophosphamide 900 mg/m² [tailored FEC] starting on day 1 and then every 21 days) or a taxane-based regimen (three cycles of docetaxel 100 mg/m², intravenously infused over 1 h on day 1 every 21 days, followed by three cycles of intravenous epirubicin 90 mg/m² and docetaxel 75 mg/m² on day 1 every 21 days [T-ET]) at 42 centres in Europe. Randomisation was by use of a minimisation method that stratified patients by institution and initial tumour stage. The primary endpoint was progression-free survival (PFS) according to TP53 status. Analysis was by intention to treat. This is the final analysis of this trial. The study is registered with ClinicalTrials.gov, number NCT00017095.
  
  
  RESULTS
  928 patients were enrolled in the FEC group and 928 in the T-ET group. TP53 status was not assessable for 183 (20%) patients in the FEC group and 204 (22%) patients in the T-ET group mainly because of low tumour-cell content in the biopsy. 361 primary endpoint events were recorded in the FEC group and 314 in the T-ET group. In patients with TP53-mutated tumours, 5-year PFS was 59·5% (95% CI 53·4-65·1) in the T-ET group (n=326) and 55·3% (49·2-60·9) in the FEC group (n=318; hazard ratio 0·84, 98% CI 0·63-1·14; p=0·17). In patients with TP53 wild-type tumours, 5-year PFS was 66·8% (95% CI 61·4-71·6) in the T-ET group (n=398) and 64·7% (59·6-69·4) in the FEC group (n=427; 0·89, 98% CI 0·68-1·18; p=0·35). For all patients, irrespective of TP53 status, 5-year PFS was 65·1% (95% CI 61·6-68·3) in the T-ET group and 60·8% (57·3-64·2) in the FEC group (0·85, 98% CI 0·71-1·02; p=0·035). At the sites using FEC100 versus T-ET, the most common grade 3 or 4 adverse events were febrile neutropenia (75 [9%] of 803 vs 173 [21%] of 809, respectively), and neutropenia (653 [81%] vs 730 [90%], respectively). At the sites using tailored FEC versus T-ET, the most common grade 3 or 4 adverse events were febrile neutropenia (ten [8%] of 118 vs 26 [22%] of 116, respectively), and neutropenia (100 [85%] vs 115 [99%], respectively). Two patients died of toxicity during or within 30 days of chemotherapy completion and without disease relapse (one in each group).
  
  
  CONCLUSIONS
  Although TP53 status was prognostic for overall survival, it was not predictive of preferential sensitivity to taxanes. TP53 status tested by use of the yeast assay in this patient population cannot be used to select patients for an anthracycline-based chemotherapy versus a taxane-based chemotherapy.
  
  
  BACKGROUND
  US National Cancer Institute, La Ligue Nationale Contre le Cancer, European Union, Pharmacia, and Sanofi-Aventis.
authors.affiliation: Institut Bergonié, Université de Bordeaux, INSERM U916, Bordeaux, France. bonnefoi@bergonie.org
authors.forename: Hervé
authors.initials: H
authors.lastname: Bonnefoi
authors.forename: Martine
authors.initials: M
authors.lastname: Piccart
authors.forename: Jan
authors.initials: J
authors.lastname: Bogaerts
authors.forename: Louis
authors.initials: L
authors.lastname: Mauriac
authors.forename: Pierre
authors.initials: P
authors.lastname: Fumoleau
authors.forename: Etienne
authors.initials: E
authors.lastname: Brain
authors.forename: Thierry
authors.initials: T
authors.lastname: Petit
authors.forename: Philippe
authors.initials: P
authors.lastname: Rouanet
authors.forename: Jacek
authors.initials: J
authors.lastname: Jassem
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Blot
authors.forename: Khalil
authors.initials: K
authors.lastname: Zaman
authors.forename: Tanja
authors.initials: T
authors.lastname: Cufer
authors.forename: Alain
authors.initials: A
authors.lastname: Lortholary
authors.forename: Elisabet
authors.initials: E
authors.lastname: Lidbrink
authors.forename: Sylvie
authors.initials: S
authors.lastname: André
authors.forename: Saskia
authors.initials: S
authors.lastname: Litière
authors.forename: Lissandra Dal
authors.initials: LD
authors.lastname: Lago
authors.forename: Véronique
authors.initials: V
authors.lastname: Becette
authors.forename: David A
authors.initials: DA
authors.lastname: Cameron
authors.forename: Jonas
authors.initials: J
authors.lastname: Bergh
authors.forename: Richard
authors.initials: R
authors.lastname: Iggo
mesh_terms: D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D001943:Breast Neoplasms / Q000737:chemistry / Q000188:drug therapy* / Q000401:mortality; D005260:Female; D006801:Humans; D008875:Middle Aged; D009154:Mutation; D020360:Neoadjuvant Therapy; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000032:analysis; D011960:Receptors, Estrogen / Q000032:analysis; D043823:Taxoids / Q000008:administration & dosage / Q000627:therapeutic use*; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000502:physiology*
chemical_list: D018719:Erb-b2 Receptor Tyrosine Kinases; D011960:Receptors, Estrogen; D043823:Taxoids; D016159:Tumor Suppressor Protein p53; C495901:TP53 protein, human; C508053:ERBB2 protein, human