title: Predictive markers of anthracycline benefit: a prospectively planned analysis of the UK National Epirubicin Adjuvant Trial (NEAT/BR9601).
abstract: BACKGROUND
  The NEAT/BR9601 trial showed benefit for addition of anthracyclines to cyclophosphamide, methotrexate, and fluorouracil (CMF) as adjuvant treatment for early breast cancer. We investigated prospectively predictive biomarkers of anthracycline benefit including HER2 and TOP2A.
  
  
  METHODS
  1941 tumours from 2391 women recruited to NEAT/BR9601 were analysed on tissue microarrays for HER2 and TOP2A amplification and deletion, HER1-3 and Ki67 expression, and duplication of chromosome 17 centromere enumeration probe (Ch17CEP). Log-rank analyses identified factors affecting relapse-free and overall survival, and regression models tested independent prognostic effect of markers, with adjustment for known prognostic factors (age, nodal status, oestrogen-receptor status, grade, and tumour size). The predictive value of markers was tested by treatment interactions for relapse-free and overall survival.
  
  
  RESULTS
  1762 patients were analysed. 21% of tumours (n=367) were HER2 amplified, 10% were TOP2A amplified (n=169), 11% showed TOP2A deleted (n=191), 23% showed Ch17CEP duplication (n=406), and 61% had high (>13.0%) Ki67 (n=1136). In univariate analyses, only HER2 amplification and TOP2A deletion were significant prognostic factors for relapse-free (hazard ratio [HR] 1.59, 95% CI 1.32-1.92, p<0.0001; and 1.52, 1.20-1.92, p=0.0006, respectively) and overall survival (1.79, 1.47-2.19, p<0.0001; and 1.62, 1.26-2.08, p=0.0002 respectively). We detected no significant interaction with anthracycline benefit for Ki67, HER2, HER1-3, or TOP2A. By contrast, in multivariate analyses, Ch17CEP duplication was associated with significant improvements in both relapse-free (HR 0.92, 95% CI 0.72-1.18 for tumours with normal Ch17CEP vs 0.52, 0.34-0.81 for tumours with abnormal Ch17CEP; p for interaction=0.004) and overall survival (0.94, 0.72-1.24 vs 0.57, 0.36-0.92; p for interaction=0.02) with anthracycline use.
  
  
  CONCLUSIONS
  In women with early breast cancer receiving adjuvant chemotherapy, the most powerful predictor of benefit from anthracyclines is Ch17CEP duplication. In view of the location of HER2/TOP2A on chromosome 17, Ch17CEP duplication might explain the inconsistencies in previous studies of factors predicting benefit from anthracyclines.
  
  
  BACKGROUND
  Cancer Research UK and the Scottish Breast Cancer Clinical Trials Group.
authors.affiliation: Endocrine Cancer Group, Edinburgh University, Edinburgh, UK. John.Bartlett@ed.ac.uk
authors.forename: John M S
authors.initials: JM
authors.lastname: Bartlett
authors.forename: Alison F
authors.initials: AF
authors.lastname: Munro
authors.forename: Janet A
authors.initials: JA
authors.lastname: Dunn
authors.forename: Christopher
authors.initials: C
authors.lastname: McConkey
authors.forename: Sarah
authors.initials: S
authors.lastname: Jordan
authors.forename: Chris J
authors.initials: CJ
authors.lastname: Twelves
authors.forename: David A
authors.initials: DA
authors.lastname: Cameron
authors.forename: Jeremy
authors.initials: J
authors.lastname: Thomas
authors.forename: Fiona M
authors.initials: FM
authors.lastname: Campbell
authors.forename: Daniel W
authors.initials: DW
authors.lastname: Rea
authors.forename: Elena
authors.initials: E
authors.lastname: Provenzano
authors.forename: Carlos
authors.initials: C
authors.lastname: Caldas
authors.forename: Paul
authors.initials: P
authors.lastname: Pharoah
authors.forename: Louise
authors.initials: L
authors.lastname: Hiller
authors.forename: Helena
authors.initials: H
authors.lastname: Earl
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Poole
mesh_terms: D000903:Antibiotics, Antineoplastic / Q000008:administration & dosage / Q000494:pharmacology*; D000951:Antigens, Neoplasm / Q000235:genetics; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology / Q000627:therapeutic use; D054316:Biomarkers, Pharmacological; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000473:pathology; D004250:DNA Topoisomerases, Type II / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics; D018572:Disease-Free Survival; D015251:Epirubicin / Q000008:administration & dosage / Q000494:pharmacology*; D005260:Female; D005784:Gene Amplification; D018734:Genes, erbB-2 / Q000235:genetics; D006801:Humans; D007150:Immunohistochemistry; D008875:Middle Aged; D015999:Multivariate Analysis; D020411:Oligonucleotide Array Sequence Analysis; D018579:Patient Selection; D000075223:Poly-ADP-Ribose Binding Proteins; D011237:Predictive Value of Tests; D011446:Prospective Studies; D016019:Survival Analysis; D014407:Tumor Cells, Cultured
chemical_list: D000903:Antibiotics, Antineoplastic; D000951:Antigens, Neoplasm; D054316:Biomarkers, Pharmacological; D004268:DNA-Binding Proteins; D000075223:Poly-ADP-Ribose Binding Proteins; D015251:Epirubicin; D004250:DNA Topoisomerases, Type II; C000618811:TOP2A protein, human