Predicting anthracycline benefit: TOP2A and CEP17 - Not only but also

Research output: Contribution to journalArticlepeer-review


  • John M S Bartlett
  • Christopher C. McConkey
  • Alison F. Munro
  • Christine Desmedt
  • Janet A. Dunn
  • Denis P. Larsimont
  • Frances P. O'Malley
  • David A. Cameron
  • Helena M. Earl
  • Christopher J. Poole
  • Lois E. Shepherd
  • Fatima Cardoso
  • Maj Britt Jensen
  • Carlos Caldas
  • Christopher J. Twelves
  • Bent Ejlertsen
  • Angelo Di Leo
  • Kathleen I. Pritchard

Colleges, School and Institutes


Purpose: Evidence supporting the clinical utility of predictive biomarkers of anthracycline activity is weak, with a recent meta-analysis failing to provide strong evidence for either HER2 or TOP2A. Having previously shown that duplication of chromosome 17 pericentromeric alpha satellite as measured with a centromere enumeration probe (CEP17) predicted sensitivity to anthracyclines, we report here an individual patient-level pooled analysis of data from five trials comparing anthracyclinebased chemotherapy with CMF (cyclophosphamide, methotrexate, and fluorouracil) as adjuvant chemotherapy for early breast cancer. Patients and Methods: Fluorescent in situ hybridization for CEP17, HER2, and TOP2A was performed in three laboratories on samples from 3,846 of 4,864 eligible patients from five trials evaluating anthracyclinecontaining chemotherapy versus CMF. Methodologic differences did not affect HER2-to-CEP17 ratios but necessitated different definitions for CEP17 duplication: > 1.86 observed copies per cell for BR9601, NEAT, Belgian, and DBCG89D trials and > 2.25 for the MA.5 trial. Results: Fluorescent in situ hybridization data were available in 89.3% (HER2), 83.9% (CEP17), and 80.6% (TOP2A) of 3,846 patient cases with available tissue. Both CEP17and TOP2A treatment-by-marker interactions remained significant in adjusted analyses for recurrence-free and overall survival, whereas HER2 did not. A combined CEP17 and TOP2A-adjusted model predicted anthracycline benefit across all five trials for both recurrence-free (hazard ratio, 0.64; 95% CI, 0.51 to 0.82; P = .001) and overall survival (hazard ratio, 0.66; 95% CI, 0.51 to 0.85; P = .005). Conclusion: This prospectively planned individual-patient pooled analysis of patient cases from five adjuvant trials confirms that patients whose tumors harbor either CEP17 duplication or TOP2A aberrations, but not HER2 amplification, benefit from adjuvant anthracycline chemotherapy.


Original languageEnglish
Pages (from-to)1680-1687
Number of pages8
JournalJournal of Clinical Oncology
Issue number15
Early online date20 Apr 2015
Publication statusPublished - 20 May 2015

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