CEF is superior to CMF for tumours with TOP2A aberrations: a Subpopulation Treatment Effect Pattern Plot (STEPP) analysis on Danish Breast Cancer Cooperative Group Study 89D

Breast Cancer Res Treat. 2010 Aug;123(1):163-9. doi: 10.1007/s10549-010-0931-y. Epub 2010 May 13.


The aim of this study was to examine TOP2A gene copy number changes as a means to identify groups of breast cancer patients with superior benefit from treatment with anthracyclines. Tumour tissue was retrospectively collected and successfully analysed for TOP2A in 773 of 980 Danish patients randomly assigned to receive intravenous CMF (cyclophosphamide, methotrexate and fluorouracil) or CEF (cyclophosphamide, epirubicin and fluorouracil) in DBCG trial 89D. Subgroup analyses on this material published by Knoop et al. (J Clin Oncol 23:7483-7490, 2005) and updated by Nielsen et al. (Acta Oncol 47:725-734, 2008) demonstrated that superiority of CEF over CMF is limited to patients with TOP2A aberrations, defined as patients whose tumours have TOP2A ratio below 0.8 or above 2.0. The Subpopulation Treatment Effect Pattern Plot (STEPP) technique was applied to these data to explore the pattern of treatment effect relative to TOP2A and to compare that pattern to the ranges previously used to define 'aberrations'. The pattern of treatment effect illustrated by the STEPP analysis confirmed that the superiority of CEF over CMF is indeed limited to patients whose tumours have high or low TOP2A ratios. The hypothesis of no treatment effect-covariate interaction was rejected (P = 0.02). Furthermore, results indicated that the interval of TOP2A ratios hitherto denoted as 'normal' could be narrower than previously assumed. A more optimal separation of TOP2A subgroups could be obtained by altering cut-points currently used to define TOP2A amplified and TOP2A deleted tumours by narrowing the TOP2A normal interval, and consequently enlarging the population with TOP2A aberrated tumours.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Antigens, Neoplasm / genetics*
  • Antineoplastic Combined Chemotherapy Protocols / therapeutic use*
  • Breast Neoplasms / drug therapy*
  • Breast Neoplasms / genetics*
  • Breast Neoplasms / mortality
  • Cisplatin
  • Cyclophosphamide / administration & dosage
  • DNA Topoisomerases, Type II / genetics*
  • DNA-Binding Proteins / genetics*
  • Data Interpretation, Statistical
  • Disease-Free Survival
  • Drug Resistance, Neoplasm / genetics
  • Epirubicin / administration & dosage
  • Female
  • Fluorouracil / administration & dosage
  • Gene Dosage
  • Humans
  • In Situ Hybridization, Fluorescence
  • Methotrexate / administration & dosage
  • Poly-ADP-Ribose Binding Proteins
  • Randomized Controlled Trials as Topic*
  • Treatment Outcome


  • Antigens, Neoplasm
  • DNA-Binding Proteins
  • Poly-ADP-Ribose Binding Proteins
  • Epirubicin
  • Cyclophosphamide
  • DNA Topoisomerases, Type II
  • TOP2A protein, human
  • Cisplatin
  • Fluorouracil
  • Methotrexate

Supplementary concepts

  • CMF protocol