Topoisomerase II alpha protein and responsiveness of breast cancer to adjuvant chemotherapy with CEF compared to CMF in the NCIC CTG randomized MA.5 adjuvant trial

  • F. P. O’Malley
  • S. Chia
  • D. Tu
  • L. E. Shepherd
  • M. N. Levine
  • D. Huntsman
  • V. H. Bramwell
  • I. L. Andrulis
  • K. I. Pritchard
Clinical Trial


Overexpression of topoisomerase II protein (topo 2α) is postulated to be more closely associated with responsiveness to anthracycline-containing chemotherapy than human epidermal growth factor receptor type 2 (HER2) gene amplification or alterations in the topoisomerase II alpha gene (TOP2A). The authors used tissue microarrays from 477 of 710 premenopausal women with node-positive breast cancer randomized to CEF or CMF adjuvant chemotherapy in the NCIC Clinical Trials Group Mammary 5 (MA.5) trial. No significant interaction was found between treatment and continuous topo 2α level in either relapse-free (RFS) or overall survival (OS). In 136 patients (28.5%) whose tumors showed topo 2α overexpression by immunohistochemistry based on a cut-off of 13%, CEF was superior to CMF for RFS (adjusted HR 0.45; 95% CI 0.25–0.82; P = 0.009) and OS (adjusted HR 0.50; 95% CI 0.26–0.96; P = 0.04). When tumors lacked topo 2α overexpression, CEF was not superior for RFS (adjusted HR 0.88; 95% CI 0.64–1.22; P = 0.46) or OS (adjusted HR 0.95; 95% CI 0.66–1.38; P = 0.80). Interaction between topo 2α and treatment was borderline significant for RFS (P = 0.04) and OS (P = 0.05) and not substantially more significant than between TOP2A gene alteration (P interaction = 0.09 for RFS and 0.02 for OS) or HER2 overexpression (P interaction = 0.002 for RFS and 0.009 for OS). Topo 2α protein overexpression based on the cut-off identified in this study, TOP2A gene alterations and HER2 protein overexpression were each associated with responsiveness to anthracycline-containing chemotherapy. The topo 2α protein analysis was exploratory and will require further validation.


Topoisomerase II alpha protein Adjuvant anthracycline chemotherapy 


Conflict of interest


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Copyright information

© Springer Science+Business Media, LLC. 2011

Authors and Affiliations

  • F. P. O’Malley
    • 1
    • 2
  • S. Chia
    • 3
    • 4
  • D. Tu
    • 5
  • L. E. Shepherd
    • 5
  • M. N. Levine
    • 6
  • D. Huntsman
    • 3
    • 4
  • V. H. Bramwell
    • 7
    • 8
  • I. L. Andrulis
    • 1
    • 9
  • K. I. Pritchard
    • 10
    • 11
  1. 1.Department of Laboratory Medicine and PathobiologyUniversity of TorontoTorontoCanada
  2. 2.Department of Laboratory Medicine, and the Keenan Research Centre of the Li Ka Shing Knowledge InstituteSt Michael’s HospitalTorontoCanada
  3. 3.British Columbia Cancer AgencyVancouverCanada
  4. 4.University of British ColumbiaVancouverCanada
  5. 5.NCIC Clinical Trials Group (NCIC CTG)KingstonCanada
  6. 6.McMaster UniversityHamiltonCanada
  7. 7.Tom Baker Cancer CentreCalgaryCanada
  8. 8.University of CalgaryCalgaryCanada
  9. 9.Fred A. Litwin Centre for Cancer Genetics, Samuel Lunenfeld Research InstituteMount Sinai HospitalTorontoCanada
  10. 10.Sunnybrook Odette Cancer CentreTorontoCanada
  11. 11.Department of MedicineUniversity of TorontoTorontoCanada

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