Breast Cancer Research and Treatment

, Volume 132, Issue 1, pp 225–234 | Cite as

TIMP-1 in combination with HER2 and TOP2A for prediction of benefit from adjuvant anthracyclines in high-risk breast cancer patients

  • Pernille Braemer Hertel
  • Dongsheng Tu
  • Bent Ejlertsen
  • Maj-Britt Jensen
  • Eva Balslev
  • Shan Jiang
  • Frances P. O’Malley
  • Kathleen I. Pritchard
  • Lois E. Shepherd
  • Annette Bartels
  • Nils Brünner
  • Torsten O. Nielsen
Clinical trial


HER2 amplification, TOP2A aberrations, and absence of tissue inhibitor of metalloproteinase (TIMP-1) expression in breast carcinomas have been shown to be associated with incremental benefit from anthracycline-containing adjuvant chemotherapy, and this study was undertaken to validate these findings in a similar, but independent, randomized clinical trial. TIMP-1 was examined by immunohistochemistry in archival tumor tissue from 403 of 716 premenopausal high-risk patients with known HER2 and TOP2A status who were randomized to cyclophosphamide, epirubicin, and fluorouracil (CEF) or cyclophosphamide, methotrexate, and fluorouracil (CMF) in the MA.5 trial. Ninety-eight (24%) patients had no TIMP-1 staining of tumor cells, 27% were HER2 amplified, and 18% were TOP2A aberrant. Forty-four percentage was classified as HT responsive (HER2 amplified and/or TIMP-1 negative) and 37% as 2T responsive (TOP2A aberrant and/or TIMP-1 negative). There was no heterogeneity in treatment effect of CEF versus CMF according to TIMP-1. In HT-responsive patients, CEF was superior to CMF with an improved RFS (adjusted HR, 0.64; 95% CI, 0.42–0.97), but this was not significant for OS (adjusted HR, 0.66; 95% CI, 0.42–1.04). A significant HT profile versus treatment interaction was detected for OS (P = 0.03). In 2T-responsive patients, CEF seemed to improve RFS compared to CMF (adjusted HR, 0.67; 95% CI, 0.43–1.03) and improved OS (adjusted HR, 0.58; 95% CI, 0.36–0.93). A significant 2T profile versus treatment interaction was detected for OS (P = 0.01). With this study, we validate a more substantial reduction in mortality by CEF compared to CMF in patients with an HT- or 2T-responsive profile; however, we could not show a similarly significant reduction in RFS events, where a benefit of CEF over CMF was found irrespective of TIMP-1 status. Further studies are necessary before the HT and 2T profiles may be used to direct the use of anthracyclines.


TIMP-1 HER2 TOP2A Prediction Breast cancer NCIC CTG MA.5 



Nils Brünner received funding from The Danish Natural Science Foundation and A Race Against Breast Cancer; Pernille Hertel received funding from Breast Friends and The Association of Young Oncologist (FYO) and AstraZeneca’s Grant for Education and Research.

Conflict of interest

The authors declare no conflicts of interest.


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Copyright information

© Springer Science+Business Media, LLC. 2011

Authors and Affiliations

  • Pernille Braemer Hertel
    • 1
    • 2
    • 3
    • 12
  • Dongsheng Tu
    • 4
  • Bent Ejlertsen
    • 3
    • 5
  • Maj-Britt Jensen
    • 5
  • Eva Balslev
    • 6
  • Shan Jiang
    • 4
  • Frances P. O’Malley
    • 7
    • 8
  • Kathleen I. Pritchard
    • 9
    • 10
  • Lois E. Shepherd
    • 4
  • Annette Bartels
    • 1
    • 2
  • Nils Brünner
    • 1
    • 2
  • Torsten O. Nielsen
    • 11
  1. 1.Department of Veterinary Disease Biology, Faculty of Life SciencesUniversity of CopenhagenFrederiksbergDenmark
  2. 2.Danish Centre for Translational Breast Cancer Research and Sino-Danish Breast Cancer Research CentreUniversity of CopenhagenFrederiksbergDenmark
  3. 3.Department of Oncology, RigshospitaletCopenhagen University HospitalCopenhagenDenmark
  4. 4.National Cancer Institute of Canada Clinical Trials GroupKingstonCanada
  5. 5.The Danish Breast Cancer Cooperative GroupStatistical CentreCopenhagenDenmark
  6. 6.Department of Pathology, Herlev HospitalCopenhagen University HospitalHerlevDenmark
  7. 7.Department of Laboratory Medicine and PathobiologyUniversity of TorontoTorontoCanada
  8. 8.Department of Laboratory Medicine and the Keenan Research Centre of the Li Ka Shing Knowledge InstituteSt Michael’s HospitalTorontoCanada
  9. 9.Sunnybrook Odette Cancer CentreTorontoCanada
  10. 10.Department of MedicineUniversity of TorontoTorontoCanada
  11. 11.Department of PathologyUniversity of British ColumbiaVancouverCanada
  12. 12.BallerupDenmark

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