Breast Cancer Research and Treatment

, Volume 150, Issue 2, pp 279–288 | Cite as

Predictive role of HER2/neu, topoisomerase-II-alpha, and tissue inhibitor of metalloproteinases (TIMP-1) for response to adjuvant taxane-based chemotherapy in patients with intermediate-risk breast cancer: results from the WSG-AGO EC-Doc trial

  • Ramona ErberEmail author
  • Oleg GluzEmail author
  • Nils Brünner
  • Hans Heinrich Kreipe
  • Enrico Pelz
  • Ronald Kates
  • Annette Bartels
  • Jens Huober
  • Svjetlana Mohrmann
  • Zehra Moustafa
  • Cornelia Liedtke
  • Volker Möbus
  • Doris Augustin
  • Christoph Thomssen
  • Fritz Jänicke
  • Marion Kiechle
  • Walther Kuhn
  • Ulrike Nitz
  • Nadia Harbeck
  • Arndt Hartmann
Preclinical Study


Taxane–anthracycline-based adjuvant chemotherapy is standard of care in patients with node-positive breast cancer (BC) but is also associated with severe side effects and significant costs. It is yet unclear, which biomarkers would predict benefit from taxanes and/or general chemoresistance. In this study, we investigate a large cohort of patients with intermediate-risk BC treated within the WSG EC-DOC Trial for the predictive impact of topoisomerase-II-alpha, HER2/neu, and TIMP-1. Tumor tissue was available in a representative cohort of 772 cases of the WSG EC-DOC Trial collective which compared 4xEC-4xDoc versus 6xCEF/CMF. In addition to hormone receptor status and Ki-67, HER2/neu+ and topoisomerase-II-alpha status using fluorescence in situ hybridisation (FISH) and immunohistochemistry, TIMP-1 using immunohistochemistry, and aneuploidy of chromosome 17 using FISH were evaluated and correlated with outcome and taxane benefit. There was significant superiority of EC-Doc over CEF regarding 5-year DFS (90 vs. 80 %, respectively, p = 0.006) particularly in patient subgroups defined by HR+, HER2/neu+, high proliferation (i.e., Ki-67 ≥ 20 %), patient age >50 years old and normal chromosome 17 status, high TIMP-1 and low topoisomerase-II-alpha protein expression. Significant prognostic factors in multivariate analysis were EC-Doc therapy (HR = 0.61; 95 %CI 0.38–0.986), age <50 years old (HR = 1.682; 95 %CI 1.025–2.579), centrally assessed grade 3 (HR = 4.657; 95 %CI 1.809–11.989), and high Ki-67 (HR = 2.232; 95 %CI 1.209–4.121). Interestingly, we observed a significant interaction between treatment arm (EC-Doc vs. CEF) and high topoisomerase-II-alpha protein expression (HR = 0.427; 95 %CI 0.203–0.900) in multivariate interaction analysis. Despite of univariate predictive effect of HER2/neu status among other factors only topoisomerase-II-alpha protein expression was associated with significant benefit from EC-Doc compared to CEF by multivariate interaction analysis.


Breast cancer Taxanes Topoisomerase-II-alpha TIMP-1 HER2/neu 



We thank Rudolf Jung for excellent technical assistance. We thank all the patients who took part in the trial and consented to provide their dataand all the investigators for treating the patients and reporting their data. We thank all pathologists who provided tumor blocks to our tumor bank. Our special thanks to D. Hofmann, D. Schindowski, I. Renner, C. Buehne, F. Werner, S. Martens, and K. Riedel for study management; G. Schuett, MD, for medical support. The present work was performed in fulfillment of the requirements for obtaining the degree “Dr. med.” at the Friedrich-Alexander.University Erlangen-Nuremberg (FAU).

Conflict of interest

The authors declare that they have no conflict of interest.


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Copyright information

© Springer Science+Business Media New York 2015

Authors and Affiliations

  • Ramona Erber
    • 1
    Email author
  • Oleg Gluz
    • 2
    • 3
    Email author
  • Nils Brünner
    • 4
  • Hans Heinrich Kreipe
    • 5
  • Enrico Pelz
    • 6
  • Ronald Kates
    • 2
  • Annette Bartels
    • 4
  • Jens Huober
    • 7
    • 8
  • Svjetlana Mohrmann
    • 9
  • Zehra Moustafa
    • 2
  • Cornelia Liedtke
    • 10
  • Volker Möbus
    • 11
  • Doris Augustin
    • 12
  • Christoph Thomssen
    • 13
  • Fritz Jänicke
    • 14
  • Marion Kiechle
    • 15
  • Walther Kuhn
    • 16
  • Ulrike Nitz
    • 2
    • 3
    • 9
  • Nadia Harbeck
    • 2
    • 17
  • Arndt Hartmann
    • 1
  1. 1.Institute of PathologyUniversity Erlangen-NürnbergErlangenGermany
  2. 2.West German Study GroupMönchengladbachGermany
  3. 3.Breast Center NiederrheinEv. Bethesda HospitalMoenchengladbachGermany
  4. 4.Section of Molecular Disease Biology, Faculty of Health and Medical Sciences, Institute of Veterinary Disease BiologyUniversity of CopenhagenCopenhagenDenmark
  5. 5.Institute of PathologyHannover Medical SchoolHannoverGermany
  6. 6.Institute of PathologyViersenGermany
  7. 7.Department of Obstetrics and GynecologyUniversity Clinics TuebingenTūebingenGermany
  8. 8.Department of Obstetrics and GynecologyUniversity Clinics UlmUlmGermany
  9. 9.Department of Obstetrics and GynecologyUniversity Clinics DüsseldorfDūsseldorfGermany
  10. 10.Department of Obstetrics and GynecologyUniversity Clinics Schleswig-HolstenLūbeckGermany
  11. 11.Department of Obstetrics and GynecologyStaedtisches KlinikumFrankfurtGermany
  12. 12.Clinics Deggendorf Mammacenter OstbayernDeggendorfGermany
  13. 13.Department of GynecologyMartin-Luther-University Halle-WittenbergHalle/SaaleGermany
  14. 14.Department of GynecologyUniversity Medical Center Hamburg-EppendorfHamburgGermany
  15. 15.Department of Obstetrics and GynecologyTechnical University Clinics Rechts der Isar MunichMunichGermany
  16. 16.Department of Obstetrics and GynecologyUniversity Clinics BonnBonnGermany
  17. 17.Breast CenterLudwig Maximilian University of MunichMunichGermany

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