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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

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Abstract

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.

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Acknowledgments

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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Authors and Affiliations

  1. Institute of Pathology, University Erlangen-Nürnberg, Krankenhausstraße 8-10, 91054, Erlangen, Germany

    Ramona Erber & Arndt Hartmann

  2. West German Study Group, Ludwig Weber Str. 15, 41061, Mönchengladbach, Germany

    Oleg Gluz, Ronald Kates, Zehra Moustafa, Ulrike Nitz & Nadia Harbeck

  3. Breast Center Niederrhein, Ev. Bethesda Hospital, Moenchengladbach, Germany

    Oleg Gluz & Ulrike Nitz

  4. Section of Molecular Disease Biology, Faculty of Health and Medical Sciences, Institute of Veterinary Disease Biology, University of Copenhagen, Copenhagen, Denmark

    Nils Brünner & Annette Bartels

  5. Institute of Pathology, Hannover Medical School, Hannover, Germany

    Hans Heinrich Kreipe

  6. Institute of Pathology, Viersen, Germany

    Enrico Pelz

  7. Department of Obstetrics and Gynecology, University Clinics Tuebingen, Tūebingen, Germany

    Jens Huober

  8. Department of Obstetrics and Gynecology, University Clinics Ulm, Ulm, Germany

    Jens Huober

  9. Department of Obstetrics and Gynecology, University Clinics Düsseldorf, Dūsseldorf, Germany

    Svjetlana Mohrmann & Ulrike Nitz

  10. Department of Obstetrics and Gynecology, University Clinics Schleswig-Holsten, Lūbeck, Germany

    Cornelia Liedtke

  11. Department of Obstetrics and Gynecology, Staedtisches Klinikum, Frankfurt, Germany

    Volker Möbus

  12. Clinics Deggendorf Mammacenter Ostbayern, Deggendorf, Germany

    Doris Augustin

  13. Department of Gynecology, Martin-Luther-University Halle-Wittenberg, Halle/Saale, Germany

    Christoph Thomssen

  14. Department of Gynecology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

    Fritz Jänicke

  15. Department of Obstetrics and Gynecology, Technical University Clinics Rechts der Isar Munich, Munich, Germany

    Marion Kiechle

  16. Department of Obstetrics and Gynecology, University Clinics Bonn, Bonn, Germany

    Walther Kuhn

  17. Breast Center, Ludwig Maximilian University of Munich, Munich, Germany

    Nadia Harbeck

Authors
  1. Ramona Erber
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  2. Oleg Gluz
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Correspondence to Ramona Erber or Oleg Gluz.

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Erber, R., Gluz, O., Brünner, N. et al. 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. Breast Cancer Res Treat 150, 279–288 (2015). https://doi.org/10.1007/s10549-015-3310-x

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