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 Erber; Oleg Gluz; 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

doi:10.1007/s10549-015-3310-x

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 Erber, Oleg Gluz, 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

8 Citations (Scopus)

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.

Original language	English
Journal	Breast Cancer Research and Treatment
Volume	150
Issue number	2
Pages (from-to)	279-288
Number of pages	10
ISSN	0167-6806
DOIs	https://doi.org/10.1007/s10549-015-3310-x
Publication status	Published - Apr 2015

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Erber, R., Gluz, O., Brünner, N., Kreipe, H. H., Pelz, E., Kates, R., Bartels, A., Huober, J., Mohrmann, S., Moustafa, Z., Liedtke, C., Möbus, V., Augustin, D., Thomssen, C., Jänicke, F., Kiechle, M., Kuhn, W., Nitz, U., Harbeck, N., & Hartmann, A. (2015). 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 Research and Treatment, 150(2), 279-288. https://doi.org/10.1007/s10549-015-3310-x

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. / Erber, Ramona; Gluz, Oleg; Brünner, Nils et al.
In: Breast Cancer Research and Treatment, Vol. 150, No. 2, 04.2015, p. 279-288.

Research output: Contribution to journal › Journal article › Research › peer-review

Erber, R, Gluz, O, Brünner, N, Kreipe, HH, Pelz, E, Kates, R, Bartels, A, Huober, J, Mohrmann, S, Moustafa, Z, Liedtke, C, Möbus, V, Augustin, D, Thomssen, C, Jänicke, F, Kiechle, M, Kuhn, W, Nitz, U, Harbeck, N & Hartmann, A 2015, '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 Research and Treatment, vol. 150, no. 2, pp. 279-288. https://doi.org/10.1007/s10549-015-3310-x

Erber R, Gluz O, Brünner N, Kreipe HH, Pelz E, Kates R 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 Research and Treatment. 2015 Apr;150(2):279-288. doi: 10.1007/s10549-015-3310-x

Erber, Ramona ; Gluz, Oleg ; Brünner, Nils 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. In: Breast Cancer Research and Treatment. 2015 ; Vol. 150, No. 2. pp. 279-288.

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title = "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",

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.",

author = "Ramona Erber and Oleg Gluz and Nils Br{\"u}nner and Kreipe, {Hans Heinrich} and Enrico Pelz and Ronald Kates and Annette Bartels and Jens Huober and Svjetlana Mohrmann and Zehra Moustafa and Cornelia Liedtke and Volker M{\"o}bus and Doris Augustin and Christoph Thomssen and Fritz J{\"a}nicke and Marion Kiechle and Walther Kuhn and Ulrike Nitz and Nadia Harbeck and Arndt Hartmann",

year = "2015",

month = apr,

doi = "10.1007/s10549-015-3310-x",

language = "English",

volume = "150",

pages = "279--288",

journal = "Breast Cancer Research and Treatment",

issn = "0167-6806",

publisher = "Springer",

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TY - JOUR

T1 - 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

T2 - results from the WSG-AGO EC-Doc trial

AU - Erber, Ramona

AU - Gluz, Oleg

AU - Brünner, Nils

AU - Kreipe, Hans Heinrich

AU - Pelz, Enrico

AU - Kates, Ronald

AU - Bartels, Annette

AU - Huober, Jens

AU - Mohrmann, Svjetlana

AU - Moustafa, Zehra

AU - Liedtke, Cornelia

AU - Möbus, Volker

AU - Augustin, Doris

AU - Thomssen, Christoph

AU - Jänicke, Fritz

AU - Kiechle, Marion

AU - Kuhn, Walther

AU - Nitz, Ulrike

AU - Harbeck, Nadia

AU - Hartmann, Arndt

PY - 2015/4

Y1 - 2015/4

N2 - 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.

AB - 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.

U2 - 10.1007/s10549-015-3310-x

DO - 10.1007/s10549-015-3310-x

M3 - Journal article

C2 - 25721604

SN - 0167-6806

VL - 150

SP - 279

EP - 288

JO - Breast Cancer Research and Treatment

JF - Breast Cancer Research and Treatment

IS - 2

ER -