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
N1 - Publisher Copyright:
© 2015, Springer Science+Business Media New York.
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.
KW - Breast cancer
KW - HER2/neu
KW - TIMP-1
KW - Taxanes
KW - Topoisomerase-II-alpha
UR - https://www.scopus.com/pages/publications/84925397297
U2 - 10.1007/s10549-015-3310-x
DO - 10.1007/s10549-015-3310-x
M3 - Article
C2 - 25721604
AN - SCOPUS:84925397297
SN - 0167-6806
VL - 150
SP - 279
EP - 288
JO - Breast Cancer Research and Treatment
JF - Breast Cancer Research and Treatment
IS - 2
ER -
