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

• Published in: Breast cancer research and treatment 2015-04, Vol.150 (2), p.279-288
• Main Authors: Erber, Ramona, Gluz, Oleg, Brünner, Nils, Kreipe, Hans Heinrich, Pelz, Enrico, Kates, Ronald, Bartels, Annette, Huober, Jens, Mohrmann, Svjetlana, Moustafa, Zehra, Liedtke, Cornelia, Möbus, Volker, Augustin, Doris, Thomssen, Christoph, Jänicke, Fritz, Kiechle, Marion, Kuhn, Walther, Nitz, Ulrike, Harbeck, Nadia, Hartmann, Arndt
• Format: Article
• Language: English
• Subjects: Adjuvant chemotherapy; Anthracyclines; Antigens, Neoplasm - genetics; Antigens, Neoplasm - metabolism; Antineoplastic Combined Chemotherapy Protocols - therapeutic use; Biomarkers, Tumor - metabolism; Breast cancer; Breast Neoplasms - drug therapy; Breast Neoplasms - metabolism; Breast Neoplasms - mortality; Cancer research; Cancer therapies; Chemotherapy; Chemotherapy, Adjuvant; Disease-Free Survival; DNA Topoisomerases, Type II - genetics; DNA Topoisomerases, Type II - metabolism; DNA-Binding Proteins - genetics; DNA-Binding Proteins - metabolism; Female; Health aspects; Humans; Immunohistochemistry; Kaplan-Meier Estimate; Medical prognosis; Medicine; Medicine & Public Health; Middle Aged; Multivariate Analysis; Oncology; Preclinical Study; Prognosis; Proportional Hazards Models; Protein expression; Receptor, ErbB-2 - genetics; Receptor, ErbB-2 - metabolism; Risk; Risk factors; Taxoids - administration & dosage; Tissue Inhibitor of Metalloproteinase-1 - metabolism; Treatment Outcome
• ISSN: 0167-6806; 1573-7217
• DOI: 10.1007/s10549-015-3310-x

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