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.
authors.affiliation: Institute of Pathology, University Erlangen-Nürnberg, Krankenhausstraße 8-10, 91054, Erlangen, Germany, Ramona.erber@uk-erlangen.de.
authors.forename: Ramona
authors.initials: R
authors.lastname: Erber
authors.forename: Oleg
authors.initials: O
authors.lastname: Gluz
authors.forename: Nils
authors.initials: N
authors.lastname: Brünner
authors.forename: Hans Heinrich
authors.initials: HH
authors.lastname: Kreipe
authors.forename: Enrico
authors.initials: E
authors.lastname: Pelz
authors.forename: Ronald
authors.initials: R
authors.lastname: Kates
authors.forename: Annette
authors.initials: A
authors.lastname: Bartels
authors.forename: Jens
authors.initials: J
authors.lastname: Huober
authors.forename: Svjetlana
authors.initials: S
authors.lastname: Mohrmann
authors.forename: Zehra
authors.initials: Z
authors.lastname: Moustafa
authors.forename: Cornelia
authors.initials: C
authors.lastname: Liedtke
authors.forename: Volker
authors.initials: V
authors.lastname: Möbus
authors.forename: Doris
authors.initials: D
authors.lastname: Augustin
authors.forename: Christoph
authors.initials: C
authors.lastname: Thomssen
authors.forename: Fritz
authors.initials: F
authors.lastname: Jänicke
authors.forename: Marion
authors.initials: M
authors.lastname: Kiechle
authors.forename: Walther
authors.initials: W
authors.lastname: Kuhn
authors.forename: Ulrike
authors.initials: U
authors.lastname: Nitz
authors.forename: Nadia
authors.initials: N
authors.lastname: Harbeck
authors.forename: Arndt
authors.initials: A
authors.lastname: Hartmann
mesh_terms: D000951:Antigens, Neoplasm / Q000235:genetics / Q000378:metabolism*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D014408:Biomarkers, Tumor / Q000378:metabolism*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000401:mortality; D017024:Chemotherapy, Adjuvant; D004250:DNA Topoisomerases, Type II / Q000235:genetics / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D018572:Disease-Free Survival; D005260:Female; D006801:Humans; D053208:Kaplan-Meier Estimate; D008875:Middle Aged; D015999:Multivariate Analysis; D011379:Prognosis; D016016:Proportional Hazards Models; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics / Q000378:metabolism*; D012306:Risk; D043823:Taxoids / Q000008:administration & dosage; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000378:metabolism*; D016896:Treatment Outcome
chemical_list: D000951:Antigens, Neoplasm; D014408:Biomarkers, Tumor; D004250:DNA Topoisomerases, Type II; D004268:DNA-Binding Proteins; D018719:Erb-b2 Receptor Tyrosine Kinases; D043823:Taxoids; D019715:Tissue Inhibitor of Metalloproteinase-1; C560822:TIMP1 protein, human; C508053:ERBB2 protein, human