title: Topoisomerase II alpha protein and responsiveness of breast cancer to adjuvant chemotherapy with CEF compared to CMF in the NCIC CTG randomized MA.5 adjuvant trial.
abstract: Overexpression of topoisomerase II protein (topo 2α) is postulated to be more closely associated with responsiveness to anthracycline-containing chemotherapy than human epidermal growth factor receptor type 2 (HER2) gene amplification or alterations in the topoisomerase II alpha gene (TOP2A). The authors used tissue microarrays from 477 of 710 premenopausal women with node-positive breast cancer randomized to CEF or CMF adjuvant chemotherapy in the NCIC Clinical Trials Group Mammary 5 (MA.5) trial. No significant interaction was found between treatment and continuous topo 2α level in either relapse-free (RFS) or overall survival (OS). In 136 patients (28.5%) whose tumors showed topo 2α overexpression by immunohistochemistry based on a cut-off of 13%, CEF was superior to CMF for RFS (adjusted HR 0.45; 95% CI 0.25-0.82; P = 0.009) and OS (adjusted HR 0.50; 95% CI 0.26-0.96; P = 0.04). When tumors lacked topo 2α overexpression, CEF was not superior for RFS (adjusted HR 0.88; 95% CI 0.64-1.22; P = 0.46) or OS (adjusted HR 0.95; 95% CI 0.66-1.38; P = 0.80). Interaction between topo 2α and treatment was borderline significant for RFS (P = 0.04) and OS (P = 0.05) and not substantially more significant than between TOP2A gene alteration (P (interaction) = 0.09 for RFS and 0.02 for OS) or HER2 overexpression (P (interaction) = 0.002 for RFS and 0.009 for OS). Topo 2α protein overexpression based on the cut-off identified in this study, TOP2A gene alterations and HER2 protein overexpression were each associated with responsiveness to anthracycline-containing chemotherapy. The topo 2α protein analysis was exploratory and will require further validation.
authors.affiliation: Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada.
authors.forename: F P
authors.initials: FP
authors.lastname: O'Malley
authors.forename: S
authors.initials: S
authors.lastname: Chia
authors.forename: D
authors.initials: D
authors.lastname: Tu
authors.forename: L E
authors.initials: LE
authors.lastname: Shepherd
authors.forename: M N
authors.initials: MN
authors.lastname: Levine
authors.forename: D
authors.initials: D
authors.lastname: Huntsman
authors.forename: V H
authors.initials: VH
authors.lastname: Bramwell
authors.forename: I L
authors.initials: IL
authors.lastname: Andrulis
authors.forename: K I
authors.initials: KI
authors.lastname: Pritchard
mesh_terms: D000328:Adult; D000951:Antigens, Neoplasm / Q000235:genetics* / Q000378:metabolism*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000473:pathology; D017024:Chemotherapy, Adjuvant; D003520:Cyclophosphamide / Q000627:therapeutic use; D004250:DNA Topoisomerases, Type II / Q000235:genetics* / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism*; D015251:Epirubicin / Q000627:therapeutic use; D005260:Female; D005472:Fluorouracil / Q000627:therapeutic use; D005784:Gene Amplification; D006801:Humans; D007124:Immunoenzyme Techniques; D017404:In Situ Hybridization, Fluorescence; D008727:Methotrexate / Q000627:therapeutic use; D008875:Middle Aged; D000075223:Poly-ADP-Ribose Binding Proteins; D012333:RNA, Messenger / Q000235:genetics; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015996:Survival Rate; D016896:Treatment Outcome
chemical_list: D000951:Antigens, Neoplasm; D003520:Cyclophosphamide; D004250:DNA Topoisomerases, Type II; D004268:DNA-Binding Proteins; D015251:Epirubicin; D005472:Fluorouracil; D008727:Methotrexate; D000075223:Poly-ADP-Ribose Binding Proteins; D012333:RNA, Messenger; D018719:Erb-b2 Receptor Tyrosine Kinases; C508053:ERBB2 protein, human; C000618811:TOP2A protein, human