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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.

Author(s): O'Malley FP, Chia S, Tu D, Shepherd LE, Levine MN, Huntsman D, Bramwell VH, Andrulis IL, Pritchard KI

Affiliation(s): Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada.

Publication date & source: 2011-07, Breast Cancer Res Treat., 128(2):401-9. Epub 2011 Apr 26.

Publication type: Randomized Controlled Trial

Overexpression of topoisomerase II protein (topo 2alpha) 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 2alpha level in either relapse-free (RFS) or overall survival (OS). In 136 patients (28.5%) whose tumors showed topo 2alpha 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 2alpha 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 2alpha 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 2alpha 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 2alpha protein analysis was exploratory and will require further validation.

Page last updated: 2011-12-09

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