Chromosome 17 centromere (CEP17) duplication as a predictor of anthracycline response: evidence from the NCIC Clinical Trials Group (NCIC CTG) MA.5 Trial |
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Authors: | Kathleen I Pritchard Alison Munro Frances P O’Malley Dongsheng Tu Xiao Li Mark N Levine Lois Shepherd Stephen Chia John M S Bartlett |
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Institution: | (1) Sunnybrook Odette Cancer Centre, The University of Toronto, 2075 Bayview Avenue, Toronto, ON, M4N 3M5, Canada;(2) University of Toronto, Toronto, ON, Canada;(3) Endocrine Cancer Group, Edinburgh Cancer Research Centre, Western General Hospital, Crewe Road South, Edinburgh, EH4 2XR, UK;(4) Department of Laboratory Medicine, St. Michael’s Hospital, Toronto, ON, Canada;(5) NCIC Clinical Trials Group (NCIC CTG) and Queen’s University, Kingston, ON, Canada;(6) McMaster University and Hamilton Health Sciences, Hamilton, ON, Canada;(7) University of British Columbia, Vancouver, BC, Canada;(8) British Columbia Cancer Agency, Vancouver, BC, Canada;(9) Ontario Institute for Cancer Research, Toronto, ON, Canada |
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Abstract: | HER2 gene amplification and topoisomerase IIα gene (TOP2A) alteration have been associated with increased benefit from anthracycline compared to non-anthracycline containing adjuvant
breast cancer chemotherapy in some but not other studies. Chromosome 17 centromere (CEP17) duplication was measured on TMAs
from formalin-fixed paraffin-embedded specimens obtained from 639 of 716 premenopausal women with node positive breast cancer
who received cyclophosphamide, epirubicin and fluorouracil (CEF) or cyclophosphamide, methotrexate and fluorouracil (CMF)
in the randomized controlled mammary 5 (MA.5) adjuvant trial. The prognostic impact of CEP17 duplication and its interactions
with treatment were studied for relapse-free survival (RFS) and overall survival (OS). Overall, CEP17 duplication was not
significantly associated with RFS or OS in multivariate analysis. For patients whose tumours had normal CEP17 copy number
there were no apparent benefits for CEF compared to CMF for RFS (HR 0.98; 95% CI 0.68–1.42) or OS (HR 1.10; 95% CI 0.72–1.69).
For patients whose tumours had CEP17 duplication, there was significant benefit for CEF compared to CMF for RFS (HR 0.54;
CI 0.33–0.89) and a trend towards significance for OS (HR 0.64; CI 0.37–1.09). The adjusted P values for interaction between treatment and CEP17 duplication were 0.09 for RFS and 0.13 for OS. This study suggests that
CEP17 duplication has a borderline association with clinical responsiveness to anthracycline containing chemotherapy similar
to previous results seen with HER2 amplification and TOP2A alteration in MA.5. An appropriately powered meta-analysis is required to discriminate the predictive value of these three
candidate markers. |
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