John M S Bartlett1, Christopher C McConkey2, Alison F Munro2, Christine Desmedt2, Janet A Dunn2, Denis P Larsimont2, Frances P O'Malley2, David A Cameron2, Helena M Earl2, Christopher J Poole2, Lois E Shepherd2, Fatima Cardoso2, Maj-Britt Jensen2, Carlos Caldas2, Christopher J Twelves2, Daniel W Rea2, Bent Ejlertsen2, Angelo Di Leo2, Kathleen I Pritchard2. 1. John M.S. Bartlett, Ontario Institute for Cancer Research; Frances P. O'Malley, St Michael's Hospital; Kathleen I. Pritchard, Sunnybrook Odette Cancer Centre and University of Toronto, Toronto; John M.S. Bartlett, Frances P. O'Malley, and Lois E. Shepherd, National Cancer Institute of Canada Clinical Trials Group; Lois E. Shepherd, Queen's University, Kingston, Canada; John M.S. Bartlett, Alison F. Munro, and David A. Cameron, University of Edinburgh, Edinburgh; Christopher C. McConkey, Janet A. Dunn, and Christopher J. Poole, University of Warwick, Coventry; Helena M. Earl and Carlos Caldas, University of Cambridge, Cambridge; Christopher J. Twelves, St James's University Hospital, Leeds; Daniel W. Rea, University of Birmingham, Birmingham, United Kingdom; Christine Desmedt and Denis P. Larsimont, Université Libre de Bruxelles, Brussels, Belgium; Fatima Cardoso, Champalimaud Cancer Centre, Lisbon, Portugal; Maj-Britt Jensen and Bent Ejlertsen, Rigshospitalet, Copenhagen, Denmark; and Angelo Di Leo, Hospital of Prato, Prato, Italy. john.bartlett@oicr.on.ca. 2. John M.S. Bartlett, Ontario Institute for Cancer Research; Frances P. O'Malley, St Michael's Hospital; Kathleen I. Pritchard, Sunnybrook Odette Cancer Centre and University of Toronto, Toronto; John M.S. Bartlett, Frances P. O'Malley, and Lois E. Shepherd, National Cancer Institute of Canada Clinical Trials Group; Lois E. Shepherd, Queen's University, Kingston, Canada; John M.S. Bartlett, Alison F. Munro, and David A. Cameron, University of Edinburgh, Edinburgh; Christopher C. McConkey, Janet A. Dunn, and Christopher J. Poole, University of Warwick, Coventry; Helena M. Earl and Carlos Caldas, University of Cambridge, Cambridge; Christopher J. Twelves, St James's University Hospital, Leeds; Daniel W. Rea, University of Birmingham, Birmingham, United Kingdom; Christine Desmedt and Denis P. Larsimont, Université Libre de Bruxelles, Brussels, Belgium; Fatima Cardoso, Champalimaud Cancer Centre, Lisbon, Portugal; Maj-Britt Jensen and Bent Ejlertsen, Rigshospitalet, Copenhagen, Denmark; and Angelo Di Leo, Hospital of Prato, Prato, Italy.
Abstract
PURPOSE: Evidence supporting the clinical utility of predictive biomarkers of anthracycline activity is weak, with a recent meta-analysis failing to provide strong evidence for either HER2 or TOP2A. Having previously shown that duplication of chromosome 17 pericentromeric alpha satellite as measured with a centromere enumeration probe (CEP17) predicted sensitivity to anthracyclines, we report here an individual patient-level pooled analysis of data from five trials comparing anthracycline-based chemotherapy with CMF (cyclophosphamide, methotrexate, and fluorouracil) as adjuvant chemotherapy for early breast cancer. PATIENTS AND METHODS: Fluorescent in situ hybridization for CEP17, HER2, and TOP2A was performed in three laboratories on samples from 3,846 of 4,864 eligible patients from five trials evaluating anthracycline-containing chemotherapy versus CMF. Methodologic differences did not affect HER2-to-CEP17 ratios but necessitated different definitions for CEP17 duplication: > 1.86 observed copies per cell for BR9601, NEAT, Belgian, and DBCG89D trials and > 2.25 for the MA.5 trial. RESULTS: Fluorescent in situ hybridization data were available in 89.3% (HER2), 83.9% (CEP17), and 80.6% (TOP2A) of 3,846 patient cases with available tissue. Both CEP17and TOP2A treatment-by-marker interactions remained significant in adjusted analyses for recurrence-free and overall survival, whereas HER2 did not. A combined CEP17 and TOP2A-adjusted model predicted anthracycline benefit across all five trials for both recurrence-free (hazard ratio, 0.64; 95% CI, 0.51 to 0.82; P = .001) and overall survival (hazard ratio, 0.66; 95% CI, 0.51 to 0.85; P = .005). CONCLUSION: This prospectively planned individual-patient pooled analysis of patient cases from five adjuvant trials confirms that patients whose tumors harbor either CEP17 duplication or TOP2A aberrations, but not HER2 amplification, benefit from adjuvant anthracycline chemotherapy.
PURPOSE: Evidence supporting the clinical utility of predictive biomarkers of anthracycline activity is weak, with a recent meta-analysis failing to provide strong evidence for either HER2 or TOP2A. Having previously shown that duplication of chromosome 17 pericentromeric alpha satellite as measured with a centromere enumeration probe (CEP17) predicted sensitivity to anthracyclines, we report here an individual patient-level pooled analysis of data from five trials comparing anthracycline-based chemotherapy with CMF (cyclophosphamide, methotrexate, and fluorouracil) as adjuvant chemotherapy for early breast cancer. PATIENTS AND METHODS: Fluorescent in situ hybridization for CEP17, HER2, and TOP2A was performed in three laboratories on samples from 3,846 of 4,864 eligible patients from five trials evaluating anthracycline-containing chemotherapy versus CMF. Methodologic differences did not affect HER2-to-CEP17 ratios but necessitated different definitions for CEP17 duplication: > 1.86 observed copies per cell for BR9601, NEAT, Belgian, and DBCG89D trials and > 2.25 for the MA.5 trial. RESULTS: Fluorescent in situ hybridization data were available in 89.3% (HER2), 83.9% (CEP17), and 80.6% (TOP2A) of 3,846 patient cases with available tissue. Both CEP17and TOP2A treatment-by-marker interactions remained significant in adjusted analyses for recurrence-free and overall survival, whereas HER2 did not. A combined CEP17 and TOP2A-adjusted model predicted anthracycline benefit across all five trials for both recurrence-free (hazard ratio, 0.64; 95% CI, 0.51 to 0.82; P = .001) and overall survival (hazard ratio, 0.66; 95% CI, 0.51 to 0.85; P = .005). CONCLUSION: This prospectively planned individual-patient pooled analysis of patient cases from five adjuvant trials confirms that patients whose tumors harbor either CEP17 duplication or TOP2A aberrations, but not HER2 amplification, benefit from adjuvant anthracycline chemotherapy.
Authors: Helena Earl; Louise Hiller; Anne-Laure Vallier; Shrushma Loi; Karen McAdam; Luke Hughes-Davies; Daniel Rea; Donna Howe; Kerry Raynes; Helen B Higgins; Maggie Wilcox; Chris Plummer; Betania Mahler-Araujo; Elena Provenzano; Anita Chhabra; Sophie Gasson; Claire Balmer; Jean E Abraham; Carlos Caldas; Peter Hall; Bethany Shinkins; Christopher McCabe; Claire Hulme; David Miles; Andrew M Wardley; David A Cameron; Janet A Dunn Journal: Health Technol Assess Date: 2020-08 Impact factor: 4.014
Authors: Melanie Spears; Fouad Yousif; Nicola Lyttle; Paul C Boutros; Alison F Munro; Chris Twelves; Kathleen I Pritchard; Mark N Levine; Lois Shepherd; John M S Bartlett Journal: Oncotarget Date: 2015-10-13
Authors: Marsela Braunstein; Linda Liao; Nicola Lyttle; Nazleen Lobo; Karen J Taylor; Paul M Krzyzanowski; Irina Kalatskaya; Cindy Q Yao; Lincoln D Stein; Paul C Boutros; Christopher J Twelves; Richard Marcellus; John M S Bartlett; Melanie Spears Journal: Breast Cancer Res Date: 2016-02-06 Impact factor: 6.466
Authors: Tommaso A Dragani; Antoni Castells; Vathany Kulasingam; Eleftherios P Diamandis; Helena Earl; Wade T Iams; Christine M Lovly; J P Michiel Sedelaar; Jack A Schalken Journal: BMC Med Date: 2016-07-28 Impact factor: 8.775