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.
J Clin Oncol. 2015 May 20;33(15):1680-7. doi: 10.1200/JCO.2013.54.7869. Epub 2015 Apr 20.
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.
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.
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).
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.
支持蒽环类药物活性预测生物标志物临床效用的证据很薄弱，最近的一项荟萃分析未能为 HER2 或 TOP2A 提供有力证据。先前我们已经表明，使用着丝粒探针（CEP17）测量的 17 号染色体着丝粒周围α卫星的重复可预测对蒽环类药物的敏感性，在此我们报告了五项试验的个体患者水平汇总分析数据，这些试验比较了蒽环类药物为基础的化疗与 CMF（环磷酰胺、甲氨蝶呤和氟尿嘧啶）作为早期乳腺癌辅助化疗。
在三个实验室对来自五个试验的 4864 名合格患者中的 3846 名患者的样本进行了 CEP17、HER2 和 TOP2A 的荧光原位杂交。方法学差异并未影响 HER2 与 CEP17 的比值，但需要对 CEP17 重复进行不同的定义：BR9601、NEAT、比利时和 DBCG89D 试验为 > 1.86 个观察到的拷贝/细胞，MA.5 试验为 > 2.25。
荧光原位杂交数据可用于 3846 例患者中 89.3%（HER2）、83.9%（CEP17）和 80.6%（TOP2A）的可用组织。在调整后的无复发生存和总生存分析中，CEP17 和 TOP2A 治疗标志物交互作用仍然显著，而 HER2 则不然。CEP17 和 TOP2A 联合调整模型预测了所有五项试验中蒽环类药物的获益，无论是无复发生存（风险比，0.64；95%置信区间，0.51 至 0.82；P =.001）还是总生存（风险比，0.66；95%置信区间，0.51 至 0.85；P =.005）。
这项对五项辅助试验患者病例的前瞻性计划的个体患者汇总分析证实，肿瘤存在 CEP17 重复或 TOP2A 异常（但不是 HER2 扩增）的患者受益于辅助蒽环类药物化疗。
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