HER2 and TOP2A as predictive markers for anthracycline-containing chemotherapy regimens as adjuvant treatment of breast cancer: a meta-analysis of individual patient data
HER2 and TOP2A as predictive markers for anthracycline-containing chemotherapy regimens as adjuvant treatment of breast cancer: a meta-analysis of individual patient data
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DOI：
10.1016/s1470-2045(11)70231-5
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发表时间：
2011-11-01
期刊：
影响因子：
51.1
通讯作者：
Buyse, Marc
中科院分区：
文献类型：
--
作者：
Di Leo, Angelo;Desmedt, Christine;Buyse, Marc
背景 对基于蒽环类药物的乳腺癌治疗的反应进行预测具有挑战性。我们的目的是评估 HER2 和 TOP2A 作为早期乳腺癌患者对基于蒽环类药物的辅助治疗反应的预测标志物的价值。方法我们对来自五项随机辅助试验的个体患者数据进行了荟萃分析，这些试验将基于蒽环类药物的方案与环磷酰胺、甲氨蝶呤和氟尿嘧啶 (CMF) 方案进行了比较。我们通过荧光原位杂交评估了 HER2 和 TOP2A 基因的状态。肿瘤样本被提交给外部实验室进行验证。我们计算了风险比 (HR)，以比较接受基于蒽环类药物治疗的患者与接受 CMF 治疗的患者在两个 HER2 队列（HER2 扩增和非扩增肿瘤）和三个 TOP2A 队列（正常、扩增和缺失肿瘤）中的无事件生存率 (EFS) 和总生存率。 结果 我们分析了 3452 名 HER2 患者和 3102 名 HER2 患者的数据。 TOP2A。对于 EFS，HER2 非扩增患者的 HR 为 0.89 (95% CI 0.79-1.01)，HER2 扩增患者的 HR 为 0.71 (0.58-0.86)（p（交互作用）= 0.0485）；对于总生存期，HER2 非扩增患者的 HR 为 0.91 (95% CI 0.79-1.05)，HER2 扩增患者的 HR 为 0.73 (0.59-0.89)（p（交互作用）= 0.0718）。在 TOP2A 状态分析中，正常 EFS 的 HR 为 0.88 (0.78-1.00)，删除的 HR 为 0.63 (0.46-0.87)，扩增的 HR 为 0.62 (0.43-0.90)（p（相互作用）= 0.0513）；正常的总生存率 HR 为 0.89 (0.78-1.03)，删除的总生存率 HR 为 0.68 (0.49-0.95)，扩增的总生存率 HR 为 0.67 (0.46-0.98)（p（交互作用）= 0.1608）。当 TOP2A 缺失和 TOP2A 扩增肿瘤患者被分组在一起（改变队列）并与正常 TOP2A 肿瘤患者的数据进行比较时，改变组 EFS 的 HR 为 0.64（0.50-0.81），正常组为 0.88（0.78-1.00）（p（交互作用）= 0.0183）；改变的总生存率 HR 为 0.67 (0.52-0.86)，正常的总生存率 HR 为 0.89 (0.78-1.03)（p（交互作用）= 0.0455）。 解释 尽管 HER2 扩增以及组合 TOP2A 扩增和缺失可能在预测对基于蒽环类药物的化疗的反应性方面具有一定价值，但我们的研究结果并不支持仅在患有以下情况的患者中使用蒽环类药物： HER2 扩增或 TOP2A 畸变肿瘤。
Background Prediction of response to anthracycline-based therapy for breast cancer is challenging. We aimed to assess the value of HER2 and TOP2A as predictive markers of response to anthracycline-based adjuvant therapy in patients with early breast cancer.Methods We did a meta-analysis of individual patient data from five randomised adjuvant trials that compared anthracycline-based regimens with cyclophosphamide, methotrexate, and fluorouracil (CMF) regimens. We assessed the status of HER2 and TOP2A genes with fluorescent in-situ hybridisation. Tumour samples were submitted to an external laboratory for validation. We calculated hazard ratios (HR) to compare event-free survival (EFS) and overall survival in patients receiving anthracycline-based treatment with those receiving CMF in two HER2 cohorts (HER2 amplified and non-amplified tumours) and in three TOP2A cohorts (normal, amplified, and deleted tumours).Findings We analysed data for 3452 patients for HER2 and 3102 patients for TOP2A. For EFS, HRs were 0.89 (95% CI 0.79-1.01) for HER2 non-amplified patients and 0.71 (0.58-0.86) for HER2-amplified patients (p(interaction) = 0.0485); for overall survival, HRs were 0.91 (95% CI 0.79-1.05) for HER2 non-amplified patients and 0.73 (0.59-0.89) for HER2-amplified patients (p(interaction) = 0.0718). In analysis of TOP2A status, HRs for EFS were 0.88 (0.78-1.00) for normal, 0.63 (0.46-0.87) for deleted, and 0.62 (0.43-0.90) for amplified (p(interaction) = 0.0513); HRs for overall survival were 0.89 (0.78-1.03) for normal, 0.68 (0.49-0.95) for deleted, and 0.67 (0.46-0.98) for amplified (p(interaction) = 0.1608). When patients with TOP2A-deleted and TOP2A-amplified tumours were grouped together (altered cohort) and compared with data from patients with normal TOP2A tumours, HRs for EFS were 0.64 (0.50-0.81) for altered and 0.88 (0.78-1.00) for normal (p(interaction) = 0.0183); HRs for overall survival were 0.67 (0.52-0.86) for altered and 0.89 (0.78-1.03) for normal (p(interaction) = 0.0455).Interpretation Although HER2 amplification and combined TOP2A amplification and deletion may have some value in the prediction of responsiveness to anthracycline-based chemotherapy, our findings do not support the use of anthracyclines only in patients with HER2-amplified or TOP2A-aberrated tumours.