Alteration of Topoisomerase II-Alpha Gene in Human Breast Cancer: Association With Responsiveness to Anthracycline-Based Chemotherapy
Alteration of Topoisomerase II-Alpha Gene in Human Breast Cancer: Association With Responsiveness to Anthracycline-Based Chemotherapy
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DOI：
10.1200/jco.2009.27.5644
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发表时间：
2011-03-01
影响因子：
45.3
通讯作者：
Slamon, Dennis J.
中科院分区：
文献类型：
--
作者：
Press, Michael F.;Sauter, Guido;Slamon, Dennis J.
研究目的：大约35%的HER 2扩增乳腺癌存在拓扑异构酶II-α（TOP 2A）基因的共扩增，该基因编码的酶是蒽环类药物的主要靶点。本研究旨在评估TOP 2A基因改变是否可以预测蒽环类药物在某些乳腺癌中的增量反应性。方法共分析了4,943例乳腺癌的TOP 2A和HER 2的改变。研究了在化疗加/减曲妥珠单抗试验中接受治疗的转移性乳腺癌患者的原发性肿瘤组织的TOP 2A和HER 2扩增/缺失，作为测试集，随后评价了来自两项独立的大型试验的恶性肿瘤，作为验证集，评价了这些相同基因的变化。这些变化和临床outcomesdetermined. Results之间的关联测试集的情况下，含有HER 2扩增治疗阿霉素和环磷酰胺（AC）加曲妥珠单抗，表现出较长的无进展生存期与AC单独治疗相比（P=.0002）。然而，肿瘤含有HER 2/TOP 2A共扩增的患者单独接受AC治疗，其生存率也有类似的改善（P=.004）。相反，对于接受紫杉醇治疗的患者，HER 2/TOP 2A共扩增与结局改善无关。这些观察结果在一个更大的验证集中得到了证实，其中与缺乏TOP 2A共扩增的HER 2阳性癌症的结果相比，当仅使用含蒽环类药物的化疗进行治疗时，HER 2/TOP 2A共扩增再次与较长的生存期相关。是临床上有用的蒽环类化疗增量反应的预测标志物。缺乏HER 2/TOP 2A共扩增可能表明乳腺癌的疗效优势比以前认为的更有限。J Clin Oncol 29：859-867. (C)2010年美国临床肿瘤学会
Purpose Approximately 35% of HER2-amplified breast cancers have coamplification of the topoisomerase II-alpha (TOP2A) gene encoding an enzyme that is a major target of anthracyclines. This study was designed to evaluate whether TOP2A gene alterations may predict incremental responsiveness to anthracyclines in some breast cancers.Methods A total of 4,943 breast cancers were analyzed for alterations in TOP2A and HER2. Primary tumor tissues from patients with metastatic breast cancer treated in a trial of chemotherapy plus/minus trastuzumab were studied for amplification/deletion of TOP2A and HER2 as a test set followed by evaluation of malignancies from two separate, large trials for changes in these same genes as a validation set. Association between these alterations and clinical outcomes was determined.Results Test set cases containing HER2 amplification treated with doxorubicin and cyclophosphamide (AC) plus trastuzumab, demonstrated longer progression-free survival compared to those treated with AC alone (P=.0002). However, patients treated with AC alone whose tumors contain HER2/TOP2A coamplification experienced a similar improvement in survival (P=.004). Conversely, for patients treated with paclitaxel, HER2/TOP2A coamplification was not associated with improved outcomes. These observations were confirmed in a larger validation set, where HER2/TOP2A coamplification was again associated with longer survival when only anthracycline-containing chemotherapy was used for treatment compared with outcome in HER2-positive cancers lacking TOP2A coamplification.Conclusion In a study involving nearly 5,000 breast malignancies, both test set and validation set demonstrate that TOP2A coamplification, not HER2 amplification, is the clinically useful predictive marker of an incremental response to anthracycline-based chemotherapy. Absence of HER2/TOP2A coamplification may indicate a more restricted efficacy advantage for breast cancers than previously thought. J Clin Oncol 29: 859-867. (C) 2010 by American Society of Clinical Oncology