拓扑异构酶 II-α 基因在人乳腺癌中的改变：与蒽环类药物化疗反应性的关联。
Alteration of topoisomerase II-alpha gene in human breast cancer: association with responsiveness to anthracycline-based chemotherapy.
机构信息
Norris Comprehensive Cancer Center, University of Southern California, CA, USA.
出版信息
J Clin Oncol. 2011 Mar 1;29(7):859-67. doi: 10.1200/JCO.2009.27.5644. Epub 2010 Dec 28.
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.
目的
大约 35%的 HER2 扩增型乳腺癌存在拓扑异构酶 II-α（TOP2A）基因的共扩增，该基因编码一种酶，是蒽环类药物的主要靶点。本研究旨在评估 TOP2A 基因改变是否可以预测某些乳腺癌对蒽环类药物的增量反应。
方法
分析了 4943 例乳腺癌的 TOP2A 和 HER2 改变。对接受曲妥珠单抗联合化疗或化疗加曲妥珠单抗治疗的转移性乳腺癌患者的原发肿瘤组织进行了 TOP2A 和 HER2 的扩增/缺失检测，作为测试集；然后，对两个独立的大型试验中的恶性肿瘤进行了相同基因的改变评估，作为验证集。确定这些改变与临床结局之间的关联。
结果
测试集病例中，接受多柔比星和环磷酰胺（AC）加曲妥珠单抗治疗的 HER2 扩增患者，无进展生存期长于单独接受 AC 治疗的患者（P=0.0002）。然而，单独接受 AC 治疗且肿瘤存在 HER2/TOP2A 共扩增的患者，其生存也有类似改善（P=0.004）。相反，对于接受紫杉醇治疗的患者，HER2/TOP2A 共扩增与改善结局无关。在一个更大的验证集中，观察到了类似的结果，其中仅使用含蒽环类化疗药物治疗时，HER2/TOP2A 共扩增与更长的生存时间相关，而 HER2 阳性且缺乏 TOP2A 共扩增的癌症则没有这种相关性。
结论
在一项涉及近 5000 例乳腺癌恶性肿瘤的研究中，测试集和验证集均表明，TOP2A 共扩增而非 HER2 扩增是蒽环类化疗增量反应的临床有用预测标志物。缺乏 HER2/TOP2A 共扩增可能表明，乳腺癌对蒽环类药物的疗效优势比以前认为的更为有限。
Zotero 插件