Gene expression profiling and correlation with outcome in clinical trials of the proteasome inhibitor bortezomib
Gene expression profiling and correlation with outcome in clinical trials of the proteasome inhibitor bortezomib
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DOI：
10.1182/blood-2006-09-044974
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发表时间：
2007-04-15
期刊：
影响因子：
20.3
通讯作者：
Anderson, Kenneth C.
中科院分区：
文献类型：
--
作者：
Mulligan, George;Mitsiades, Constantine;Anderson, Kenneth C.
本研究的目的是评估硼替佐米治疗多发性骨髓瘤的多中心国际临床试验中前瞻性药物基因组学研究的可行性，并开发硼替佐米缓解和生存的预测分类器。复发性骨髓瘤患者参加了硼替佐米的2期和3期临床试验，并同意对治疗前肿瘤样本进行基因组分析。骨髓穿刺液进行阴性选择程序，以丰富的肿瘤细胞，这些样品用于基因表达谱使用DNA微阵列。数据质量和与试验结果的相关性由多组进行评估。该数据集中的基因表达与新诊断多发性骨髓瘤的单中心研究中发表的数据一致。通过对独立数据的测试，开发了缓解和生存分类器，并显示其与结局显著相关。生存分类改进了国际分期系统提供的风险分层。反应的预测模型和生物学相关性显示硼替佐米而不是地塞米松具有一定的特异性。预测临床结果的信息性基因表达数据和基因组分类器可以来自新抗癌剂的前瞻性临床试验。
The aims of this study were to assess the feasibility of prospective pharmacogenomics research in multicenter international clinical trials of bortezomib in multiple myeloma and to develop predictive classifiers of response and survival with bortezomib. Patients with relapsed myeloma enrolled in phase 2 and phase 3 clinical trials of bortezomib and consented to genomic analyses of pretreatment tumor samples. Bone marrow aspirates were subject to a negative-selection procedure to enrich for tumor cells, and these samples were used for gene expression profiling using DNA microarrays. Data quality and correlations with trial outcomes were assessed by multiple groups. Gene expression in this dataset was consistent with data published from a single-center study of newly diagnosed multiple myeloma. Response and survival classifiers were developed and shown to be significantly associated with outcome via testing on independent data. The survival classifier improved on the risk stratification provided by the International Staging System. Predictive models and biologic correlates of response show some specificity for bortezomib rather than dexamethasone. Informative gene expression data and genomic classifiers that predict clinical outcome can be derived from prospective clinical trials of new anticancer agents.