Evaluating predictive pharmacogenetic signatures of adverse events in colorectal cancer patients treated with fluoropyrimidines.
Evaluating predictive pharmacogenetic signatures of adverse events in colorectal cancer patients treated with fluoropyrimidines.
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DOI：
10.1371/journal.pone.0078053
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发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Willis G
中科院分区：
文献类型：
--
作者：
Jennings BA;Loke YK;Skinner J;Keane M;Chu GS;Turner R;Epurescu D;Barrett A;Willis G
尽管进行了广泛的研究，但与结直肠癌患者对氟尿嘧啶治疗反应相关的遗传标记物的潜在临床应用仍存在争议。我们的目的是在广泛的临床环境中测试新的和以前确定的不良事件标志物的临床有效性。我们对254例接受5-氟尿嘧啶或卡培他滨治疗的结直肠癌患者进行了一项早期不良事件的观察性药物遗传学研究。已分析了9种关键叶酸（药效学）和药物代谢（药代动力学）酶的16种变体作为个体标记物和/或标记物的特征。我们发现TYMP S471 L（rs 11479）与早期剂量调整和/或严重不良事件之间存在显著相关性（分别为校正OR = 2.02 [1.03; 4.00]，p = 0.042，校正OR = 2.70 [1.23; 5.92]，p = 0.01）。这些表型与DPYD突变特征之间也存在显著相关性（分别为校正OR = 3.96 [1.17; 13.33]，p = 0.03，校正OR = 6.76 [1.99; 22.96]，p = 0.002）。我们未发现单个候选药效学标志物与毒性之间存在任何显著相关性。如果早期不良事件的预测测试将TYMP和DPYD变体作为特征进行分析，则灵敏度将为45.5%，阳性预测值仅为33.9%，因此临床有效性较差。迄今为止，大多数研究在同时考虑多种药代动力学和药效学变体方面的把握度不足，但可以在荟萃分析中合并该数据集和类似的个体化数据集，以解决这些标志物潜在临床效用的不确定性。
The potential clinical utility of genetic markers associated with response to fluoropyrimidine treatment in colorectal cancer patients remains controversial despite extensive study. Our aim was to test the clinical validity of both novel and previously identified markers of adverse events in a broad clinical setting. We have conducted an observational pharmacogenetic study of early adverse events in a cohort study of 254 colorectal cancer patients treated with 5-fluorouracil or capecitabine. Sixteen variants of nine key folate (pharmacodynamic) and drug metabolising (pharmacokinetic) enzymes have been analysed as individual markers and/or signatures of markers. We found a significant association between TYMP S471L (rs11479) and early dose modifications and/or severe adverse events (adjusted OR = 2.02 [1.03; 4.00], p = 0.042, adjusted OR = 2.70 [1.23; 5.92], p = 0.01 respectively). There was also a significant association between these phenotypes and a signature of DPYD mutations (Adjusted OR = 3.96 [1.17; 13.33], p = 0.03, adjusted OR = 6.76 [1.99; 22.96], p = 0.002 respectively). We did not identify any significant associations between the individual candidate pharmacodynamic markers and toxicity. If a predictive test for early adverse events analysed the TYMP and DPYD variants as a signature, the sensitivity would be 45.5 %, with a positive predictive value of just 33.9 % and thus poor clinical validity. Most studies to date have been under-powered to consider multiple pharmacokinetic and pharmacodynamic variants simultaneously but this and similar individualised data sets could be pooled in meta-analyses to resolve uncertainties about the potential clinical utility of these markers.
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影响因子：
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作者：
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通讯作者：
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