Upfront Genotyping of DPYD*2A to Individualize Fluoropyrimidine Therapy: A Safety and Cost Analysis
Upfront Genotyping of DPYD*2A to Individualize Fluoropyrimidine Therapy: A Safety and Cost Analysis
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DOI：
10.1200/jco.2015.63.1325
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发表时间：
2016-01-20
影响因子：
45.3
通讯作者：
Schellens, Jan H. M.
中科院分区：
文献类型：
--
作者：
Deenen, Maarten J.;Meulendijks, Didier;Schellens, Jan H. M.
目的氟嘧啶是常用的抗癌药物。氟嘧啶代谢酶二氢嘧啶脱氢酶（DPD；即DPYD*2A）的多态性与氟嘧啶引起的严重且危及生命的毒性密切相关。本研究确定了 DPYD*2A 基因型指导给药的可行性、安全性和成本。患者和方法打算接受基于氟嘧啶的化疗的患者在治疗开始前前瞻性地进行了 DPYD*2A 基因分型。变异等位基因携带者接受初始剂量减少> = 50%，然后根据耐受性进行剂量滴定。毒性是主要终点，并与历史对照（即接受文献中描述的标准剂量的 DPYD*2A 变异等位基因携带者）以及本研究中接受标准剂量治疗的 DPYD*2A 野生型患者进行比较。次要终点包括基于模型的成本分析，以及药代动力学和 DPD 酶活性分析。 结果 共有 2,038 名患者接受了 DPYD*2A 前瞻性筛查，其中 22 名 (1.1%) 为杂合多态性。 DPYD*2A 变异等位基因携带者接受的中位剂量强度为 48%（范围为 17% 至 91%）。因此，通过基因型指导给药，≥3级毒性的风险从历史对照（n=48）的73%（95% CI，58%至85%）显着降低至28%（95% CI，10%至53%）（与接受标准剂量（23%；P = 0.64）的野生型患者相比，P= 3毒性，并通过类似的全身氟尿嘧啶（活性药物）暴露。此外，每名患者的平均总治疗费用（(原文如此)2,772 [$3,767]）低于非筛查（(原文如此)2,817 [$3,828]），超过了筛选费用。 结论 DPYD*2A 与氟嘧啶引起的严重和危及生命的毒性密切相关。美国临床肿瘤学会 (C) 2015 在人群水平上对个体患者进行氟嘧啶治疗似乎可以节省成本。
PurposeFluoropyrimidines are frequently prescribed anticancer drugs. A polymorphism in the fluoropyrimidine metabolizing enzyme dihydropyrimidine dehydrogenase (DPD; ie, DPYD*2A) is strongly associated with fluoropyrimidine-induced severe and life-threatening toxicity. This study determined the feasibility, safety, and cost of DPYD*2A genotype-guided dosing.Patients and MethodsPatients intended to be treated with fluoropyrimidine-based chemotherapy were prospectively genotyped for DPYD*2A before start of therapy. Variant allele carriers received an initial dose reduction of >= 50% followed by dose titration based on tolerance. Toxicity was the primary end point and was compared with historical controls (ie, DPYD*2A variant allele carriers receiving standard dose described in literature) and with DPYD*2A wild-type patients treated with the standard dose in this study. Secondary end points included a model-based cost analysis, as well as pharmacokinetic and DPD enzyme activity analyses.ResultsA total of 2,038 patients were prospectively screened for DPYD*2A, of whom 22 (1.1%) were heterozygous polymorphic. DPYD*2A variant allele carriers were treated with a median dose-intensity of 48% (range, 17% to 91%). The risk of grade >= 3 toxicity was thereby significantly reduced from 73% (95% CI, 58% to 85%) in historical controls (n=48) to 28% (95% CI, 10% to 53%) by genotype-guided dosing (P= 3 toxicity compared with wild-type patients receiving the standard dose (23%; P = .64) and by similar systemic fluorouracil (active drug) exposure. Furthermore, average total treatment cost per patient was lower for screening ((sic)2,772 [$3,767]) than for nonscreening ((sic)2,817 [$3,828]), outweighing screening costs.ConclusionDPYD*2A is strongly associated with fluoropyrimidine-induced severe and life-threatening toxicity. DPYD*2A genotype-guided dosing results in adequate systemic drug exposure and significantly improves safety of fluoropyrimidine therapy for the individual patient. On a population level, upfront genotyping seemed cost saving. (C) 2015 by American Society of Clinical Oncology