Pharmacogenetics of capecitabine in advanced breast cancer patients
Pharmacogenetics of capecitabine in advanced breast cancer patients
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DOI：
10.1158/1078-0432.ccr-06-0320
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发表时间：
2006-09-15
影响因子：
11.5
通讯作者：
Milano, Gerard
中科院分区：
文献类型：
--
作者：
Largillier, Rmy;Etienne-Grimaldi, Marie-Christine;Milano, Gerard
目的：生发基因多态性可以部分解释抗肿瘤药物，特别是氟嘧啶类药物的患者间药效学差异。多态性可能潜在影响氟嘧啶（包括卡培他滨）药效学的基因有胸苷酸合成酶（TS）、亚甲基四氢叶酸还原酶（MTHFR）和二氢嘧啶脱氢酶（DPD）。实验设计：本前瞻性先导研究的目的是分析TS、MTHFR和DPD基因多态性对接受卡培他滨单药治疗的晚期乳腺癌患者毒性和疗效的影响。在105例连续患者中测定了TS（3′区6 bp缺失和28 bp重复，包括5′区G>C突变）、MTHFR （677>T和1298A>C）和DPD （IVS14 + 1G>A）的生发多态性。结果：TS 3RG等位基因纯合子的患者与3RG等位基因杂合子的患者或不携带3RG等位基因的患者相比，整体毒性等级为3级和4级的趋势更高（分别为50%、19%和13%，P = 0.064）。唯一一位携带DPD IVS14 + 1G>A突变（杂合）的患者死于血液毒性。中位反应持续时间为5.8个月（95%可信区间4.3-7.2）。3RG等位基因纯合子患者的反应时间明显缩短（P = 0.037）。结论：目前的数据表明，3RG3RG乳腺癌患者不适合卡培他滨治疗。此外，在接受卡培他滨治疗的乳腺癌患者中，应注意DPD缺乏。这些初步数据需要在更多患者身上得到进一步证实。
Purpose: Germinal gene polymorphisms can explain a part of the interpatient pharmacodynamic variability of anticancer drugs, particularly fluoropyrimidines. Genes for which polymorphisms may potentially influence pharmacodynamics of fluoropyrimidines, including capecitabine, are thymidylate synthase (TS), methylenetetrahydrofolate reductase (MTHFR), and dihydropyrimidine dehydrogenase (DPD).Experimental design: The aim of this prospective pilot study was to analyze the effect of TS, MTHFR, and DPD gene polymorphisms on toxicity and efficacy in advanced breast cancer patients receiving capecitabine as monotherapy. Germinal polymorphisms of TS (6 bp deletion in the 3' region and 28 bp repeats, including G>C mutation in the 5' region), MTHFR (677>T and 1298A>C), and DPD (IVS14 + 1G>A) were determined in 105 consecutive patients.Results: A trend toward a higher global toxicity grade 3 and 4 was observed in patients homozygous for the TS 3RG allele compared with patients heterozygous for the 3RG allele or patients not carrying the 3RG allele (50% versus 19% versus 13% respectively, P = 0.064). The sole patient bearing the DPD IVS14 + 1G>A mutation (heterozygous) deceased from hematologic toxicity. The median response duration was 5.8 months (95% confidence interval, 4.3-7.2). Duration of response was significantly shortened in patients homozygous for the 3RG allele compared with others (P = 0.037).Conclusions: The present data suggest that 3RG3RG breast cancer patients are not good candidates for capecitabine therapy. In addition, attention should be paid to DPD deficiency in breast cancer patients receiving capecitabine. These preliminary data require further confirmation on a larger number of patients.