Predictive Role of the UGT1A1, UGT1A7, and UGT1A9 Genetic Variants and Their Haplotypes on the Outcome of Metastatic Colorectal Cancer Patients Treated With Fluorouracil, Leucovorin, and Irinotecan
Predictive Role of the UGT1A1, UGT1A7, and UGT1A9 Genetic Variants and Their Haplotypes on the Outcome of Metastatic Colorectal Cancer Patients Treated With Fluorouracil, Leucovorin, and Irinotecan
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DOI：
10.1200/jco.2008.19.0314
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发表时间：
2009-05-20
影响因子：
45.3
通讯作者：
Toffoli, Giuseppe
中科院分区：
文献类型：
--
作者：
Cecchin, Erika;Innocenti, Federico;Toffoli, Giuseppe
UGT 1A 1 *28被认为是伊立替康治疗患者毒性结局的主要药物遗传学预测因子。我们评估了参与7-乙基-10-羟基喜树碱（SN-38）葡萄糖醛酸化的其它UGT 1A变体和单倍型对氟尿嘧啶、亚叶酸和伊立替康（FOLFIRI）的严重毒性和功效的影响。并评估其与严重血液学和非血液学毒性、客观缓解、疾病进展时间（TTP）和总生存期的相关性。结果UGT 1A 7 *3是多变量分析中第一周期后严重血液学毒性的唯一标志物（OR = 3.94; 95%CI = 1.05 ~ 14.82; P = 0.04）。其还与葡萄糖醛酸化率（SN-38 G曲线下面积[AUC]/SN-38 AUC）和胆汁指数（伊立替康AUC）X（SN-38 AUC/SN-38 G AUC）相关。单倍型I（除UGT 1A 9 *22外的所有参考序列等位基因）是整个治疗过程中重度血液学毒性的预测因子（OR，0.39; 95% CI，0.19 - 0.82; P = 0.01），与性别（OR，2.08; 95% CI，1.01 - 4.28; P = 0.05）一起。除UGT 1A 1 *28外，单倍型II（除UGT 1A 9 *22外的所有变异等位基因）与缓解率相关（OR，8.61; 95% CI，1.75 - 42.38; P = 0.01）。UGT 1A 1 *28是唯一的标记物与TTP.ConclusionWe建议，UGT 1A的变异UGT 1A 1 *28可能会提高预测结直肠癌患者的结果与FOLFIRI治疗。基于UGT 1A单倍型的方法可能是实现FOLFIRI治疗个体化的有效策略。
PurposeUGT1A1*28 is considered the main pharmacogenetic predictor of the toxicity outcome of irinotecan-treated patients. We evaluated the effect of other UGT1A variants and haplotypes involved in 7-ethyl-10-hydroxycamptothecin (SN-38) glucuronidation on severe toxicity and efficacy of fluorouracil, leucovorin, and irinotecan (FOLFIRI).Patients and MethodsIn addition to UGT1A1*28, UGT1A1*60, UGT1A1*93, UGT1A7*3, and UGT1A9*22 were geno-typed in 250 metastatic colorectal cancer patients, and associations with severe hematologic and nonhematologic toxicity, objective response, time to progression (TTP), and overall survival were evaluated. In a subset of 71 patients, pharmacokinetic data were also available.ResultsUGT1A7*3 was the only marker of severe hematologic toxicity after the first cycle ( odds ratio [ OR], 3.94; 95% CI, 1.05 to 14.82; P = .04) in a multivariate analysis. It was also associated with glucuronidation ratio (SN-38G area under the curve [AUC]/SN-38 AUC) and biliary index ( irinotecan AUC) X (SN-38 AUC/SN-38G AUC). Haplotype I (all the reference sequence alleles but UGT1A9*22) was a predictor of severe hematologic toxicity during the entire course of therapy (OR, 0.39; 95% CI, 0.19 to 0.82; P = .01), together with sex (OR, 2.08; 95% CI, 1.01 to 4.28; P = .05). In addition to UGT1A1*28, haplotype II (all the variant alleles but UGT1A9*22) was associated with a response rate (OR, 8.61; 95% CI, 1.75 to 42.38; P = .01). UGT1A1*28 was the only marker associated with TTP.ConclusionWe propose that UGT1A variants additional to UGT1A1*28 might improve the prediction of the outcome of colorectal cancer patients treated with FOLFIRI. A UGT1A haplotype-based approach might be an efficacious strategy to achieve treatment individualization of FOLFIRI.