University of North Carolina Institute for Pharmacogenomics and Individualized Therapy, University of North Carolina, Chapel Hill, NC 27599-7360, USA.
J Clin Oncol. 2010 Jul 10;28(20):3227-33. doi: 10.1200/JCO.2009.21.7943. Epub 2010 Jun 7.
With three available chemotherapy drugs for advanced colorectal cancer (CRC), response rate (RR) and survival outcomes have improved with associated morbidity, accentuating the need for tools to select optimal individualized treatment. Pharmacogenetics identifies the likelihood of adverse events or response based on variants in genes involved in drug transport, metabolism, and cellular targets.
Germline DNA was extracted from 520 patients on the North American Gastrointestinal Intergroup N9741 study. Three study arms were evaluated: IFL (fluorouracil [FU] + irinotecan [IRN]), FOLFOX (FU + oxaliplatin), and IROX (IRN + oxaliplatin). Information on adverse events, response, and disease-free survival was available. Thirty-four variants in 15 candidate genes for analysis based on previous associations with adverse events or outcome were assessed. Genotyping was performed using pyrosequencing.
All variants were polymorphic. The homozygous UGT1A1*28 allele observed in 9% of patients was associated with risk of grade 4 neutropenia in patients on IROX (55% v 15%; P = .002). Deletion in GSTM1 was associated with grade 4 neutropenia after FOLFOX (28% v 16%; P = .02). Patients with a homozygous variant genotype for GSTP1 were more likely to discontinue FOLFOX because of neurotoxicity (24% v 10%; P = .01). The presence of a CYP3A5 variant was significantly associated with RR on IFL (29% v 60%; P = .0074). Most previously published genotype-toxicity or -efficacy relationships were not validated in this study.
This study provides a platform to evaluate pharmacogenetic predictors of response or severe adverse events in advanced CRC. Pharmacogenetic studies can be conducted in multicenter trials, and our findings demonstrate that with continued research, clinical application is practical.
对于晚期结直肠癌（CRC），有三种可用的化疗药物，其反应率（RR）和生存结果随着相关发病率的提高而改善，这凸显了需要工具来选择最佳个体化治疗的必要性。药物遗传学根据参与药物转运、代谢和细胞靶标的基因的变异来确定不良反应或反应的可能性。
从北美胃肠肿瘤组 N9741 研究中的 520 名患者中提取了种系 DNA。评估了三个研究组：IFL（氟尿嘧啶[FU]+伊立替康[IRN]）、FOLFOX（FU+奥沙利铂）和 IROX（IRN+奥沙利铂）。获得了不良反应、反应和无病生存的信息。根据先前与不良反应或结果的关联，对 15 个候选基因的 34 个变体进行了分析。使用焦磷酸测序进行基因分型。
所有变体都是多态的。在接受 IROX 治疗的患者中，观察到 9%的患者携带 UGT1A1*28 纯合等位基因，与 4 级中性粒细胞减少症的风险相关（55%比 15%；P=0.002）。GSTM1 缺失与 FOLFOX 后 4 级中性粒细胞减少症相关（28%比 16%；P=0.02）。GSTP1 纯合变体基因型的患者更有可能因神经毒性而停止 FOLFOX（24%比 10%；P=0.01）。CYP3A5 变体的存在与 IFL 的 RR 显著相关（29%比 60%；P=0.0074）。在这项研究中，大多数先前发表的基因型-毒性或疗效关系没有得到验证。
本研究为评估晚期 CRC 反应或严重不良反应的药物遗传学预测因子提供了一个平台。药物遗传学研究可以在多中心试验中进行，我们的研究结果表明，随着进一步研究，临床应用是切实可行的。
