PDF(Pubmed)
Abstract：
UNASSIGNED: Imatinib mesylate (IM) is a first-line treatment option for the majority of patients diagnosed with gastrointestinal stromal tumors (GISTs). Although the clinical benefit is high, interindividual response is variable. This study thus aimed to assess how genetic polymorphisms can affect the blood levels of IM and treatment outcomes in patients with GIST.
UNASSIGNED: A total of 31 single-nucleotide polymorphisms (SNPs) in selected cytochrome P450 (P450), ATP-binding cassette transporter (ABC), solute carrier family (SLC), interleukin-4 receptor (IL4R), and vascular endothelial growth factor (VEGF) genes were genotyped using an SNP mass array platform. A total of 192 consecutive patients with GIST who received 400 mg of IM daily were enrolled into the study, with 1,485 blood samples being analyzed. According to genotypes, IM trough concentrations were tested and compared. Progression-free survival (PFS) and overall survival (OS) were also assessed.
UNASSIGNED: With a mean follow-up of 75.99 months, trough concentrations of imatinib were examined at average time points of 7.73 for each patient. Polymorphism in ABCB1 rs1045642 was found to be associated with steady-state IM trough plasma levels (P=0.008). Patients with the C genotype (CT + CC) of rs1045642 exhibited higher IM trough concentrations (1,271.09±306.69 ng/mL) compared to those with the TT genotype (1,106.60±206.05 ng/mL). No statistically significant differences in IM plasma concentration were observed for the other SNPs tested. None of the tested SNPs displayed a significant association with patients\' survival in this study.
UNASSIGNED: This is the largest cohort study evaluating the associations of SNP and imatinib blood trough levels. The ABCB1 rs1045642 genetic polymorphism may exert an effect on the pharmacokinetics of imatinib. The presence of the C allele in ABCB1 rs1045642 is predictive of a higher plasma concentration of IM.
UNASSIGNED: A total of 31 single-nucleotide polymorphisms (SNPs) in selected cytochrome P450 (P450), ATP-binding cassette transporter (ABC), solute carrier family (SLC), interleukin-4 receptor (IL4R), and vascular endothelial growth factor (VEGF) genes were genotyped using an SNP mass array platform. A total of 192 consecutive patients with GIST who received 400 mg of IM daily were enrolled into the study, with 1,485 blood samples being analyzed. According to genotypes, IM trough concentrations were tested and compared. Progression-free survival (PFS) and overall survival (OS) were also assessed.
UNASSIGNED: With a mean follow-up of 75.99 months, trough concentrations of imatinib were examined at average time points of 7.73 for each patient. Polymorphism in ABCB1 rs1045642 was found to be associated with steady-state IM trough plasma levels (P=0.008). Patients with the C genotype (CT + CC) of rs1045642 exhibited higher IM trough concentrations (1,271.09±306.69 ng/mL) compared to those with the TT genotype (1,106.60±206.05 ng/mL). No statistically significant differences in IM plasma concentration were observed for the other SNPs tested. None of the tested SNPs displayed a significant association with patients\' survival in this study.
UNASSIGNED: This is the largest cohort study evaluating the associations of SNP and imatinib blood trough levels. The ABCB1 rs1045642 genetic polymorphism may exert an effect on the pharmacokinetics of imatinib. The presence of the C allele in ABCB1 rs1045642 is predictive of a higher plasma concentration of IM.
摘要：
■甲磺酸伊马替尼（IM）是大多数诊断为胃肠道间质瘤（GIST）的患者的一线治疗选择。虽然临床获益很高，个体间的反应是可变的。因此，这项研究旨在评估遗传多态性如何影响GIST患者的IM血液水平和治疗结果。
■选定的细胞色素P450（P450）中共有31个单核苷酸多态性（SNP），ATP结合盒转运蛋白（ABC），溶质载体家族(SLC)，白细胞介素4受体（IL4R），使用SNP质量阵列平台对血管内皮生长因子(VEGF)基因进行基因分型。共有192例GIST患者每天接受400mgIM治疗，纳入本研究。分析了1485份血液样本.根据基因型,测试并比较IM谷浓度。还评估了无进展生存期（PFS）和总生存期（OS）。
■平均随访75.99个月，对每位患者的平均时间点7.73的伊马替尼的谷浓度进行了检查.发现ABCB1rs1045642中的多态性与稳态IM谷血浆水平有关（P=0.008）。与具有TT基因型（1,106.60±206.05ng/mL）的患者相比，具有rs1045642的C基因型（CTCC）的患者表现出更高的IM谷浓度（1,271.09±306.69ng/mL）。对于测试的其他SNP,没有观察到IM血浆浓度的统计学显著差异。在这项研究中，测试的SNP均未显示出与患者生存的显着关联。
■这是评估SNP与伊马替尼血谷水平相关性的最大队列研究。ABCB1rs1045642基因多态性可能对伊马替尼的药代动力学产生影响。ABCB1rs1045642中C等位基因的存在预示着IM的较高血浆浓度。
■选定的细胞色素P450（P450）中共有31个单核苷酸多态性（SNP），ATP结合盒转运蛋白（ABC），溶质载体家族(SLC)，白细胞介素4受体（IL4R），使用SNP质量阵列平台对血管内皮生长因子(VEGF)基因进行基因分型。共有192例GIST患者每天接受400mgIM治疗，纳入本研究。分析了1485份血液样本.根据基因型,测试并比较IM谷浓度。还评估了无进展生存期（PFS）和总生存期（OS）。
■平均随访75.99个月，对每位患者的平均时间点7.73的伊马替尼的谷浓度进行了检查.发现ABCB1rs1045642中的多态性与稳态IM谷血浆水平有关（P=0.008）。与具有TT基因型（1,106.60±206.05ng/mL）的患者相比，具有rs1045642的C基因型（CTCC）的患者表现出更高的IM谷浓度（1,271.09±306.69ng/mL）。对于测试的其他SNP,没有观察到IM血浆浓度的统计学显著差异。在这项研究中，测试的SNP均未显示出与患者生存的显着关联。
■这是评估SNP与伊马替尼血谷水平相关性的最大队列研究。ABCB1rs1045642基因多态性可能对伊马替尼的药代动力学产生影响。ABCB1rs1045642中C等位基因的存在预示着IM的较高血浆浓度。
