Department of Medical Oncology, Leiden University Medical Center, Leiden, The Netherlands.
Department of Medical Oncology, Erasmus MC Cancer Institute, Rotterdam, The Netherlands.
Pharmacogenomics J. 2019 Oct;19(5):473-479. doi: 10.1038/s41397-019-0079-z. Epub 2019 Feb 4.
Imatinib has a mild toxicity profile, although severe adverse events may develop. In this pharmacogenetic pathway analysis the need for dose reduction and cessation of therapy was tested for an association with single nucleotide polymorphisms (SNPs) in genes related to imatinib pharmacology. Retrospective data from 315 patients with a gastrointestinal stromal tumor who received imatinib 400 mg o.d. was associated with 36 SNPs. SNPs that showed a trend in univariate testing were tested in a multivariate model with clinical factors and correction for multiple testing was performed. Dose reduction was associated with carriership of the A-allele in rs2231137 in ABCG2 (OR 7.35, p = 0.0002) and two C-alleles in rs762551 in CYP1A2 (OR 7.12, p = 0.001). Results remained significant after correction for multiple testing. Therapy cessation did not show an association with any of the tested SNPs. These results may help identifying patients at increased risk for toxicity who could benefit from intensified follow-up.
伊马替尼的毒性谱较轻，但仍可能发生严重不良反应。在这项药物遗传学途径分析中，我们检验了与伊马替尼药理学相关基因的单核苷酸多态性（SNP）与剂量减少和停药的相关性。对 315 例接受伊马替尼 400mg 每日一次治疗的胃肠道间质瘤患者的回顾性数据分析显示，与 36 个 SNP 相关。对单变量检验中呈趋势的 SNP 进行了多变量模型检验，并进行了多次检验校正。结果显示，ABCG2 基因 rs2231137 的 A 等位基因（OR 7.35，p=0.0002）和 CYP1A2 基因 rs762551 的两个 C 等位基因（OR 7.12，p=0.001）携带者更容易发生剂量减少。即使经过多次检验校正，结果仍具有统计学意义。停药与任何检测到的 SNP 均无相关性。这些结果可能有助于识别有发生毒性风险的患者，从而使他们受益于强化随访。
