在一个多样化的儿科肿瘤人群中，昂丹司琼失败的遗传药理学和临床预测因子。
Pharmacogenetic and clinical predictors of ondansetron failure in a diverse pediatric oncology population.
机构信息
Division of Oncology, Children's National Hospital, Washington, DC, USA.
George Washington University School of Medicine and Health Sciences, Washington, DC, USA.
出版信息
Support Care Cancer. 2022 Apr;30(4):3513-3520. doi: 10.1007/s00520-022-06818-9. Epub 2022 Jan 11.
PURPOSE
Chemotherapy-induced nausea and vomiting (CINV) is a frequently seen burdensome adverse event of cancer therapy. The 5-HT3 receptor antagonist ondansetron has improved the rates of CINV but, unfortunately, up to 30% of patients do not obtain satisfactory control. This study examined whether genetic variations in a relevant drug-metabolizing enzyme (CYP2D6), transporter (ABCB1), or receptor (5-HT3) were associated with ondansetron failure.
METHODS
DNA was extracted from blood and used to genotype: ABCB1 (3435C > T (rs1045642) and G2677A/T (rs2032582)), 5-HT3RB (rs3758987 T > C and rs45460698 (delAAG/dupAAG)), and CYP2D6 variants. Ondansetron failure was determined by review of the medical records and by patient-reported outcomes (PROs).
RESULTS
One hundred twenty-nine patients were approached; 103 consented. Participants were less than 1 to 33 years (mean 6.85). A total of 39.8% was female, 58.3% was White (22.3% Black, 19.4% other), and 24.3% was Hispanic. A majority had leukemia or lymphoma, and 41 (39.8%) met the definition of ondansetron failure. Of variants tested, rs45460698 independently showed a significant difference in risk of ondansetron failure between a mutant (any deletion) and normal allele (p = 0.0281, OR 2.67). Age and BMI were both predictive of ondansetron failure (age > 12 (OR 1.12, p = 0.0012) and higher BMI (OR 1.13, p = 0.0119)). In multivariate analysis, age > 12 was highly predictive of ondansetron failure (OR 7.108, p = 0.0008). rs45460698 was predictive when combined with an increased nausea phenotype variant of rs1045642 (OR 3.45, p = 0.0426).
CONCLUSION
Select phenotypes of 5-HT3RB and ABCB1, age, and potentially BMI can help predict increased risk for CINV in a diverse pediatric oncology population.
目的
化疗引起的恶心和呕吐（CINV）是癌症治疗中常见的一种负担性不良事件。5-HT3 受体拮抗剂昂丹司琼提高了 CINV 的控制率，但不幸的是，多达 30%的患者无法获得满意的控制。本研究探讨了相关药物代谢酶（CYP2D6）、转运体（ABCB1）或受体（5-HT3）的遗传变异是否与昂丹司琼失败相关。
方法
从血液中提取 DNA，用于基因分型：ABCB1（3435C>T(rs1045642)和 G2677A/T(rs2032582)）、5-HT3RB(rs3758987T>C 和 rs45460698(缺失 AAG/dupAAG))和 CYP2D6 变体。通过审查病历和患者报告的结果（PROs）确定昂丹司琼失败。
结果
共接触了 129 名患者，其中 103 名同意参与。参与者年龄在 1 岁至 33 岁之间（平均 6.85 岁）。女性占 39.8%，白人占 58.3%（黑人占 22.3%，其他种族占 19.4%），西班牙裔占 24.3%。大多数患者患有白血病或淋巴瘤，41 名（39.8%）符合昂丹司琼失败的定义。在所测试的变体中，rs45460698 突变（任何缺失）与正常等位基因（p=0.0281，OR 2.67）在昂丹司琼失败风险方面表现出显著差异。年龄和 BMI 均为昂丹司琼失败的预测因素（年龄>12（OR 1.12，p=0.0012）和较高的 BMI（OR 1.13，p=0.0119））。在多变量分析中，年龄>12 是昂丹司琼失败的高度预测因素（OR 7.108，p=0.0008）。当与 rs1045642 的增加恶心表型变体 rs45460698 结合时，rs45460698 具有预测性（OR 3.45，p=0.0426）。
结论
5-HT3RB 和 ABCB1 的特定表型、年龄以及潜在的 BMI 可以帮助预测在多样化的儿科肿瘤人群中 CINV 的风险增加。
Zotero 插件