Division of Oncology, Children's National Hospital, Washington, DC, USA.
George Washington University School of Medicine and Health Sciences, Washington, DC, USA.
Support Care Cancer. 2022 Apr;30(4):3513-3520. doi: 10.1007/s00520-022-06818-9. Epub 2022 Jan 11.
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.
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).
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).
Select phenotypes of 5-HT3RB and ABCB1, age, and potentially BMI can help predict increased risk for CINV in a diverse pediatric oncology population.
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。
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。
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）。
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。
