Department of General Medical Oncology, University Hospitals Leuven, Leuven, Belgium.
Department of Clinical Biochemistry, Aarhus University Hospital, Aarhus, Denmark; Department of Clinical Medicine, Aarhus University, Aarhus, Denmark.
Clin Genitourin Cancer. 2024 Oct;22(5):102180. doi: 10.1016/j.clgc.2024.102180. Epub 2024 Jul 27.
Genetic variants of UGT1A1, involved in glucuronidation and clearance of bilirubin, are associated with reduced bilirubin metabolization and drug-induced isolated hyperbilirubinemia. We studied the impact of the UGT1A1*28 polymorphism on drug-induced isolated hyperbilirubinemia in metastatic renal cell carcinoma patients treated with pazopanib, cabozantinib, and axitinib.
We genotyped the UGT1A1*28 TA6/TA6-TA6/TA7-TA7/TA7 polymorphism and correlated with median baseline, on-treatment and peak bilirubin levels during therapy, incidence of grade-1- or -2 (G1/2)-hyperbilirubinemia and time-to-G1-hyperbilirubinemia.
Of the 66 patients treated with pazopanib, 29 received axitinib and 28 cabozantinib upon progression. Median baseline bilirubin was higher in TA7/TA7-carriers versus TA6/TA6+TA6/TA7-carriers at start of pazopanib (P < .0001), cabozantinib (P < .0001), and axitinib (P = .007). During pazopanib therapy, median bilirubin increased 1.4-fold in TA7/TA7+TA6/TA7-carriers but not in TA6/TA6-carriers. On cabozantinib, bilirubin increased 1.5-fold in TA7/TA7-carriers but not in TA6/TA6+TA6/TA7-carriers. Axitinib did not increase bilirubin in any genotype. Peak bilirubin in TA7/TA7- versus TA6/TA6+TA6/TA7-carriers was higher on pazopanib (P < .0001) or cabozantinib (P < .0001). With pazopanib, G1-hyperbilirubinemia occurred in 57% of TA7/TA7- and 12% of TA6/TA6+TA6/TA7-carriers (P = .0009) and G2-hyperbilirubinemia in 36% and 6% of the patients, respectively (P = .004). On cabozantinib, G1-hyperbilirubinemia occurred in 100% of TA7/TA7- and 5% of TA6/TA6+TA6/TA7-carriers (P < .0001) and G2-hyperbilirubinemia in 33% and 0% of the patients, respectively (P = .04). On axitinib, no correlation between the genotypes and G1/2-hyperbilirubinemia was observed.
We validate the previously described impact of the UGT1A1*28 polymorphism on isolated bilirubin increase on pazopanib. We report for the first time that cabozantinib also interferes with UGT1A1 and causes isolated bilirubin increase.
参与胆红素葡萄糖醛酸化和清除的 UGT1A1 基因变异与胆红素代谢减少和药物引起的孤立性高胆红素血症有关。我们研究了 UGT1A1*28 多态性对接受帕唑帕尼、卡博替尼和阿昔替尼治疗的转移性肾细胞癌患者药物引起的孤立性高胆红素血症的影响。
我们对 UGT1A1*28 TA6/TA6-TA6/TA7-TA7/TA7 多态性进行基因分型，并与治疗期间中位基线、治疗期间和峰值胆红素水平、1 级或 2 级（G1/2）-高胆红素血症的发生率以及发生 G1 高胆红素血症的时间相关联。
在接受帕唑帕尼治疗的 66 例患者中，29 例在进展时接受了阿昔替尼治疗，28 例接受了卡博替尼治疗。在开始接受帕唑帕尼治疗时，TA7/TA7 携带者的中位基线胆红素水平高于 TA6/TA6+TA6/TA7 携带者（P<0.0001）、卡博替尼（P<0.0001）和阿昔替尼（P=0.007）。在帕唑帕尼治疗期间，TA7/TA7+TA6/TA7 携带者的胆红素增加了 1.4 倍，但 TA6/TA6 携带者的胆红素没有增加。在卡博替尼治疗中，TA7/TA7 携带者的胆红素增加了 1.5 倍，但 TA6/TA6+TA6/TA7 携带者的胆红素没有增加。阿昔替尼在任何基因型中均未增加胆红素。与 TA6/TA6+TA6/TA7 携带者相比，TA7/TA7 携带者的帕唑帕尼（P<0.0001）或卡博替尼（P<0.0001）的峰值胆红素更高。在接受帕唑帕尼治疗时，57%的 TA7/TA7-和 12%的 TA6/TA6+TA6/TA7-携带者发生 1 级高胆红素血症（P=0.0009），36%和 6%的患者分别发生 2 级高胆红素血症（P=0.004）。在接受卡博替尼治疗时，100%的 TA7/TA7-和 5%的 TA6/TA6+TA6/TA7-携带者发生 1 级高胆红素血症（P<0.0001），33%和 0%的患者分别发生 2 级高胆红素血症（P=0.04）。在接受阿昔替尼治疗时，未观察到基因型与 G1/2 高胆红素血症之间存在相关性。
我们验证了先前描述的 UGT1A1*28 多态性对帕唑帕尼引起的孤立性胆红素升高的影响。我们首次报道卡博替尼也会干扰 UGT1A1 并引起孤立性胆红素升高。
