Sajedeh Mobaraki , Peter Henrik Nissen , Frede Donskov , Agnieszka Wozniak , Yannick Van Herck , Lina Coosemans , Tine van Nieuwenhuyse , Diether Lambrechts , Oliver Bechter , Marcella Baldewijns , Eduard Roussel , Annouschka Laenen , Benoit Beuselinck
{"title":"卡博替尼会诱发携带 UGT1A1*28 多态性的肾细胞癌患者出现孤立的高胆红素血症","authors":"Sajedeh Mobaraki , Peter Henrik Nissen , Frede Donskov , Agnieszka Wozniak , Yannick Van Herck , Lina Coosemans , Tine van Nieuwenhuyse , Diether Lambrechts , Oliver Bechter , Marcella Baldewijns , Eduard Roussel , Annouschka Laenen , Benoit Beuselinck","doi":"10.1016/j.clgc.2024.102180","DOIUrl":null,"url":null,"abstract":"<div><h3>Background</h3><p>Genetic variants of <em>UGT1A1</em>, involved in glucuronidation and clearance of bilirubin, are associated with reduced bilirubin metabolization and drug-induced isolated hyperbilirubinemia. We studied the impact of the <em>UGT1A1*28</em> polymorphism on drug-induced isolated hyperbilirubinemia in metastatic renal cell carcinoma patients treated with pazopanib, cabozantinib, and axitinib.</p></div><div><h3>Methods</h3><p>We genotyped the <em>UGT1A1*28</em> 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.</p></div><div><h3>Results</h3><p>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 (<em>P</em> < .0001), cabozantinib (<em>P</em> < .0001), and axitinib (<em>P</em> = .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 (<em>P</em> < .0001) or cabozantinib (<em>P</em> < .0001). With pazopanib, G1-hyperbilirubinemia occurred in 57% of TA7/TA7- and 12% of TA6/TA6+TA6/TA7-carriers (<em>P</em> = .0009) and G2-hyperbilirubinemia in 36% and 6% of the patients, respectively (<em>P</em> = .004). On cabozantinib, G1-hyperbilirubinemia occurred in 100% of TA7/TA7- and 5% of TA6/TA6+TA6/TA7-carriers (<em>P</em> < .0001) and G2-hyperbilirubinemia in 33% and 0% of the patients, respectively (<em>P</em> = .04). On axitinib, no correlation between the genotypes and G1/2-hyperbilirubinemia was observed.</p></div><div><h3>Conclusion</h3><p>We validate the previously described impact of the <em>UGT1A1*28</em> polymorphism on isolated bilirubin increase on pazopanib. We report for the first time that cabozantinib also interferes with <em>UGT1A1</em> and causes isolated bilirubin increase.</p></div>","PeriodicalId":10380,"journal":{"name":"Clinical genitourinary cancer","volume":"22 5","pages":"Article 102180"},"PeriodicalIF":2.3000,"publicationDate":"2024-07-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Cabozantinib Induces Isolated Hyperbilirubinemia in Renal Cell Carcinoma Patients carrying the UGT1A1*28 Polymorphism\",\"authors\":\"Sajedeh Mobaraki , Peter Henrik Nissen , Frede Donskov , Agnieszka Wozniak , Yannick Van Herck , Lina Coosemans , Tine van Nieuwenhuyse , Diether Lambrechts , Oliver Bechter , Marcella Baldewijns , Eduard Roussel , Annouschka Laenen , Benoit Beuselinck\",\"doi\":\"10.1016/j.clgc.2024.102180\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<div><h3>Background</h3><p>Genetic variants of <em>UGT1A1</em>, involved in glucuronidation and clearance of bilirubin, are associated with reduced bilirubin metabolization and drug-induced isolated hyperbilirubinemia. We studied the impact of the <em>UGT1A1*28</em> polymorphism on drug-induced isolated hyperbilirubinemia in metastatic renal cell carcinoma patients treated with pazopanib, cabozantinib, and axitinib.</p></div><div><h3>Methods</h3><p>We genotyped the <em>UGT1A1*28</em> 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.</p></div><div><h3>Results</h3><p>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 (<em>P</em> < .0001), cabozantinib (<em>P</em> < .0001), and axitinib (<em>P</em> = .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 (<em>P</em> < .0001) or cabozantinib (<em>P</em> < .0001). With pazopanib, G1-hyperbilirubinemia occurred in 57% of TA7/TA7- and 12% of TA6/TA6+TA6/TA7-carriers (<em>P</em> = .0009) and G2-hyperbilirubinemia in 36% and 6% of the patients, respectively (<em>P</em> = .004). On cabozantinib, G1-hyperbilirubinemia occurred in 100% of TA7/TA7- and 5% of TA6/TA6+TA6/TA7-carriers (<em>P</em> < .0001) and G2-hyperbilirubinemia in 33% and 0% of the patients, respectively (<em>P</em> = .04). On axitinib, no correlation between the genotypes and G1/2-hyperbilirubinemia was observed.</p></div><div><h3>Conclusion</h3><p>We validate the previously described impact of the <em>UGT1A1*28</em> polymorphism on isolated bilirubin increase on pazopanib. We report for the first time that cabozantinib also interferes with <em>UGT1A1</em> and causes isolated bilirubin increase.</p></div>\",\"PeriodicalId\":10380,\"journal\":{\"name\":\"Clinical genitourinary cancer\",\"volume\":\"22 5\",\"pages\":\"Article 102180\"},\"PeriodicalIF\":2.3000,\"publicationDate\":\"2024-07-27\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Clinical genitourinary cancer\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://www.sciencedirect.com/science/article/pii/S1558767324001514\",\"RegionNum\":3,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q3\",\"JCRName\":\"ONCOLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Clinical genitourinary cancer","FirstCategoryId":"3","ListUrlMain":"https://www.sciencedirect.com/science/article/pii/S1558767324001514","RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q3","JCRName":"ONCOLOGY","Score":null,"Total":0}
Cabozantinib Induces Isolated Hyperbilirubinemia in Renal Cell Carcinoma Patients carrying the UGT1A1*28 Polymorphism
Background
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.
Methods
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.
Results
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.
Conclusion
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.
期刊介绍：
Clinical Genitourinary Cancer is a peer-reviewed journal that publishes original articles describing various aspects of clinical and translational research in genitourinary cancers. Clinical Genitourinary Cancer is devoted to articles on detection, diagnosis, prevention, and treatment of genitourinary cancers. The main emphasis is on recent scientific developments in all areas related to genitourinary malignancies. Specific areas of interest include clinical research and mechanistic approaches; drug sensitivity and resistance; gene and antisense therapy; pathology, markers, and prognostic indicators; chemoprevention strategies; multimodality therapy; and integration of various approaches.
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