Pharmacogenetic determinants associated with sunitinib-induced toxicity and ethnic difference in Korean metastatic renal cell carcinoma patients
Pharmacogenetic determinants associated with sunitinib-induced toxicity and ethnic difference in Korean metastatic renal cell carcinoma patients
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DOI：
10.1007/s00280-013-2258-y
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发表时间：
2013-10-01
影响因子：
3
通讯作者：
Rha, Sun Young
中科院分区：
文献类型：
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作者：
Kim, Hye Ryun;Park, Hyung Soon;Rha, Sun Young
本研究旨在探讨舒尼替尼相关毒性的药物遗传学决定因素以及韩国转移性肾细胞癌（mRCC）患者的种族差异，对65例mRCC患者进行舒尼替尼标准治疗方案（50 mg口服，每日1次，持续4周/停药2周）的药物遗传学研究。在临床试验项目（n = 38）或标准肿瘤学实践（n = 27）中前瞻性收集了关于舒尼替尼毒性的详细数据，包括血小板减少症、中性粒细胞减少症、贫血和手足综合征（HFS）。8个候选基因共12个遗传多态性使用Pearson卡方检验分析了CYP 1A 1、CYP 3A 5、ABCB 1、ABCG 2、PDGFR α、VEGFR 2、RET和FLT 3与舒尼替尼治疗相关毒性的相关性。中性粒细胞减少症（18.4%，12/65）、贫血（7.7%，5/65）和HFS（12.3%，8/65）。携带ABCG 2 421 AA基因型的患者发生3级或4级血小板减少症、中性粒细胞减少症和HFS（根据年龄、性别、东部肿瘤协作组体力状态和体表面积进行校正）的比例显著高于携带ABCG 2 421 AA基因型的患者（与AC/CC基因型比较的比值比[OR] 9.90，P = 0.04，血小板减少; OR 18.20，P = 0.02，中性粒细胞减少; OR 28.46，P = 0.01，HFS）。此外，ABCG 2 421 AA突变体细胞中ABCG 2蛋白的总表达和表面蛋白的表达均较野生型细胞降低。在12种基因多态性中，ABCG 2 421 C> A基因多态性可能与mRCC患者舒尼替尼相关毒性的风险最相关。考虑到421 C> A SNP在亚洲人中的高频率，这可能与种族群体之间的差异毒性有关。
The aim of this study was to investigate the pharmacogenetic determinants of sunitinib-related toxicity and ethnic difference in metastatic renal cell carcinoma (mRCC) among Korean patients.A pharmacogenetic study was performed in 65 patients with mRCC treated with the standard schedule of sunitinib (50 mg orally once daily for 4 weeks-on/2 weeks-off). Detailed data regarding the toxicity of sunitinib, including thrombocytopenia, neutropenia, anemia, and hand-foot syndrome (HFS), were prospectively collected in a clinical trial program (n = 38) or standard oncology practice (n = 27). Total of 12 genetic polymorphisms in 8 candidate genes (CYP1A1, CYP3A5, ABCB1, ABCG2, PDGFR alpha, VEGFR2, RET, and FLT3) were analyzed for an association with treatment-related toxicity from sunitinib using Pearson chi (2) test.Common grade 3 or grade 4 treatment-related toxicities were thrombocytopenia (36.9 %, 24/65), neutropenia (18.4 %, 12/65), anemia (7.7 %, 5/65), and HFS (12.3 %, 8/65). Patients carrying an ABCG2 421 AA genotype developed significantly more grade 3 or grade 4 thrombocytopenia, neutropenia, and HFS adjusted for age, sex, and Eastern Cooperative Oncology Group performance status, and body surface area (odds ratio compared with AC/CC genotypes [OR] 9.90, P = 0.04, thrombocytopenia; OR 18.20, P = 0.02, neutropenia; and OR 28.46, P = 0.01, HFS). In addition, total and surface protein ABCG2 protein expression was decreased in ABCG2 421 AA mutant cells compared to wild type.Among 12 genetic polymorphisms, polymorphism in the ABCG2 421C > A gene may be mostly associated with the risk of sunitinib-related toxicity in mRCC patients. Considering the high frequency of 421C > A SNP in Asian, this may be related to differential toxicities among ethnic groups.