Department of Internal Medicine, College of Medicine, Yonsei University, Seoul, Korea.
Cancer Chemother Pharmacol. 2013 Oct;72(4):825-35. doi: 10.1007/s00280-013-2258-y. Epub 2013 Sep 8.
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, PDGFRα, VEGFR2, RET, and FLT3) were analyzed for an association with treatment-related toxicity from sunitinib using Pearson χ (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.
本研究旨在探讨韩国转移性肾细胞癌（mRCC）患者中舒尼替尼相关毒性的药物遗传学决定因素和种族差异。
对 65 例接受舒尼替尼标准方案治疗的 mRCC 患者（50mg 口服，每日一次，连续 4 周，停药 2 周）进行药物遗传学研究。在临床试验计划（n=38）或标准肿瘤学实践（n=27）中前瞻性收集了舒尼替尼相关毒性的详细数据，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）。分析了 8 个候选基因（CYP1A1、CYP3A5、ABCB1、ABCG2、PDGFRα、VEGFR2、RET 和 FLT3）中 12 个遗传多态性与舒尼替尼治疗相关毒性的关系，采用 Pearson χ 2 检验。
常见的 3 级或 4 级治疗相关毒性为血小板减少症（36.9%，24/65）、中性粒细胞减少症（18.4%，12/65）、贫血（7.7%，5/65）和 HFS（12.3%，8/65）。与 AC/CC 基因型相比，携带 ABCG2 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 的风险显著更高，调整年龄、性别和东部合作肿瘤学组体能状态以及体表面积后（与 AC/CC 基因型相比，比值比[OR] 9.90，P=0.04，血小板减少症；OR 18.20，P=0.02，中性粒细胞减少症；OR 28.46，P=0.01，HFS）。此外，与野生型相比，ABCG2 421 AA 突变细胞的 ABCG2 总蛋白和表面蛋白表达降低。
在 12 个遗传多态性中，ABCG2 421C>A 基因的多态性可能与 mRCC 患者舒尼替尼相关毒性的风险最相关。考虑到亚洲人群中 421C>A SNP 的高频率，这可能与种族间的毒性差异有关。
