Pharmacogenetic determinants associated with sunitinib-induced toxicity and ethnic difference in Korean metastatic renal cell carcinoma patients

Purpose 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. Methods 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. Results 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. Conclusion 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.