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

Hye Ryun Kim, Hyung Soon Park, Woo Sun Kwon, Ji Hyun Lee, Yusuke Tanigawara, Sun Min Lim, Hyo Song Kim, Sang Jun Shin, Jung Bae Ahn, Sun Young Rha

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42 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)825-835
Number of pages11
JournalCancer Chemotherapy and Pharmacology
Volume72
Issue number4
DOIs
Publication statusPublished - 2013 Oct 1

Keywords

  • Polymorphism
  • Renal cell carcinoma
  • Sunitinib
  • Toxicity

ASJC Scopus subject areas

  • Oncology
  • Toxicology
  • Pharmacology
  • Cancer Research
  • Pharmacology (medical)

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