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

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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.

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Acknowledgments

This study was supported by a grant from the Korea Healthcare Technology R&D Project of the Ministry of Health and Welfare of Korea (A110641) by grant of Health Fellowship Foundation, and by the Public Welfare & Safety research program through the National Research Foundation of Korea (NRF), funded by the Ministry of Science, ICT & Future Planning (2010-0020841).

Conflict of interest

The authors have no potential conflicts of interest to disclose.

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Authors and Affiliations

  1. Department of Internal Medicine, College of Medicine, Yonsei University, Seoul, Korea

    Hye Ryun Kim, Sun Min Lim, Hyo Song Kim, Sang Jun Shin, Jung Bae Ahn & Sun Young Rha

  2. Division of Medical Oncology, Yonsei Cancer Center, College of Medicine, Yonsei University, 50 Yonsei-ro, 134 Shinchon-dong, Seodaemun-gu, Seoul, 120-752, Korea

    Hye Ryun Kim, Sun Min Lim, Hyo Song Kim, Sang Jun Shin & Jung Bae Ahn

  3. Department of Pharmacology, Pharmacogenomic Research Center for Membrane Transporters, College of Medicine, Yonsei University, Seoul, Korea

    Hyung Soon Park & Ji Hyun Lee

  4. Cancer Metastasis Research Center, College of Medicine, Yonsei University, Seoul, Korea

    Woo Sun Kwon

  5. Brain Korea 21 Project for Medical Sciences, College of Medicine, Yonsei University, Seoul, Korea

    Woo Sun Kwon

  6. Research Center for Human Natural Defense System, College of Medicine, Yonsei University, Seoul, Korea

    Ji Hyun Lee

  7. Department of Clinical Pharmacokinetics and Pharmacodynamics, School of Medicine, Keio University, Minato, Japan

    Yusuke Tanigawara

  8. Yonsei Cancer Research Institute, College of Medicine, Yonsei University, Seoul, Korea

    Sun Young Rha

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  1. Hye Ryun Kim
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Correspondence to Sun Young Rha.

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Kim, H.R., Park, H.S., Kwon, W.S. et al. Pharmacogenetic determinants associated with sunitinib-induced toxicity and ethnic difference in Korean metastatic renal cell carcinoma patients. Cancer Chemother Pharmacol 72, 825–835 (2013). https://doi.org/10.1007/s00280-013-2258-y

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