Genetic predisposition of hand‐foot skin reaction after sorafenib therapy in patients with hepatocellular carcinoma |
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| Authors: | Joo Ho Lee MD Young‐Hwa Chung MD PhD Jeong A. Kim MS Ju Hyun Shim MD Danbi Lee MD Han Chu Lee MD Eun‐Soon Shin PhD Jung Hwan Yoon MD Byung Ik Kim MD Si Hyun Bae MD Kwang Cheol Koh MD Neung‐Hwa Park MD |
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| Affiliation: | 1. Department of Internal Medicine, University of Ulsan College of Medicine, Asan Medical Center, Seoul, Republic of Korea;2. Department of Internal Medicine, University of Ulsan College of Medicine, Asan Medical Center, Seoul, Republic of KoreaFax: (011) 82‐2‐476‐0824;3. DNALink, Inc., Seoul, Republic of Korea;4. Department of Internal Medicine, Seoul National University College of Medicine, Seoul National University Hospital, Seoul, Republic of Korea;5. Department of Internal Medicine, Sungkyunkwan University School of Medicine, Kangbuk Samsung Hospital, Seoul, Republic of Korea;6. Department of Internal Medicine, The Catholic University of Korea College of Medicine, Seoul St. Mary's Hospital, Seoul, Republic of Korea;7. Department of Internal Medicine, Sungkyunkwan University School of Medicine, Seoul Samsung Hospital, Seoul, Republic of Korea;8. Department of Internal Medicine, University of Ulsan College of Medicine, Ulsan University Hospital;9. Ulsan, Republic of Korea |
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| Abstract: | BACKGROUND: Sorafenib currently sets the new standard for advanced hepatocellular carcinoma (HCC). It has been suggested that Asian patients with HCC have increased susceptibility to hand‐foot skin reaction (HFSR) related to sorafenib therapy. The authors investigated the association between sorafenib‐induced HFSR and genetic polymorphisms in Korean patients with HCC. METHODS: For this prospective cohort study, the authors enrolled 59 consecutive patients with intermediate stage HCC from 5 centers in Korea. All patients received sorafenib 400 mg twice daily in combination with transarterial chemoembolization (TACE). Genotyping was performed on a total of 49 single nucleotide polymorphisms (SNPs) in 8 candidate genes (minor allelic frequency ≥5%). Serum levels of vascular endothelial growth factor (VEGF) and tumor necrosis factor‐alpha (TNF‐α) were measured using enzyme‐linked immunosorbent assays before therapy and 1 month after therapy. RESULTS: During a median treatment period of 18 months, 55 patients (93%) developed sorafenib‐induced HFSR, including grade 1 reactions in 15 patients, grade 2 reactions in 27 patients, and grade 3 reaction in 13 patients. The SNPs TNF‐α ?308GG, VEGF ?94GG, VEGF 1991CC, VEGF IVS3‐28CC, and uridine diphosphate glucuronosyltransferase 1 family‐polypeptide A9 (UGT1A9) IVS1‐37431AA were associated significantly with the development of high‐grade (grade 2 or 3) HFSR in univariate analysis (P < .05). In multivariate analysis, the SNPs VEGF 1991CC (odds ratio, 45.7), TNF‐α ?308GG (odds ratio, 44.1), and UGT1A9 IVS1‐37431AA (odds ratio, 18.7) were identified as independent risk factors for the development of high‐grade HFSR (P = .01, P = .02, and P = .02, respectively). He serum TNF‐α level measured 1 month after sorafenib therapy was correlated significantly with the development of high‐grade HFSR (odds ratio, 3.56; P = .026). CONCLUSIONS: Differences in the incidence of HFSR may have been caused by ethnic differences in genetic polymorphisms of the TNF‐α, VEGF, and UGT1A9 genes, especially in relation to the expression of serum TNF‐α after sorafenib therapy. Cancer 2013. © 2012 American Cancer Society. |
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| Keywords: | hepatocellular carcinoma sorafenib hand‐foot skin reaction vascular endothelial growth factor tumor necrosis factor‐alpha |
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