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Genetic predisposition of hand-foot skin reaction after sorafenib therapy in patients with hepatocellular carcinoma†
Article first published online: 26 JUN 2012
Copyright © 2012 American Cancer Society
Volume 119, Issue 1, pages 136–142, 1 January 2013
How to Cite
Lee, J. H., Chung, Y.-H., Kim, J. A., Shim, J. H., Lee, D., Lee, H. C., Shin, E.-S., Yoon, J. H., Kim, B. I., Bae, S. H., Koh, K. C. and Park, N.-H. (2013), Genetic predisposition of hand-foot skin reaction after sorafenib therapy in patients with hepatocellular carcinoma. Cancer, 119: 136–142. doi: 10.1002/cncr.27705
Presented in part at The EASL International Liver Congress 2011/46th Annual Meeting of the European Association for the Study of the Liver; March 30 to April 3, 2011; Berlin, Germany; and at the 62nd Annual Meeting of the American Association for the Study of the Liver Diseases/The Liver Meeting 2011; November 4-8, 2011; San Francisco, California.
- Issue published online: 17 DEC 2012
- Article first published online: 26 JUN 2012
- Manuscript Accepted: 14 MAY 2012
- Manuscript Revised: 4 APR 2012
- Manuscript Received: 23 JAN 2012
- hepatocellular carcinoma;
- hand-foot skin reaction;
- vascular endothelial growth factor;
- tumor necrosis factor-alpha
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.
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.
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).
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.