Genetic predisposition of hand-foot skin reaction after sorafenib therapy in patients with hepatocellular carcinoma.
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.
Department of Internal Medicine, University of Ulsan College of Medicine, Asan Medical Center, Seoul, Republic of Korea.
Joo Ho
JH
Lee
Young-Hwa
YH
Chung
Jeong A
JA
Kim
Ju Hyun
JH
Shim
Danbi
D
Lee
Han Chu
HC
Lee
Eun-Soon
ES
Shin
Jung Hwan
JH
Yoon
Byung Ik
BI
Kim
Si Hyun
SH
Bae
Kwang Cheol
KC
Koh
Neung-Hwa
NH
Park
D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000009:adverse effects*; D001557:Benzenesulfonates / Q000009:adverse effects*; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy* / Q000208:ethnology / Q000235:genetics*; D005260:Female; D020022:Genetic Predisposition to Disease; D060831:Hand-Foot Syndrome / Q000209:etiology* / Q000235:genetics*; D006801:Humans; D007723:Korea; D008113:Liver Neoplasms / Q000188:drug therapy* / Q000208:ethnology / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D009536:Niacinamide / Q000031:analogs & derivatives; D010671:Phenylurea Compounds; D020641:Polymorphism, Single Nucleotide; D011725:Pyridines / Q000009:adverse effects*; D000077157:Sorafenib; D014409:Tumor Necrosis Factor-alpha / Q000097:blood / Q000235:genetics; D042461:Vascular Endothelial Growth Factor A / Q000097:blood
D000970:Antineoplastic Agents; D001557:Benzenesulfonates; D010671:Phenylurea Compounds; D011725:Pyridines; D014409:Tumor Necrosis Factor-alpha; D042461:Vascular Endothelial Growth Factor A; D009536:Niacinamide; D000077157:Sorafenib