Department of Internal Medicine, University of Ulsan College of Medicine, Asan Medical Center, Seoul, Republic of Korea.
Cancer. 2013 Jan 1;119(1):136-42. doi: 10.1002/cncr.27705. Epub 2012 Jun 26.
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.
索拉非尼目前为晚期肝细胞癌（HCC）设定了新的标准。有人认为，亚洲 HCC 患者对索拉非尼治疗相关的手足皮肤反应（HFSR）更敏感。作者研究了韩国 HCC 患者中索拉非尼诱导的 HFSR 与遗传多态性之间的关系。
本前瞻性队列研究纳入了来自韩国 5 个中心的 59 例中期 HCC 连续患者。所有患者均接受索拉非尼 400mg，每日两次，联合经动脉化疗栓塞术（TACE）。对总共 8 个候选基因（次要等位基因频率≥5%）的 49 个单核苷酸多态性（SNP）进行基因分型。在治疗前和治疗后 1 个月使用酶联免疫吸附试验测量血管内皮生长因子（VEGF）和肿瘤坏死因子-α（TNF-α）的血清水平。
中位治疗期为 18 个月期间，55 例（93%）患者发生索拉非尼诱导的 HFSR，其中 15 例为 1 级反应，27 例为 2 级反应，13 例为 3 级反应。TNF-α-308GG、VEGF-94GG、VEGF 1991CC、VEGF IVS3-28CC 和尿苷二磷酸葡萄糖醛酸基转移酶 1 家族多肽 A9（UGT1A9）IVS1-37431AA 的 SNP 与高等级（2 级或 3 级）HFSR 的发生在单变量分析中显著相关（P<0.05）。在多变量分析中，SNP VEGF 1991CC（优势比，45.7）、TNF-α-308GG（优势比，44.1）和 UGT1A9 IVS1-37431AA（优势比，18.7）被确定为高等级 HFSR 发生的独立危险因素（P=0.01、P=0.02 和 P=0.02，分别）。索拉非尼治疗后 1 个月时测量的血清 TNF-α 水平与高等级 HFSR 的发生显著相关（优势比，3.56；P=0.026）。
HFSR 发生率的差异可能是由于 TNF-α、VEGF 和 UGT1A9 基因的遗传多态性在种族上的差异引起的，尤其是与索拉非尼治疗后血清 TNF-α 的表达有关。
Zotero 插件