Risk factors for sorafenib-induced high-grade skin rash in Japanese patients with advanced renal cell carcinoma

Abstract

The aim of this study was to evaluate the clinical factors, drug-related genetic polymorphisms, and human leukocyte antigen (HLA) types to determine the association with sorafenib-induced high-grade skin rash (HGSR) in Japanese patients with advanced renal cell carcinoma (RCC). A total of 55 patients with advanced RCC treated with sorafenib were analyzed retrospectively. Of these, 33 patients were subjected to HLA typing and polymorphism analyses of CYP3A5, ABCB1, ABCC2, and UGT1A1, which are involved in the metabolism and membrane transport of sorafenib. Grade 3 or higher SR developed in 12 (22%), and a higher incidence was observed in female patients than in male patients (40 vs. 15%, P=0.046). The initial dose, initial dose per body weight, and initial dose per body surface area in patients with HGSR were significantly higher than those in patients without HGSR. Patients with the ABCC2 -24CC genotype were at a significantly higher risk of SR than those with the CT genotype (35 vs. 0%, P=0.032). HLA-A*24 was significantly associated with the occurrence of HGSR (P=0.049). Our finding suggested that women, higher initial dose per body weight or body surface area, the ABCC2 -24CC genotype, and HLA-A*24 are associated with the risk of sorafenib-induced HGSR in Japanese RCC patients.

Stevens-Johnson Syndrome Induced by Sorafenib for Metastatic Renal Cell Carcinoma

“…A recent study by Ikeda et al [7] revealed that the incidence of EM induced by sorafenib was higher (25%) than previous reports. Kodaira et al [8] and Tsuchiya et al [9] also reported that 19-22% patients experienced EM induced by sorafenib. It is possible, however, that the occurrence rate of toxic skin reactions such as EM and SJS might be different between Japanese people and white people.…”

Multikinase Inhibitor-Induced Hand–Foot Skin Reaction: A Review of Clinical Presentation, Pathogenesis, and Management

“…This has been validated for many agents in this group, including sorafenib, sunitinib, axitinib, and cabozantinib [16,[46][47][48][49]. Higher initial dose, initial dose per body weight, and initial dose per body surface area all result in a significant incidence of high-grade HFSR [50]. Moreover, Hilger et al [51] demonstrated that sorafenib-induced skin toxicity was associated with both maximal plasma concentration and area under the curve.…”

A decade of pharmacogenomics research on tyrosine kinase inhibitors in metastatic renal cell cancer: a systematic review

“…Only two pharmacogenetic studies on sorafenib were found in which genetic polymorphisms in ABCC2 and HLA-A were associated with high-grade skin rash and rs2071559 in VEGF-R2 was associated with PFS and OS. For axitinib, no associations were reported [40][41][42][43][44].…”

“…In a study of 55 Japanese mRCC patients, Tsuchiya et al [43] reported that the CC genotype of rs717620 in ABCC2 compared to the CT genotype and the HLA-A*24 allele were both associated with an increased risk for sorafenib-induced high-grade skin rash. In 2015, Escudier et al [44] reported a set of 305 mRCC patients (n = 159 axitinib and n = 146 sorafenib), in which 15 SNPs were investigated in VEGF-A, VEGF-R1, VEGF-R2, and HIF-1A for the association with blood pressure or efficacy outcomes.…”