Association of IL12RB2, RORC, and class II HLA polymorphisms with severe erythema multiforme of regorafenib in Japanese patients with colorectal cancer.

[PURPOSE] The anticancer drug regorafenib can induce erythema multiforme (EM), an immune-mediated cutaneous and mucosal hypersensitivity reaction. We prospectively analyzed regorafenib in patients with metastatic colorectal cancer (mCRC) and found that seven of 40 patients had grade 3 EM, which resulted in treatment discontinuation. In this study, we retrospectively examined genetic polymorphisms associated with regorafenib-induced severe EM.

[METHODS] To identify associated polymorphisms, exploratory whole-exome sequencing was performed focusing on factors related to type IV hypersensitivity reaction in seven patients each, with and without grade 3 EM. The identified EM-related polymorphisms were analyzed in all 40 patients. Class II human leukocyte antigen (HLA) typing was also performed for all patients.

[RESULTS] The frequency of interleukin 12 receptor (IL12R)B2 rs2229546 A/A was higher in patients with grade 3 EM than in those without it (P = 0.00622, Pc = 0.0622 [Bonferroni corrections]). Polymorphisms of the retinoic acid receptor-related orphan receptor (ROR)C, rs2280471 G, rs12145375 T, rs12144914 G, and rs55841824 T comprised haplotype I. The frequency of patients homozygous or heterozygous for haplotype I was lower in those with grade 3 EM than in those without EM (P = 0.0108, Pc = 0.108). The combination of the risk genotype of IL12RB2 rs2229546 A/A and the risk diplotype that did not contain RORC haplotype I was significantly associated with a higher incidence of grade 3 EM (P = 0.000383, Pc = 0.00153). The class II HLA haplotypes were not associated with EM.

[CONCLUSIONS] Type IV hypersensitivity reaction-related polymorphisms were associated with regorafenib-induced EM.

[TRIAL REGISTRATION NUMBER AND DATE] UMIN000013939, registered on May 12, 2014, when six months after approval by the Institutional Review Board of Showa Medical University.