300MO - Impact of dihydropyrimidine dehydrogenase (DPD) genotype on fluoropyrimidine-related toxicity in Asian population

Background

Fluoropyrimidine is a key drug for a variety of cancers but rarely associated with severe toxicities such as diarrhea, mucositis, hand-foot syndrome, and neutropenia. Dihydropyrimidine dehydrogenase (DPD) plays a pivotal role in fluoropyrimidine metabolism and dozens of genetic variant are known to reduce the activity of this gene. Approximately 3-5% of patients are estimated to have reduced DPD genotype in Caucasian population and Clinical Pharmacogenetics Implementation Consortium (CPIC) has released 82 DPD variants which could increase the risk of fluoropyrimidine-related severe toxicity; however, it remains unclear whether DPD genotype-guided fluoropyrimidine dosing strategy is applicable for Asian population. We aimed to clarify the prevalence of impaired DPD genotype and its association with fluoropyrimidine-related severe toxicities.

Methods

We comprehensively searched nonsynonymous variants in DPD using Japanese Haplotype Reference Panel (JHRP, n = 3,135). Then the variants and 82 DPD variants listed in the CPIC guideline were investigated for the 1,362 patients with colon cancer who were enrolled in adjuvant clinical trials (JOIN and ACHIEVE) and received mFOLFOX6 or CAPOX, with documented informed consent for the prospective pharmacogenomics study.

Results

We found 39 nonsynonymous variants among 12,611 DPD variants in the JHRP. Of those variants, only 7 variants were listed in CPIC guideline. In our study cohort of 1,362 patients with colon cancer, 74 variants were genotyped among the 82 DPD variants listed in the CPIC guideline and only 8 variants were confirmed. Minor allele frequency of these 8 variants ranged from 0.0003.6 to 0.28. Association study between these 8 variants and fluoropyrimidine-related toxicities (diarrhea, mucositis, hand-foot syndrome, and neutropenia) revealed no significant correlation. Lower prevalence of DPD variants were consistent with the registry data of JHRP, which represented the general Japanese population.

Conclusions

Considering the lower prevalence of impaired DPD genotype, the distinct ethnic difference exists. DPD genotype-guided fluoropyrimidine dosing strategy may not be applicable in Japan.

Clinical trial identification

Editorial acknowledgement

Legal entity responsible for the study

The authors.

Funding

Yakulto Honsha Co., Ltd.

Disclosure

M. Kanai: Shareholder/Stockholder/Stock options: TheraBioPharma Inc.; Honoraria (self): Chugai Pharam. M. Kotaka: Honoraria (self): Chugai; Yakult; Takeda. J. Hasegawa: Speaker Bureau/Expert testimony: Chugai ; Honoraria (self): Yakult. T. Kato: Honoraria (self): Ono; Honoraria (self), Research grant/Funding (institution): Chugai; Takeda; Honoraria (self): Taiho. T. Mizushima: Research grant/Funding (institution): Takeda; Shire Japan; Chugai; Yakult; Eli Lilly Japan; Ono; Sanofi; Mitsubishi Tanabe; Kaken; Japan Blood Products Organization; Tsumura; Astellas; Pfizer Japan; Daiichi Sankyo; Merck Biopharma; MSD. S. Matsumoto: Research grant/Funding (institution): NTT Ltd.; H.U. Group; Canon Medical Systems. A. Ohtsu: Honoraria (self), Research grant/Funding (institution): BMS; Honoraria (self): Ono; Taiho; Chugai. T. Yoshino: Honoraria (self), Research grant/Funding (institution): Taiho; Chugai; Honoraria (self): Eli Lilly Japan; Bayer; Merk; Takeda; Research grant/Funding (institution): MSD; Ono; Daiichi Sankyo; Sumitomo Dainippon Pharma; Parexel International Inc; Sanofi; Amgen; GlaxoSmithKline. F. Matsuda: Research grant/Funding (institution): Yakult. All other authors have declared no conflicts of interest.