Dihydropyrimidine dehydrogenase gene (DPYD) polymorphism among Caucasian patients (pts) with 5-FU and capecitabine (CAP)-related toxicity

Abstract

e14588 Background: As many as 1 in 3 pts receiving 5-FU/CAP experience dose-limiting toxicity including diarrhea, hand-foot syndrome (HFS), mucositis and myelosupression. Deficiency of DPD, a rate limiting enzyme in 5-FU catabolism can lead to life- threatening complications. DPD deficiency was found to be related to > 40 sequence variations in DPYD. Known deleterious mutations explain only a limited proportion of 5-FU's adverse events. Full sequence analysis of DPYD gene increases sensitivity by 20% vs. simple identification of two most common deleterious mutations (IVS14 +1 G>A, D949V). Pretreatment detection could prevent serious, potentially lethal side effects. We present analysis of DPYD genotyping in untreated Caucasian pts (control group) and Caucasian pts with 5-FU/CAP-related grade 3/4 toxicities (toxicity group) who underwent TheraGuide 5-FU testing. Methods: Full sequencing of DPYD was performed by Myriad Genetic Laboratories, Inc. as part of TheraGuide 5-FU test. DNA was extracted and purified from white blood cells. Genetic variants within pt's DPYD were detected by comparison with a consensus wild-type DPYD sequence. Results: Among 227 pts from toxicity group 27 (12%) had deleterious mutations in DPYD: 12 (5%) had IVS14 +1 G>A, 11 (5%) had D949V and 4 (2%) other mutations. Only 7/192 (4%) pts from control group had DPYD genotype abnormalities: 2 (1%) had IVS14 +1 G>A, 4 (2%) had D949V and 1 (1%) other mutation. Genotype abnormalities were seen more frequently in toxicity group (p=0.001). Among 49 pts with HFS 9/49 (18%) had mutated DPYD. 9/46 (20%) pts with myelosupression were found to have a deleterious mutation. Mutations were more frequent in both subgroups when compared to control group: p=0.001 and 0.0007 respectively. Among 65 pts with toxicities due to CAP 9 (14%) had mutated DPYD which was more frequent than in control group (p=0.006). Conclusions: Mutated DPYD is frequently observed in Caucasian pts who experience toxicities while receiving 5-FU/CAP. Screening pts for DPYD mutations prior to administration of 5-FU/CAP using new pharmacogenetic testing methods may help to identify those pts who are at greatest risk for adverse effects, allowing a more individualized approach to their chemotherapy management. [Table: see text]