Tailored treatment and clinical management for DPYD compound heterozygous: a multidisciplinary teamwork

Abstract Dihydropyrimidine dehydrogenase (DPD), encoded by the DPYD gene, is the rate-limiting enzyme governing fluoropyrimidines (FPs) catabolism. Impaired or abrogated DPD enzyme activity is often caused by genetic polymorphisms in the DPYD gene that are well-validated predictors of FP-associated toxicity. Presently, four DPYD variants are included in FP genetic-based dosing guidelines. Patient safety of FP treatment has been significantly improved by pre-emptive screening for DPYD genotype variants and dose adjustments in individuals carrying heterozygous DPYD variant alleles. Nonetheless, managing carriers of multiple DPYD gene variants remains still challenging We conducted a study involving patients undergoing standard-of-care fluoropyrimidine treatment who underwent preemptive DPYD genotyping for DPYD*2A, DPYD*13, D949V, and IVS10. Additionally, patients were screened for the DPYD*6. Adverse drug reactions (ADRs) were graded according to the Common Terminology Criteria for Adverse Events (CTCAE) version 5.0. Adverse events (AEs) ≥ grade 3 were considered severe. Herein, we report 4 cases of patients carrying double-site heterozygous variants of the DPYD gene (IVS10 and DPYD*6), diagnosed with either colon adenocarcinoma or breast cancer. These patients underwent pharmacogenetic-guided dose reduction of the standard by 25–50%, showing varying treatment responses. In conclusion, the management of patients carrying double-site heterozygous IVS10 and DPYD*6 variants should be performed by a multidisciplinary team due to the need for tailored treatment approaches including precision dosing, integrative deep analysis and therapeutic drug monitoring for early detection of AEs in order to maintain effectiveness and safety for each case.