CPIC Comment on Pending DPYD Guideline Update

Although the updated CPIC guideline for DPYD and fluoropyrimidines is still in development, the authors have concluded, based on current evidence, that c.1129-5923C>G, the minor allele at rs75017182 and causal allele associated with the “HapB3” haplotype, will be assigned an allele value of 0.75. For a heterozygous carrier, this corresponds to an activity score of 1.75. For these patients, the recommendation is to initiate treatment at 75% of the intended dose in cycle 1. The intended dose refers to the regimen-specific dose that would be selected based on standard prescribing practices and patient-specific clinical factors, independent of DPYD genotype. Careful evaluation for fluoropyrimidine dose escalation in subsequent treatment cycles is strongly recommended, with dose increases guided by tolerability and consideration of escalation toward standard dosing in patients without clinically significant toxicity. The full guideline, including dose recommendations for other variants and activity scores, as well as expanded guidance for dose escalation, is expected to be finalized in fall 2026. Note that the changes described herein are specific to c.1129-5923C>G and should not be applied to other variants which may have previously shared the same allele value.

Please note this change will not be made on the website or database until the guideline is published; DPYD c.1129-5923C>G and DPYD c.1129-5923C>G, c.1236G>A (HapB3) will remain at AV=0.5 until then.