Abstract 488P
Background
Fluoropyrimidines (FPs), 5-fluorouracil and capecitabine, are pyrimidine analogues which are mainly used in gastrointestinal and breast cancers. They are metabolised by dihydropyrimidine dehydrogenase (DPD), an enzyme coded by the DPYD gene. Germline DPYD gene variants result in reduced or absent DPD activity, posing increased risk of severe toxicities. In European populations, partial DPD deficiency prevalence is 3-9% and complete deficiency is 0.01-0.5%. The NHS commissioned routine DPYD variant screening for patients receiving FPs. Dosing guidance for heterozygous DPYD variants advises an initial treatment dose of 50% with dose escalation if tolerated. FP avoidance is sometimes advised for homozygous or compound heterozygous DPYD variants.
Methods
This is a retrospective analysis of DPYD variant patients identified from Jan 21 - Jun 23. We recorded treatment received, tolerance, FP toxicities and dose escalations.
Results
Of the 157 DPYD variant patients identified, 153 (97%) were heterozygous, 1 (1%) was compound heterozygous and 3 (2%) were homozygous. This represents partial DPD deficiency in 6.9% of tested patients and complete deficiency in 0.11%. FPs were contraindicated in the complete deficiency patients. Grade 3-4 FP-related toxicities occurred in 11 (9%) patients. Of 117 (75%) patients who received FPs, 108 (92%) were planned for multiple cycles and 9 (8%) received FPs with concurrent radiotherapy. Of 108 patients planned for multiple cycles, 10 stopped after 1 cycle, although only 3 cases were due to FP-related toxicity. Five patients who received prior FPs before DPYD testing were excluded from the analysis. In the remaining 93 patients who received multiple cycles, tolerance enabled dose escalation in 38 (41%) cases, with 74% tolerating this. Only 2 patients discontinued FPs due to toxicity post dose escalation.
Conclusions
Patients with DPYD variants who commenced on reduced dose FPs experience similar grade 3-4 toxicity rates as non-variant patients receiving full dose FPs. This demonstrates that the initial dose reduction effectively mitigates the risk of significant toxicities. Dose escalation in patients tolerating treatment is successful in most cases.
Clinical trial identification
Editorial acknowledgement
Legal entity responsible for the study
The authors.
Funding
Has not received any funding.
Disclosure
All authors have declared no conflicts of interest.