Impact of pharmacogenomic DPYD variant guided dosing on toxicity in patients receiving fluoropyrimidines for gastrointestinal cancers in a high-volume tertiary centre.
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Embargo End Date
ICR Authors
Authors
Lau, DK
Fong, C
Arouri, F
Cortez, L
Katifi, H
Gonzalez-Exposito, R
Razzaq, MB
Li, S
Macklin-Doherty, A
Hernandez, MA
Hubank, M
Fribbens, C
Watkins, D
Rao, S
Chau, I
Cunningham, D
Starling, N
Fong, C
Arouri, F
Cortez, L
Katifi, H
Gonzalez-Exposito, R
Razzaq, MB
Li, S
Macklin-Doherty, A
Hernandez, MA
Hubank, M
Fribbens, C
Watkins, D
Rao, S
Chau, I
Cunningham, D
Starling, N
Document Type
Journal Article
Date
2023-04-26
Date Accepted
2023-04-17
Abstract
BACKGROUND: Dihydropyrimidine dehydrogenase (DPD) is a key enzyme in the metabolism of fluoropyrimidines. Variations in the encoding DPYD gene are associated with severe fluoropyrimidine toxicity and up-front dose reductions are recommended. We conducted a retrospective study to evaluate the impact of implementing DPYD variant testing for patients with gastrointestinal cancers in routine clinical practice in a high volume cancer centre in London, United Kingdom. METHODS: Patients receiving fluoropyrimidine chemotherapy for gastrointestinal cancer prior to, and following the implementation of DPYD testing were identified retrospectively. After November 2018, patients were tested for DPYD variants c.1905+1G>A (DPYD*2A), c.2846A>T (DPYD rs67376798), c.1679T>G (DPYD*13), c.1236G>A (DPYD rs56038477), c.1601G>A (DPYD*4) prior to commencing fluoropyrimidines alone or in combination with other cytotoxics and/or radiotherapy. Patients with a DPYD heterozygous variant received an initial dose reduction of 25-50%. Toxicity by CTCAE v4.03 criteria was compared between DPYD heterozygous variant and wild type carriers. RESULTS: Between 1st December 2018 and 31st July 2019, 370 patients who were fluoropyrimidine naïve underwent a DPYD genotyping test prior to receiving a capecitabine (n = 236, 63.8%) or 5FU (n = 134, 36.2%) containing chemotherapy regimen. 33 patients (8.8%) were heterozygous DPYD variant carriers and 337 (91.2%) were wild type. The most prevalent variants were c.1601G > A (n = 16) and c.1236G > A (n = 9). Mean relative dose intensity for the first dose was 54.2% (range 37.5-75%) for DPYD heterozygous carriers and 93.2% (42.9-100%) for DPYD wild type carriers. Overall grade 3 or worse toxicity was similar in DPYD variant carriers (4/33, 12.1%) as compared to wild-type carriers (89/337, 25.7%; P = 0.0924). CONCLUSIONS: Our study demonstrates successful routine DPYD mutation testing prior to the initiation of fluoropyrimidine chemotherapy with high uptake. In patients with DPYD heterozygous variants with pre-emptive dose reductions, high incidence of severe toxicity was not observed. Our data supports routine DPYD genotype testing prior to commencement of fluoropyrimidine chemotherapy.
Citation
BMC Cancer, 2023, 23 (1), pp. 380 -
Source Title
BMC Cancer
Publisher
BMC
ISSN
1471-2407
eISSN
1471-2407
1471-2407
1471-2407
Collections
Research Team
Aetiological Epidemiology
Medicine (RMH)
Medicine (RMH)