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. 2023 Apr 26;23(1):380.
doi: 10.1186/s12885-023-10857-8.

Impact of pharmacogenomic DPYD variant guided dosing on toxicity in patients receiving fluoropyrimidines for gastrointestinal cancers in a high-volume tertiary centre

David K Lau  1 , Caroline Fong  1 , Faten Arouri  1 , Lillian Cortez  2 , Hannah Katifi  1 , Reyes Gonzalez-Exposito  1 , Muhammad Bilal Razzaq  1 , Su Li  1 , Aislinn Macklin-Doherty  1 , Monica Arenas Hernandez  3 , Michael Hubank  4 , Charlotte Fribbens  1 , David Watkins  1 , Sheela Rao  1 , Ian Chau  1 , David Cunningham  1 , Naureen Starling  5
Affiliations

Impact of pharmacogenomic DPYD variant guided dosing on toxicity in patients receiving fluoropyrimidines for gastrointestinal cancers in a high-volume tertiary centre

David K Lau et al. BMC Cancer. .

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.

Keywords: 5-fluorouracil; Capecitabine; DPYD; Dihydropyrimidine dehydrogenase; Pharmacogenomics.

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Conflict of interest statement

DL is the recipient of the Australasian Gastro-Intestinal Trials Group/Merck Clinical Research Fellowship. SR has served in a consulting role or on the advisory boards for Bayer, Boehringer Ingelheim, Hookipa Biotech, Incyte and Merck Serono.IC has served in a consulting role or on the advisory boards for Eli Lilly, Bristol Meyers Squibb, MSD, Bayer, Roche, Merck Serono, Five Prime Therapeutics, Astra Zeneca, OncXerna, Pierre Fabre, Boehringer Ingelheim, Incyte, Astellas, GSK, Sotio, Eisai and Daiichi Sankyo; received research funding from Eli Lilly, Janssen-Cilag; and honoraria from Eli Lilly, Eisai and Servier.DC has served in a consulting role or on the advisory boards for OVIBIO; received institutional research funding from 4SC, Bayer, Celgene, Clovis Oncology, Leap Oncology, Eli Lilly, MedImmune, Roche; and has ownership interests in OVIBIO.NS has served in a consulting role or on the advisory boards for AstraZeneca, MSD, Pfizer, Servier; received institutional research funding from AstraZeneca, BMS, Pfizer/ EMD Serono; honoraria from Amgen, GlaxoSmithKline, Lilly, Merck Serono, MSD Oncology, Pierre Fabre, Servier; and travel accommodation expenses from AstraZeneca, BMS, Lilly, Merck, MSD Oncology and Roche. C Fong, FA, LC, HK, RGE, MBR, SL, AMD, MAH, MH, C Fribbens and DW have no disclosures.

Figures

Fig. 1
Fig. 1
CONSORT diagram Abbreviations: FP – fluoropyrimidine, DPYD – dihydropyrimidine dehydrogenase
See this image and copyright information in PMC

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