Impact of pharmacogenomic DPYD variant guided dosing on toxicity in patients receiving fluoropyrimidines for gastrointestinal cancers in a high-volume tertiary centre
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...
| Main Authors: | , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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BMC
2023-04-01
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| Series: | BMC Cancer |
| Subjects: | |
| Online Access: | https://doi.org/10.1186/s12885-023-10857-8 |
| _version_ | 1827956759997710336 |
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| author | David K. Lau Caroline Fong Faten Arouri Lillian Cortez Hannah Katifi Reyes Gonzalez-Exposito Muhammad Bilal Razzaq Su Li Aislinn Macklin-Doherty Monica Arenas Hernandez Michael Hubank Charlotte Fribbens David Watkins Sheela Rao Ian Chau David Cunningham Naureen Starling |
| author_facet | David K. Lau Caroline Fong Faten Arouri Lillian Cortez Hannah Katifi Reyes Gonzalez-Exposito Muhammad Bilal Razzaq Su Li Aislinn Macklin-Doherty Monica Arenas Hernandez Michael Hubank Charlotte Fribbens David Watkins Sheela Rao Ian Chau David Cunningham Naureen Starling |
| author_sort | David K. Lau |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-04-09T15:08:41Z |
| format | Article |
| id | doaj.art-8c4c528d564e402aa51ff80d19849ea5 |
| institution | Directory Open Access Journal |
| issn | 1471-2407 |
| language | English |
| last_indexed | 2024-04-09T15:08:41Z |
| publishDate | 2023-04-01 |
| publisher | BMC |
| record_format | Article |
| series | BMC Cancer |
| spelling | doaj.art-8c4c528d564e402aa51ff80d19849ea52023-04-30T11:18:52ZengBMCBMC Cancer1471-24072023-04-012311810.1186/s12885-023-10857-8Impact of pharmacogenomic DPYD variant guided dosing on toxicity in patients receiving fluoropyrimidines for gastrointestinal cancers in a high-volume tertiary centreDavid K. Lau0Caroline Fong1Faten Arouri2Lillian Cortez3Hannah Katifi4Reyes Gonzalez-Exposito5Muhammad Bilal Razzaq6Su Li7Aislinn Macklin-Doherty8Monica Arenas Hernandez9Michael Hubank10Charlotte Fribbens11David Watkins12Sheela Rao13Ian Chau14David Cunningham15Naureen Starling16Gastrointestinal and Lymphoma Unit, Royal Marsden NHS Foundation TrustGastrointestinal and Lymphoma Unit, Royal Marsden NHS Foundation TrustGastrointestinal and Lymphoma Unit, Royal Marsden NHS Foundation Trust Department of Pharmacy, Royal Marsden NHS Foundation TrustGastrointestinal and Lymphoma Unit, Royal Marsden NHS Foundation TrustGastrointestinal and Lymphoma Unit, Royal Marsden NHS Foundation TrustGastrointestinal and Lymphoma Unit, Royal Marsden NHS Foundation TrustGastrointestinal and Lymphoma Unit, Royal Marsden NHS Foundation TrustGastrointestinal and Lymphoma Unit, Royal Marsden NHS Foundation TrustPurine Research Laboratory, Synnovis, St Thomas’ HospitalCentre for Molecular Pathology, Royal Marsden Hospital and Institute of Cancer ResearchGastrointestinal and Lymphoma Unit, Royal Marsden NHS Foundation TrustGastrointestinal and Lymphoma Unit, Royal Marsden NHS Foundation TrustGastrointestinal and Lymphoma Unit, Royal Marsden NHS Foundation TrustGastrointestinal and Lymphoma Unit, Royal Marsden NHS Foundation TrustGastrointestinal and Lymphoma Unit, Royal Marsden NHS Foundation TrustGastrointestinal and Lymphoma Unit, Royal Marsden NHS Foundation TrustAbstract 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.https://doi.org/10.1186/s12885-023-10857-8DPYDDihydropyrimidine dehydrogenaseCapecitabine5-fluorouracilPharmacogenomics |
| spellingShingle | David K. Lau Caroline Fong Faten Arouri Lillian Cortez Hannah Katifi Reyes Gonzalez-Exposito Muhammad Bilal Razzaq Su Li Aislinn Macklin-Doherty Monica Arenas Hernandez Michael Hubank Charlotte Fribbens David Watkins Sheela Rao Ian Chau David Cunningham Naureen Starling Impact of pharmacogenomic DPYD variant guided dosing on toxicity in patients receiving fluoropyrimidines for gastrointestinal cancers in a high-volume tertiary centre BMC Cancer DPYD Dihydropyrimidine dehydrogenase Capecitabine 5-fluorouracil Pharmacogenomics |
| title | Impact of pharmacogenomic DPYD variant guided dosing on toxicity in patients receiving fluoropyrimidines for gastrointestinal cancers in a high-volume tertiary centre |
| title_full | Impact of pharmacogenomic DPYD variant guided dosing on toxicity in patients receiving fluoropyrimidines for gastrointestinal cancers in a high-volume tertiary centre |
| title_fullStr | Impact of pharmacogenomic DPYD variant guided dosing on toxicity in patients receiving fluoropyrimidines for gastrointestinal cancers in a high-volume tertiary centre |
| title_full_unstemmed | Impact of pharmacogenomic DPYD variant guided dosing on toxicity in patients receiving fluoropyrimidines for gastrointestinal cancers in a high-volume tertiary centre |
| title_short | Impact of pharmacogenomic DPYD variant guided dosing on toxicity in patients receiving fluoropyrimidines for gastrointestinal cancers in a high-volume tertiary centre |
| title_sort | impact of pharmacogenomic dpyd variant guided dosing on toxicity in patients receiving fluoropyrimidines for gastrointestinal cancers in a high volume tertiary centre |
| topic | DPYD Dihydropyrimidine dehydrogenase Capecitabine 5-fluorouracil Pharmacogenomics |
| url | https://doi.org/10.1186/s12885-023-10857-8 |
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