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 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. Ausführliche Beschreibung

Gespeichert in:

Autor*in:	David K. Lau [verfasserIn] Caroline Fong [verfasserIn] Faten Arouri [verfasserIn] Lillian Cortez [verfasserIn] Hannah Katifi [verfasserIn] Reyes Gonzalez-Exposito [verfasserIn] Muhammad Bilal Razzaq [verfasserIn] Su Li [verfasserIn] Aislinn Macklin-Doherty [verfasserIn] Monica Arenas Hernandez [verfasserIn] Michael Hubank [verfasserIn] Charlotte Fribbens [verfasserIn] David Watkins [verfasserIn] Sheela Rao [verfasserIn] Ian Chau [verfasserIn] David Cunningham [verfasserIn] Naureen Starling [verfasserIn]

Format:	E-Artikel
Sprache:	Englisch

Erschienen:	2023

Schlagwörter:	DPYD Dihydropyrimidine dehydrogenase Capecitabine 5-fluorouracil Pharmacogenomics

Übergeordnetes Werk:	In: BMC Cancer - BMC, 2003, 23(2023), 1, Seite 8
Übergeordnetes Werk:	volume:23 ; year:2023 ; number:1 ; pages:8

Links:	Link aufrufen Link aufrufen Link aufrufen Journal toc

DOI / URN:	10.1186/s12885-023-10857-8

Katalog-ID:	DOAJ089679962

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245	1	0	\|a 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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520			\|a 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 (DPYD2A), c.2846A<T (DPYD rs67376798), c.1679T<G (DPYD13), 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.
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653		0	\|a Neoplasms. Tumors. Oncology. Including cancer and carcinogens
700	0		\|a Caroline Fong \|e verfasserin \|4 aut
700	0		\|a Faten Arouri \|e verfasserin \|4 aut
700	0		\|a Lillian Cortez \|e verfasserin \|4 aut
700	0		\|a Hannah Katifi \|e verfasserin \|4 aut
700	0		\|a Reyes Gonzalez-Exposito \|e verfasserin \|4 aut
700	0		\|a Muhammad Bilal Razzaq \|e verfasserin \|4 aut
700	0		\|a Su Li \|e verfasserin \|4 aut
700	0		\|a Aislinn Macklin-Doherty \|e verfasserin \|4 aut
700	0		\|a Monica Arenas Hernandez \|e verfasserin \|4 aut
700	0		\|a Michael Hubank \|e verfasserin \|4 aut
700	0		\|a Charlotte Fribbens \|e verfasserin \|4 aut
700	0		\|a David Watkins \|e verfasserin \|4 aut
700	0		\|a Sheela Rao \|e verfasserin \|4 aut
700	0		\|a Ian Chau \|e verfasserin \|4 aut
700	0		\|a David Cunningham \|e verfasserin \|4 aut
700	0		\|a Naureen Starling \|e verfasserin \|4 aut
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allfields	10.1186/s12885-023-10857-8 doi (DE-627)DOAJ089679962 (DE-599)DOAJ8c4c528d564e402aa51ff80d19849ea5 DE-627 ger DE-627 rakwb eng RC254-282 David K. Lau verfasserin aut Impact of pharmacogenomic DPYD variant guided dosing on toxicity in patients receiving fluoropyrimidines for gastrointestinal cancers in a high-volume tertiary centre 2023 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier 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 (DPYD2A), c.2846A<T (DPYD rs67376798), c.1679T<G (DPYD13), 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. DPYD Dihydropyrimidine dehydrogenase Capecitabine 5-fluorouracil Pharmacogenomics Neoplasms. Tumors. Oncology. Including cancer and carcinogens Caroline Fong verfasserin aut Faten Arouri verfasserin aut Lillian Cortez verfasserin aut Hannah Katifi verfasserin aut Reyes Gonzalez-Exposito verfasserin aut Muhammad Bilal Razzaq verfasserin aut Su Li verfasserin aut Aislinn Macklin-Doherty verfasserin aut Monica Arenas Hernandez verfasserin aut Michael Hubank verfasserin aut Charlotte Fribbens verfasserin aut David Watkins verfasserin aut Sheela Rao verfasserin aut Ian Chau verfasserin aut David Cunningham verfasserin aut Naureen Starling verfasserin aut In BMC Cancer BMC, 2003 23(2023), 1, Seite 8 (DE-627)326643710 (DE-600)2041352-X 14712407 nnns volume:23 year:2023 number:1 pages:8 https://doi.org/10.1186/s12885-023-10857-8 kostenfrei https://doaj.org/article/8c4c528d564e402aa51ff80d19849ea5 kostenfrei https://doi.org/10.1186/s12885-023-10857-8 kostenfrei https://doaj.org/toc/1471-2407 Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_702 GBV_ILN_2001 GBV_ILN_2003 GBV_ILN_2005 GBV_ILN_2006 GBV_ILN_2008 GBV_ILN_2009 GBV_ILN_2010 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2015 GBV_ILN_2020 GBV_ILN_2021 GBV_ILN_2025 GBV_ILN_2031 GBV_ILN_2038 GBV_ILN_2044 GBV_ILN_2048 GBV_ILN_2050 GBV_ILN_2055 GBV_ILN_2056 GBV_ILN_2057 GBV_ILN_2061 GBV_ILN_2111 GBV_ILN_2113 GBV_ILN_2190 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 23 2023 1 8
spelling	10.1186/s12885-023-10857-8 doi (DE-627)DOAJ089679962 (DE-599)DOAJ8c4c528d564e402aa51ff80d19849ea5 DE-627 ger DE-627 rakwb eng RC254-282 David K. Lau verfasserin aut Impact of pharmacogenomic DPYD variant guided dosing on toxicity in patients receiving fluoropyrimidines for gastrointestinal cancers in a high-volume tertiary centre 2023 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier 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 (DPYD2A), c.2846A<T (DPYD rs67376798), c.1679T<G (DPYD13), 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. DPYD Dihydropyrimidine dehydrogenase Capecitabine 5-fluorouracil Pharmacogenomics Neoplasms. Tumors. Oncology. Including cancer and carcinogens Caroline Fong verfasserin aut Faten Arouri verfasserin aut Lillian Cortez verfasserin aut Hannah Katifi verfasserin aut Reyes Gonzalez-Exposito verfasserin aut Muhammad Bilal Razzaq verfasserin aut Su Li verfasserin aut Aislinn Macklin-Doherty verfasserin aut Monica Arenas Hernandez verfasserin aut Michael Hubank verfasserin aut Charlotte Fribbens verfasserin aut David Watkins verfasserin aut Sheela Rao verfasserin aut Ian Chau verfasserin aut David Cunningham verfasserin aut Naureen Starling verfasserin aut In BMC Cancer BMC, 2003 23(2023), 1, Seite 8 (DE-627)326643710 (DE-600)2041352-X 14712407 nnns volume:23 year:2023 number:1 pages:8 https://doi.org/10.1186/s12885-023-10857-8 kostenfrei https://doaj.org/article/8c4c528d564e402aa51ff80d19849ea5 kostenfrei https://doi.org/10.1186/s12885-023-10857-8 kostenfrei https://doaj.org/toc/1471-2407 Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_702 GBV_ILN_2001 GBV_ILN_2003 GBV_ILN_2005 GBV_ILN_2006 GBV_ILN_2008 GBV_ILN_2009 GBV_ILN_2010 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2015 GBV_ILN_2020 GBV_ILN_2021 GBV_ILN_2025 GBV_ILN_2031 GBV_ILN_2038 GBV_ILN_2044 GBV_ILN_2048 GBV_ILN_2050 GBV_ILN_2055 GBV_ILN_2056 GBV_ILN_2057 GBV_ILN_2061 GBV_ILN_2111 GBV_ILN_2113 GBV_ILN_2190 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 23 2023 1 8
allfields_unstemmed	10.1186/s12885-023-10857-8 doi (DE-627)DOAJ089679962 (DE-599)DOAJ8c4c528d564e402aa51ff80d19849ea5 DE-627 ger DE-627 rakwb eng RC254-282 David K. Lau verfasserin aut Impact of pharmacogenomic DPYD variant guided dosing on toxicity in patients receiving fluoropyrimidines for gastrointestinal cancers in a high-volume tertiary centre 2023 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier 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 (DPYD2A), c.2846A<T (DPYD rs67376798), c.1679T<G (DPYD13), 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. DPYD Dihydropyrimidine dehydrogenase Capecitabine 5-fluorouracil Pharmacogenomics Neoplasms. Tumors. Oncology. Including cancer and carcinogens Caroline Fong verfasserin aut Faten Arouri verfasserin aut Lillian Cortez verfasserin aut Hannah Katifi verfasserin aut Reyes Gonzalez-Exposito verfasserin aut Muhammad Bilal Razzaq verfasserin aut Su Li verfasserin aut Aislinn Macklin-Doherty verfasserin aut Monica Arenas Hernandez verfasserin aut Michael Hubank verfasserin aut Charlotte Fribbens verfasserin aut David Watkins verfasserin aut Sheela Rao verfasserin aut Ian Chau verfasserin aut David Cunningham verfasserin aut Naureen Starling verfasserin aut In BMC Cancer BMC, 2003 23(2023), 1, Seite 8 (DE-627)326643710 (DE-600)2041352-X 14712407 nnns volume:23 year:2023 number:1 pages:8 https://doi.org/10.1186/s12885-023-10857-8 kostenfrei https://doaj.org/article/8c4c528d564e402aa51ff80d19849ea5 kostenfrei https://doi.org/10.1186/s12885-023-10857-8 kostenfrei https://doaj.org/toc/1471-2407 Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_702 GBV_ILN_2001 GBV_ILN_2003 GBV_ILN_2005 GBV_ILN_2006 GBV_ILN_2008 GBV_ILN_2009 GBV_ILN_2010 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2015 GBV_ILN_2020 GBV_ILN_2021 GBV_ILN_2025 GBV_ILN_2031 GBV_ILN_2038 GBV_ILN_2044 GBV_ILN_2048 GBV_ILN_2050 GBV_ILN_2055 GBV_ILN_2056 GBV_ILN_2057 GBV_ILN_2061 GBV_ILN_2111 GBV_ILN_2113 GBV_ILN_2190 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 23 2023 1 8
allfieldsGer	10.1186/s12885-023-10857-8 doi (DE-627)DOAJ089679962 (DE-599)DOAJ8c4c528d564e402aa51ff80d19849ea5 DE-627 ger DE-627 rakwb eng RC254-282 David K. Lau verfasserin aut Impact of pharmacogenomic DPYD variant guided dosing on toxicity in patients receiving fluoropyrimidines for gastrointestinal cancers in a high-volume tertiary centre 2023 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier 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 (DPYD2A), c.2846A<T (DPYD rs67376798), c.1679T<G (DPYD13), 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. DPYD Dihydropyrimidine dehydrogenase Capecitabine 5-fluorouracil Pharmacogenomics Neoplasms. Tumors. Oncology. Including cancer and carcinogens Caroline Fong verfasserin aut Faten Arouri verfasserin aut Lillian Cortez verfasserin aut Hannah Katifi verfasserin aut Reyes Gonzalez-Exposito verfasserin aut Muhammad Bilal Razzaq verfasserin aut Su Li verfasserin aut Aislinn Macklin-Doherty verfasserin aut Monica Arenas Hernandez verfasserin aut Michael Hubank verfasserin aut Charlotte Fribbens verfasserin aut David Watkins verfasserin aut Sheela Rao verfasserin aut Ian Chau verfasserin aut David Cunningham verfasserin aut Naureen Starling verfasserin aut In BMC Cancer BMC, 2003 23(2023), 1, Seite 8 (DE-627)326643710 (DE-600)2041352-X 14712407 nnns volume:23 year:2023 number:1 pages:8 https://doi.org/10.1186/s12885-023-10857-8 kostenfrei https://doaj.org/article/8c4c528d564e402aa51ff80d19849ea5 kostenfrei https://doi.org/10.1186/s12885-023-10857-8 kostenfrei https://doaj.org/toc/1471-2407 Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_702 GBV_ILN_2001 GBV_ILN_2003 GBV_ILN_2005 GBV_ILN_2006 GBV_ILN_2008 GBV_ILN_2009 GBV_ILN_2010 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2015 GBV_ILN_2020 GBV_ILN_2021 GBV_ILN_2025 GBV_ILN_2031 GBV_ILN_2038 GBV_ILN_2044 GBV_ILN_2048 GBV_ILN_2050 GBV_ILN_2055 GBV_ILN_2056 GBV_ILN_2057 GBV_ILN_2061 GBV_ILN_2111 GBV_ILN_2113 GBV_ILN_2190 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 23 2023 1 8
allfieldsSound	10.1186/s12885-023-10857-8 doi (DE-627)DOAJ089679962 (DE-599)DOAJ8c4c528d564e402aa51ff80d19849ea5 DE-627 ger DE-627 rakwb eng RC254-282 David K. Lau verfasserin aut Impact of pharmacogenomic DPYD variant guided dosing on toxicity in patients receiving fluoropyrimidines for gastrointestinal cancers in a high-volume tertiary centre 2023 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier 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 (DPYD2A), c.2846A<T (DPYD rs67376798), c.1679T<G (DPYD13), 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. DPYD Dihydropyrimidine dehydrogenase Capecitabine 5-fluorouracil Pharmacogenomics Neoplasms. Tumors. Oncology. Including cancer and carcinogens Caroline Fong verfasserin aut Faten Arouri verfasserin aut Lillian Cortez verfasserin aut Hannah Katifi verfasserin aut Reyes Gonzalez-Exposito verfasserin aut Muhammad Bilal Razzaq verfasserin aut Su Li verfasserin aut Aislinn Macklin-Doherty verfasserin aut Monica Arenas Hernandez verfasserin aut Michael Hubank verfasserin aut Charlotte Fribbens verfasserin aut David Watkins verfasserin aut Sheela Rao verfasserin aut Ian Chau verfasserin aut David Cunningham verfasserin aut Naureen Starling verfasserin aut In BMC Cancer BMC, 2003 23(2023), 1, Seite 8 (DE-627)326643710 (DE-600)2041352-X 14712407 nnns volume:23 year:2023 number:1 pages:8 https://doi.org/10.1186/s12885-023-10857-8 kostenfrei https://doaj.org/article/8c4c528d564e402aa51ff80d19849ea5 kostenfrei https://doi.org/10.1186/s12885-023-10857-8 kostenfrei https://doaj.org/toc/1471-2407 Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_702 GBV_ILN_2001 GBV_ILN_2003 GBV_ILN_2005 GBV_ILN_2006 GBV_ILN_2008 GBV_ILN_2009 GBV_ILN_2010 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2015 GBV_ILN_2020 GBV_ILN_2021 GBV_ILN_2025 GBV_ILN_2031 GBV_ILN_2038 GBV_ILN_2044 GBV_ILN_2048 GBV_ILN_2050 GBV_ILN_2055 GBV_ILN_2056 GBV_ILN_2057 GBV_ILN_2061 GBV_ILN_2111 GBV_ILN_2113 GBV_ILN_2190 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 23 2023 1 8
language	English
source	In BMC Cancer 23(2023), 1, Seite 8 volume:23 year:2023 number:1 pages:8
sourceStr	In BMC Cancer 23(2023), 1, Seite 8 volume:23 year:2023 number:1 pages:8
format_phy_str_mv	Article
institution	findex.gbv.de
topic_facet	DPYD Dihydropyrimidine dehydrogenase Capecitabine 5-fluorouracil Pharmacogenomics Neoplasms. Tumors. Oncology. Including cancer and carcinogens
isfreeaccess_bool	true
container_title	BMC Cancer
authorswithroles_txt_mv	David K. Lau @@aut@@ Caroline Fong @@aut@@ Faten Arouri @@aut@@ Lillian Cortez @@aut@@ Hannah Katifi @@aut@@ Reyes Gonzalez-Exposito @@aut@@ Muhammad Bilal Razzaq @@aut@@ Su Li @@aut@@ Aislinn Macklin-Doherty @@aut@@ Monica Arenas Hernandez @@aut@@ Michael Hubank @@aut@@ Charlotte Fribbens @@aut@@ David Watkins @@aut@@ Sheela Rao @@aut@@ Ian Chau @@aut@@ David Cunningham @@aut@@ Naureen Starling @@aut@@
publishDateDaySort_date	2023-01-01T00:00:00Z
hierarchy_top_id	326643710
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Lau</subfield><subfield code="e">verfasserin</subfield><subfield code="4">aut</subfield></datafield><datafield tag="245" ind1="1" ind2="0"><subfield code="a">Impact of pharmacogenomic DPYD variant guided dosing on toxicity in patients receiving fluoropyrimidines for gastrointestinal cancers in a high-volume tertiary centre</subfield></datafield><datafield tag="264" ind1=" " ind2="1"><subfield code="c">2023</subfield></datafield><datafield tag="336" ind1=" " ind2=" "><subfield code="a">Text</subfield><subfield code="b">txt</subfield><subfield code="2">rdacontent</subfield></datafield><datafield tag="337" ind1=" " ind2=" "><subfield code="a">Computermedien</subfield><subfield code="b">c</subfield><subfield code="2">rdamedia</subfield></datafield><datafield tag="338" ind1=" " ind2=" "><subfield code="a">Online-Ressource</subfield><subfield code="b">cr</subfield><subfield code="2">rdacarrier</subfield></datafield><datafield tag="520" ind1=" " ind2=" "><subfield code="a">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 (DPYD2A), c.2846A<T (DPYD rs67376798), c.1679T<G (DPYD13), 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. 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callnumber-first	R - Medicine
author	David K. Lau
spellingShingle	David K. Lau misc RC254-282 misc DPYD misc Dihydropyrimidine dehydrogenase misc Capecitabine misc 5-fluorouracil misc Pharmacogenomics misc Neoplasms. Tumors. Oncology. Including cancer and carcinogens Impact of pharmacogenomic DPYD variant guided dosing on toxicity in patients receiving fluoropyrimidines for gastrointestinal cancers in a high-volume tertiary centre
authorStr	David K. Lau
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topic_title	RC254-282 Impact of pharmacogenomic DPYD variant guided dosing on toxicity in patients receiving fluoropyrimidines for gastrointestinal cancers in a high-volume tertiary centre DPYD Dihydropyrimidine dehydrogenase Capecitabine 5-fluorouracil Pharmacogenomics
topic	misc RC254-282 misc DPYD misc Dihydropyrimidine dehydrogenase misc Capecitabine misc 5-fluorouracil misc Pharmacogenomics misc Neoplasms. Tumors. Oncology. Including cancer and carcinogens
topic_unstemmed	misc RC254-282 misc DPYD misc Dihydropyrimidine dehydrogenase misc Capecitabine misc 5-fluorouracil misc Pharmacogenomics misc Neoplasms. Tumors. Oncology. Including cancer and carcinogens
topic_browse	misc RC254-282 misc DPYD misc Dihydropyrimidine dehydrogenase misc Capecitabine misc 5-fluorouracil misc Pharmacogenomics misc Neoplasms. Tumors. Oncology. Including cancer and carcinogens
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title	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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title_full	Impact of pharmacogenomic DPYD variant guided dosing on toxicity in patients receiving fluoropyrimidines for gastrointestinal cancers in a high-volume tertiary centre
author_sort	David K. Lau
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author_browse	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
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title_sort	impact of pharmacogenomic dpyd variant guided dosing on toxicity in patients receiving fluoropyrimidines for gastrointestinal cancers in a high-volume tertiary centre
callnumber	RC254-282
title_auth	Impact of pharmacogenomic DPYD variant guided dosing on toxicity in patients receiving fluoropyrimidines for gastrointestinal cancers in a high-volume tertiary centre
abstract	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 (DPYD2A), c.2846A<T (DPYD rs67376798), c.1679T<G (DPYD13), 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.
abstractGer	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 (DPYD2A), c.2846A<T (DPYD rs67376798), c.1679T<G (DPYD13), 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.
abstract_unstemmed	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 (DPYD2A), c.2846A<T (DPYD rs67376798), c.1679T<G (DPYD13), 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.
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title_short	Impact of pharmacogenomic DPYD variant guided dosing on toxicity in patients receiving fluoropyrimidines for gastrointestinal cancers in a high-volume tertiary centre
url	https://doi.org/10.1186/s12885-023-10857-8 https://doaj.org/article/8c4c528d564e402aa51ff80d19849ea5 https://doaj.org/toc/1471-2407
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author2	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
author2Str	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
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doi_str	10.1186/s12885-023-10857-8
callnumber-a	RC254-282
up_date	2024-07-04T00:11:23.556Z
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Lau</subfield><subfield code="e">verfasserin</subfield><subfield code="4">aut</subfield></datafield><datafield tag="245" ind1="1" ind2="0"><subfield code="a">Impact of pharmacogenomic DPYD variant guided dosing on toxicity in patients receiving fluoropyrimidines for gastrointestinal cancers in a high-volume tertiary centre</subfield></datafield><datafield tag="264" ind1=" " ind2="1"><subfield code="c">2023</subfield></datafield><datafield tag="336" ind1=" " ind2=" "><subfield code="a">Text</subfield><subfield code="b">txt</subfield><subfield code="2">rdacontent</subfield></datafield><datafield tag="337" ind1=" " ind2=" "><subfield code="a">Computermedien</subfield><subfield code="b">c</subfield><subfield code="2">rdamedia</subfield></datafield><datafield tag="338" ind1=" " ind2=" "><subfield code="a">Online-Ressource</subfield><subfield code="b">cr</subfield><subfield code="2">rdacarrier</subfield></datafield><datafield tag="520" ind1=" " ind2=" "><subfield code="a">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 (DPYD2A), c.2846A<T (DPYD rs67376798), c.1679T<G (DPYD13), 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. 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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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