PMID- 33620159 OWN - NLM STAT- MEDLINE DCOM- 20220214 LR - 20220214 IS - 1752-8062 (Electronic) IS - 1752-8054 (Print) IS - 1752-8054 (Linking) VI - 14 IP - 4 DP - 2021 Jul TI - Impact of pretreatment dihydropyrimidine dehydrogenase genotype-guided fluoropyrimidine dosing on chemotherapy associated adverse events. PG - 1338-1348 LID - 10.1111/cts.12981 [doi] AB - Consensus guidelines exist for genotype-guided fluoropyrimidine dosing based on variation in the gene dihydropyrimidine dehydrogenase (DPYD). However, these guidelines have not been widely implemented in North America and most studies of pretreatment DPYD screening have been conducted in Europe. Given regional differences in treatment practices and rates of adverse events (AEs), we investigated the impact of pretreatment DPYD genotyping on AEs in a Canadian context. Patients referred for DPYD genotyping prior to fluoropyrimidine treatment were enrolled from December 2013 through November 2019 and followed until completion of fluoropyrimidine treatment. Patients were genotyped for DPYD c.1905+1G>A, c.2846A>T, c.1679T>G, and c.1236G>A. Genotype-guided dosing recommendations were informed by Clinical Pharmacogenetics Implementation Consortium guidelines. The primary outcome was the proportion of patients who experienced a severe fluoropyrimidine-related AE (grade >/=3, Common Terminology Criteria for Adverse Events version 5.0). Secondary outcomes included early severe AEs, severe AEs by toxicity category, discontinuation of fluoropyrimidine treatment due to AEs, and fluoropyrimidine-related death. Among 1394 patients, mean (SD) age was 64 (12) years, 764 (54.8%) were men, and 47 (3.4%) were DPYD variant carriers treated with dose reduction. Eleven variant carriers (23%) and 418 (31.0%) noncarriers experienced a severe fluoropyrimidine-related AE (p = 0.265). Six carriers (15%) and 284 noncarriers (21.1%) experienced early severe fluoropyrimidine-related AEs (p = 0.167). DPYD variant carriers treated with genotype-guided dosing did not experience an increased risk for severe AEs. Our data support a role for DPYD genotyping in the use of fluoropyrimidines in North America. CI - (c) 2021 The Authors. Clinical and Translational Science published by Wiley Periodicals LLC on behalf of the American Society for Clinical Pharmacology and Therapeutics. FAU - Wigle, Theodore J AU - Wigle TJ AD - Department of Physiology and Pharmacology, University of Western Ontario, London, Canada. FAU - Povitz, Brandi L AU - Povitz BL AD - Lawson Health Research Institute, London, Canada. FAU - Medwid, Samantha AU - Medwid S AD - Department of Physiology and Pharmacology, University of Western Ontario, London, Canada. AD - Department of Medicine, University of Western Ontario, London, Canada. FAU - Teft, Wendy A AU - Teft WA AD - Department of Medicine, University of Western Ontario, London, Canada. FAU - Legan, Robin M AU - Legan RM AD - Department of Medicine, University of Western Ontario, London, Canada. FAU - Lenehan, John AU - Lenehan J AD - Department of Oncology, University of Western Ontario, London, Canada. FAU - Nevison, Stephanie AU - Nevison S AD - School of Medicine, University of Toronto, Mississauga, Canada. FAU - Panuganty, Veera AU - Panuganty V AD - Department of Oncology, University of Western Ontario, London, Canada. FAU - Keller, Denise AU - Keller D AD - London Health Sciences Centre, London, Canada. FAU - Mailloux, Jaymie AU - Mailloux J AD - Department of Physiology and Pharmacology, University of Western Ontario, London, Canada. AD - Department of Medicine, University of Western Ontario, London, Canada. FAU - Siebring, Victoria AU - Siebring V AD - London Health Sciences Centre, London, Canada. FAU - Sarma, Sisira AU - Sarma S AD - Department of Epidemiology and Biostatistics, University of Western Ontario, London, Canada. FAU - Choi, Yun-Hee AU - Choi YH AD - Department of Epidemiology and Biostatistics, University of Western Ontario, London, Canada. FAU - Welch, Stephen AU - Welch S AD - Department of Oncology, University of Western Ontario, London, Canada. FAU - Winquist, Eric AU - Winquist E AD - Department of Oncology, University of Western Ontario, London, Canada. FAU - Schwarz, Ute I AU - Schwarz UI AD - Department of Medicine, University of Western Ontario, London, Canada. FAU - Kim, Richard B AU - Kim RB AD - Department of Physiology and Pharmacology, University of Western Ontario, London, Canada. AD - Department of Medicine, University of Western Ontario, London, Canada. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20210223 PL - United States TA - Clin Transl Sci JT - Clinical and translational science JID - 101474067 RN - 0 (Antimetabolites, Antineoplastic) RN - 6804DJ8Z9U (Capecitabine) RN - EC 1.3.1.2 (Dihydrouracil Dehydrogenase (NADP)) RN - U3P01618RT (Fluorouracil) SB - IM MH - Aged MH - Antimetabolites, Antineoplastic/administration & dosage/*adverse effects/pharmacokinetics MH - Canada MH - Capecitabine/administration & dosage/adverse effects/pharmacokinetics MH - Dihydropyrimidine Dehydrogenase Deficiency/*diagnosis/genetics MH - Dihydrouracil Dehydrogenase (NADP)/*genetics/metabolism MH - Female MH - Fluorouracil/administration & dosage/adverse effects/pharmacokinetics MH - Heterozygote MH - Humans MH - Male MH - Medical Oncology/standards MH - Middle Aged MH - Neoplasms/*drug therapy/genetics MH - Pharmacogenomic Testing/standards MH - Pharmacogenomic Variants MH - Practice Guidelines as Topic MH - Precision Medicine/standards/statistics & numerical data MH - Retrospective Studies PMC - PMC8301551 COIS- The authors declared no competing interests for this work. EDAT- 2021/02/24 06:00 MHDA- 2022/02/15 06:00 PMCR- 2021/07/01 CRDT- 2021/02/23 08:40 PHST- 2020/12/08 00:00 [revised] PHST- 2020/12/08 00:00 [received] PHST- 2020/12/13 00:00 [accepted] PHST- 2021/02/24 06:00 [pubmed] PHST- 2022/02/15 06:00 [medline] PHST- 2021/02/23 08:40 [entrez] PHST- 2021/07/01 00:00 [pmc-release] AID - CTS12981 [pii] AID - 10.1111/cts.12981 [doi] PST - ppublish SO - Clin Transl Sci. 2021 Jul;14(4):1338-1348. doi: 10.1111/cts.12981. Epub 2021 Feb 23.