Pharmacogenetic-guided dosing for fluoropyrimidine (DPYD) and irinotecan (UGT1A1*28) chemotherapies for patients with cancer (PACIFIC-PGx): A multicenter clinical trial.

Autor: Glewis S; Department of Pharmacy, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia.; Sir Peter MacCallum Department of Oncology, University of Melbourne, Parkville, Victoria, Australia., Lingaratnam S; Department of Pharmacy, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia., Lee B; Department of Pharmacy, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia., Campbell I; Sir Peter MacCallum Department of Oncology, University of Melbourne, Parkville, Victoria, Australia.; Cancer Genetics Laboratory, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia., IJzerman M; Sir Peter MacCallum Department of Oncology, University of Melbourne, Parkville, Victoria, Australia.; Cancer Health Services Research Unit, Centre for Cancer Research, Faculty of Medicine, Dentistry and Health Sciences, University of Melbourne, Parkville, Victoria, Australia.; Cancer Health Services Research Unit, Centre for Health Policy, Melbourne School of Population and Global Health, Faculty of Medicine, Dentistry and Health Sciences, University of Melbourne, Parkville, Victoria, Australia.; Erasmus School of Health Policy and Management, Erasmus University Rotterdam, Rotterdam, The Netherlands., Fagery M; Cancer Health Services Research Unit, Centre for Cancer Research, Faculty of Medicine, Dentistry and Health Sciences, University of Melbourne, Parkville, Victoria, Australia.; Cancer Health Services Research Unit, Centre for Health Policy, Melbourne School of Population and Global Health, Faculty of Medicine, Dentistry and Health Sciences, University of Melbourne, Parkville, Victoria, Australia., Harris S; Department of Medical Oncology, Bendigo Health, Bendigo, Victoria, Australia., Georgiou C; Department of Medical Oncology, Bendigo Health, Bendigo, Victoria, Australia., Underhill C; VCCC Alliance, Parkville, Victoria, Australia.; Border Medical Oncology Research Unit, Albury Wodonga Regional Cancer Centre, East Albury, New South Wales, Australia.; UNSW Rural Medical School, Albury Campus, New South Wales, East Albury, Australia., Warren M; Department of Medical Oncology, Bendigo Health, Bendigo, Victoria, Australia., Campbell R; Department of Medical Oncology, Bendigo Health, Bendigo, Victoria, Australia., Jayawardana M; Sir Peter MacCallum Department of Oncology, University of Melbourne, Parkville, Victoria, Australia.; Office of Cancer Research, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia., Silva SSM; Centre for Health Systems and Safety Research, Australian Institute of Health Innovation, Macquarie University, Macquarie Park, New South Wales, Australia., Martin JH; School of Medicine and Public Health, University of Newcastle, Callaghan, New South Wales, Australia., Tie J; Sir Peter MacCallum Department of Oncology, University of Melbourne, Parkville, Victoria, Australia.; Department of Medical Oncology, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia.; Personalised Oncology Division, Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia., Alexander M; Department of Pharmacy, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia.; Sir Peter MacCallum Department of Oncology, University of Melbourne, Parkville, Victoria, Australia., Michael M; Sir Peter MacCallum Department of Oncology, University of Melbourne, Parkville, Victoria, Australia.; Department of Medical Oncology, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia.
Jazyk: angličtina
Zdroj: Clinical and translational science [Clin Transl Sci] 2024 Dec; Vol. 17 (12), pp. e70083.
DOI: 10.1111/cts.70083
Abstrakt: PACIFIC-PGx evaluated the feasibility of implementing pharmacogenetics (PGx) screening in Australia and the impact of DPYD/UGT1A1 genotype-guided dosing on severe fluoropyrimidine (FP) and irinotecan-related toxicities and hospitalizations, compared to historical controls. This prospective single arm trial enrolled patients starting FP/irinotecan for any cancer between 7 January 2021 and 25 February 2022 from four Australian hospitals (one metropolitan, three regional). During the accrual period, 462/487 (95%) consecutive patients screened for eligibility for DPYD and 50/109 (46%) for UGT1A1 were enrolled and genotyped (feasibility analysis), with 276/462 (60%) for DPYD and 30/50 (60%) for UGT1A1 received FP/irinotecan (safety analysis). DPYD genotyping identified 96% (n = 443/462) Wild-Type, 4% (n = 19/462) Intermediate Metabolizers (50% dose reduction), and 0% Poor Metabolizers. UGT1A1 genotyping identified 52% (n = 26/50) Wild-Type, 40% (n = 20/50) heterozygous, and 8% (n = 4/50) homozygous (30% dose reduction). Key demographics for the FP/irinotecan safety cohorts included: age range 23-89/34-74 years, male 56%/73%, Caucasian 83%/73%, lower gastrointestinal cancer 50%/57%. Genotype results were reported prior to cycle-1 (96%), average 5-7 days from sample collection. PGx-dosing for DPYD variant allele carriers reduced high-grade toxicities compared to historic controls (7% vs. 39%; OR = 0.11, 95% CI 0.01-0.97, p = 0.024). High-grade toxicities among Wild-Type were similar (14% vs. 14%; OR = 0.99, 95% CI 0.64-1.54, p = 0.490). PGx-dosing reduced FP-related hospitalizations (-22%) and deaths (-3.7%) compared to controls. There were no high-grade toxicities or hospitalizations for UGT1A1*28 homozygotes. PGx screening and prescribing were feasible in routine oncology care and improved patient outcomes. Findings may inform expanded PGx programs within cancer and other disease settings.
(© 2024 The Author(s). Clinical and Translational Science published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.)
Databáze: MEDLINE
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