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

Glewis, S; Lingaratnam, S; Lee, B; Campbell, I; IJzerman M; Fagery, M; Harris, S; Georgiou, C; Underhill, C; Warren, M; Campbell, R; Jayawardana, M; Silva, SSM; Martin, JH; Tie, J; Alexander, M; Michael, M

Author(s): Glewis, S; Lingaratnam, S; Lee, B; Campbell, I; IJzerman M; Fagery, M; Harris, S; Georgiou, C; Underhill, C; Warren, M; Campbell, R; Jayawardana, M; Silva, SSM; Martin, JH; Tie, J; Alexander, M; Michael, M;
Details: Publication Year 2024-12,Volume 17,Issue #12,Page e70083
Journal Title: Clinical and Translational Science
Abstract: 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.
Publisher: Wiley
Keywords: Humans; *Glucuronosyltransferase/genetics; Male; *Irinotecan/administration & dosage/adverse effects; Middle Aged; Female; Aged; *Neoplasms/drug therapy/genetics; Adult; *Dihydrouracil Dehydrogenase (NADP)/genetics; *Antineoplastic Combined Chemotherapy Protocols/administration & dosage/adverse; effects; Prospective Studies; *Pharmacogenomic Testing; Pharmacogenomic Variants; Feasibility Studies; Genotype; Australia; Fluorouracil/administration & dosage/adverse effects; Aged, 80 and over; Young Adult
Research Division(s): Personalised Oncology
PubMed ID: 39614408
Publisher's Version: https://doi.org/10.1111/cts.70083
Open Access at Publisher's Site: https://doi.org/ 10.1111/cts.70083.
Terms of Use/Rights Notice: Refer to copyright notice on published article.

Creation Date: 2024-12-05 11:26:32

Last Modified: 2024-12-05 01:09:45