TY - JOUR
T1 - Pharmacogenetic-guided dosing for fluoropyrimidine (DPYD) and irinotecan (UGT1A1*28) chemotherapies for patients with cancer (PACIFIC-PGx)
T2 - A multicenter clinical trial
AU - Glewis, Sarah
AU - Lingaratnam, Senthil
AU - Lee, Benjamin
AU - Campbell, Ian
AU - IJzerman, Maarten
AU - Fagery, Mussab
AU - Harris, Sam
AU - Georgiou, Chloe
AU - Underhill, Craig
AU - Warren, Mark
AU - Campbell, Robert
AU - Jayawardana, Madawa
AU - Silva, S. Sandun M.
AU - Martin, Jennifer H.
AU - Tie, Jeanne
AU - Alexander, Marliese
AU - Michael, Michael
N1 - Publisher Copyright:
© 2024 The Author(s). Clinical and Translational Science published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.
PY - 2024/12
Y1 - 2024/12
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85211244052&partnerID=8YFLogxK
U2 - 10.1111/cts.70083
DO - 10.1111/cts.70083
M3 - Article
C2 - 39614408
AN - SCOPUS:85211244052
SN - 1752-8054
VL - 17
JO - Clinical and Translational Science
JF - Clinical and Translational Science
IS - 12
M1 - e70083
ER -