Pre-emptive <i>DPYD</i> genotyping and fluoropyrimidine dose optimisation: Dose tolerance and survival in cancer patients

Introduction Despite evidence for dose reductions in DPYD variant allele carriers; efficacy concerns remain; we examined survival and dose tolerance in Australian fluoropyrimidine (FP) treated patients. Methods Data originated from the multi-centre PACIFIC-PGx trial (ANZCTR 12621000251820), where DPYD variant allele carriers started at a reduced FP dose with clinical up-titration, and wild-type received full dose. Dose titrations were recorded over 6-cycles, with survival and response assessed at 6 and 12-months, and at study end (12-months post last enrolment). Results This analysis included 169 (96.0%) wild-type and 7 (4.0%) DPYD variant allele carriers. Among the seven variant allele carriers, all commenced FP with a reduced dose, including five receiving curative treatment. Despite experiencing only grade 0–1 toxicity, four patients/clinicians declined subsequent dose escalation. One patient discontinued treatment due to grade 3-4 toxicities. Of three patients titrated, maximum doses achieved were 57%, 70% and 112%. Overall response rate was 40.0% (68/170) at 6-months and 36.6% (63/172) at 12-months among evaluable patients. The overall survival (OS) rate was 83.0% (146/176) at 6-months and 71.0% (125/176) at 12-months. In WT, OS rate was 82.2% (139/169) and 70.4% (119/169), and in DPYD variant allele carriers 100.0% (7/7) and 85.7% (6/7) at 6 and 12-months, respectively. Conclusions Although limited by the small number of DPYD variant allele carriers, OS rates in this heterogeneous cohort were broadly consistent with larger studies, with no signal suggesting that upfront dose reductions compromised efficacy in this small sample. However, prospective larger statistically powered studies are needed to confirm these findings. Dose escalations among carriers were inconsistent, underscoring the need for greater clinician and patient guidance and education in real-world dosing decisions.