Implementation of DPYD and UGT1A1 Testing in Patients With GI Cancer: A Prospective, Nonrandomized Clinical Trial

Abstract

Purpose: To determine the feasibility and effectiveness of implementing pretreatment DPYD/UGT1A1 testing in patients with gastrointestinal cancer and its impact compared with a biobank population.

Materials and methods: A prospective, nonrandomized implementation trial of pretreatment DPYD/UGT1A1 testing with preemptive dose reduction was conducted in patients initiating treatment with a fluoropyrimidine (FP, [fluorouracil or capecitabine]) or irinotecan. The primary end point was feasibility, defined as proportion of results available prior to cycle 1 of treatment. Secondarily, occurrence of severe treatment-related adverse events (TRAEs), defined as toxicity resulting in hospitalization or emergency department visit, was compared with a biobank population receiving standard dose chemotherapy.

Results: Of the 288 patients prospectively tested, 225 (median age 60.7 years, 54% male, 18% Black, 47% colorectal cancer) received a qualifying chemotherapy. Eight of 11 DPYD variant carriers received an FP and eight of 39 UGT1A1 poor metabolizers received irinotecan. The median test turnaround time was 10 days (IQR, 9-13) with 57.4% of results available before cycle 1. Eleven of 16 (69%) participants with a drug-gene interaction (DGI) had results available before chemotherapy initiation and received pharmacogenetic-recommended dose reductions. Compared with the biobank cohort (n = 229), the prospective DGI group experienced fewer severe TRAEs (38% v 65%, P = .123), treatment discontinuations (31% v 47%, P = .356), and treatment modifications (38% v 76%, P = .028).

Conclusion: Pretreatment DPYD/UGT1A1 testing and dose reduction was feasible, enabling clinicians to make the appropriate chemotherapy dose reductions, reducing occurrence of adverse outcomes. DPYD/UGT1A1 testing is an important precision oncology approach to optimize patient safety.

FIG 1.

Application of the (EPIS) framework for the implementation of DPYD/UGT1A1 testing in GI cancer. EPIS is an implementation science framework used to guide and measure the success of implementing a new evidence-based practice. In the baseline period, which included both exploration and preparation stages, we assessed institutional needs for the service, stakeholder buy-in, and developed strategies needed to overcome identified barriers. During the implementation phase, educational sessions were presented to GI clinicians, and patients were enrolled into the study to receive testing. We are currently in the sustainment phase and continue to make process improvements to improve the testing workflow, with the goal of expanding to all oncology care sites within our health care system. CDS, Clinical Decision Support; CLIA, Clinical Laboratory Improvement Amendments; DGI, drug-gene interaction; EHR, electronic health record; EPIS, Exploration, Preparation, Implementation, and Sustainment; FDA, US Food and Drug Administration; FP, fluoropyrimidine; NCCN, National Comprehensive Cancer Network; PGx, pharmacogenetic.

FIG 2.

IMPACT-GI participant enrollment and exclusion reasons. Between March 2021 and December 2022, 1,299 patients were screened for eligibility. Of these, 356 patients met the study inclusion criteria, and 315 patients were enrolled for the trial. We genotyped 288 patients and identified 11 (3.8%) DPYD variant carriers and 39 (13.5%) UGT1A1 poor metabolizers. Patients were further excluded from analysis because of various reasons including changes in their treatment plan to no longer including a fluoropyrimidine or irinotecan (6.7%) or patient transferred oncology treatment to another institution (6.0%). Patients who were ordered PGx testing after their first cycle of chemotherapy (ie, confirmatory testing) because of clinician request were also excluded from the final analysis (6.3%). ^aOne of the three participants withdrawn was lost to follow-up after the participant did not attend any subsequent oncology appointments after cycle one for unknown reasons. DGI, drug-gene interaction; PGx, pharmacogenetic.