Atrium Health Levine Cancer
Charlotte, North Carolina
There is a 4-fold higher risk of fluoropyrimidine-related toxicity and a 25-fold higher risk of treatment-related mortality in patients carrying reduced or no-function genetic variants in DPYD, the gene encoding for the catabolic enzyme dihydropyrimidine dehydrogenase (DPD). We developed an in-house DPYD genotyping test to improve patient safety by mitigating fluoropyrimidine-related toxicities through identification of DPYD variant carriers and genotype-guided dose reductions.
In March 2020, DPYD genotyping was established as a standard of care test to those starting (pre-treatment testing) or continuing (reactive testing) fluoropyrimidine-based chemotherapy, per provider discretion. A multidisciplinary workflow was developed at each clinic where buccal swabs were collected by a pharmacist or nurse and transported to the in-house genomics laboratory where testing is performed twice weekly. A pharmacogenomics pharmacist reviews genotype results and communicates dose reduction recommendations for variant carriers, which are applied at the provider’s discretion. By 2022, testing increased drastically after expansion to 14 clinics and integration of discrete test results in the electronic medical record and clinical decision support (CDS). Alerts embedded within fluoropyrimidine order sets prompted either pre-testing recommendation for patients without documented DPYD results or post-testing dose modification for DPYD variant carriers.
From March 2020-May 2023, 757 patients across 14 oncology clinics received DPYD testing (median age 63; 54% male, 74% Caucasian, 19% African American, 88% gastrointestinal cancers). Median test turnaround time was 6 (IQR 3-7) days from sample collection to results. Pre-treatment testing was ordered in 621 (82%) patients, of whom 561 (90.3%) had results before treatment initiation. Among 136 (18%) reactive testing patients, 59 (43%) had specimens collected the same day of treatment start, most often due to patients not having a clinic visit between time of test ordering and treatment start. Overall, 45 patients (5.9%) were identified as heterozygous DPYD variant carriers; 5.2% among pre-treatment testing patients and 9.6% among reactive testing patients. All 27 (100%) pre-treatment carriers who started fluoropyrimidine-based chemotherapy received upfront dose reductions. Of 13 reactive testing carriers, nine (69.2%) received dose reductions upon result return. A subset of 442 patients with up to three months of follow-up data (those tested from March 2020-December 2022) were evaluated for toxicity outcomes. Fluoropyrimidine-related grade 3+ toxicities occurred in 31% of pretreatment carriers, 64% of reactive carriers, and 30% of wild-type patients (p=0.085). Fluoropyrimidine-related hospitalizations occurred in 25% of pretreatment carriers, 64% of reactive carriers, and 13% of wild-type patients (p<0.001). In multivariate analysis, reactive carriers had a nearly 10-fold higher odds of hospitalizations compared to wild-type patients (p=0.001), whereas no significant difference was noted between pre-treatment carriers and wild-type patients. Cumulative incidence curves showed a significantly higher and earlier risk of grade 3+ toxicities and hospitalizations in reactive carriers compared to pre-treatment carriers and wild-type (log-rank p-value <0.001).
We implemented a novel pharmacist-led DPYD testing program with CDS integration and demonstrated pre-treatment testing with genotype-guided fluoropyrimidine dosing improves patient safety by mitigating severe toxicities and hospitalizations in DPYD variant carriers.
References:
1 Morris SA, Moore DC, Musselwhite LW, et al. Addressing barriers to increased adoption of DPYD genotyping at a large multisite cancer center. Am J Health Syst Pharm. 2023;80(19):1342-1349.
2 Amstutz U, Henricks LM, Offer SM, et al. Clinical Pharmacogenetics Implementation Consortium (CPIC) Guideline for Dihydropyrimidine Dehydrogenase Genotype and Fluoropyrimidine Dosing: 2017 Update. Clin Pharmacol Ther. 2018;103(2):210-216.
3 Hertz DL. Assessment of the Clinical Utility of Pretreatment DPYD Testing for Patients Receiving Fluoropyrimidine Chemotherapy. J Clin Oncol. 2022;40(33):3882-3892.
Front Row, Left to Right: Jai N. Patel, Synthia Bethea, Sarah Hanson, Grace Nguyen
Second Row, Left to Right: Nury Steuerwald, Sarah Morris
Third Row, Left to Right: Donald C. Moore, Simeon Owuor, Katie Mroz
Fourth Row, Left to Right: James Symanowski, Mat Smith, Kunal Kadakia
Not pictured: Alicia Hamilton, Karine Eboli Lopes, Chris Larck, Laura Musselwhite, Brinda Koya, Seungjean Chai, Kwabena Osei-Boateng, Sini Kalapurakal, Kristen Swift, Jimmy Hwang