DPYD and UGT1A1 Pharmacogenetic Testing in Patients with Gastrointestinal Malignancies: An Overview of the Evidence and Considerations for Clinical Implementation

Abstract

Gastrointestinal (GI) malignancies are among the most commonly diagnosed cancers worldwide. Despite the introduction of targeted and immunotherapy agents in the treatment landscape, cytotoxic agents, such as fluoropyrimidines and irinotecan, remain as the cornerstone of chemotherapy for many of these tumors. Pharmacogenetics (PGx) is a rapidly evolving field that accounts for interpatient variability in drug metabolism to predict therapeutic response and toxicity. Given the significant incidence of severe treatment-related adverse events associated with cytotoxic agents, utilizing PGx can allow clinicians to better anticipate drug tolerability while minimizing treatment interruptions or delays. In this review, the PGx profiles of drug-gene pairs with potential impact in GI malignancy therapy-DPYD-5-fluorouracil/capecitabine and UGT1A1-irinotecanand the available clinical evidence of their roles in reducing severe adverse events are discussed. Considerations for clinical implementation, such as optimal laboratory workflows, electronic health record integration, and stakeholder engagement, as well as provider education, are addressed. Last, exploratory PGx markers in GI malignancy treatment are described. As the PGx knowledge base rapidly evolves, pharmacists will be vital in leveraging their pharmacology knowledge and clinical skills to implement PGx testing in the clinic.

Clinical Implementation of DPYD Pharmacogenetic Testing to Prevent Early-Onset Fluoropyrimidine-Related Toxicity in Cancer Patients in Switzerland

“…For three cases, it took more than 7 days (five working days) to report the result including an average “time to lab” of 2.0 days (range 0–7 days) and an “internal TAT” of 1.1 day (range 0–6 days). A TAT of 7 days is considered to be adequate to avoid therapy delays ( Henricks et al, 2018 ; Hamzic et al, 2020 ; Varughese et al, 2020 ; Jolivet et al, 2021 ). For the 97 requests indicating a planned therapy start, 77.3% of the reports ( n = 75) were returned to the ordering institution before planned therapy start or on the same day.…”

Implementing DPYD*2A Genotyping in Clinical Practice: The Quebec, Canada, Experience

“…DPYD*2A mutation is associated with significant decrease in the DPD enzyme activity. Other DPYD variants have different prevalence in other populations and variable impact on enzyme activity, as some can cause only 25% decrease, associated with variable toxicity profile [17]. Combined, detection rate might increase, and further toxicities can be prevented.…”

“…Several trials assessed the feasibility of DPD phenotyping using different methods, either by measuring the DPD enzyme activity in peripheral blood mononuclear cells or by measuring the uracil or its metabolite dihydrouracil concentrations in plasma or urine [17,19,20]. It should be noted that despite the high sensitivity of the DPD enzymatic activity method to detect all cases of enzyme deficiency, it is technically delicate, and interpretation requires the determination and the validation of threshold values of enzyme activity to distinguish DPD-deficient patients from normal ones.…”

Ethnic Diversity of DPD Activity and the DPYD Gene: Review of the Literature

“… 1 , 9 Between 3% and 5% of the people are partially DPD deficient within the Caucasian populations, and 0.02% are totally deficient. 10 , 11 …”