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DPYD and UGT1A1 Pharmacogenetic Testing in Patients with Gastrointestinal Malignancies: An Overview of the Evidence
Lisa A Varughese1, Kelsey S Lau-Min2, Christine Cambareri3
1Division of Translational Medicine and Human Genetics, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
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-irinotecan - and 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.
Insights
Pharmacogenetics (PGx) can personalize chemotherapy for gastrointestinal (GI) cancers. PGx testing for DPYD and UGT1A1 gene variants helps predict patient response to 5-fluorouracil, capecitabine, and irinotecan, reducing severe adverse events.
Area of Science:
- Oncology
- Pharmacogenetics
- Genomics
Background:
- Gastrointestinal (GI) malignancies are common worldwide.
- Cytotoxic chemotherapy agents like fluoropyrimidines and irinotecan are standard treatments.
- Severe treatment-related adverse events are a significant concern with these agents.
Purpose of the Study:
- To review the role of pharmacogenetics (PGx) in optimizing chemotherapy for GI malignancies.
- To discuss specific drug-gene pairs (DPYD-5-fluorouracil/capecitabine and UGT1A1-irinotecan) and their clinical evidence.
- To address considerations for implementing PGx testing in clinical practice.
Main Methods:
- Review of existing literature on pharmacogenetics in GI cancer therapy.
- Analysis of clinical evidence for DPYD and UGT1A1 gene variants impacting drug toxicity.
- Discussion of practical aspects of PGx implementation.
Main Results:
- Pharmacogenetic profiles, particularly DPYD and UGT1A1, can predict patient response and toxicity to key chemotherapy drugs.
- Evidence supports the use of PGx to reduce severe adverse events associated with 5-fluorouracil, capecitabine, and irinotecan.
- Exploratory PGx markers also show potential in GI cancer treatment.
Conclusions:
- Pharmacogenetics offers a valuable tool for personalizing chemotherapy in GI malignancies.
- Clinical implementation requires attention to laboratory workflows, EHR integration, and education.
- Pharmacists play a crucial role in integrating PGx testing into routine care.
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