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Published on: September 20, 2016
DPYD genotyping and predicting fluoropyrimidine toxicity: where do we stand?
Lucija Lešnjaković1, Lana Ganoci2, Ivan Bilić1,3
1Department of Oncology, University Hospital Centre Zagreb, Zagreb, Croatia.
Abstract:
Fluoropyrimidines (FPs) are antineoplastic drugs widely used in the treatment of various solid tumors. Nearly 30% of patients treated with FP chemotherapy experience severe FP-related toxicity, and in some cases, toxicity can be fatal. Patients with reduced activity of DPD, the main enzyme responsible for the breakdown of FP, are at an increased risk of experiencing severe FP-related toxicity. While European regulatory agencies and clinical societies recommend pre-treatment DPD deficiency screening for patients starting treatment with FPs, this is not the case with American ones. Pharmacogenomic guidelines issued by several pharmacogenetic organizations worldwide recommend testing four DPD gene (DPYD) risk variants, but these can predict only a proportion of toxicity cases. New evidence on additional common DPYD polymorphisms, as well as identification and functional characterization of rare DPYD variants, could partially address the missing heritability of DPD deficiency and FP-related toxicity.
Insights
Fluoropyrimidine chemotherapy can cause severe toxicity due to DPD deficiency. Genetic testing of the DPYD gene for variants can help predict and prevent these life-threatening reactions in patients.
Area of Science:
- Oncology
- Pharmacogenomics
- Clinical Chemistry
Background:
- Fluoropyrimidines (FPs) are crucial antineoplastic drugs for solid tumors.
- Severe fluoropyrimidine toxicity affects up to 30% of patients, sometimes fatally.
- Dihydropyrimidine dehydrogenase (DPD) deficiency is a major risk factor for FP toxicity.
Purpose of the Study:
- To highlight the clinical need for DPD deficiency screening in FP chemotherapy.
- To discuss current pharmacogenomic guidelines and their limitations.
- To explore novel genetic variants in the DPYD gene for improved toxicity prediction.
Main Methods:
- Review of current clinical practice and regulatory recommendations for DPD screening.
- Analysis of existing pharmacogenomic guidelines for DPYD variant testing.
- Discussion of emerging research on common and rare DPYD polymorphisms.
Main Results:
- European agencies recommend DPD screening, but American agencies do not.
- Current DPYD variant testing predicts only a portion of FP toxicity.
- New common polymorphisms and rare variants in DPYD show promise for explaining missing heritability.
Conclusions:
- Improved DPD deficiency screening is essential for safe FP chemotherapy.
- Expanded genetic testing of the DPYD gene is needed to identify more patients at risk.
- Further research into DPYD variants can enhance personalized cancer treatment strategies.
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