Review
Health Care Sciences & Services
Woorim Kim, Young-Ah Cho, Dong-Chul Kim, Kyung-Eun Lee
Summary: This study aimed to evaluate the risk of fluoropyrimidine-associated toxicity in patients with DPYD rs1801160 polymorphism. The systematic literature review and meta-analysis revealed an association between rs1801160 polymorphism and fluoropyrimidine-associated toxicity.
JOURNAL OF PERSONALIZED MEDICINE
(2022)
Article
Pharmacology & Pharmacy
Paula Soria-Chacartegui, Gonzalo Villapalos-Garcia, Luis A. Lopez-Fernandez, Marcos Navares-Gomez, Gina Mejia-Abril, Francisco Abad-Santos, Pablo Zubiaur
Summary: DPYD gene polymorphism can help predict toxicity in cancer patients treated with fluoropyrimidines, but its current predictive capacity is limited due to unknown mutations affecting enzyme function. Variant rs367619008, rs200643089, and rs76387818 were found to increase the percentage of explained toxicities, while further studies are needed to confirm the clinical relevance of variant rs944174134.
Article
Pharmacology & Pharmacy
Ursina B. M. Begre, Markus Jorger, Stefan Aebi, Ursula Amstutz, Carlo R. Largiader
Summary: Despite policies introduced for pre-treatment testing of DPYD gene risk variants in Switzerland, there was no significant increase in testing requests until the release of recommendations by the European Medicines Agency in April 2020, leading to a 14-fold increase in DPYD testing.
FRONTIERS IN PHARMACOLOGY
(2022)
Review
Oncology
K. Hodroj, D. Barthelemy, J-C Lega, G. Grenet, M-C Gagnieu, T. Walter, J. Guitton, L. Payen-Gay
Summary: Fluoropyrimidine-based chemotherapies are widely used to treat various cancers, but may cause toxicities, hence EMA recommends DPD testing before treatment. Different assays, including direct phenotyping, indirect phenotyping, and genotyping, are used to predict DPD deficiency.
Article
Oncology
Kyoin Koo, Amy L. Pasternak, N. Lynn Henry, Vaibhav Sahai, Daniel L. Hertz
Summary: This study describes the current practice of pretreatment DPYD testing in the United States and identifies factors deterring oncologists from ordering testing. The results show that the clinical adoption of pretreatment DPYD testing is extremely limited in the United States, with low prevalence of DPD deficiency and lack of clinical practice guideline recommendations being the main barriers.
JCO ONCOLOGY PRACTICE
(2022)
Review
Pharmacology & Pharmacy
Jonathan E. Knikman, Hans Gelderblom, Jos H. Beijnen, Annemieke Cats, Henk-Jan Guchelaar, Linda M. Henricks
Summary: Fluoropyrimidines are widely used in the treatment of solid tumors, but severe toxicity can occur in a significant percentage of patients. Individualized dosing strategies, including upfront genotyping of the DPYD gene, monitoring of DPD enzyme activity, and pharmacokinetically guided follow-up of 5-FU, have shown promise in reducing toxicity. Baseline characteristics such as sex, age, body composition, and renal function also play a role in predicting severe toxicity and should be considered in dose-individualization strategies.
CLINICAL PHARMACOLOGY & THERAPEUTICS
(2021)
Review
Oncology
Bhavina B. Sharma, Karan Rai, Heather Blunt, Wenyan Zhao, Tor D. Tosteson, Gabriel A. Brooks
Summary: This study systematically evaluated the risk of treatment-related death associated with DPYD gene variants during fluoropyrimidine chemotherapy, and found that patients with pathogenic DPYD gene variants have a significantly increased risk of treatment-related death.
Article
Oncology
Daniel L. L. Hertz
Summary: This article calls for clinicians and clinical guidelines committees in the United States to re-evaluate the clinical utility of pretreatment DPYD testing. There is no direct evidence of efficacy reduction, and the available indirect evidence suggests that DPYD-guided FP dosing is well calibrated and minimizes the risk of reducing treatment efficacy.
JOURNAL OF CLINICAL ONCOLOGY
(2022)
Article
Oncology
Mirjam de With, Gemma Brufau, Laila A. van den Berg, Femke M. de Man, Marija Trajkovic, Martine F. Thijs, Rob Castel, Henricus J. Vermeer, Samira el Bouazzaoui, Amber van Hemel, Maja Matic, Ron H. J. Mathijssen, Sander Bins, Ron H. N. van Schaik
Summary: The study confirms that 46% of patients carrying the DPYD*7 variant allele develop severe treatment-related adverse events, even with initial dose reductions. This highlights the need for prospective studies to investigate the required fluoropyrimidine dose for DPYD*7 carriers.
JCO PRECISION ONCOLOGY
(2022)
Article
Oncology
Claire Palles, Susan Fotheringham, Laura Chegwidden, Marie Lucas, Rachel Kerr, Guy Mozolowski, Dan Rosmarin, Jenny C. Taylor, Ian Tomlinson, David Kerr
Summary: 5-Fluorouracil (5-FU) is a chemotherapy drug that can cause severe toxicity in some patients, due to variations in a protein called dihydropyrimidine dehydrogenase (DPD) impacting the clearance of the drug. This study aims to assess the frequency of DPD deficiency variants in patients and their predictive value for 5-FU induced toxicity, providing important insights for identifying high-risk patients and optimizing treatment strategies. Genotyping specific alleles can significantly improve the accuracy of predicting adverse events associated with 5-FU chemotherapy.
Article
Biochemistry & Molecular Biology
Ottavia De Luca, Gerardo Salerno, Donatella De Bernardini, Maria Simona Torre, Maurizio Simmaco, Luana Lionetto, Giovanna Gentile, Marina Borro
Summary: NGS exon sequencing can explain approximately 42.5% of DPD deficiencies, significantly improving the prediction of DPD deficiencies, but more genotype-phenotype association data is needed for clinical use.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2022)
Article
Pharmacology & Pharmacy
Eiji Hishinuma, Yoko Narita, Kai Obuchi, Akiko Ueda, Sakae Saito, Shu Tadaka, Kengo Kinoshita, Masamitsu Maekawa, Nariyasu Mano, Noriyasu Hirasawa, Masahiro Hiratsuka
Summary: In this study, an in vitro analysis was conducted on 41 DPD allelic variants to investigate changes in enzymatic activity, with 7 variants showing significantly decreased activity and 2 variants displaying no enzymatic activity. Our findings suggest that DPD dimerization is essential for enzymatic activity and these variants may contribute to the observed inter-individual variability in the pharmacokinetics and pharmacodynamics of 5-FU. Additionally, rare DPYD variants, although at low frequencies, could serve as important pharmacogenomic markers associated with severe 5-FU toxicity in the Japanese population.
FRONTIERS IN PHARMACOLOGY
(2022)
Review
Pharmacology & Pharmacy
Lucija Lesnjakovic, Lana Ganoci, Ivan Bilic, Livija Simicevic, Iva Mucalo, Stjepko Plestina, Nada Bozina
Summary: FPs are widely used antineoplastic drugs for solid tumors treatment, but they can cause severe toxicity, especially in patients with reduced DPD activity. European agencies recommend pre-treatment DPD deficiency screening, but American ones do not. Current guidelines recommend testing four DPD gene risk variants, but new evidence on additional common DPYD polymorphisms and rare DPYD variants may help address the missing heritability of DPD deficiency and FP-related toxicity.
Article
Pharmacology & Pharmacy
Nada Bozina, Ivan Bilic, Lana Ganoci, Livija Simicevic, Stjepko Plestina, Lucija Lesnjakovic, Vladimir Trkulja
Summary: Pathologists found that DPYD c.496A>G and possibly c.2194G>A variants may need to be considered for inclusion in the DPYD genotyping panel.
BRITISH JOURNAL OF CLINICAL PHARMACOLOGY
(2022)
Review
Oncology
Sarah Glewis, Marliese Alexander, Muhammad N. H. Khabib, Annabelle Brennan, Smaro Lazarakis, Jennifer Martin, Jeanne Tie, Senthil Lingaratnam, Michael Michael
Summary: Pharmacogenetics Guided Dosing (PGD) improves treatment outcomes by reducing the incidence of toxicities, particularly overall toxicity and diarrhea, without impacting treatment response in patients receiving 5-fluorouracil/capecitabine therapy.
BRITISH JOURNAL OF CANCER
(2022)