Evaluation of Clinical Implementation of Prospective
            <i>DPYD</i>
            Genotyping in 5-Fluorouracil- or Capecitabine-Treated Patients

Lunenburg, Carin A.T.C.; Staveren, Maurice C. van; Gelderblom, Hans; Guchelaar, Henk‐Jan; Swen, Jesse J.

doi:10.2217/pgs-2016-0013

Cited by 29 publications

(21 citation statements)

References 16 publications

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“…Several gene/drug examples have been described for decades, 1 with various degrees of implementation across oncology institutions and practices. [42][43][44] We used a previously published method 19 to critically assess the vast number of germline pharmacogenomic studies about oncology drugs. It is noteworthy that the majority of drugs have had positive pharmacogenomic associations described about them (67 of the 125 drugs), with published associations for 12 drugs withstanding rigorous evidence standards required for clinical actionability.…”

Section: Discussionmentioning

confidence: 99%

Analyzing the clinical actionability of germline pharmacogenomic findings in oncology

Wellmann

Borden

Danahey

et al. 2018

Cancer

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Section: Discussionmentioning

confidence: 99%

Analyzing the clinical actionability of germline pharmacogenomic findings in oncology

Wellmann

Borden

Danahey

et al. 2018

Cancer

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“…Although the pharmacogenetics guidelines for the management of FL-based chemotherapy toxicity in colorectal cancer agree upon the clinical validity of DPYD*2A DPYD*13, c.2846A>T and c.1236G>A-HapB3, a pre-emptive genotyping to avoid severe and unpredictable adverse drug reactions, translating such recommendations in the clinical practice remains a matter of open debate [21,22]. Prospective evidences of increased FL safety and efficacy when applying a DPYD*2A-guided dose reduction was reported, which strongly justify a drug label update limited to the well-known DPYD*2A variant [23,24].…”

Section: Discussionmentioning

confidence: 99%

DPYD gene activity score (GAS) predicts dose-limiting toxicity in fluoropyrimidine-treated colorectal cancer patients

2018

J. Mol. Clin. Med.

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Pre-treatment DPYD genotyping of a panel of 4-single nucleotide polymorphism (SNP) including DPYD*2A, DPYD*13, c.2846A>T and c.1236A>G-HapB3, has been strongly recommended by the current pharmacogenetics guidelines in order to avoid severe fluoropyrimidine (FL)-related toxicity. However, translation to clinical practice is still lagging behind. This requires a better definition of the relationship between genetic variants of DPYD and dose-limiting toxicities (DLTs) and development of new methods to investigate the effect of DPYD variants, such as the DPYD activity score. The aim of the current study was to support the clinical implementation of DPYD genetic testing, by assessing the relationship between DPYD variants in the 4-SNP panel and the risk to develop DLTs and by stratifying patients according to the DPYD gene activity score (GAS) model. (GAS = 1.0 if carriers of one DPYD*2A or DPYD*13 alleles and GAS = 1.5, if carriers of one c.2846A>T or c.1236G>A-HapB3 allele. Non-carriers GAS = 2.0). A retrospective population of 763 colorectal cancer patients treated with FL-based chemotherapy, was selected and genotyped. Patients carrying at least one decreased function DPYD variant in the 4-SNP panel, displayed a significant association with the risk of developing DLT (i.e. grade ≥ 3 non-hematological toxicity or grade ≥ 4 hematological toxicity) either within the first three cycles of chemotherapy (OR= 2.7, 95% CI = 1.33-5.41) or during the entire course of treatment (OR = 2.7, 95% CI = 1.42-5.04). Patients' GAS was found to better define the risk of DLT for both acute (GAS = 1.5, OR = 1.80, 95% CI = 0.78-4.15 and GAS = 1.0, OR = 10.12, 95% CI = 2.55-40.20) and total toxicity (GAS = 1.5, OR = 2.08, 95% CI = 1.02-4.27 and GAS = 1, OR = 7.09, 95% CI = 1.69-29.65). In conclusion, the present study demonstrates that the DPYD 4-SNP panel and the associated GAS can predict the occurrence of DLT related to treatment with FL. These findings further support the implementation of pre-emptive DPYD genotyping in the routine clinical practice.

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“…Among the studies with a DPYD-PGx/clinical monitoring combination, five out of eleven studies confirmed the importance of DPYD variants in predicting FP-related toxicity, although a too-short clinical monitoring was performed (only two treatment cycles) [21,23,29,31,39]. Two studies [24,34] analysed only DPYD*2A of the DPYD SNPs currently recommended.…”

Section: Systematic Reviewmentioning

confidence: 97%

A Genotyping/Phenotyping Approach with Careful Clinical Monitoring to Manage the Fluoropyrimidines-Based Therapy: Clinical Cases and Systematic Review of the Literature

Conti

Bellis

Manzo

et al. 2020

JPM

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Fluoropyrimidines (FP) are mainly metabolised by dihydropyrimidine dehydrogenase (DPD), encoded by the DPYD gene. FP pharmacogenetics, including four DPYD polymorphisms (DPYD-PGx), is recommended to tailor the FP-based chemotherapy. These polymorphisms increase the risk of severe toxicity; thus, the DPYD-PGx should be performed prior to starting FP. Other factors influence FP safety, therefore phenotyping methods, such as the measurement of 5-fluorouracil (5-FU) clearance and DPD activity, could complement the DPYD-PGx. We describe a case series of patients in whom we performed DPYD-PGx (by real-time PCR), 5-FU clearance and a dihydrouracil/uracil ratio (as the phenotyping analysis) and a continuous clinical monitoring. Patients who had already experienced severe toxicity were then identified as carriers of DPYD variants. The plasmatic dihydrouracil/uracil ratio (by high-performance liquid chromatography (HPLC)) ranged between 1.77 and 7.38. 5-FU clearance (by ultra-HPLC with tandem mass spectrometry) was measured in 3/11 patients. In one of them, it reduced after the 5-FU dosage was halved; in the other case, it remained high despite a drastic dosage reduction. Moreover, we performed a systematic review on genotyping/phenotyping combinations used as predictive factors of FP safety. Measuring the plasmatic 5-FU clearance and/or dihydrouracil/uracil (UH2/U) ratio could improve the predictive potential of DPYD-PGx. The upfront DPYD-PGx combined with clinical monitoring and feasible phenotyping method is essential to optimising FP-based chemotherapy.

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Evaluation of Clinical Implementation of Prospective DPYD Genotyping in 5-Fluorouracil- or Capecitabine-Treated Patients

Abstract: Prospective DPYD screening can be implemented successfully in a real world clinical setting, is well accepted by physicians and results in low toxicity.

Cited by 29 publications

References 16 publications

Analyzing the clinical actionability of germline pharmacogenomic findings in oncology

Analyzing the clinical actionability of germline pharmacogenomic findings in oncology

DPYD gene activity score (GAS) predicts dose-limiting toxicity in fluoropyrimidine-treated colorectal cancer patients

A Genotyping/Phenotyping Approach with Careful Clinical Monitoring to Manage the Fluoropyrimidines-Based Therapy: Clinical Cases and Systematic Review of the Literature

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