Clinical importance of risk variants in the dihydropyrimidine dehydrogenase gene for the prediction of early‐onset fluoropyrimidine toxicity

Froehlich, Tanja K.; Amstutz, Ursula; Aebi, Stefan; Joerger, Markus; Largiadèr, Carlo R.

doi:10.1002/ijc.29025

Cited by 91 publications

(119 citation statements)

References 43 publications

(85 reference statements)

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“…These data are consistent with previously published studies. 10,11 In particular, within the group of patients with Grade 3 toxicity, 44/95 (46.3%) developed non-hematological toxicities, 28/95 (29.5%) hematological toxicities and 23/95 (24.2%) both.…”

Section: Patients' Characteristicsmentioning

confidence: 98%

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confidence: 99%

“…Up to date, 160 single nucleotide polymorphisms (SNPs) that alter the DPD aminoacids sequence have been identified within the gene (DPYD) codifying for this enzyme 5,6 and many clinical studies have been trying to investigate their association with FL-related severe toxicities. 3,[7][8][9][10][11] Recently the discussion in the scientific community about the clinical effectiveness of pharmacogenetics has given rise to the publication of drug dosing guidelines with indications and recommendations about drug-related genetic tests and their integration in the clinical routine. In particular, the Clinical Pharmacogenetics Implementation Consortium (CPIC) 12,13 and the Dutch Pharmacogenetics Working Group of the Royal Dutch Association for the Advancement of Pharmacy (DPWG) 14 have published drug-specific guidelines based on the patient genotype.…”

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confidence: 99%

“…15 Particularly, CPIC guidelines recommend choosing an alternative drug for patients who present two variant alleles (compound heterozygous or homozygous variant genotypes) and a 50% reduction of FL starting dose for patients with only one variant allele (heterozygous genotype) for any of these SNPs (http://www.pharmgkb.org/guideline/PA166122686). 1 Despite a number of studies and meta-analyses assessed the association between the DPYD genotyping test and the occurrence of severe toxicity related to FL, [8][9][10][11][16][17][18] its use is still scarcely widespread among clinicians possibly because the rarity of the considered DPYD SNPs renders the three DPYD-markers test sensitivity rather low. In addition, only scanty information is available about the cost-effectiveness of this analysis.…”

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confidence: 99%

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Clinical validity of a DPYD‐based pharmacogenetic test to predict severe toxicity to fluoropyrimidines

Toffoli

Giodini

Buonadonna

et al. 2015

Intl Journal of Cancer

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Pre-therapeutic DPYD pharmacogenetic test to prevent fluoropyrimidines (FL)-related toxicities is not yet common practice in medical oncology. We aimed at investigating the clinical validity of DPYD genetic analysis in a large series of oncological patients. Six hundred three cancer patients, treated with FL, have been retrospectively tested for eight DPYD polymorphisms (DPYD-rs3918290, DPYD-rs55886062, DPYD-rs67376798, DPYD-rs2297595, DPYD-rs1801160, DPYD-rs1801158, DPYDrs1801159, DPYD-rs17376848) for association with Grade 3 toxicity, developed within the first three cycles of therapy. DPYD-rs3918290 and DPYD-rs67376798 were associated to Grade 3 toxicity after bootstrap validation and Bonferroni correction (p 5 0.003, p 5 0.048). DPYD-rs55886062 was not significant likely due to its low allelic frequency, nonetheless one out of two heterozygous patients (compound heterozygous with DPYD-rs3918290) died from toxicity after one cycle. Test specificity for the analysis of DPYD-rs3918290, DPYD-rs55886062 and DPYD-rs67376798 was assessed to 99%. Among the seven patients carrying one variant DPYD-rs3918290, DPYD-rs55886062 or DPYD-rs67376798 allele, not developing Grade 3 toxicity, 57% needed a FL dose or schedule modification for moderate chronic toxicity. No other DPYD polymorphism was associated with Grade 3 toxicity. Our data demonstrate the clinical validity and specificity of the DPYD-rs3918290, DPYDrs55886062, DPYD-rs67376798 genotyping test to prevent FL-related Grade 3 toxicity and to preserve treatment compliance, and support its introduction in the clinical practice.The identification of the genetic bases of inter-individual variability in terms of response or toxicity to pharmacological treatments is a key point in the field of personalized therapy. Specifically, in the oncological setting the high variability observed in the tumor response to treatment and in the severity of toxicity emphasizes the importance of improving the knowledge on the clinical validity of the pharmacogenetic tests.Fluoropyrimidines (FL) are listed among the drugs with pharmacogenetic warnings. 1 Despite the acknowledged efficacy of these drugs in the treatment of different solid tumors, 2 the FL treatment remains challenging as a result of a considerable inter-patient variability in terms of efficacy and toxicity. 3,4 The pharmacogenetic research, aimed at defining predictive markers of FL response, mainly focused on the dihydropyrimidine dehydrogenase (DPD), which is the first and rate-limiting enzyme of FL catabolic pathway. Up to date, 160 single nucleotide polymorphisms (SNPs) that alter the DPD aminoacids sequence have been identified within the gene (DPYD) codifying for this enzyme 5,6 and many clinical studies have been trying to investigate their association with FL-related severe toxicities. 3,[7][8][9][10][11] Recently the discussion in the scientific community about the clinical effectiveness of pharmacogenetics has given rise to the publication of drug dosing guidelines with indications and recommendations about drug...

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Section: Patients' Characteristicsmentioning

confidence: 98%

mentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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Clinical validity of a DPYD‐based pharmacogenetic test to predict severe toxicity to fluoropyrimidines

Toffoli

Giodini

Buonadonna

et al. 2015

Intl Journal of Cancer

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“…14,15 A fifth variant, c.1601G>A (DPYD*4, rs1801158), has also been linked to altered DPD activity and fluoropyrimidine-associated toxicity, but the available evidence on clinical validity is less consistent. 9,[15][16][17] In a recent meta-analysis, the c.1601G>A variant was not found to be significantly associated with fluoropyrimidine-associated toxicity (relative risk: 1.52, 95% CI: 0.86-2.70, p 5 0.15), but all analyzed studies had a relative risk above 1.0, suggesting some effect on toxicity risk. 15 The positive predictive value (PPV) of DPYD variants to identify patients who will experience severe toxicity varies widely, and is typically 40-80%, depending on the DPYD variant, the population and the window in which toxicity is studied.…”

mentioning

confidence: 97%

Rs895819 in MIR27A improves the predictive value of DPYD variants to identify patients at risk of severe fluoropyrimidine‐associated toxicity

Meulendijks

Henricks

Amstutz

et al. 2016

Intl Journal of Cancer

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The objective of this study was to determine whether genotyping of MIR27A polymorphisms rs895819A>G and rs11671784C>T can be used to improve the predictive value of DPYD variants to identify patients at risk of severe fluoropyrimidine-associated toxicity (FP-toxicity). Patients treated previously in a prospective study with fluoropyrimidine-based chemotherapy were genotyped for rs895819 and rs11671784, and DPYD c.2846A>T, c.1679T>G, c.1129-5923C>G and c.1601G>A. The predictive value of MIR27A variants for early-onset grade 3 FP-toxicity, alone or in combination with DPYD variants, was tested in multivariable logistic regression models. Random-effects meta-analysis was performed, including previously published data. A total of 1,592 patients were included. Allele frequencies of rs895819 and rs11671784 were 0.331 and 0.020, respectively. In DPYD wild-type patients, MIR27A variants did not affect risk of FP-toxicity (OR 1.3 for 1 variant MIR27A allele vs. none, 95% CI: 0.87-1.82, p 5 0.228). In contrast, in patients carrying DPYD variants, the presence of 1 rs895819 variant allele was associated with increased risk of FP-toxicity (OR 4.9, 95% CI: 1.24-19.7, p 5 0.023). Rs11671784 was not associated with FP-toxicity (OR 2.9, 95% CI: 0.47218.0, p 5 0.253). Patients carrying a DPYD variant and rs895819 were at increased risk of FP-toxicity compared to patients wild type for rs895819 and DPYD (OR 2.4, 95% CI: 1.27-4.37, p 5 0.007), while patients with a DPYD variant but without a MIR27A variant were not (OR 0.3 95% CI: 0.0621.17, p 5 0.081). In meta-analysis, rs895819 remained significantly associated with FP-toxicity in DPYD variant allele carriers, OR 5.4 (95% CI: 1.83-15.7, p 5 0.002). This study demonstrates the clinical validity of combined MIR27A/DPYD screening to identify patients at risk of severe FP-toxicity.Fluoropyrimidines are among the most frequently prescribed anticancer drugs for gastrointestinal, breast and head and neck cancers. Of the patients treated, 10-30% experiences severe, potentially lethal, fluoropyrimidine-associated toxicity. [1][2][3][4] The most well-established cause of intolerance to fluoropyrimidines is deficiency of the main 5-fluorouracil (5-FU) metabolic enzyme, dihydropyrimidine dehydrogenase (DPD).5-8 DPD deficiency can be the result of polymorphisms in DPYD-the gene encoding DPD-and DPYD variants have therefore received wide-spread attention as predictors of fluoropyrimidine-associated toxicity. 3,[9][10][11][12]

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Genotyping of a family with a novel deleterious DPYD mutation supports the pretherapeutic screening of DPD deficiency with dihydrouracil/uracil ratio

Thomas

Hennebelle

Delmas

et al. 2015

Clin Pharma and Therapeutics

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Despite the growing evidence that dihydropyrimidine dehydrogenase deficiency (DPD, encoded by the DPYD gene) confers a higher risk of developing severe toxicity, most patients are not screened for DPD deficiency before fluoropyrimidine treatment. We report here the genetic and phenotypic analyses of DPD in a family related to a patient who died after a first cycle of 5-fluorouracil and in 15 additional retrospective patients having a partial DPD deficiency (as measured by plasma dihydrouracil/uracil ratio). The patient with lethal toxicity was found to be a compound heterozygote for two DPYD mutations: a novel 8-bp duplication (c.168_175dupGAATAATT, p.Phe59Ter) and c.1679T>G (Ile560Ser). The patient's dihydrouracil/uracil ratio indicates complete DPD deficiency. The novel mutation was found in two members of the patient's family. Deleterious DPYD mutations were identified in 9 out of the 15 patients. The relationship between genotype and dihydrouracil/uracil values in the 22 patients of the present study was significant (P = 0.01).

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Clinical importance of risk variants in the dihydropyrimidine dehydrogenase gene for the prediction of early‐onset fluoropyrimidine toxicity

Cited by 91 publications

References 43 publications

Clinical validity of a DPYD‐based pharmacogenetic test to predict severe toxicity to fluoropyrimidines

Clinical validity of a DPYD‐based pharmacogenetic test to predict severe toxicity to fluoropyrimidines

Rs895819 in MIR27A improves the predictive value of DPYD variants to identify patients at risk of severe fluoropyrimidine‐associated toxicity

Genotyping of a family with a novel deleterious DPYD mutation supports the pretherapeutic screening of DPD deficiency with dihydrouracil/uracil ratio

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