Upfront Genotyping of <i>DPYD</i>*<i>2A</i> to Individualize Fluoropyrimidine Therapy: A Safety and Cost Analysis

Deenen, Maarten J.; Meulendijks, Didier; Cats, Annemieke; Sechterberger, Marjolein K.; Severens, Johan L.; Boot, H.; Smits, Paul H.M.; Rosing, Hilde; Mandigers, Caroline; Soesan, Marcel; Beijnen, Jos H.; Schellens, Jan H.M.

doi:10.1200/jco.2015.63.1325

Cited by 274 publications

(355 citation statements)

References 31 publications

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“…Deenen et al recently reported on 2,038 patients who were prospectively screened for DPD*2A variant, of whom 22 were found to be heterozygous [80]. The most common tumor type in this study was colorectal cancer, and 90% of patients were treated with the oral fluoropyrimidine capecitabine while the remaining 10% of patients were treated with intravenous 5-FU.…”

Section: Dihydropyrimidine Dehydrogenase (Dpd)mentioning

confidence: 84%

Therapeutic drug monitoring of 5-fluorouracil

Lee

Beumer

Chu

2016

Cancer Chemother Pharmacol

163

142

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Purpose For over 50 years, 5-FU has played a critical role in the systemic chemotherapy of cancer patients. 5-FU serves as the main backbone of combination chemotherapy for patients with colorectal cancer (CRC) in both the adjuvant and metastatic disease settings. Herein, we review the current status of 5-FU therapeutic drug monitoring (TDM) and discuss its potential role in the clinical practice setting. Method PubMed and abstracts from the American Society of Clinical Oncology (ASCO) were searched up through September 2015 for clinical data relating to 5-FU TDM. Results 5-FU dosing has been typically determined by using body surface area (BSA). However, it is now well-established that BSA-based 5-FU dosing is correlated with a wide variation of 5-FU systemic exposure. Pharmacokinetic (PK) studies of 5-FU systemic exposure have shown a wide range of interpatient variation of 5-FU plasma drug levels. Over the past 30 years, increasing efforts have been placed on optimizing 5-FU dosing with the main goals of increasing antitumor efficacy while reducing drug-associated toxicity. There is growing evidence to show that 5-FU dosing based on plasma 5-FU drug level is feasible and that 5-FU TDM can improve clinical outcomes by improving efficacy of 5-FU-based combination regimens and reducing toxicities. Conclusion Dose adjustment of 5-FU is feasible and PK-based dosing can significantly improve clinical outcomes by reducing toxicities and improving efficacy.

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Section: Dihydropyrimidine Dehydrogenase (Dpd)mentioning

confidence: 84%

Therapeutic drug monitoring of 5-fluorouracil

Lee

Beumer

Chu

2016

Cancer Chemother Pharmacol

163

142

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“…Quellen: [1064,1065] Konsens Hintergrund Die Dihydropyrimidin-Dehydrogenase (DPD) ist das Schlüssel-enzym für den 5-FU Metabolismus. DPD inaktiviert etwa 80 -90 % des verabreichten 5-FU zu 5,6-Dihydrofluorouracil.…”

Section: Level Of Evidence 2bunclassified

“…Der Genpolymorphismus des kodierenden DPYD-Gens ist die am besten beschriebene Ursache eines DPD-Mangels. Etwa 3 -5 % der Kaukasier weisen einen partiellen und 0,2 % einen kompletten DPDMangel auf [1064]. Nicht funktionelle Allele sind u. a. die Varianten DPYD*2A und DPYD*13, DPYD*9A sowie die SNP-Variante rs67 376 798. Der DPYD*2A Polymorphismus ist mit einer Häufigkeit von 1 -2 % in den westlichen Nationen die klinisch relevanteste Variante.…”

Section: Level Of Evidence 2bunclassified

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S3-Leitlinie – Kolorektales Karzinom

Schmiegel

Buchberger

Follmann³

et al. 2017

Z Gastroenterol

132

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“…3,[9][10][11][12] Importantly, upfront screening for risk-associated DPYD variants and dose adaptation in patients carrying variant alleles has shown to be a feasible strategy to improve the safety of patients who carry DPYD variants. 13 At present, clinical validity has been demonstrated for four DPYD variants: c.1905 1 1G>A (DPYD*2A, IVS14 1 1G>A, rs3918290), c. 2846A>T (rs67376798), c.1679T>G (DPYD*13, rs55886062) and c.1129-5923C>G (rs75017182; in complete linkage with the haplotype HapB3). 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.…”

mentioning

confidence: 99%

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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Upfront Genotyping of *DPYD**2A to Individualize Fluoropyrimidine Therapy: A Safety and Cost Analysis

Cited by 274 publications

References 31 publications

Therapeutic drug monitoring of 5-fluorouracil

Therapeutic drug monitoring of 5-fluorouracil

S3-Leitlinie – Kolorektales Karzinom

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

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Upfront Genotyping of DPYD*2A to Individualize Fluoropyrimidine Therapy: A Safety and Cost Analysis

Cited by 274 publications

References 31 publications

Therapeutic drug monitoring of 5-fluorouracil

Therapeutic drug monitoring of 5-fluorouracil

S3-Leitlinie – Kolorektales Karzinom

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

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Upfront Genotyping of *DPYD**2A to Individualize Fluoropyrimidine Therapy: A Safety and Cost Analysis