Clinical relevance of DPYD variants c.1679T&gt;G, c.1236G&gt;A/HapB3, and c.1601G&gt;A as predictors of severe fluoropyrimidine-associated toxicity: a systematic review and meta-analysis of individual patient data

Meulendijks, Didier; Henricks, Linda M.; Sonke, Gabe S.; Deenen, Maarten J.; Froehlich, Tanja K.; Amstutz, Ursula; Largiadèr, Carlo R.; Jennings, Barbara; Marinaki, Anthony M.; Sanderson, Jeremy; Kleibl, Zdeněk; Kleiblová, Petra; Schwab, Matthias; Zanger, Ulrich M.; Palles, Claire; Tomlinson, Ian; Groß, Eva; Kuilenburg, André B. P.; Punt, Cornelis J.A.; Koopman, Miriam; Beijnen, Jos H.; Cats, Annemieke; Schellens, Jan H.M.

doi:10.1016/s1470-2045(15)00286-7

Cited by 281 publications

(321 citation statements)

References 44 publications

Supporting

Mentioning

303

Contrasting

Unclassified

Order By: Relevance

“…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

“…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. Bei heterozygoten Trägern wird eine Dosisreduktion von 5-FU empfohlen, bei den sehr viel selteneren homozygoten Trägern ist die Gabe von 5-FU aufgrund von potenziell lebensbedrohlicher Toxizität (Neutropenie) kontraindiziert [1065].…”

Section: Level Of Evidence 2bunclassified

See 1 more Smart Citation

S3-Leitlinie – Kolorektales Karzinom

Schmiegel

Buchberger

Follmann³

et al. 2017

Z Gastroenterol

132

View full text Add to dashboard Cite

Section: Level Of Evidence 2bunclassified

S3-Leitlinie – Kolorektales Karzinom

Schmiegel

Buchberger

Follmann³

et al. 2017

Z Gastroenterol

132

View full text Add to dashboard Cite

“…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. 9,10,17 One factor that contributes to a PPV lower than 100% is the fact that in a proportion of DPYD variant allele carriers DPD activity is not found to be reduced to a clinically relevant extent.…”

mentioning

confidence: 97%

“…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. 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.…”

mentioning

confidence: 99%

“…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: 99%

See 1 more Smart Citation

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

Self Cite

View full text Add to dashboard Cite

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]

show abstract

ToxNav germline genetic testing and PROMinet digital mobile application toxicity monitoring: Results of a prospective single‐center clinical utility study—PRECISE study

Starkey

Sivakumar

et al. 2019

Cancer Medicine

View full text Add to dashboard Cite

IntroductionIn this study (PRECISE), we assess the clinical utility of a germline DNA sequencing‐based test (ToxNav) for mutations in DPYD and ENOSF1 genes to alter clinician‐prescribed fluoropyrimidine doses and the use of a digital application (PROMinet) to record patient‐reported chemotherapy toxicity.Materials and methodsAdult patients with a histological diagnosis of colorectal cancer (CRC) who consented to fluoropyrimidine‐based chemotherapy were recruited prospectively and given a digital application to monitor and record associated toxicities. Patient samples were analyzed for 18 germline coding variants in DPYD and 1 ENOSF1 variant.ResultsGenetic testing was performed for 60 patients and identified one patient at increased risk of fluoropyrimidine‐based toxicities. Uptake of genetic testing was high and results were available on average 17 days from initial clinical encounter. Patient‐reported chemotherapy toxicity identified differences in 5‐fluorouracil vs capecitabine regime profiles and identified profiles associated with subsequent need for chemotherapy dose reduction and hospital admission.DiscussionThe PRECISE clinical trial demonstrated that a germline DNA sequencing‐based test can provide clinically relevant information to alter clinicians' fluoropyrimidine prescription. The study also obtained high volume, high granularity patient‐reported toxicity data that might allow the improvement and personalization of chemotherapy management.

show abstract

Clinical relevance of DPYD variants c.1679T>G, c.1236G>A/HapB3, and c.1601G>A as predictors of severe fluoropyrimidine-associated toxicity: a systematic review and meta-analysis of individual patient data

Cited by 281 publications

References 44 publications

S3-Leitlinie – Kolorektales Karzinom

S3-Leitlinie – Kolorektales Karzinom

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

ToxNav germline genetic testing and PROMinet digital mobile application toxicity monitoring: Results of a prospective single‐center clinical utility study—PRECISE study

Contact Info

Product

Resources

About