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N Pella - One of the best experts on this subject based on the ideXlab platform.
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Dihydropyrimidine dehydrogenase pharmacogenetics for predicting Fluoropyrimidine-related toxicity in the randomised, phase III adjuvant TOSCA trial in high-risk colon cancer patients
British Journal of Cancer, 2017Co-Authors: A Ruzzo, F Graziano, F Galli, Eliana Rulli, Sara Lonardi, Monica Ronzoni, B Massidda, Vittorina Zagonel, Fabio Galli, N PellaAbstract:Background: Dihydropyrimidine dehydrogenase (DPD) catabolises ∼85% of the administered dose of Fluoropyrimidines. Functional DPYD gene variants cause reduced/abrogated DPD activity. DPYD variants analysis may help for defining individual patients’ risk of Fluoropyrimidine-related severe toxicity. Methods: The TOSCA Italian randomised trial enrolled colon cancer patients for 3 or 6 months of either FOLFOX-4 or XELOX adjuvant chemotherapy. In an ancillary pharmacogenetic study, 10 DPYD variants (*2A rs3918290 G>A, *13 rs55886062 T>G, rs67376798 A>T, *4 rs1801158 G>A, *5 rs1801159 A>G, *6 rs1801160 G>A, *9A rs1801265 T>C, rs2297595 A>G, rs17376848 T>C, and rs75017182 C>G), were retrospectively tested for associations with ⩾grade 3 Fluoropyrimidine-related adverse events (FAEs). An association analysis and a time-to-toxicity (TTT) analysis were planned. To adjust for multiple testing, the Benjamini and Hochberg’s False Discovery Rate (FDR) procedure was used. Results: FAEs occurred in 194 out of 508 assessable patients (38.2%). In the association analysis, FAEs occurred more frequently in *6 rs1801160 A allele carriers (FDR=0.0083). At multivariate TTT analysis, significant associations were found for *6 rs1801160 A allele carriers (FDR
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Dihydropyrimidine dehydrogenase pharmacogenetics for predicting Fluoropyrimidine-related toxicity in the randomised, phase III adjuvant TOSCA trial in high-risk colon cancer patients
British Journal of Cancer, 2017Co-Authors: A Ruzzo, F Graziano, F Galli, Eliana Rulli, Sara Lonardi, Monica Ronzoni, B Massidda, Vittorina Zagonel, Fabio Galli, N PellaAbstract:Background: Dihydropyrimidine dehydrogenase (DPD) catabolises ∼85% of the administered dose of Fluoropyrimidines. Functional DPYD gene variants cause reduced/abrogated DPD activity. DPYD variants analysis may help for defining individual patients’ risk of Fluoropyrimidine-related severe toxicity. Methods: The TOSCA Italian randomised trial enrolled colon cancer patients for 3 or 6 months of either FOLFOX-4 or XELOX adjuvant chemotherapy. In an ancillary pharmacogenetic study, 10 DPYD variants (*2A rs3918290 G>A, *13 rs55886062 T>G, rs67376798 A>T, *4 rs1801158 G>A, *5 rs1801159 A>G, *6 rs1801160 G>A, *9A rs1801265 T>C, rs2297595 A>G, rs17376848 T>C, and rs75017182 C>G), were retrospectively tested for associations with ⩾grade 3 Fluoropyrimidine-related adverse events (FAEs). An association analysis and a time-to-toxicity (TTT) analysis were planned. To adjust for multiple testing, the Benjamini and Hochberg’s False Discovery Rate (FDR) procedure was used. Results: FAEs occurred in 194 out of 508 assessable patients (38.2%). In the association analysis, FAEs occurred more frequently in *6 rs1801160 A allele carriers (FDR=0.0083). At multivariate TTT analysis, significant associations were found for *6 rs1801160 A allele carriers (FDR
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dihydropyrimidine dehydrogenase pharmacogenetics for predicting Fluoropyrimidine related toxicity in the randomised phase iii adjuvant tosca trial in high risk colon cancer patients
British Journal of Cancer, 2017Co-Authors: A Ruzzo, F Graziano, F Galli, Eliana Rulli, Sara Lonardi, Monica Ronzoni, B Massidda, Vittorina Zagonel, N PellaAbstract:Dihydropyrimidine dehydrogenase (DPD) catabolises ∼85% of the administered dose of Fluoropyrimidines. Functional DPYD gene variants cause reduced/abrogated DPD activity. DPYD variants analysis may help for defining individual patients’ risk of Fluoropyrimidine-related severe toxicity. The TOSCA Italian randomised trial enrolled colon cancer patients for 3 or 6 months of either FOLFOX-4 or XELOX adjuvant chemotherapy. In an ancillary pharmacogenetic study, 10 DPYD variants (*2A rs3918290 G>A, *13 rs55886062 T>G, rs67376798 A>T, *4 rs1801158 G>A, *5 rs1801159 A>G, *6 rs1801160 G>A, *9A rs1801265 T>C, rs2297595 A>G, rs17376848 T>C, and rs75017182 C>G), were retrospectively tested for associations with ⩾grade 3 Fluoropyrimidine-related adverse events (FAEs). An association analysis and a time-to-toxicity (TTT) analysis were planned. To adjust for multiple testing, the Benjamini and Hochberg’s False Discovery Rate (FDR) procedure was used. FAEs occurred in 194 out of 508 assessable patients (38.2%). In the association analysis, FAEs occurred more frequently in *6 rs1801160 A allele carriers (FDR=0.0083). At multivariate TTT analysis, significant associations were found for *6 rs1801160 A allele carriers (FDR<0.0001), *2A rs3918290 A allele carriers (FDR<0.0001), and rs2297595 GG genotype carriers (FDR=0.0014). Neutropenia was the most common FAEs (28.5%). *6 rs1801160 (FDR<0.0001), and *2A rs3918290 (FDR=0.0004) variant alleles were significantly associated with time to neutropenia. This study adds evidence on the role of DPYD pharmacogenetics for safety of patients undergoing Fluoropyrimidine-based chemotherapy.
A Ruzzo - One of the best experts on this subject based on the ideXlab platform.
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Dihydropyrimidine dehydrogenase pharmacogenetics for predicting Fluoropyrimidine-related toxicity in the randomised, phase III adjuvant TOSCA trial in high-risk colon cancer patients
British Journal of Cancer, 2017Co-Authors: A Ruzzo, F Graziano, F Galli, Eliana Rulli, Sara Lonardi, Monica Ronzoni, B Massidda, Vittorina Zagonel, Fabio Galli, N PellaAbstract:Background: Dihydropyrimidine dehydrogenase (DPD) catabolises ∼85% of the administered dose of Fluoropyrimidines. Functional DPYD gene variants cause reduced/abrogated DPD activity. DPYD variants analysis may help for defining individual patients’ risk of Fluoropyrimidine-related severe toxicity. Methods: The TOSCA Italian randomised trial enrolled colon cancer patients for 3 or 6 months of either FOLFOX-4 or XELOX adjuvant chemotherapy. In an ancillary pharmacogenetic study, 10 DPYD variants (*2A rs3918290 G>A, *13 rs55886062 T>G, rs67376798 A>T, *4 rs1801158 G>A, *5 rs1801159 A>G, *6 rs1801160 G>A, *9A rs1801265 T>C, rs2297595 A>G, rs17376848 T>C, and rs75017182 C>G), were retrospectively tested for associations with ⩾grade 3 Fluoropyrimidine-related adverse events (FAEs). An association analysis and a time-to-toxicity (TTT) analysis were planned. To adjust for multiple testing, the Benjamini and Hochberg’s False Discovery Rate (FDR) procedure was used. Results: FAEs occurred in 194 out of 508 assessable patients (38.2%). In the association analysis, FAEs occurred more frequently in *6 rs1801160 A allele carriers (FDR=0.0083). At multivariate TTT analysis, significant associations were found for *6 rs1801160 A allele carriers (FDR
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Dihydropyrimidine dehydrogenase pharmacogenetics for predicting Fluoropyrimidine-related toxicity in the randomised, phase III adjuvant TOSCA trial in high-risk colon cancer patients
British Journal of Cancer, 2017Co-Authors: A Ruzzo, F Graziano, F Galli, Eliana Rulli, Sara Lonardi, Monica Ronzoni, B Massidda, Vittorina Zagonel, Fabio Galli, N PellaAbstract:Background: Dihydropyrimidine dehydrogenase (DPD) catabolises ∼85% of the administered dose of Fluoropyrimidines. Functional DPYD gene variants cause reduced/abrogated DPD activity. DPYD variants analysis may help for defining individual patients’ risk of Fluoropyrimidine-related severe toxicity. Methods: The TOSCA Italian randomised trial enrolled colon cancer patients for 3 or 6 months of either FOLFOX-4 or XELOX adjuvant chemotherapy. In an ancillary pharmacogenetic study, 10 DPYD variants (*2A rs3918290 G>A, *13 rs55886062 T>G, rs67376798 A>T, *4 rs1801158 G>A, *5 rs1801159 A>G, *6 rs1801160 G>A, *9A rs1801265 T>C, rs2297595 A>G, rs17376848 T>C, and rs75017182 C>G), were retrospectively tested for associations with ⩾grade 3 Fluoropyrimidine-related adverse events (FAEs). An association analysis and a time-to-toxicity (TTT) analysis were planned. To adjust for multiple testing, the Benjamini and Hochberg’s False Discovery Rate (FDR) procedure was used. Results: FAEs occurred in 194 out of 508 assessable patients (38.2%). In the association analysis, FAEs occurred more frequently in *6 rs1801160 A allele carriers (FDR=0.0083). At multivariate TTT analysis, significant associations were found for *6 rs1801160 A allele carriers (FDR
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dihydropyrimidine dehydrogenase pharmacogenetics for predicting Fluoropyrimidine related toxicity in the randomised phase iii adjuvant tosca trial in high risk colon cancer patients
British Journal of Cancer, 2017Co-Authors: A Ruzzo, F Graziano, F Galli, Eliana Rulli, Sara Lonardi, Monica Ronzoni, B Massidda, Vittorina Zagonel, N PellaAbstract:Dihydropyrimidine dehydrogenase (DPD) catabolises ∼85% of the administered dose of Fluoropyrimidines. Functional DPYD gene variants cause reduced/abrogated DPD activity. DPYD variants analysis may help for defining individual patients’ risk of Fluoropyrimidine-related severe toxicity. The TOSCA Italian randomised trial enrolled colon cancer patients for 3 or 6 months of either FOLFOX-4 or XELOX adjuvant chemotherapy. In an ancillary pharmacogenetic study, 10 DPYD variants (*2A rs3918290 G>A, *13 rs55886062 T>G, rs67376798 A>T, *4 rs1801158 G>A, *5 rs1801159 A>G, *6 rs1801160 G>A, *9A rs1801265 T>C, rs2297595 A>G, rs17376848 T>C, and rs75017182 C>G), were retrospectively tested for associations with ⩾grade 3 Fluoropyrimidine-related adverse events (FAEs). An association analysis and a time-to-toxicity (TTT) analysis were planned. To adjust for multiple testing, the Benjamini and Hochberg’s False Discovery Rate (FDR) procedure was used. FAEs occurred in 194 out of 508 assessable patients (38.2%). In the association analysis, FAEs occurred more frequently in *6 rs1801160 A allele carriers (FDR=0.0083). At multivariate TTT analysis, significant associations were found for *6 rs1801160 A allele carriers (FDR<0.0001), *2A rs3918290 A allele carriers (FDR<0.0001), and rs2297595 GG genotype carriers (FDR=0.0014). Neutropenia was the most common FAEs (28.5%). *6 rs1801160 (FDR<0.0001), and *2A rs3918290 (FDR=0.0004) variant alleles were significantly associated with time to neutropenia. This study adds evidence on the role of DPYD pharmacogenetics for safety of patients undergoing Fluoropyrimidine-based chemotherapy.
Didier Meulendijks - One of the best experts on this subject based on the ideXlab platform.
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dpyd genotype guided dose individualisation of Fluoropyrimidine therapy in patients with cancer a prospective safety analysis
Lancet Oncology, 2018Co-Authors: Linda M. Henricks, Arnold Baars, Didier Meulendijks, Vincent O Dezentje, Carin A T C Lunenburg, Femke M De Man, Geert W J Frederix, Emma Kienhuis, Geert Jan Creemers, Alexander L T ImholzAbstract:Background: Fluoropyrimidine treatment can result in severe toxicity in up to 30% of patients and is often the result of reduced activity of the key metabolic enzyme dihydropyrimidine dehydrogenase (DPD), mostly caused by genetic variants in the gene encoding DPD (DPYD). We assessed the effect of prospective screening for the four most relevant DPYD variants (DPYD*2A [rs3918290, c.1905+1G>A, IVS14+1G>A], c.2846A>T [rs67376798, D949V], c.1679T>G [rs55886062, DPYD*13, I560S], and c.1236G>A [rs56038477, E412E, in haplotype B3]) on patient safety and subsequent DPYD genotype-guided dose individualisation in daily clinical care. Methods: In this prospective, multicentre, safety analysis in 17 hospitals in the Netherlands, the study population consisted of adult patients (≥18 years) with cancer who were intended to start on a Fluoropyrimidine-based anticancer therapy (capecitabine or fluorouracil as single agent or in combination with other chemotherapeutic agents or radiotherapy). Patients with all tumour types for which Fluoropyrimidine-based therapy was considered in their best interest were eligible. We did prospective genotyping for DPYD*2A, c.2846A>T, c.1679T>G, and c.1236G>A. Heterozygous DPYD variant allele carriers received an initial dose reduction of 25% (c.2846A>T and c.1236G>A) or 50% (DPYD*2A and c.1679T>G), and DPYD wild-type patients were treated according to the current standard of care. The primary endpoint of the study was the frequency of severe (National Cancer Institute Common Terminology Criteria for Adverse Events version 4.03 grade ≥3) overall Fluoropyrimidine-related toxicity across the entire treatment duration. We compared toxicity incidence between DPYD variant allele carriers and DPYD wild-type patients on an intention-to-treat basis, and relative risks (RRs) for severe toxicity were compared between the current study and a historical cohort of DPYD variant allele carriers treated with full dose Fluoropyrimidine-based therapy (derived from a previously published meta-analysis). This trial is registered with ClinicalTrials.gov, number NCT02324452, and is complete. Findings: Between April 30, 2015, and Dec 21, 2017, we enrolled 1181 patients. 78 patients were considered non-evaluable, because they were retrospectively identified as not meeting inclusion criteria, did not start Fluoropyrimidine-based treatment, or were homozygous or compound heterozygous DPYD variant allele carriers. Of 1103 evaluable patients, 85 (8%) were heterozygous DPYD variant allele carriers, and 1018 (92%) were DPYD wild-type patients. Overall, Fluoropyrimidine-related severe toxicity was higher in DPYD variant carriers (33 [39%] of 85 patients) than in wild-type patients (231 [23%] of 1018 patients; p=0·0013). The RR for severe Fluoropyrimidine-related toxicity was 1·31 (95% CI 0·63–2·73) for genotype-guided dosing compared with 2·87 (2·14–3·86) in the historical cohort for DPYD*2A carriers, no toxicity compared with 4·30 (2·10–8·80) in c.1679T>G carriers, 2·00 (1·19–3·34) compared with 3·11 (2·25–4·28) for c.2846A>T carriers, and 1·69 (1·18–2·42) compared with 1·72 (1·22–2·42) for c.1236G>A carriers. Interpretation: Prospective DPYD genotyping was feasible in routine clinical practice, and DPYD genotype-based dose reductions improved patient safety of Fluoropyrimidine treatment. For DPYD*2A and c.1679T>G carriers, a 50% initial dose reduction was adequate. For c.1236G>A and c.2846A>T carriers, a larger dose reduction of 50% (instead of 25%) requires investigation. Since Fluoropyrimidines are among the most commonly used anticancer agents, these findings suggest that implementation of DPYD genotype-guided individualised dosing should be a new standard of care. Funding: Dutch Cancer Society.
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Pretreatment serum uracil concentration as a predictor of severe and fatal Fluoropyrimidine-associated toxicity
British Journal of Cancer, 2017Co-Authors: Didier Meulendijks, Linda M. Henricks, Hilde Rosing, Maarten J Deenen, Bart A W Jacobs, Abidin Aliev, Niels De Vries, Erik Van Werkhoven, Anthonius De Boer, Jos H BeijnenAbstract:Background: We investigated the predictive value of dihydropyrimidine dehydrogenase (DPD) phenotype, measured as pretreatment serum uracil and dihydrouracil concentrations, for severe as well as fatal Fluoropyrimidine-associated toxicity in 550 patients treated previously with Fluoropyrimidines during a prospective multicenter study. Methods: Pretreatment serum concentrations of uracil and dihydrouracil were measured using a validated LC-MS/MS method. The primary endpoint of this analysis was global (any) severe Fluoropyrimidine-associated toxicity, that is, grade ⩾3 toxicity according to the NCI CTC-AE v3.0, occurring during the first cycle of treatment. The predictive value of uracil and the uracil/dihydrouracil ratio for early severe Fluoropyrimidine-associated toxicity were compared. Pharmacogenetic variants in DPYD (c.2846A>T, c.1679T>G, c.1129-5923C>G, and c.1601G>A) and TYMS ( TYMS 5′-UTR VNTR and TYMS 3′-UTR 6-bp ins/del) were measured and tested for associations with severe Fluoropyrimidine-associated toxicity to compare predictive value with DPD phenotype. The Benjamini-Hochberg false discovery rate method was used to control for type I errors at level q
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improving safety of Fluoropyrimidine chemotherapy by individualizing treatment based on dihydropyrimidine dehydrogenase activity ready for clinical practice
Cancer Treatment Reviews, 2016Co-Authors: Didier Meulendijks, Annemieke Cats, Jan H.m. Schellens, Jos H BeijnenAbstract:Fluoropyrimidines remain the cornerstone of treatment for different types of cancer, and are used by an estimated two million patients annually. The toxicity associated with Fluoropyrimidine therapy is substantial, however, and affects around 30% of the patients, with 0.5-1% suffering fatal toxicity. Activity of the main 5-fluorouracil (5-FU) metabolic enzyme, dihydropyrimidine dehydrogenase (DPD), is the key determinant of 5-FU pharmacology, and accounts for around 80% of 5-FU catabolism. There is a consistent relationship between DPD activity and 5-FU exposure on the one hand, and risk of severe and potentially lethal Fluoropyrimidine-associated toxicity on the other hand. Therefore, there is a sound rationale for individualizing treatment with Fluoropyrimidines based on DPD status in order to improve patient safety. The field of individualized treatment with Fluoropyrimidines is now rapidly developing. The main strategies that are available, are based on genotyping of the gene encoding DPD (DPYD) and measuring of pretreatment DPD phenotype. Clinical validity of additional approaches, including genotyping of MIR27A has also recently been demonstrated. Here, we critically review the evidence on clinical validity and utility of strategies available to clinicians to identify patients at risk of developing severe and potentially fatal toxicity as a result of DPD deficiency. We evaluate the advantages and limitations of these methods when used in clinical practice, and discuss for which strategies clinical implementation is currently justified based on the available evidence and, in addition, which additional data will be required before implementing other, as yet less developed strategies.
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increased risk of severe Fluoropyrimidine associated toxicity in patients carrying a g to c substitution in the first 28 bp tandem repeat of the thymidylate synthase 2r allele
International Journal of Cancer, 2016Co-Authors: Didier Meulendijks, Annemieke Cats, Maarten J Deenen, Bart A W Jacobs, Abidin Aliev, Dick Pluim, Erik Van Werkhoven, Jos H Beijnen, Jan H.m. SchellensAbstract:The Fluoropyrimidines act by inhibiting thymidylate synthase (TS). Recent studies have shown that patients' risk of severe Fluoropyrimidine-associated toxicity is affected by polymorphisms in the 5′-untranslated region of TYMS, the gene encoding TS. A G>C substitution in the promoter enhancer region of TYMS, rs183205964 (known as the 2RC allele), markedly reduces TS activity in vitro, but its clinical relevance is unknown. We determined rs183205964 in 1605 patients previously enrolled in a prospective multicenter study. Associations between putative low TS expression genotypes (3RC/2RC, 2RG/2RC, and 2RC/2RC) and severe toxicity were investigated using univariable and multivariable logistic regression. Activity of TS and TYMS gene expression were determined in peripheral blood mononuclear cells (PBMCs) of a patient carrying genotype 2RC/2RC and of a control group of healthy individuals. Among 1,605 patients, 28 patients (1.7%) carried the 2RC allele. Twenty patients (1.2%) carried a risk-associated genotype (2RG/2RC, n=13; 3RC/2RC, n=6; and 2RC/2RC, n=1), the eight remaining patients had genotype 3RG/2RC. Early severe toxicity and toxicity-related hospitalization were significantly more frequent in risk-associated genotype carriers (OR 3.0, 95%CI 1.04-8.93, p=0.043 and OR 3.8, 95%CI 1.19-11.9, p=0.024, respectively, in multivariable analysis). The patient with genotype 2RC/2RC was hospitalized twice and had severe febrile neutropenia, diarrhea, and hand-foot syndrome. Baseline TS activity and gene expression in PBMCs of this patient, and a healthy individual with the 2RC allele, were found to be within the normal range. Our study suggests that patients carrying rs183205964 are at strongly increased risk of severe, potentially life-threatening, toxicity when treated with Fluoropyrimidines. What's new? Fluoropyrimidines are among the most commonly used anticancer drugs. Fluoropyrimidines act by inhibiting thymidylate synthase, encoded by the gene TYMS. A G>C substitution in the promoter enhancer region of TYMS, rs183205964, has been shown to reduce TS activity in vitro, but its effect in patients is unknown. We determined the clinical relevance of this variant as a predictor of severe Fluoropyrimidine-induced toxicity in a cohort of 1605 patients treated with Fluoropyrimidine-based chemotherapy, and demonstrate for the first time that rs183205964 is associated with risk of early severe toxicity.
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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
Lancet Oncology, 2015Co-Authors: Didier Meulendijks, Linda M. Henricks, Gabe S Sonke, Maarten J Deenen, Tanja K Froehlich, Ursula Amstutz, Carlo R Largiader, Barbara A Jennings, A M Marinaki, Jeremy D SandersonAbstract:Summary Background The best-known cause of intolerance to Fluoropyrimidines is dihydropyrimidine dehydrogenase (DPD) deficiency, which can result from deleterious polymorphisms in the gene encoding DPD ( DPYD ), including DPYD *2A and c.2846A>T. Three other variants— DPYD c.1679T>G, c.1236G>A/HapB3, and c.1601G>A—have been associated with DPD deficiency, but no definitive evidence for the clinical validity of these variants is available. The primary objective of this systematic review and meta-analysis was to assess the clinical validity of c.1679T>G, c.1236G>A/HapB3, and c.1601G>A as predictors of severe Fluoropyrimidine-associated toxicity. Methods We did a systematic review of the literature published before Dec 17, 2014, to identify cohort studies investigating associations between DPYD c.1679T>G, c.1236G>A/HapB3, and c.1601G>A and severe (grade ≥3) Fluoropyrimidine-associated toxicity in patients treated with Fluoropyrimidines (fluorouracil, capecitabine, or tegafur-uracil as single agents, in combination with other anticancer drugs, or with radiotherapy). Individual patient data were retrieved and analysed in a multivariable analysis to obtain an adjusted relative risk (RR). Effect estimates were pooled by use of a random-effects meta-analysis. The threshold for significance was set at a p value of less than 0·0167 (Bonferroni correction). Findings 7365 patients from eight studies were included in the meta-analysis. DPYD c.1679T>G was significantly associated with Fluoropyrimidine-associated toxicity (adjusted RR 4·40, 95% CI 2·08–9·30, p A/HapB3 (1·59, 1·29–1·97, p A and Fluoropyrimidine-associated toxicity was not significant (adjusted RR 1·52, 95% CI 0·86–2·70, p=0·15). Analysis of individual types of toxicity showed consistent associations of c.1679T>G and c.1236G>A/HapB3 with gastrointestinal toxicity (adjusted RR 5·72, 95% CI 1·40–23·33, p=0·015; and 2·04, 1·49–2·78, p DPYD *2A and c.2846A>T were also significantly associated with severe Fluoropyrimidine-associated toxicity (adjusted RR 2·85, 95% CI 1·75–4·62, p Interpretation DPYD variants c.1679T>G and c.1236G>A/HapB3 are clinically relevant predictors of Fluoropyrimidine-associated toxicity. Upfront screening for these variants, in addition to the established variants DPYD *2A and c.2846A>T, is recommended to improve the safety of patients with cancer treated with Fluoropyrimidines. Funding None.
F Galli - One of the best experts on this subject based on the ideXlab platform.
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Dihydropyrimidine dehydrogenase pharmacogenetics for predicting Fluoropyrimidine-related toxicity in the randomised, phase III adjuvant TOSCA trial in high-risk colon cancer patients
British Journal of Cancer, 2017Co-Authors: A Ruzzo, F Graziano, F Galli, Eliana Rulli, Sara Lonardi, Monica Ronzoni, B Massidda, Vittorina Zagonel, Fabio Galli, N PellaAbstract:Background: Dihydropyrimidine dehydrogenase (DPD) catabolises ∼85% of the administered dose of Fluoropyrimidines. Functional DPYD gene variants cause reduced/abrogated DPD activity. DPYD variants analysis may help for defining individual patients’ risk of Fluoropyrimidine-related severe toxicity. Methods: The TOSCA Italian randomised trial enrolled colon cancer patients for 3 or 6 months of either FOLFOX-4 or XELOX adjuvant chemotherapy. In an ancillary pharmacogenetic study, 10 DPYD variants (*2A rs3918290 G>A, *13 rs55886062 T>G, rs67376798 A>T, *4 rs1801158 G>A, *5 rs1801159 A>G, *6 rs1801160 G>A, *9A rs1801265 T>C, rs2297595 A>G, rs17376848 T>C, and rs75017182 C>G), were retrospectively tested for associations with ⩾grade 3 Fluoropyrimidine-related adverse events (FAEs). An association analysis and a time-to-toxicity (TTT) analysis were planned. To adjust for multiple testing, the Benjamini and Hochberg’s False Discovery Rate (FDR) procedure was used. Results: FAEs occurred in 194 out of 508 assessable patients (38.2%). In the association analysis, FAEs occurred more frequently in *6 rs1801160 A allele carriers (FDR=0.0083). At multivariate TTT analysis, significant associations were found for *6 rs1801160 A allele carriers (FDR
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Dihydropyrimidine dehydrogenase pharmacogenetics for predicting Fluoropyrimidine-related toxicity in the randomised, phase III adjuvant TOSCA trial in high-risk colon cancer patients
British Journal of Cancer, 2017Co-Authors: A Ruzzo, F Graziano, F Galli, Eliana Rulli, Sara Lonardi, Monica Ronzoni, B Massidda, Vittorina Zagonel, Fabio Galli, N PellaAbstract:Background: Dihydropyrimidine dehydrogenase (DPD) catabolises ∼85% of the administered dose of Fluoropyrimidines. Functional DPYD gene variants cause reduced/abrogated DPD activity. DPYD variants analysis may help for defining individual patients’ risk of Fluoropyrimidine-related severe toxicity. Methods: The TOSCA Italian randomised trial enrolled colon cancer patients for 3 or 6 months of either FOLFOX-4 or XELOX adjuvant chemotherapy. In an ancillary pharmacogenetic study, 10 DPYD variants (*2A rs3918290 G>A, *13 rs55886062 T>G, rs67376798 A>T, *4 rs1801158 G>A, *5 rs1801159 A>G, *6 rs1801160 G>A, *9A rs1801265 T>C, rs2297595 A>G, rs17376848 T>C, and rs75017182 C>G), were retrospectively tested for associations with ⩾grade 3 Fluoropyrimidine-related adverse events (FAEs). An association analysis and a time-to-toxicity (TTT) analysis were planned. To adjust for multiple testing, the Benjamini and Hochberg’s False Discovery Rate (FDR) procedure was used. Results: FAEs occurred in 194 out of 508 assessable patients (38.2%). In the association analysis, FAEs occurred more frequently in *6 rs1801160 A allele carriers (FDR=0.0083). At multivariate TTT analysis, significant associations were found for *6 rs1801160 A allele carriers (FDR
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dihydropyrimidine dehydrogenase pharmacogenetics for predicting Fluoropyrimidine related toxicity in the randomised phase iii adjuvant tosca trial in high risk colon cancer patients
British Journal of Cancer, 2017Co-Authors: A Ruzzo, F Graziano, F Galli, Eliana Rulli, Sara Lonardi, Monica Ronzoni, B Massidda, Vittorina Zagonel, N PellaAbstract:Dihydropyrimidine dehydrogenase (DPD) catabolises ∼85% of the administered dose of Fluoropyrimidines. Functional DPYD gene variants cause reduced/abrogated DPD activity. DPYD variants analysis may help for defining individual patients’ risk of Fluoropyrimidine-related severe toxicity. The TOSCA Italian randomised trial enrolled colon cancer patients for 3 or 6 months of either FOLFOX-4 or XELOX adjuvant chemotherapy. In an ancillary pharmacogenetic study, 10 DPYD variants (*2A rs3918290 G>A, *13 rs55886062 T>G, rs67376798 A>T, *4 rs1801158 G>A, *5 rs1801159 A>G, *6 rs1801160 G>A, *9A rs1801265 T>C, rs2297595 A>G, rs17376848 T>C, and rs75017182 C>G), were retrospectively tested for associations with ⩾grade 3 Fluoropyrimidine-related adverse events (FAEs). An association analysis and a time-to-toxicity (TTT) analysis were planned. To adjust for multiple testing, the Benjamini and Hochberg’s False Discovery Rate (FDR) procedure was used. FAEs occurred in 194 out of 508 assessable patients (38.2%). In the association analysis, FAEs occurred more frequently in *6 rs1801160 A allele carriers (FDR=0.0083). At multivariate TTT analysis, significant associations were found for *6 rs1801160 A allele carriers (FDR<0.0001), *2A rs3918290 A allele carriers (FDR<0.0001), and rs2297595 GG genotype carriers (FDR=0.0014). Neutropenia was the most common FAEs (28.5%). *6 rs1801160 (FDR<0.0001), and *2A rs3918290 (FDR=0.0004) variant alleles were significantly associated with time to neutropenia. This study adds evidence on the role of DPYD pharmacogenetics for safety of patients undergoing Fluoropyrimidine-based chemotherapy.
Jan H.m. Schellens - One of the best experts on this subject based on the ideXlab platform.
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Capecitabine-based treatment of a patient with a novel DPYD genotype and complete dihydropyrimidine dehydrogenase deficiency.
International Journal of Cancer, 2017Co-Authors: Linda M. Henricks, Judith Meijer, Lida Zoetekouw, Ester J.m. Siemerink, Hilde Rosing, Susan M. I. Goorden, Abeltje M. Polstra, Annemieke Cats, Jan H.m. Schellens, A.b.p. Van KuilenburgAbstract:Fluoropyrimidines are frequently used anti-cancer drugs. It is known that patients with reduced activity of dihydropyrimidine dehydrogenase (DPD), the key metabolic enzyme in Fluoropyrimidine inactivation, are at increased risk of developing severe Fluoropyrimidine-related toxicity. Upfront screening for DPD deficiency and dose reduction in patients with partial DPD deficiency is recommended and improves patient safety. For patients with complete DPD deficiency, Fluoropyrimidine-treatment has generally been discouraged. During routine pretreatment screening, we identified a 59-year-old patient with a sigmoid adenocarcinoma who proved to have a complete DPD deficiency. Genetic analyses showed that this complete absence of DPD activity was likely to be caused by a novel DPYD genotype, consisting of a combination of amplification of exons 17 and 18 of DPYD and heterozygosity for DPYD*2A. Despite absence of DPD activity, the patient was treated with capecitabine-based chemotherapy, but capecitabine dose was drastically reduced to 150 mg once every 5 days (0.8% of original dose). Pharmacokinetic analyses showed that the area under the concentration-time curve (AUC) and half-life of 5-fluorouracil were respectively tenfold and fourfold higher than control values of patients receiving capecitabine 850 mg/m2 . When extrapolating from the dosing schedule of once every 5 days to twice daily, the AUC of 5-fluorouracil was comparable to controls. Treatment was tolerated well for eight cycles by the patient without occurrence of capecitabine-related toxicity. This case report demonstrates that a more comprehensive genotyping and phenotyping approach, combined with pharmacokinetically-guided dose administration, enables save Fluoropyrimidine-treatment with adequate drug exposure in completely DPD deficient patients.
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improving safety of Fluoropyrimidine chemotherapy by individualizing treatment based on dihydropyrimidine dehydrogenase activity ready for clinical practice
Cancer Treatment Reviews, 2016Co-Authors: Didier Meulendijks, Annemieke Cats, Jan H.m. Schellens, Jos H BeijnenAbstract:Fluoropyrimidines remain the cornerstone of treatment for different types of cancer, and are used by an estimated two million patients annually. The toxicity associated with Fluoropyrimidine therapy is substantial, however, and affects around 30% of the patients, with 0.5-1% suffering fatal toxicity. Activity of the main 5-fluorouracil (5-FU) metabolic enzyme, dihydropyrimidine dehydrogenase (DPD), is the key determinant of 5-FU pharmacology, and accounts for around 80% of 5-FU catabolism. There is a consistent relationship between DPD activity and 5-FU exposure on the one hand, and risk of severe and potentially lethal Fluoropyrimidine-associated toxicity on the other hand. Therefore, there is a sound rationale for individualizing treatment with Fluoropyrimidines based on DPD status in order to improve patient safety. The field of individualized treatment with Fluoropyrimidines is now rapidly developing. The main strategies that are available, are based on genotyping of the gene encoding DPD (DPYD) and measuring of pretreatment DPD phenotype. Clinical validity of additional approaches, including genotyping of MIR27A has also recently been demonstrated. Here, we critically review the evidence on clinical validity and utility of strategies available to clinicians to identify patients at risk of developing severe and potentially fatal toxicity as a result of DPD deficiency. We evaluate the advantages and limitations of these methods when used in clinical practice, and discuss for which strategies clinical implementation is currently justified based on the available evidence and, in addition, which additional data will be required before implementing other, as yet less developed strategies.
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increased risk of severe Fluoropyrimidine associated toxicity in patients carrying a g to c substitution in the first 28 bp tandem repeat of the thymidylate synthase 2r allele
International Journal of Cancer, 2016Co-Authors: Didier Meulendijks, Annemieke Cats, Maarten J Deenen, Bart A W Jacobs, Abidin Aliev, Dick Pluim, Erik Van Werkhoven, Jos H Beijnen, Jan H.m. SchellensAbstract:The Fluoropyrimidines act by inhibiting thymidylate synthase (TS). Recent studies have shown that patients' risk of severe Fluoropyrimidine-associated toxicity is affected by polymorphisms in the 5′-untranslated region of TYMS, the gene encoding TS. A G>C substitution in the promoter enhancer region of TYMS, rs183205964 (known as the 2RC allele), markedly reduces TS activity in vitro, but its clinical relevance is unknown. We determined rs183205964 in 1605 patients previously enrolled in a prospective multicenter study. Associations between putative low TS expression genotypes (3RC/2RC, 2RG/2RC, and 2RC/2RC) and severe toxicity were investigated using univariable and multivariable logistic regression. Activity of TS and TYMS gene expression were determined in peripheral blood mononuclear cells (PBMCs) of a patient carrying genotype 2RC/2RC and of a control group of healthy individuals. Among 1,605 patients, 28 patients (1.7%) carried the 2RC allele. Twenty patients (1.2%) carried a risk-associated genotype (2RG/2RC, n=13; 3RC/2RC, n=6; and 2RC/2RC, n=1), the eight remaining patients had genotype 3RG/2RC. Early severe toxicity and toxicity-related hospitalization were significantly more frequent in risk-associated genotype carriers (OR 3.0, 95%CI 1.04-8.93, p=0.043 and OR 3.8, 95%CI 1.19-11.9, p=0.024, respectively, in multivariable analysis). The patient with genotype 2RC/2RC was hospitalized twice and had severe febrile neutropenia, diarrhea, and hand-foot syndrome. Baseline TS activity and gene expression in PBMCs of this patient, and a healthy individual with the 2RC allele, were found to be within the normal range. Our study suggests that patients carrying rs183205964 are at strongly increased risk of severe, potentially life-threatening, toxicity when treated with Fluoropyrimidines. What's new? Fluoropyrimidines are among the most commonly used anticancer drugs. Fluoropyrimidines act by inhibiting thymidylate synthase, encoded by the gene TYMS. A G>C substitution in the promoter enhancer region of TYMS, rs183205964, has been shown to reduce TS activity in vitro, but its effect in patients is unknown. We determined the clinical relevance of this variant as a predictor of severe Fluoropyrimidine-induced toxicity in a cohort of 1605 patients treated with Fluoropyrimidine-based chemotherapy, and demonstrate for the first time that rs183205964 is associated with risk of early severe toxicity.