The Association of Polymorphisms in 5-Fluorouracil Metabolism Genes with Outcome in Adjuvant Treatment of Colorectal Cancer

Afzal, Shoaib; Gusella, Milena; Jensen, Søren Astrup; Vainer, Ben; Vogel, Ulla; Andersen, Jón Trærup; Brødbæk, Kasper; Petersen, Marian; Jimenez-Solem, Espen; Adleff, Vilmos; Budai, Barna; Hitre, Erika; Láng, István; Orosz, Enikő; Bertolaso, Laura; Barile, Carmen; Padrini, Roberto; Kralovánszky, Judit; Pasini, Felice; Poulsen, Henrik E.

doi:10.2217/pgs.11.83

Cited by 28 publications

(23 citation statements)

References 44 publications

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“…However, the published data are inconclusive, the majority of the possible genotypes have not been examined in relation to 5-FU sensitivity; different methods have been used to test gene expression; and conclusions about the putative functional effects have not been congruent [28,42-45]. Another haplotype of clinical interest [46] comprises the 5’ and 3’ TYMS variants, rs45445694 and rs16430 (also referred to as rs34489327) for which there is linkage disequilibrium [9,12,32]; but again there have been conflicting findings about the functional impact of the 3’ polymorphism [19,32,47]. …”

Section: Discussionmentioning

confidence: 99%

“…Only a few pharmacogenetic studies of the genotypes described have considered the role of epistasis but some interactions have been identified that warrant further analysis [19,46,49,50]. Most studies to date have been under-powered to consider multiple pharmacokinetic and pharmacodynamic variants simultaneously but this (Table S3) and similar individualised data sets can be pooled in meta-analyses to resolve uncertainties about the potential clinical utility of these markers and their combined signatures.…”

Section: Discussionmentioning

confidence: 99%

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Evaluating Predictive Pharmacogenetic Signatures of Adverse Events in Colorectal Cancer Patients Treated with Fluoropyrimidines

et al. 2013

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The potential clinical utility of genetic markers associated with response to fluoropyrimidine treatment in colorectal cancer patients remains controversial despite extensive study. Our aim was to test the clinical validity of both novel and previously identified markers of adverse events in a broad clinical setting. We have conducted an observational pharmacogenetic study of early adverse events in a cohort study of 254 colorectal cancer patients treated with 5-fluorouracil or capecitabine. Sixteen variants of nine key folate (pharmacodynamic) and drug metabolising (pharmacokinetic) enzymes have been analysed as individual markers and/or signatures of markers. We found a significant association between TYMP S471L (rs11479) and early dose modifications and/or severe adverse events (adjusted OR = 2.02 [1.03; 4.00], p = 0.042, adjusted OR = 2.70 [1.23; 5.92], p = 0.01 respectively). There was also a significant association between these phenotypes and a signature of DPYD mutations (Adjusted OR = 3.96 [1.17; 13.33], p = 0.03, adjusted OR = 6.76 [1.99; 22.96], p = 0.002 respectively). We did not identify any significant associations between the individual candidate pharmacodynamic markers and toxicity. If a predictive test for early adverse events analysed the TYMP and DPYD variants as a signature, the sensitivity would be 45.5 %, with a positive predictive value of just 33.9 % and thus poor clinical validity. Most studies to date have been under-powered to consider multiple pharmacokinetic and pharmacodynamic variants simultaneously but this and similar individualised data sets could be pooled in meta-analyses to resolve uncertainties about the potential clinical utility of these markers.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Evaluating Predictive Pharmacogenetic Signatures of Adverse Events in Colorectal Cancer Patients Treated with Fluoropyrimidines

et al. 2013

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“…This manuscript builds on two recent papers by the present authors: (i) Afzal et al . and (ii) Sarac et al . .…”

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confidence: 93%

Data‐Driven Assessment of the Association of Polymorphisms in 5‐Fluorouracil Metabolism Genes with Outcome in Adjuvant Treatment of Colorectal Cancer

Sarac

Rasmussen

Afzal

et al. 2012

Basic Clin Pharma Tox

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A major challenge in the assessment of medicines, treatment options, etc., is to establish a framework for the comparison of risks and benefits of many different types and magnitudes, a framework that at the same time allows a clear distinction between the roles played by the statistical analyses of data and by judgements based on personal experience and expertise. The purpose of this study was to demonstrate how clinical data can be weighted, scored and presented by the use of an eight-step data-driven benefit-risk assessment method, where two genetic profiles are compared. Our aim was to present a comprehensive approach that is simple to apply, allows direct comparison of different types of risks and benefits, quantifies the clinical relevance of data and is tailored for the comparison of different options. We analysed a cohort of 302 patients with colorectal cancer treated with 5-Fluorouracil (5-FU). Endpoints were cure rate, survival rate, time-to-death (TTD), time-to-relapse (TTR) and main adverse drug reactions. Multifactor dimensionality reduction (MDR) was used to identify genetic interaction profiles associated with outcome. We have been able to demonstrate that a specific MDR-derived combination (the MDR-1 group) of dihydropyrimidine dehydrogenase and thymidylate synthase polymorphisms is associated with increased and clinically significant difference for cure and survival rates, TTD and probably also for TTR, which are seen as the most important endpoints. An inferior profile was observed for severe myocardial ischaemia. A probably inferior profile was seen for severe arthralgia/myalgia and severe infections. A clear superior profile was seen for severe mucositis/stomatitis. The proposed approach offers comprehensive, data-driven assessment that can facilitate decision processes, for example, in a clinical setting. It employs descriptive statistical methods to highlight the clinically relevant differences between options.

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“…However, the results are conflicting and there is no consensus on the clinical value of these variants [9][10][11]. For instance, while some studies report association between a favorable clinical response and variants at the 5′UTR and 3′UTR regulatory regions of the TYMS gene, other reports have failed to replicate such results [12][13][14][15][16]. None of these studies was performed on the Latin-American populations and studies in this group may contribute to the understanding of the biological significance of TYMS variants and their pharmacological relevance for CRC patients undergoing chemotherapy.…”

Section: Introductionmentioning

confidence: 99%

Thymidylate synthase gene variants as predictors of clinical response and toxicity to fluoropyrimidine-based chemotherapy for colorectal cancer

Castro-Rojas

Esparza-Mota

Hernandez-Cabrera

et al. 2017

Drug Metabolism and Personalized Therapy

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Background: Fluoropyrimidines form the chemotherapy backbone of advanced and metastatic colorectal cancer (CRC). These drugs are frequently associated with toxicity events that result in dose adjustments and even suspension of the treatment. The thymidylate synthase (TYMS) gene is a potential marker of response and toxicity to fluoropyirimidines as this enzyme is the molecular target of these drugs. Our aim was to assess the association between variants of TYMS with response and toxicity to fluoropyrimidines in patients with CRC in independent retrospective and prospective studies. Methods: Variants namely rs45445694, rs183205964, rs2853542 and rs151264360 of TYMS were genotyped in 105

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The Association of Polymorphisms in 5-Fluorouracil Metabolism Genes with Outcome in Adjuvant Treatment of Colorectal Cancer

Cited by 28 publications

References 44 publications

Evaluating Predictive Pharmacogenetic Signatures of Adverse Events in Colorectal Cancer Patients Treated with Fluoropyrimidines

Evaluating Predictive Pharmacogenetic Signatures of Adverse Events in Colorectal Cancer Patients Treated with Fluoropyrimidines

Data‐Driven Assessment of the Association of Polymorphisms in 5‐Fluorouracil Metabolism Genes with Outcome in Adjuvant Treatment of Colorectal Cancer

Thymidylate synthase gene variants as predictors of clinical response and toxicity to fluoropyrimidine-based chemotherapy for colorectal cancer

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