Role of Genetic and Nongenetic Factors for Fluorouracil Treatment-Related Severe Toxicity: A Prospective Clinical Trial by the German 5-FU Toxicity Study Group

Schwab, Matthias; Zanger, Ulrich M.; Marx, Claudia; Schaeffeler, Elke; Klein, Kathrin; Dippon, Jürgen; Kerb, Reinhold; Blievernicht, Julia; Fischer, Joachim E.; Hofmann, Ute; Bokemeyer, Carsten; Eichelbaum, Michel

doi:10.1200/jco.2006.10.4182

Cited by 353 publications

(309 citation statements)

References 26 publications

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“…The novel DPYD variants c.187A>G (K63E) and c.1050 G>A (R357H) were found only in one woman (with neutropenia grade 4 and diarrhea grade 3) and one man (with diarrhea grade 4), respectively. Rare alteration c.775A>G (K259E), reported previously twice in high-and low-toxicity German patients, respectively, was found in combination with C29R and V732I in one man (with leucopenia grade 3 and neutropenia grade 4) [14,27].…”

Section: Dpyd Alterations In the Group Of High-toxicity Patientsmentioning

confidence: 66%

“…However, the involvement of other genetic factors [e.g. downstream enzymes of 5-FU degradation pathway -DPYS and UBP1, or other enzymes -thimidylate synthetase (TYMS; OMIM 188350) or methylenetetrahydrofolate reductase (MTHFR; OMIM 607093)] to the development of fluoropyrimidines-related toxicity has been also considered [27,[29][30][31]. Since eighties, the numerous methods based on determination of DPD status were advised to predict serious 5-FU-related toxicity.…”

Section: Discussionmentioning

confidence: 99%

“…3). Because the risk of toxicity development differed between men and women in our study as well as in previously published trials with 5-FU treated patients, we performed this analysis with respect to the gender groups [27,19].…”

Section: Dpyd Alterations In the Group Of High-toxicity Patientsmentioning

confidence: 99%

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Influence of dihydropyrimidine dehydrogenase gene (DPYD) coding sequence variants on the development of fluoropyrimidine-related toxicity in patients with high-grade toxicity and patients with excellent tolerance of fluoropyrimidine-based chemotherapy

Kleibl

Fidlerová²,

Kleiblová³

et al. 2009

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Alterations in dihydropyrimidine dehydrogenase gene (DPYD) coding for the key enzyme (DPD) of fluoropyrimidines (FPs) catabolism contribute to the development of serious FPs-related toxicity. We performed mutation analysis of DPYD based on cDNA sequencing in 76 predominantly colorectal cancer patients treated by FPs with early development of high (grade 3-4) hematological and/or gastrointestinal toxicity. Six previously described [85T>C (C29R), 496A>G (M166V), 775A>G (K259E), 1601G>A (S534N), 1627A>G (I543V), IVS14+1G>A, 2194G>A (V732I)] and two novel [187A>G (K63E) and 1050 G>A (R357H)] non-synonymous DPYD variants were found in 56/76 (73.7%) high-toxicity patients. Subsequently, these alterations were analyzed in 48 patients with excellent long-term tolerance of FPs and in 243 controls and were detected in 37/48 (77.1%) and 166/243 (68.3%) cases, respectively. Analysis of these alterations as risk factors for development of toxicity in pooled FPs-treated population demonstrated that C29R negatively correlated with overall gastrointestinal toxicity (OR = 0.48; 95%CI 0.23-1.0) and M166V in women protected against overall hematological toxicity and neutropenia (both OR = 0.26; 95%CI 0.07-0.89), whereas IVS14+1G>A (found in five high-toxicity patients only) increased risk of mucositis in overall population (OR = 7.0; 95%CI 1.1-44.53), and thrombocytopenia in women (OR = 10.8; 95%CI 1.24-93.98). Moreover, we identified a strong association of V732I with leucopenia (OR = 8.17; 95%CI 2.44 -27.31) and neutropenia (OR=2.78; 95% CI 1.03-7.51). Our data enabled characterization of "high risk" haplotypes (carriers of IVS14+1G>A or V732 lacking M166V) representing small (22% female and 11% male patients), population in high risk of serious hematological toxicity development, and in patients with "lower risk" that unlikely develop serious hematological toxicity [carriers of M166V without IVS14+1G>A and V732I in females (32% women), and non-carriers of C29R, M166V, IVS14+1G>A, and V732I in males (46% men)]. Our results indicate that genotyping of several DPYD variants may lead to stratification of patients with respect to the risk of serious hematological toxicity development during FPs treatment. Key words: dihydropyrimidine dehydrogenase gene [DPYD], fluoropyrimidines, 5-fluorouracil toxicity, mutation analysis, haplotypes, association study* Corresponding author † These authors contributed equally to this work.Fluoropyrimidines -5-fluorouracil (5-FU) and its derivates (e.g. capecitabine) -belong to the most frequently used anticancer drugs in treatment of solid cancers. Mechanism of action of 5-FU involves its anabolic conversions to 5-fluoropyrimidine nucleotides that exert profound inhibitory effect on thymidylate synthetase activity and interfere with RNA and DNA metabolism [1]. The development of severe toxicity is the critical complication of 5-FU-based therapy. It occurs in nearly one third of cases with progression to life-threatening complications in approximately 0.5% patients [2].About 80% of 5-FU is quickly ina...

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Section: Dpyd Alterations In the Group Of High-toxicity Patientsmentioning

confidence: 66%

Section: Discussionmentioning

confidence: 99%

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Influence of dihydropyrimidine dehydrogenase gene (DPYD) coding sequence variants on the development of fluoropyrimidine-related toxicity in patients with high-grade toxicity and patients with excellent tolerance of fluoropyrimidine-based chemotherapy

Kleibl

Fidlerová²,

Kleiblová³

et al. 2009

neo

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“…48 Patients gender in combination with a particular genetic profile could be an additional response marker, in line with recently reported sex-specific reaction to cancer chemotherapy both in terms of toxicity or efficacy. 49,50 In summary, the complexity of tumor response to chemo-RT is reflected by the CART approach, nonetheless CART analysis is a machine-learning approach that uses available data to define a model. The interactions highlighted by this study should be verified and validated in independent studies.…”

Section: Discussionmentioning

confidence: 99%

Tumor response is predicted by patient genetic profile in rectal cancer patients treated with neo-adjuvant chemo-radiotherapy

et al. 2010

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The aim of the study was the identification of a pharmacogenetic profile predictive of the tumor regression grade (TRG), considered as tumor response parameter, after neo-adjuvant treatment in rectal cancer patients. A total of 238 rectal cancer patients treated in a neo-adjuvant setting by a fluoropyrimidines-based chemo-radiotherapy (RT) were genotyped for 25 genetic polymorphisms in 16 genes relevant for treatment-associated pathways. Two polymorphisms were associated with TRG in a multivariate analysis: hOGG1-1245C4G, which can affect radiosensitivity and MTHFR-677C4T, which is involved in fluoropyrimidines action. Patients bearing at least one variant allele had a lower chance to get TRGp2 (OR ¼ 0.46 95% CI 0.23-0.90, P ¼ 0.024; and OR ¼ 0.48 95% CI 0.24-0.96, P ¼ 0.034; respectively). An association trend was observed for ABCB1-3435C4T, which is responsible for the multi-drug resistance (odds ratio (OR) ¼ 1.96, 95% confidence interval (CI) 0.98-3.95, P ¼ 0.057). Exploratory classification and regression tree (CART) analysis highlighted high-order gene-gene and gene-environment interactions and a genetic signature associated with differential response, with hOGG1-1245C4G as the most predictive factor. Other significant variables were: ABCB1-3435C4T, MTHFR-677C4T, ERCC1-8092C4A, ABCC2-1249G4A, XRCC1-28152G4A, XRCC3-4541A4G and patients gender. On the basis of CART results, patients were categorized into three groups according to tumor response probability: intermediate and high profiles had a higher probability to get TRGp2 as compared with low profiles (OR ¼ 4.12 95% CI 1. Po0.001 and OR ¼ 12.44, Po0.0001, respectively). This study evidences a major role of hOGG1-1245C4G and MTHFR-677C4T polymorphisms in the tumor response of rectal cancer patients treated with chemo-RT in neo-adjuvant setting, and shows the relevance of gene-gene and gene-environment interactions for complex phenotypes as tumor response.

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“…1,10 These polymorphisms have been previously observed in patients with low DPD enzymatic activity 20 and in some cases were associated to toxicity Grade 3 in the clinical setting. [21][22][23][24] The first aim of our study is to validate the specificity of three DPYD SNPs recommended by CPIC guidelines (i.e., DPYD-rs3918290, DPYD-rs55886062, and DPYD-rs67376798) in predicting the occurrence of severe toxicity events in a large set of oncological patients treated with FL in different clinical settings. 1 The second aim is to evaluate whether the additional testing of other investigational DPYD variants (DPYD-rs2297595, DPYD-rs1801160, DPYD-rs1801158, DPYD-rs1801159, and DPYD-rs17376848) could increase the pharmacogenetic test sensitivity and is worthy to be integrated in the FL dosing guidelines.…”

mentioning

confidence: 99%

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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Role of Genetic and Nongenetic Factors for Fluorouracil Treatment-Related Severe Toxicity: A Prospective Clinical Trial by the German 5-FU Toxicity Study Group

Abstract: DPYD, TYMS, and MTHFR play a limited role for FU related toxicity but a pronounced DPYD gene/sex-interaction increases prediction rate for male patients. Toxicity risk assessment should include sex, mode of administration, and folinic acid as additional predictive factors.

Cited by 353 publications

References 26 publications

Influence of dihydropyrimidine dehydrogenase gene (DPYD) coding sequence variants on the development of fluoropyrimidine-related toxicity in patients with high-grade toxicity and patients with excellent tolerance of fluoropyrimidine-based chemotherapy

Influence of dihydropyrimidine dehydrogenase gene (DPYD) coding sequence variants on the development of fluoropyrimidine-related toxicity in patients with high-grade toxicity and patients with excellent tolerance of fluoropyrimidine-based chemotherapy

Tumor response is predicted by patient genetic profile in rectal cancer patients treated with neo-adjuvant chemo-radiotherapy

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

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