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• W4386768782 abstract "This issue of Clinical Pharmacology and Therapeutics features an impressive article by Hertz et al.1 who vehemently call for a change of the current policy of the US Federal Food and Drug Administration (FDA) not to recommend genetic testing of the dihydropyrimidine dehydrogenase (DPYD) gene prior to initiation of systemic fluoropyrimidine therapy. The authors address in great detail the issues of the relationship among genetic variants, fluoropyrimidine toxicity, as well as the possible influence of non-genetic factors. The goal is to significantly reduce severe adverse effects while maintaining therapeutic success. The background of this proposal on this old drug goes back to observations made already decades ago. Fluoropyrimidines such as 5-fluorouracil (5-FU) have been used since 1962 as antimetabolites for the treatment of numerous solid tumors. Despite considerable, occasionally lethal side effects, 5-FU and its prodrugs capecitabine and tegafur are still among the most widely used cytostatic drugs today and are used in particular for standard adjuvant therapy, especially of colorectal carcinomas and advanced or metastatic disease.2 The effect is based on the incorrect incorporation of fluorinated pyrimidines into DNA and RNA as well as after intracellular phosphorylation on the inhibition of thymidylate synthase, thereby inhibiting DNA synthesis. In combination therapies with irinotecan or oxaliplatin, the overall survival of patients with metastatic colorectal carcinoma is about 30 months. The problem of its use is the narrow therapeutic range, that is, the ratio between effective and toxic doses is low, thus the prevention of adverse effects is hardly possible without achieving a therapeutic effect. Problems exist in pronounced myelosuppression, gastrointestinal disorders occurring in about 30% of cases, cardiotoxicity, hand-foot syndromes, and neurological disorders up to encephalopathies. The lethality of treatment is 0.2–1%. However, only a small percentage of the dose contributes to the efficacy and side effects; more than 80% of 5-FU is degraded by dihydropyrimidine dehydrogenase (DPD), the activity of which shows great interindividual variability. Thus, phenotypic DPD deficiency was identified as the cause of thymine-uraciluria in 1985.3 The genetic basis of DPD variability was first elucidated by Wei et al. in 1996.4 There is now overwhelming evidence that part of the severe, occasionally lethal, adverse effects of fluoropyrimidines are due to the hereditary deficiency of DPD present in 1–2% of the population (see Figure 1).5, 6 Prospective studies showed that heterozygous carriers of the inactive DPYD*2A allele (rs3918290, allelic frequency in Europeans 1.0–1.2%) had the same overall survival and progression-related survival as wild-type carriers at 50% dose reduction.7 Based on these and other studies, guidelines have been developed by international consortia such as Clinical Pharmacogenetics Implementation Consortium (CPIC) and the Dutch Pharmacogenetics Working Group (DPWG) that provide clear guidance on dose reduction or complete avoidance of fluoropyrimidines depending on the presence of defined genetic variants.8-10 Certain clinics successfully implemented routine DPYD testing as comprehensively reported by the National Cancer Center in Aviano, Italy.11 Here, a reimbursement model for genetic testing was introduced first at the regional level in 2013 and then at the national level a few years later. Currently, the number of samples referred for pretreatment genotyping is 97.4% in this center. However, it took until 2020 when the European Medicine Agency (EMA) recommended genotyping of the DPYD gene or DPD phenotyping prior to initiation of systemic fluoropyrimidine therapy.12 The 2020 European EMA guideline was quickly translated into national consensus guidelines (e.g., ref. 13) followed by reimbursement models and DPYD testing is now routine in many European countries.14 The question comes up, why is DPYD testing not yet recommended globally,15 see also some examples of capecitabine drug label annotations from different regulatory agencies (Table 1). As outlined in the article of Hertz et al.,1 the clinical practice guidelines from the US National Comprehensive Cancer Network (NCCN) is still not endorsing pretreatment testing of DPYD and this was used as a rational for the FDA to not recommend testing. In addition, the American Society of Clinical Oncology (ASCO) still does not support testing for DPYD genetic variants before fluoropyrimidine chemotherapy. Patients with complete DPD deficiency are at high risk for life-threatening or fatal toxicity and should not be treated with capecitabine. Patients with partial DPD deficiency are at increased risk for serious and potentially life-threatening toxicity. A reduced starting dose should be considered to limit this toxicity. It is recommended that phenotype and/or genotype testing be performed prior to initiation of treatment with capecitabine, although there is uncertainty regarding the optimal testing methods prior to treatment. Patients with certain homozygous or certain compound heterozygous mutations in the DPD gene that result in complete or near complete absence of DPD activity are at increased risk for acute early-onset of toxicity and severe, life-threatening, or fatal adverse reactions caused by capecitabine. Patients with partial DPD activity may also have increased risk of severe, life-threatening, or fatal adverse reactions caused by capecitabine. Withhold or permanently discontinue capecitabine based on clinical assessment of the onset, duration, and severity of the observed toxicities in patients with evidence of acute early-onset or unusually severe toxicity, which may indicate near complete or total absence of DPD activity. No capecitabine dose has been proven safe for patients with complete absence of DPD activity. There is insufficient data to recommend a specific dose in patients with partial DPD activity as measured by any specific test. Patients with complete DPD deficiency are at high risk for life-threatening or fatal toxicity and should not be treated with capecitabine. Patients with partial DPD deficiency are at increased risk for serious and potentially life-threatening toxicity. A reduced initial dose should be considered to limit this toxicity. … Reduction of the initial dose may affect the efficacy of treatment. In the absence of serious toxicity, subsequent doses may be increased under close monitoring. Capecitabine is contraindicated in patients who have complete absence DPD activity. Testing for DPD deficiency should be considered prior to treatment, based on the local availability and current guidelines. Patients with certain homozygous or certain compound heterozygous mutations in the DPYD gene locus that cause complete or near complete absence of DPD activity, are at the highest risk for severe, life-threatening, or fatal adverse reactions caused by fluorouracil. These patients should not be treated with capecitabine. No dose has been proven safe for patients with complete absence of DPD activity. For patients with partial DPD deficiency where the benefits of capecitabine are considered to outweigh the risks (taking into account the suitability of an alternative non-fluoropyrimidine chemotherapeutic regimen), these patients must be treated with extreme caution, initially with a substantial dose reduction and frequent subsequent monitoring and dose adjustment according to toxicity. Testing for DPD deficiency should be considered prior to treatment, based on the local availability and current guidelines. There is no evidence to date that dose reduction in DPYD*2A carriers would affect the efficacy of fluoropyrimidines. Without doubt, however, current prediction of DPD activity by genetic testing is not optimal, especially because consideration of ethnicities of non-European ancestry requires increased coverage of variants that are often not part of targeted genotyping sets.16, 17 DPYD sequencing could be an alternative, although more laborious and costly.18 Overall, genetic testing cannot provide full assurance of reducing adverse effects. In the view of many authors, however, there is convincing evidence that DPYD genotyping significantly reduces life-threatening toxicities, as pointed out by Hertz et al.1 when demanding implementation of DPYD testing in the United States. In a recent article, Baker et al.19 also expressly underlined the need that the FDA should reconsider its view concerning recommendations of DPYD testing. Both groups of authors point out that in other cases, such as the HIV therapeutic abacavir, regulatory agencies quickly concluded that HLA-B*57:01 testing helps to prevent severe toxicities and that testing is therefore mandatory worldwide. The cases are not fully identical, as the absence of the HLA trait is associated with almost 100% probability of the absence of severe hypersensitivity reactions20; this is not the case with DPYD testing, however, absence of DPYD variants reduces significantly the risk of severe toxicity. Concerns that the cost of genotyping would be high because only a small proportion of the total number of patients (5.4% in White patients) who have severe or decreased DPD deficiency would benefit from testing, have already been dismissed by cost-effectiveness analyses.21 Furthermore, Hertz et al.,1 as well as Baker et al.,19 rightly pointed out that DNA analyses are part of modern cancer therapy and that DPYD diagnostics do not represent a significant additional expense. The authors of a survey on implementation of DPYD testing in Europe state that key factors are reimbursement models and clear clinical guidelines. In addition, clinicians need to be further educated on the use of pharmacogenetics.14 It is worth mentioning that UGT1A1 genotyping applied to reduce irinotecan toxicity is reimbursed by statutory health insurances in Germany since the year 2022. As fluoropyrimidines and the topoisomerase inhibitor irinotecan are prescribed together in the FOLFIRI regimen in colorectal cancer, pretreatment genotyping of both genes, DPYD and UGT1A1, makes sense to reduce potential toxicities.22 It is hoped that the clear article by Hertz et al.,1 as well as the parallel publication by Baker et al.,19 will contribute to further discussion on the implementation of DPYD testing. From a pharmacological point of view, the evidence in favor of testing and consideration of existing guidelines from the CPIC9 and/or the DPWG10 is overwhelming. No funding was received for this work. The author declared no competing interests for this work." @default.
• W4386768782 created "2023-09-16" @default.
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• W4386768782 date "2023-09-15" @default.
• W4386768782 modified "2023-09-26" @default.
• W4386768782 title "Why is There Still Debate About Recommending <i>DPYD</i>‐Testing Before Fluoropyrimidine Treatment?" @default.
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• W4386768782 doi "https://doi.org/10.1002/cpt.3016" @default.
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