Dihydropyrimidine Dehydrogenase Enzyme Research Articles

Assessing the Hepatotoxic Effects of Fluoropyrimidine Chemotherapy in Male Iraqi Colorectal Cancer Patients.

Colorectal cancer (CRC) is one the most frequently occurring cancer types among various populations. Fluoropyrimidine is the backbone of first-line chemotherapy, the oral capecitabine, or intravenous 5-fluorouracil (5-FU) in various combinations and schedules the chemotherapy regime in the treatment of a wide variety of gastrointestinal cancers. The enzyme dihydropyrimidine dehydrogenase (DPD) functions as the rate-limiting step in the metabolism of fluoropyrimidine chemotherapies, and patients with complete or partial DPD deficiency are at increased risk of severe and fatal toxicity during treatment with fluorouracil. This study aimed to examine thechemotoxicity of the 5-FU drug on hepatocytes in male Iraqi CRC patients. This research is a cross-sectional study conducted between November 2022 and April 2023. The study included 80 male participants who had undergone surgical intervention for stage III CRC under the care of the Misan Health Directorate, Misan Center for Tumors Treatment, located in Misan, Iraq. Based on their subsequent surgical treatment, the participants were divided into two groups. The first group, comprising 45 males aged between 41 and 71 years, experienced a relapse despite receiving adjuvant therapy, which involved a singular cycle of fluoropyrimidine-based chemotherapy (5-FU). The second group consisted of 35 male patients with CRC, aged between 40 and 57 years, who did not experience a relapse post-adjuvant therapy. Their adjuvant therapy involved a single round of fluoropyrimidine-based chemotherapy with 5-FU. Relapse in patients was determined by assessing the white blood cell count(WBC). Liver enzymes were significantly increased after 5-FU treatment, while the concentration of albumin was significantly decreased. The findings of our study clearly indicate that 5-FU induced hepatic injury, lowering the hepatocytefunction with elevated levels of hepatic enzymes and low concentration of albumin in the blood, which is an important predictive marker of chemotherapy toxicity.

Fluoropyrimidine Toxicity: the Hidden Secrets of DPYD.

Fluoropyrimidine-induced toxicity is a main limitation of therapy. Currently, polymorphisms in the DPYD gene, which encodes the 5-FU activation enzyme dihydropyrimidine dehydrogenase (DPD), are used to adjust the dosage and prevent toxicity. Despite the predictive value of DPYD genotyping, a great proportion of fluoropyrimidine toxicity cannot be solely explained by DPYD variations. We herein summarize additional sources of DPD enzyme activity variability, spanning from epigenetic regulation of DPYD expression, factors potentially inducing protein modifications, as well as drug-enzyme interactions that contribute to fluoropyrimidine toxicity. While seminal in vitro studies provided evidence that DPYD promoter methylation downregulates DPD expression, the association of DPYD methylation with fluoropyrimidine toxicity was not replicated in clinical studies. Different non-coding RNA molecules, such as microRNA, piwi-RNAs, circular-RNAs and long non-coding RNAs, are involved in post-transcriptional DPYD regulation. DPD protein modifications and environmental factors affecting enzyme activity may also add a proportion to the pooled variability of DPD enzyme activity. Lastly, DPD-drug interactions are common in therapeutics, with the most well-characterized paradigm the withdrawal of sorivudine due to fluoropyrimidine toxicity deaths in 5-FU treated cancer patients; a mechanism involving DPD severe inhibition. DPYD polymorphisms are the main source of DPD variability. A study on DPYD epigenetics (both transcriptionally and post-transcriptionally) holds promise to provide insights into molecular pathways of fluoropyrimidine toxicity. Additional post-translational DPD modifications, as well as DPD inhibition by other drugs, may explain a proportion of enzyme activity variability. Therefore, there is still a lot we can learn about the DPYD/DPD fluoropyrimidine-induced toxicity machinery.

Pharmacogenetic Variants Can Influence Optical Medication Use.

Single Nucleotide Polymorphisms (SNPs) are used as drug susceptibility biomarkers in metabolic diseases. Alterations in the gene encoding triggers the enzyme flavin monooxygenase 3 (FMO3), involved in the Sulindac metabolization, which also is responsible for the inherited metabolic disorder. Trimethylaminuria (TMAu, OMIM: 602079). DPYD gene variants are associated with the enzyme dihydropyrimidine dehydrogenase deficiency (DPD; OMIM: 274270). This autosomal recessive metabolic disorder, ultimately leads to the inability to metabolize fluoropyrimidines, which causes severe toxicity in individuals treated with these drugs. Variants in genes responsible for the expression of enzymes that encode transporters or receptors involved in the metabolization pathways of certain drugs may condition the individuals response to certain drugs, compromising the therapeutic response and clinical prognosis. Thus the sequencing and identification of variants become relevant, not only gain knowledge on effects of these variants' on disease causality but also in terms of its side effects resulting from the coding enzymes responsible for drug metabolization. It was found that patients with the c.472G>A (p.Glu158Lys) and c.923A>G (p.Glu308Gly) polymorphisms, in homozygosity, in FMO3 gene did not develop polyps, thus have a protective effect in the treatment of Familial Adenomatous Polyposis (PAF). However, in the case of the DPYD gene, c.1905+1G>A (IVS14+1G>A), c.1679T>G (p.Ile560Ser), c.2846A>T (p.Asp949Val) e c.1236G>A/HapB3 variants can be lethal in cancer patients indicated for fluoropyrimidine-based chemotherapy. Knowledge on the drug mechanisms will affect the therapeutic response of patients treated with a given drug. Thus, pharmacogenetics is an essential tool in personalized medicine, since molecular studies allows the clinician to predict the probability of efficacy and toxicity of certain drugs, resulting higher efficiency in individualizing treatment and also improving the safety of the patient. From a personalized medicine perspective, the study of the characteristics of the drug and its metabolization site, the genes involved in the encoding of enzymes responsible for its metabolization will be of great interest.

Developing DPYD Genotyping Method for Personalized Fluoropyrimidines Therapy.

Fluoropyrimidine drugs are widely used in chemotherapy to treat solid tumors. However, severe toxicity has been reported in 10% to 40% of patients. The DPYD gene encodes the rate-limiting enzyme dihydropyrimidine dehydrogenase responsible for fluoropyrimidine catabolism. The DPYD variants resulting in decreased or no enzyme activity are associated with increased risk of fluoropyrimidine toxicity. This study aims to develop a pharmacogenetic test for screening DPYD variants to guide fluoropyrimidine therapy. A multiplex allele-specific polymerase chain reaction (AS-PCR) assay, followed by capillary electrophoresis, was developed to detect 5 common DPYD variants (c.557A > G, c.1129-5923C > G, c.1679T > G, c.1905 + 1G > A, and c.2846A > T). Deidentified population samples were used for screening positive controls and optimizing assay conditions. Proficiency testing samples with known genotypes were analyzed for test validation. All variants detected were confirmed by Sanger sequencing. From the deidentified population samples, 5 samples were heterozygous for c.557A > G, 2 samples were heterozygous for c.1129-5923C > G (HapB3), and 1 sample was heterozygous for c.2846A > T. The 20 proficiency samples matched with their assigned genotypes, including 13 wild-type samples, 3 samples heterozygous for c.1679T > G, 2 samples heterozygous for c.1905 + 1G > A, and 2 samples heterozygous for c.2846A > T. One of the 3 patient samples was heterozygous for c.1129-5923C > G (HapB3). All the variants detected by the multiplex AS-PCR assay were concordant with Sanger sequencing results. A robust multiplex AS-PCR assay was developed to rapidly detect 5 variants in the DPYD gene. It can be used for screening DPYD variants to identify patients with increased risk of toxicity when prescribed fluoropyrimidine therapy.

Implementing a high-reliability, system-wide program for pre-emptive DPD deficiency testing for patients planned for a systemic fluoropyrimidine.

396 Background: Systemic fluoropyrimidine indications span several solid tumor types including gastrointestinal, breast, and head and neck malignancies. Dihydropyrimidine dehydrogenase (DPD) is the primary enzyme involved in fluoropyrimidine metabolism. Pathogenic polymorphisms of the gene encoding DPD (DPYD), occur at a rate of 4-7% and correlate with DPD enzyme deficiency. Failure to detect patients with DPD deficiency, and adjust the dosage preemptively, may result in severe toxicity, including death. Methods: Between December 2022 and May 2023, Dana-Farber Cancer Institute (DFCI) implemented a program across all sites of care to simplify and standardize preemptive DPYD testing for patient planned for a systemic fluoropyrimidine. The opt-out program includes an automated alert recommending DPYD testing when an oncologist orders a new regimen containing either 5FU or capecitabine, education for providers, pharmacists and nurses, patient education materials, standardized tracking of pending results, closed loop notification of providers of abnormal test results, dose adjustment guidelines, and patient tracking. DPYD allelic variants tested: *2A, *7, *8, *10, *13, rs67376798, rs75017182, rs115232898. Results: DPYD testing has increased from a baseline of 14% to 89%. Abnormal DPYD activity (score <2) has been detected in 5.1% of cases (28 of 553). 23 tests were performed preemptively and 5 reactively (all 5 after > grade 3 toxicity events). 27 cases had a single abnormal allele (activity score 1.5 or 1.0); a single case had 2 abnormal alleles (homozygous for rs75017182). Among 11 of the original 23 preemptively tested patients who continued fluoropyrimidine treatment at our facility, standardized dosage reductions were successfully applied for 10 (90.9%). None have experienced > grade 3 toxicity and subsequent dose escalation was possible for 5 (45.5%) patients. Conclusions: We have implemented a voluntary approach to facilitate routine preemptive DPYD testing for patients planned for a systemic fluoropyrimidine achieving an 89% usage rate. 28 of 553 (5.1%) patients were found to have at least a single allelic variant. Preemptive dose reductions were successfully applied for 90.9% of cases. The results provide proof of principle that pharmacogenomic testing can be applied in routine clinical practice and sets the stage for testing additional genes.

The Evaluation of Dihydropyrimidine Dehydrogenase Enzyme Level in the Serum of Colorectal Cancer Iraqi Males on Fluoropyrimidine-Based Chemotherapy (Capecitabine).

The cornerstone of systemic chemotherapy for colorectal cancer (CRC) revolves around fluoropyrimidines. This class encompasses 5-fluorouracil (5-FU), which is administered intravenously, along with its oral prodrug counterpart, capecitabine. Central to the metabolism of both 5-FU and capecitabine is the pivotal enzyme dihydropyrimidine dehydrogenase (DPD). Operating at the rate-limiting juncture, DPD assumes a critical role. Notably, a deficiency in DPD significantly elevates the risk quotient for encountering unfavorable outcomes linked to the administration of fluoropyrimidines. This study seeks to assess the significance of DPD enzyme levels in the serum of Iraqi colorectal cancer male patients undergoing fluoropyrimidine-based chemotherapy, specifically with capecitabine. It adopts a case-control design and comprises 80 male participants. Those males are divided into two distinct groups. Group 1 comprises 45 male patients diagnosed with CRC who have experienced relapse subsequent to undergoing chemotherapy based on fluoropyrimidine (capecitabine). Their ages span from 41 to 71 years, and they were treated at the Misan Health Directorate/Misan Center for Tumor Treatment. Group 2 encompasses 35 male patients diagnosed with CRC who underwent fluoropyrimidine-based chemotherapy (capecitabine) without encountering relapse. Their ages range from 40 to 57 years. All participants were provided with comprehensive information regarding the research, and data collection occurred through a structured questionnaire. Subsequent to capecitabine-based treatment, serum samples were collected from CRC patients (stage III). The findings from this research indicate a notable elevation in DPD enzyme activity. Furthermore, a significant reduction in enzyme activity was observed among patients who experienced relapse, in contrast to those who remained non-relapsed.The results indicate that individuals with an insufficiency in DPD are notably more vulnerable to experiencing severe and potentially life-threatening side effects upon exposure to the commonly utilized chemotherapy drug, 5-FU.

Implementation of upfront DPYD genotyping with a low-cost and high-throughput assay to guide fluoropyrimidine treatment in cancer patients.

Genetic variants in the dihydropyrimidine dehydrogenase (DPYD) gene are associated with reduced dihydropyrimidine dehydrogenase enzyme activity and can cause severe fluoropyrimidine-related toxicity. We assessed the frequency of the four most common and well-established DPYD variants associated with fluoropyrimidine toxicity and implemented a relatively low-cost and high-throughput genotyping assay for their detection. This study includes 457 patients that were genotyped for the DPYD c.1129-5923C>G, c.1679T>G, c.1905 + 1G>A and c.2846A>T variants, either by Sanger sequencing or kompetitive allele specific PCR (KASP) technology. Of these, 172 patients presented toxicity during treatment with fluoropyrimidines (post-treatment group), and 285 were tested before treatment (pretreatment group). Heterozygous DPYD variants were identified in 7.4% of the entire series of 457 patients, being the c.2846A>T the most frequent variant. In the post-treatment group, 15.7% of the patients presented DPYD variants, whereas only 2.5% of the patients in the pretreatment group presented a variant. The KASP assays designed in this study presented 100% genotype concordance with the results obtained by Sanger sequencing. The combined assessment of the four DPYD variants in our population increases the identification of patients at high risk for developing fluoropyrimidine toxicity, supporting the upfront routine implementation of DPYD variant genotyping. Furthermore, the KASP genotyping assay described in this study presents a rapid turnaround time and relatively low cost, making upfront DPYD screening feasible in clinical practice.

DPD deficiency in an Irish oncology centre: Prevalence and clinical implications.

Fluorouracil (5FU) and capecitabine are metabolised by dihydropyrimidine dehydrogenase (DPD). Up to 9% of people have low levels of a working DPD enzyme and are at risk of severe toxicity from 5FU/capecitabine. In April 2020, the EMEA recommended patients undergo prospective screening for DPD deficiency before starting treatment, and this was introduced in our hospital. We retrospectively reviewed records of all patients receiving 5FU/capecitabine in a tertiary Irish cancer centre from May 2020 to April 2021 (n = 197), and those starting first-line treatment in May 2019-April 2020 (n = 97). Our primary outcome was to estimate the prevalence of DPYD variant genes by prospective genotypic screening, with secondary outcomes including variant prevalence by prospective and reactive screening in patients receiving first-line treatment, and 5FU toxicity/tolerability in those with detected variants. In those treated 2020-2021, cancer subtypes included colorectal (n = 120, 61%), breast (n = 34, 17%), and biliary/pancreatic cancers (n = 21, 11%). Median patient age was 62 (range 25-86 years); 40% (n = 79) of patients were screened overall, with a prospective-screening deficiency prevalence of 6.8% (n = 3 of 44). Three patients had pathogenic DPYD-variants detected by prospective screening and tolerated treatment with 50% up-front dose reduction of 5FU, two had variants of uncertain significance detected by reactive screening. Other Irish studies estimated prevalence at 11-12%. As the number of variants detected was small, and screening rates were incomplete, our study may have underestimated prevalence. Approximately 6.8% of Irish patients may carry DPD deficiencies, prospective screening is essential to reduce the risk of life-threatening toxicity in these patients.

Addressing Resistance to Therapy in Colorectal Cancer

Addressing Resistance to Therapy in Colorectal Cancer

Frequency of fluoropyrimidine-related toxicity in patients with colon cancer from a Mexican oncology center.

e15616 Background: Fluoropyrimidines are chemotherapeutic agents used in various types of cancer such as colorectal, breast, gastric, etc. Approximately 30% of patients treated with fluoropyrimidines present severe toxicity, which can lead to death in around 1% of them. Reduced activity of the enzyme dihydropyrimidine dehydrogenase (DPD) can cause severe fluoropyrimidine-related toxicity. The objective of this study was to identify the frequency of fluoropyrimidine-related toxicity in patients treated at an oncology center from Northeast Mexico. Methods: Retrospective and observational study of patients treated at the Centro Universitario contra el Cáncer (CUCC) in Monterrey, Mexico. Patients older than 18 years with a diagnosis of colon cancer who were treated during 2021 with the diagnosis of colon and considered candidates for fluoropyrimidine-based chemotherapy (5-FU, capecitabine) were included. Pregnant patients were excluded. None of them had a DPYD testing performed. Results: We analyzed 88 patients, of whom 51 (58%) were men, 6 (7%) in stage I, 16 (18%) in stage II, 31 (35%) in stage III, and 35 (40%) in stage IV. The mean age was 59 years, 15 (17%) of them had a PS>2, overall, 94% of patients received fluoropyrimidine-based CT, presenting up to 47 (57%) of toxicities, 26 (32%) in G1, 11 (13%) in G2, and 10 (12%) in G3; no G > 4 toxicities were documented. There were 7 patients (9%) that required CT discontinuation due to toxicity at some point during their treatment (see Table 1). In the subgroup of patients in stage IV, 8 (24%) had PS>2, and 6 (18%) of them had some mutational panel. Conclusions: This is one of the few descriptive studies of toxicities in a population from northeastern Mexico undergoing treatment with fluoropyrimidine-based CT, in which up to 9% of the patients discontinue treatment due to toxicity. Our findings evidence a high percentage of patients with fluoropyrimidine-related toxicity. DPYD testing has not been widely adopted in most oncology centers in Mexico, mostly because of the limited access to genome sequencing. Genetic studies in this population could identify poor metabolizers patients with a high risk of toxicity before starting treatment. [Table: see text]

A Detailed Review on Dihydropyrimidine Dehydrogenase Enzyme Deficiency-Autosomal Recessive Condition

Abstract: Dihydropyrimidine dehydrogenase deficiency (DPD) is an autosomal recessive condition. The DPD enzyme is in charge of the 5-fluorouracil drug’s metabolism. Patients having DPD deficiency, when get administered with 5-fluorouracil drug, leads to drug toxicity due to increased concentration of drug in the body. Determining the DPYD (gene encoding DPD) genotyping and DPYD phenotyping will provide the best strategy to know the DPD deficiency in patients. Tegafur and Capecitabine are available prodrugs for the 5-fluorouracil medication. Genomic techniques appear to be a superior indirect evaluation for screening DPD deficiency in the clinical environment. Other than this there are several diagnostic tests such as Uracil oral loading dose, Uracil Breath test, Rapid UPLC-UV (Ultra performance liquid chromatography-Ultravoilet) method, and DPD activity in mononuclear cells from the peripheral circulation. An antidote Uridine Triacetate is available for treating the toxicity produced by 5-FU (5-Fluorouracil) in DPD deficient patient. Hence, this review explains briefly about the DPD enzyme, its deficiency, its diagnosis, and how to manage the DPD deficient patient undergoing chemotherapy. Keywords: DPD, 5-Fluorouracil, Capecitabine, Tegafur, Uracil Breath test, Uridine triacetate.

Implementation of dihydropyrimidine dehydrogenase deficiency testing in Europe

The main cause for fluoropyrimidine-related toxicity is deficiency of the metabolizing enzyme dihydropyrimidine dehydrogenase (DPD). In 2020, the European Medicines Agency (EMA) recommended two methods for pre-treatment DPD deficiency testing in clinical practice: phenotyping using endogenous uracil concentration or genotyping for DPYD risk variant alleles. This study assessed the DPD testing implementation status in Europe before (2019) and after (2021) the release of the EMA recommendations. The survey was conducted from 16 March 2022 to 31 July 2022. An electronic form with seven closed and three open questions was e-mailed to 251 professionals with DPD testing expertise of 34 European countries. A descriptive analysis was conducted. We received 79 responses (31%) from 23 countries. Following publication of the EMA recommendations, 87% and 75% of the countries reported an increase in the amount of genotype and phenotype testing, respectively. Implementation of novel local guidelines was reported by 21 responders (27%). Countries reporting reimbursement of both tests increased in 2021, and only four (18%) countries reported no coverage for any testing type. In 2019, major implementation drivers were 'retrospective assessment of fluoropyrimidine-related toxicity' (39%), and in 2021, testing was driven by 'publication of guidelines' (40%). Although the major hurdles remained the same after EMA recommendations-'lack of reimbursement' (26%; 2019 versus 15%; 2021) and 'lack of recognizing the clinical relevance by medical oncologists' (25%; 2019 versus 8%; 2021)-the percentage of specialists citing these decreased. Following EMA recommendations, 25% of responders reported no hurdles at all in the adoption of the new testing practice in the clinics. The EMA recommendations have supported the implementation of DPD deficiency testing in Europe. Key factors for successful implementation were test reimbursement and clear clinical guidelines. Further efforts to improve the oncologists' awareness of the clinical relevance of DPD testing in clinical practice are needed.

A pilot study using immunohistochemical staining to characterize dihydropyrimidine dehydrogenase expression in keratinocyte neoplasms

To the Editor: Topical 5-fluorouracil (5-FU) is a chemotherapeutic agent used to treat actinic keratoses (AK), superficial basal cell carcinoma, and squamous cell carcinoma in situ (SCCis). 5-FU is metabolized and inactivated by the enzyme dihydropyrimidine dehydrogenase (DPD), which is highly active in the liver but can be expressed in tumors as well. In several visceral malignancies, tumor DPD expression predicts response to systemic 5-FU: tumors with lower DPD expression correlate with higher 5-FU reactivity and better clinical response.1Horiguchi J. Yoshida T. Koibuchi Y. et al.DPD activity and immunohistochemical DPD expression in human breast cancer.Oncol Rep. 2004; 11: 65-72PubMed Google Scholar, 2Oi K. Makino M. Ozaki M. et al.Immunohistochemical dihydropyrimidine dehydrogenase expression is a good prognostic indicator for patients with Dukes' C colorectal cancer.Anticancer Res. 2004; 24: 273-279PubMed Google Scholar, 3Fukuda H. Takiguchi N. Koda K. Oda K. Seike K. Miyazaki M. Thymidylate synthase and dihydropyrimidine dehydrogenase are related to histological effects of 5-fluorouracil and cisplatin neoadjuvant chemotherapy for primary gastric cancer patients.Cancer Invest. 2006; 24: 235-241https://doi.org/10.1080/07357900600632082Crossref PubMed Scopus (18) Google Scholar Although this association has been studied in visceral tumors, the expression of DPD in keratinocyte neoplasms is not known. In this pilot study, we assessed DPD expression in benign, premalignant, and malignant keratinocyte neoplasms to assess the range and level of DPD activity. We performed DPD immunohistochemistry (IHC) staining of 26 superficial and nodular basal cell carcinomas (BCCs), 10 SCCis, 16 AKs, and 8 seborrheic keratoses from formalin-fixed paraffin-embedded specimens collected within the past 3 years. Diagnoses were confirmed by dermatopathologists (B.H., B.D.). DPD IHC was performed with anti-DPD antibody (Abcam #134922, 1:500 dilution). DPD expression was scored by intensity ranging from 0 to 3 by 2 authors (O.I. and B.D.), with hepatic staining as a positive control (Table I). Fisher’s exact test was used to compare DPD scores between classes of keratinocyte neoplasms (R software, version 4.0.3, https://www.r-project.org).Table IDihydropyrimidine dehydrogenase immunohistochemistry intensity score in patient samples (n = 60)DPD IHC intensity score0123Seborrheic keratosis0422Actinic keratosis1960SCC in situ0442Basal cell carcinoma21410Basal cell carcinoma includes both superficial and nodular subtypes. DPD IHC intensity was scored from 0 to 3 (0: no expression, 1: weak expression, 2: moderate expression, 3: strong expression). Fisher’s exact test P value = 3.95 × 10−9.DPD, Dihydropyrimidine dehydrogenase; IHC, immunohistochemistry; SCC, squamous cell carcinoma. Open table in a new tab Basal cell carcinoma includes both superficial and nodular subtypes. DPD IHC intensity was scored from 0 to 3 (0: no expression, 1: weak expression, 2: moderate expression, 3: strong expression). Fisher’s exact test P value = 3.95 × 10−9. DPD, Dihydropyrimidine dehydrogenase; IHC, immunohistochemistry; SCC, squamous cell carcinoma. The results showed a significantly enriched proportion of BCCs (81%, 21/26) displaying no DPD expression (DPD IHC intensity score of 0), compared to 0% (0/10) of SCCis and 6% (1/16) of AKs (P = 3.95 × 10−9, Table I). By contrast, 15% of BCC, 40% of SCCis, and 56% of AK had an intensity score of 1; 3% of BCC, 40% of SCCis, and 37.5% of AK had an intensity score of 2; and 0% of BCC, 20% of SCCis, and 0% of AK had an intensity score of 3 (Table I). The DPD intensity scores of seborrheic keratoses, a noncancerous keratinocyte neoplasm control, were distributed between 1 and 3. Our results suggest that DPD expression varies both within and across different keratinocyte neoplasms, and that a substantial fraction of BCC may have lower DPD expression compared to AK, squamous cell carcinoma (SCC), and seborrheic keratoses. Clinical studies have reported a wide range of efficacy in the use of topical 5-FU treatment for early-stage BCC and SCC, with success rates in SCC ranging from 27% to 93%.4Love W.E. Bernhard J.D. Bordeaux J. Topical imiquimod or fluorouracil therapy for basal and squamous cell carcinoma.Arch Dermatol. 2009; 145: 1431-1438Crossref PubMed Scopus (191) Google Scholar,5Neale H. Michelon M. Jacob S. et al.Topical 5% 5-fluorouracil versus procedural modalities for squamous cell carcinoma in situ and superficial basal cell carcinoma: a retrospective cohort analysis.J Am Acad Dermatol. 2022; 87: 423-425https://doi.org/10.1016/j.jaad.2021.08.045Abstract Full Text Full Text PDF PubMed Scopus (1) Google Scholar While differences in treatment regimens and study design are likely to contribute to this variability, our results raise the possibility that differences in keratinocyte tumor DPD expression could also play a role in topical 5-FU treatment efficacy. The results of this pilot study support the value of a larger prospective study to investigate if DPD expression predicts clinical response of low-grade BCC and SCC to topical 5-FU. If true, then DPD IHC staining could be performed by pathology services to identify keratinocyte neoplasms that are more likely to respond favorably to topical 5-FU, reducing the uncertainty of treatment efficacy to this useful therapeutic option. None disclosed.

Dihydropyrimidine dehydrogenase phenotype in peripheral blood mononuclear cells is related to adverse events of fluoropyrimidine-therapy.

The primary objective of this study was to determine if dihydropyrimidine dehydrogenase (DPD) activity measured in peripheral blood mononuclear cells (PBMCs) is related to adverse events during fluoropyrimidine therapy. A retrospective cohort study was conducted. The study population included 481 patients who received fluoropyrimidine treatment and for whom relevant patient characteristics were known and adverse events were noted in the electronic health records. Factors besides DPD phenotype that could affect the incidence of adverse events were corrected for using log regression. These log regression models were used to identify an association between the DPD phenotype measured in PBMCs and adverse events. Patients with a decreased DPD activity measured in PBMCs suffered more adverse events. Results from log regression data show that this effect remains significant after correcting for dosage, chemotherapy regimen and relevant patient characteristics. A significant correlation was found between reduced DPD enzyme activity in PBMCs and adverse events. The findings in this paper support further exploring DPD phenotyping as a method for preventing fluoropyrimidine-related adverse events. Further assessment of DPD phenotyping will require clinical validation in a prospective study.

Personalized therapy: the crucial role of the DPYD c.2194G>A (V732I) allele in the treatment of colorectal cancer patients candidates for therapy with fluoropyrimidines

5-Fluorouracil (5FU) is a chemotherapeutic agent belonging to the class of antimetabolite drugs, which exert a toxic action causing death of neoplastic cells. 5FU is mostly used as a standard treatment for colorectal cancer; the development of toxicity phenomena is related to the partial or complete deficiency of the enzyme dihydropyrimidine dehydrogenase (DPD), limiting factor of the catabolism of fluoropyrimidines. Only 3-5% of 5-FU is converted to an active metabolite, while 85% of the drug is inactivated by DPD to 5-fluoro-dihydrouracil (5-FDHU). A reduced enzymatic activity of the DPD can be the cause for the presence of adverse drug reactions and toxicity in the patient, with multiorgan involvement, which can sometimes lead to death. The variants of the DPYD gene recommended by the AIOM (Associazione Italiana di Oncologia Medica)guidelines are: DPYD*2A (IVS14+1G>A, c.1905+1G>A); DPYD*13 (c.1679T>G); DPYD c.2846A>T, D949V; DPYD c.1236G>A (HapB3); DPYD c.2194G>A (V732I).Patients with complete DPD deficiency are at high risk of life-threatening or fatal toxicity and should not be treated with fluoropyrimidines, but this is a rare condition; while patients with partial deficiency should be treated with a reduced dose of the drug. Before starting treatment it’s crucial to determine the genetic profile of the patients candidates to therapy with fluoropyrimidines. In our cohort of the 370 samples analyzed by Real Time PCR, 294(~80%) are wild type for each variant screened. : DPYD c.2194G>A (V732I) alleleis significantly represented in the population examinated: considering the 15% reduction in drug administration imposed by this genotype, molecular profiling is essential before starting therapy with 5FU.In our study we also found a rare variant DPYD F632F rs17376848 c.1896 T> C in a patient, whose relevancefor therapeutic purposes is currently of uncertain significance.

71P Capecitabine-induced adverse events: A pharmacogenetic study beyond DPYD

Capecitabine treatment is frequently accompanied by adverse events such as hand-foot syndrome (HFS), leading to interruption --or even discontinuation-- of treatment in approximately 26% of patients. These adverse events can be mitigated with pre-emptive dose reductions in case of single nucleotide polymorphisms (SNPs) in DPYD, encoding the main fluoropyrimidine-metabolizing enzyme dihydropyrimidine dehydrogenase. However, HFS still occurs in 53-77% of patients treated with capecitabine. In this study, we investigated if SNPs in other genes involved in capecitabine metabolism are predictive for capecitabine-induced HFS.

Awareness and attitudes of oncology specialists toward dihydropyrimidine dehydrogenase testing in Saudi Arabia.

Fluoropyrimidines (FP) are among the most common class of prescribed anti-neoplastic drugs. This class has severe to moderate toxicity in around 10%-40% of those who take 5-fluorouracil (5-FU) or capecitabine for the treatment of cancer. In practice many patients with severe toxicities from FP use had dihydropyrimidine dehydrogenase (DPD) enzyme deficiency. Several studies have proposed DPD screening before treatment with 5-fluorouracil (5-FU) and capecitabine or other drugs belonging to the FP group. This study aims to assess the level of awareness and attitudes of oncology specialists in Saudi Arabia toward genetic screening for DPD prior to giving FP. This highlights the importance of health guidelines required for implementation in our health care system, as a framework to adopt testing as a regular practice in clinical care. Based on the findings in this study, guidelineshave been suggested for the Middle East North Africa region. A cross-sectional survey study was conducted during 2021 targeting oncologists and clinical pharmacists working in the oncology departments across Saudi Arabia. A total of 130 oncologists and pharmacists completed the questionnaire representing a response rate of 87%. Most of the respondents indicated that they prescribe FP in clinical practice, but 41% of respondents reported that they have never ordered a specific molecular test during their practice. Only 20% of respondents reported that they often screen for DPD deficiency prior to prescribing FP. Significantly higher rates of awareness of potential dihydropyrimidine dehydrogenase gene (DPYD) mutation were observed among respondents in governmental hospitals (81.1% vs. 47.4% in private hospitals), and among those with more years of practice (80.6% if 5 or more years of practice vs. 59.3% if less than 5 years of practice). Also, higher rates of observing the impact of DPD testing were present among respondents with a PharmD (35% vs. 11% for oncologists and 18% for other professions) and among those with 5 or more years of practice (24.6% vs. 7.7% among those with less than 5 years). While in some institutions there is a high level of awareness among oncology specialists in Saudi Arabia regarding the effect of the potentially serious DPD enzyme deficiency as a result of gene mutations, screening for these mutations prior to prescribing FP is not a routine practice in hospitals across the country. The findings of this study should promote personalized medicine with recognition of interpatient variability via DPD testing to manage the risks of FP prescribing more effectively in the Kingdom of Saudi Arabia.

Testing for Dihydropyrimidine Dehydrogenase Deficiency to Individualize 5-Fluorouracil Therapy.

Simple Summary5-Fluorouracil (5-FU) is a chemotherapy drug that is commonly used to treat multiple cancers. Many people who are treated with 5-FU experience severe toxicity to the drug, and in severe cases, patients can die. This review discusses current methods for identifying people who are at high risk for severe side effects to 5-FU therapy.Severe adverse events (toxicity) related to the use of the commonly used chemotherapeutic drug 5-fluorouracil (5-FU) affect one in three patients and are the primary reason cited for premature discontinuation of therapy. Deficiency of the 5-FU catabolic enzyme dihydropyrimidine dehydrogenase (DPD, encoded by DPYD) has been recognized for the past 3 decades as a pharmacogenetic syndrome associated with high risk of 5-FU toxicity. An appreciable fraction of patients with DPD deficiency that receive 5-FU-based chemotherapy die as a result of toxicity. In this manuscript, we review recent progress in identifying actionable markers of DPD deficiency and the current status of integrating those markers into the clinical decision-making process. The limitations of currently available tests, as well as the regulatory status of pre-therapeutic DPYD testing, are also discussed.

Endogenous metabolic markers for predicting the activity of dihydropyrimidine dehydrogenase.

Five‐fluorouracil (5‐FU) is a chemotherapeutic agent that is mainly metabolized by the rate‐limiting enzyme dihydropyrimidine dehydrogenase (DPD). The DPD enzyme activity deficiency involves a wide range of severities. Previous studies have demonstrated the effect of a DPYD single nucleotide polymorphism on 5‐FU efficacy and highlighted the importance of studying such genes for cancer treatment. Common polymorphisms of DPYD in European ancestry populations are less frequently present in Koreans. DPD is also responsible for the conversion of endogenous uracil (U) into dihydrouracil (DHU). We quantified U and DHU in plasma samples of healthy male Korean subjects, and samples were classified into two groups based on DHU/U ratio. The calculated DHU/U ratios ranged from 0.52 to 7.12, and the two groups were classified into the 10th percentile and 90th percentile for untargeted metabolomics analysis using liquid chromatography‐quantitative time‐of‐flight‐mass spectrometry. A total of 4440 compounds were detected and filtered out based on a coefficient of variation below 30%. Our results revealed that six metabolites differed significantly between the high activity group and low activity group (false discovery rate q‐value < 0.05). Uridine was significantly higher in the low DPD activity group and is a precursor of U involved in pyrimidine metabolism; therefore, we speculated that DPD deficiency can influence uridine levels in plasma. Furthermore, the cutoff values for detecting DPD deficient patients from previous studies were unsuitable for Koreans. Our metabolomics approach is the first study that reported the DHU/U ratio distribution in healthy Korean subjects and identified a new biomarker of DPD deficiency.

Ethnic Diversity of DPD Activity and the DPYD Gene: Review of the Literature.

Pharmacogenomic screening can identify patients with gene variants that predispose them to the development of severe toxicity from fluoropyrimidine (FP) chemotherapy. Deficiency of the critical metabolic enzyme dihydropyrimidine dehydrogenase (DPD) leads to excessive toxicity on exposure to fluoropyrimidine chemotherapy. This can result in hospitalisation, intensive care admissions and even death. Upfront screening of the gene that encodes for DPD (DPYD) has recently been implemented in regions throughout Europe and the United Kingdom. Current screening evaluates DPYD variants that are well described within Caucasian patient populations and provides genotyped-guided dose adjustment recommendations based upon the presence of these variants. This article reviews the differences in DPYD gene variants within non-Caucasian populations compared to Caucasian populations, with regard to the implications for clinical tolerance of fluoropyrimidine chemotherapies and genotype guided dose adjustment guidelines.