Dihydropyrimidine Dehydrogenase Deficiency Research Articles

Evaluation of the Tasso-SST® capillary blood microsampling device for the measurement of endogenous uracil levels

BackgroundUracil (U) plasma or serum levels can be used as surrogates of dihydropyrimidine dehydrogenase (DPD) activity, which is strongly related to the occurrence of severe or fatal toxicity after administration of fluoropyrimidines (FP) chemotherapy. Obtaining blood plasma or serum for U measurement usually requires a phlebotomy procedure by a qualified professional. An alternative to conventional blood drawn is the use of the Tasso-SST® device, which allows the collection of a small blood volume from skin capillaries. This study aimed to implement a sensitive liquid chromatography-tandem mass spectrometry (LC-MS/MS) assay for the determination of U in small serum samples and to compare U concentrations measured in venous plasma, obtained after phlebotomy, and serum obtained with the Tasso-SST® device. MethodsFifty microliter samples were prepared through simple protein precipitation with trichloroacetic acid. Chromatographic separation was performed with a porous graphitic carbon stationary phase and mass spectrometric detection used positive electrospray ionization. The assay was validated according to international guidelines. ResultsThe linear range of the assay was 5–250 ng/mL. Measurement accuracy was in the range of 98.8–108.2%, inter-assay precision was 4.3–7.3%, and intra-assay precision was 3.4–6.1%. The average matrix effect was −6.42%. The extraction yield was 95–103.3%. U concentrations measured in serum obtained with the Tasso-SST® device and venous blood plasma were highly correlated (rs = 0.910, P < 0.0001), and no systematic or proportional bias between U levels measured in both matrices was found. ConclusionsThe use of blood microsampling with the Tasso-SST® device is a useful alternative for the measurement of U and the identification of patients with DPD deficiency.

Dihydropyrimidine Dehydrogenase Deficiency and Implementation of Upfront DPYD Genotyping.

Fluoropyrimidines (FP; 5-fluorouracil, capecitabine, and tegafur) are a commonly prescribed class of antimetabolite chemotherapies, used for various solid organ malignancies in over 2 million patients globally per annum. Dihydropyrimidine dehydrogenase (DPD), encoded by the DPYD gene, is the critical enzyme implicated in FP metabolism. DPYD variant genotypes can result in decreased DPD production, leading to the development of severe toxicities resulting in hospitalization, intensive care admission, and even death. Management of toxicity incurs financial burden on both patients and healthcare systems alike. Upfront DPYD genotyping to identify variant carriers allows an opportunity to identify patients who are at high risk to suffer from serious toxicities and allow prospective dose adjustment of FP treatment. This approach has been shown to reduce patient morbidity, as well as improve the cost-effectiveness of managing FP treatment. Upfront DPYD genotyping has been recently endorsed by several countries in Europe and the United Kingdom. This review summarizes current knowledge about DPD deficiency and upfront DPYD genotyping, including clinical and cost-effectiveness outcomes, with the intent of supporting implementation of an upfront DPYD genotyping service with individualized dose-personalization.

SO-29 Dihydropyrimidine dehydrogenase (DPD) genotype and phenotype among Danish cancer patients: Prevalence and correlation between DPYD-genotype mutations and P-uracil concentrations

Fluoropyrimidines (FP) are the cornerstone of chemotherapy of several, mainly gastrointestinal, solid tumors. FP includes 5-fluorouracil, capecitabine, and tegafur, all metabolized by dihydropyrimidine dehydrogenase (DPD) enzyme. Patients with decreased DPD-activity have a higher risk of getting severe toxicity if treated with standard FP doses. The DPD-activity is currently a standard test in Denmark with a DPYD-genotype-test and/or a measurement of the endogenous compound uracil (DPD-phenotype test). In Denmark, the recommended FP starting dose for patients diagnosed with partial DPD-deficiency is 50%. FP treatment is contraindicated in patients with complete DPD-deficiency due to a high risk of life-threatening adverse effects. Patients with one variant SNP and/or uracil concentrations above 16 ng/ml are categorized as having partial DPD deficiency. However, patients are categorized as having complete DPD deficiency if they are homozygous for one variant SNP or compound heterozygous (patients with≥ 2 different variant SNPs) and/or have uracil concentrations above 150 ng/ml. In France and the Netherlands, the prevalence of clinically relevant DPYD variants was 4.7% and 7.7% respectively. No studies have reported data on the prevalence of DPYD variants or P-uracil in Danish cancer patients. We collected data from all Danish public hospital laboratories performing DPYD-genotype and DPD-phenotype analysis from the 1st of July 2020 to the 31st of December 2021. Patients were genotyped for the four clinically relevant DPYD-variants: rs3918290, rs67376798, rs55886062, and rs56038477/rs75018182. Most of the samples were genotyped using the LAMP (loop-mediated isothermal amplification) technology (Lc-Dpd4mut-Lp-24-Lacar Mdx Technologies). Plasma uracil concentrations were measured using liquid chromatography-mass spectrometry (LC-MS). In total 4228 Danish cancer patients were tested. 1985 of the patients were only tested using one method (P-uracil=17, DPYD-genotype=1968). 2243 patients were tested using P-uracil and DPYD-genotyping. Of the 4215 DPYD-genotyped patients, 3895 (92.4%) was wild type and 316 (7.5%) was heterozygous for one of the tested variants (SNP'S). rs3918290 (1%, n=43), rs67376798 (1.4%, n=57), rs55886062 (0.2%, n=8) and rs56038477/rs75018182 (4.9%, n=208). Four patients (0.1%) were compound heterozygous. Among 2260 patients tested, 2132 (94.3%) had an uracil concentration below 16 ng/ml. The remaining 128 (5.7%) patients had uracil concentrations ≥ 16 ng/mL and < 150 ng/ml. No values above 150 ng/ml was found. Median uracil concentration was 8 ng/ml (range 5-82 ng/ml). Both geno- and phenotype were available for 2243 of the patients. Uracil concentrations among wild type patients were lower (mean 8.6 ng/ml) compared to patients with DPYD-variants (mean 11.2 ng/ml), mean difference of 2.7 ng/ml. (95% CI; 1.9-3.4 ng/ml). In 4.8% (n=99) of wild type patients, the uracil concentration was ≥ 16 ng/ml compared to 16.8% (n=29) in the group with DPYD-mutations. The prevalence of clinically relevant DPYD-mutations in Danish cancer patients is 7.6% and is in line with results from similar studies of other European populations. 5.7% of phenotyped patients had uracil concentrations ≥ 16 ng/ml. Patients with DPYD-variants had higher mean uracil concentrations compared to wild type, but the uracil concentrations varied substantially in both groups. Data regarding adverse events are needed to conclude on the clinical implications.

P-177 Sex differences in chemotherapy-induced toxicities in gastric cancer patients

Female patients have a higher risk for chemotherapy toxicities due to sex differences related to pharmacokinetics and pharmacodinamics. In the era of evolving gender-medicine, sex-adjusted therapies are earning a role and may become a reality. In this study we aim to detect sex differences for toxicities in gastric cancer patients. This retrospective analysis included all gastric cancer patients treated with curative intent between january 1st 2017 and december 31st 2021, in a Portuguese hospital. All patients included did a minimum of 5 chemotherapy cycles. Patients with dihydropyrimidine dehydrogenase deficiency were excluded. Data regarding treatment and related toxicity was collected and compared between male and female sex. Toxicities were recorded using Common Terminology Criteria for Adverse Events, version 5. A descriptive analysis was performed using SPSS®, the Mann-Whitney and Chi-square test were used for continuous and categorical variables, respectively. A total of 72 patients were included, 61,1% were men and 38,9% women with a median age of 66 vs 62 years, respectively (p=0.441) and an ECOG of 0-1. 22 patients did adjuvant chemotherapy preferably with CAPOX regimen (women: 62,5%, men: 64,3%) and 50 patients underwent perioperative chemotherapy mostly with FLOT regimen (women: 75%, men: 83,3%). For grade ≥ 3 reported toxicities, there were no differences between women and men (71,4% vs 59,1%, p=0,288). Higher rates of nausea and vomiting were reported in female sex, both all grade (82,1% vs 52,3%, p=0,015), and grade ≥ 2 (46,4% vs 15,9%, p=0.005). Women experienced more mucositis episodes, both all grade (32,1% vs 11,4%, p=0.034) and grade ≥ 2 (10,7% vs 0%, p=0.027). Other gastrointestinal toxicities such as diarrhea grade ≥ 2 and all grade anorexia were more likely experienced by women (21,4 vs 18,2% and 64,3% vs 45,4%), although statistical significance was not reached. There were no differences in all grade hematologic toxicities, although women tendentially had higher rates of all grade anemia (82,1% vs 59,1%, p=0,120) and neutropenia (42,8% vs 34%, p=0,657), still men experienced more thrombocytopenia (68,2% vs 42,8%, p=0.161). All grade neuropathy was more prevalent in men, particularly with FLOT regimen (92% vs 73,4%, p=0,105). Of all patients, both sexes underwent a median of 8 cycles. The percentage dose of fluoropyrimidine, oxaliplatin and docetaxel administered was lower in women, with results closer to significance with docetaxel (75,3% vs 88%, p=0,058). Women experienced dose reductions more frequently than men (92,9 vs 72,7%, p=0,035), and also dose delays (75% vs 59,1%, p=0,167). Our results showed that women experience more gastrointestinal toxicities such as nausea/vomiting and mucositis, and tendentially more hematologic toxicities than men. Consequently, dose reductions were significantly more frequent in women, which reinforces the importance of future sex-related interventions in systemic therapy to improve treatment tolerability. Study limitations must be considered such as: its retrospective nature and small sample size, possibly underreported toxicities by clinicians and differences in reporting due to different perceptions of toxicities by both sexes. The consequences of toxicity sex differences must be taken in consideration and its impact in treatment compliance, efficacy and survival further studied.

Investigation of the DPYD, TYMS, ENOSF1, MTHFR, CDA, CES2, and UGT1A1 genes in patients who developed fatal fluoropyrimidine-associated toxicity in Northern Brazil.

e15532 Background: Fluoropyrimidine-based treatments are still considered challenging due to the wide variability in efficacy and toxicity rates presented by patients. This variability can be explained, partially, by individual genetic differences that contribute significantly to the response of the drug, with 30% of patients experiencing severe toxicity related to dihydropyrimidine dehydrogenase (DPD) deficiency and 5-Fluorouracil (5-FU) metabolism. Methods: This study analyzed the exome of the main genes involved in the fluoropyrimidine metabolism pathway ( DPYD, TYMS / ENOSF1, MTHFR, CDA, CES2, and UGT1A1) in seven patient who developed fatal 5-FU toxicity diagnosed with gastric or colorectal adenocarcinoma and underwent fluoropyrimidine-based cancer treatment. The genotyping service was carried out at CEGEN-PRB3-ISCIII; it is supported by grant PT17/0019, of the PE I+D+i 2013-2016, funded by ISCIII and ERDF. Results: A total of 74 genetic polymorphisms were identified, 25 of which stand out due to their potential role in the safety of 5-FU administration. Eight variants are exclusive of the studied population (two found in the DPYD gene, two in the MHFR, one in the CES2, and three in the UGT1A1 gene) and 17 have already been associated with fluoropyrimidine efficacy and/or toxicity events: 10 of them are located in the DPYD gene (rs1801159, rs2297595, rs72728438, rs17376848, rs1801160, rs1801265, rs22447512, rs5568, rs56038477, rs56276561, and rs56293913), two in the intergenic region of the TYMS/ ENOSF1 genes (rs11280056 and rs699517), two in the MTHFR gene (rs1801131 and rs1801133) and three in the CDA gene (rs1048977, rs2072671, and rs3215400). Conclusions: The current study has allowed us to obtain a global profile of genetic variants in the pharmacokinetic and pharmacodynamic pathways of fluoropyrimidines in patients with high genetic miscegenation in the northern region of Brazil who have evolved to death due to the fatal toxicity resulting from 5-FU-based therapies. Keywords: Pharmacogenomics; Exome; 5-Fluorouracil; Drug toxicity; Brazil.

Cancer genomic profiling identified dihydropyrimidine dehydrogenase deficiency in bladder cancer promotes sensitivity to gemcitabine

Chemotherapy is a standard therapy for muscle-invasive bladder cancer (MIBC). However, genomic alterations associated with chemotherapy sensitivity in MIBC have not been fully explored. This study aimed to investigate the genomic landscape of MIBC in association with the response to chemotherapy and to explore the biological role of genomic alterations. Genomic alterations in MIBC were sequenced by targeted exome sequencing of 409 genes. Gene expression in MIBC tissues was analyzed by western blotting, immunohistochemistry, and RNA microarray. Cellular sensitivity to gemcitabine and gemcitabine metabolite was examined in bladder cancer cells after modulation of candidate gene. Targeted exome sequencing in 20 cases with MIBC revealed various genomic alterations including pathogenic missense mutation of DPYD gene encoding dihydropyrimidine dehydrogenase (DPD). Conversely, high DPYD and DPD expression were associated with poor response to gemcitabine-containing chemotherapy among patients with MIBC, as well as gemcitabine resistance in bladder cancer cells. DPD suppression rendered cells sensitive to gemcitabine, while DPD overexpression made cells gemcitabine-resistant through reduced activity of the cytotoxic gemcitabine metabolite difluorodeoxycytidine diphosphate. This study revealed the novel role of DPD in gemcitabine metabolism. It has been suggested that DPYD genomic alterations and DPD expression are potential predictive biomarkers in gemcitabine treatment.

Dihydropyrimidine Dehydrogenase Phenotyping Using Pretreatment Uracil: A Note of Caution Based on a Large Prospective Clinical Study.

In clinical practice, 25–30% of the patients treated with fluoropyrimidines experience severe fluoropyrimidine‐related toxicity. Extensively clinically validated DPYD genotyping tests are available to identify patients at risk of severe toxicity due to decreased activity of dihydropyrimidine dehydrogenase (DPD), the rate limiting enzyme in fluoropyrimidine metabolism. In April 2020, the European Medicines Agency recommended that, as an alternative for DPYD genotype‐based testing for DPD deficiency, also phenotype testing based on pretreatment plasma uracil levels is a suitable method to identify patients with DPD deficiency. Although the evidence for genotype‐directed dosing of fluoropyrimidines is substantial, the level of evidence supporting plasma uracil levels to predict DPD activity in clinical practice is limited. Notwithstanding this, uracil‐based phenotyping is now used in clinical practice in various countries in Europe. We aimed to determine the value of pretreatment uracil levels in predicting DPD deficiency and severe treatment‐related toxicity. To this end, we determined pretreatment uracil levels in 955 patients with cancer, and assessed the correlation with DPD activity in peripheral blood mononuclear cells (PBMCs) and fluoropyrimidine‐related severe toxicity. We identified substantial issues concerning the use of pretreatment uracil in clinical practice, including large between‐center study differences in measured pretreatment uracil levels, most likely as a result of pre‐analytical factors. Importantly, we were not able to correlate pretreatment uracil levels with DPD activity nor were uracil levels predictive of severe treatment‐related toxicity. We urge that robust clinical validation should first be performed before pretreatment plasma uracil levels are used in clinical practice as part of a dosing strategy for fluoropyrimidines.

Pharmacogenomics: Relevance and opportunities for clinical pharmacology

Pharmacogenomics: Relevance and opportunities for clinical pharmacology

Survey of US Medical Oncologists' Practices and Beliefs Regarding DPYD Testing Before Fluoropyrimidine Chemotherapy.

Patients who carry reduced-activity DPYD polymorphisms have increased fluoropyrimidine (FP) toxicity risk. Although pretreatment DPYD testing is recommended throughout most of Europe, it is not recommended in the United States, and adoption has been limited. The objective of this survey was to describe the current practice in the United States regarding pretreatment DPYD testing and understand the factors deterring oncologists from ordering testing. Survey invitations were e-mailed to 325 medical oncologists practicing in the United States who are members of the SWOG Cancer Research Network Gastrointestinal Cancer, Breast Cancer, or Early Therapeutics Committees. Descriptive statistics were used to evaluate survey responses. Responses were collected from 59 (18.2%) US medical oncologists, of whom 98% strongly or somewhat agree that patients with dihydropyrimidine dehydrogenase (DPD) deficiency have increased toxicity risk and 96% would modify FP dosing for a patient with known DPD deficiency. However, only 32% strongly or somewhat agree that pretreatment DPYD testing is useful to inform FP treatment, 20% have ever ordered pretreatment testing, and 3% order testing for at least 10% of their FP-treated patients. The most important factors that deter oncologists from ordering testing were low prevalence of DPD deficiency (54%) and lack of clinical practice guideline recommendations (48%). Clinical adoption of pretreatment DPYD testing is extremely limited in the United States. Utilization may be substantially increased by inclusion in the oncology clinical practice guideline recommendations, coverage through health insurance, and potentially education of medical oncologists regarding available treatment modification guidelines.

Elevated Risk of Fluoropyrimidine-Associated Toxicity in European Patients with DPYD Genetic Polymorphism: A Systematic Review and Meta-Analysis.

Background: Fluoropyrimidine is widely used owing to its clinical efficacy, however, patients with dihydropyrimidine dehydrogenase (DPD) deficiency can experience fluoropyrimidine-associated toxicity. The dihydropyrimidine dehydrogenase (DPYD) gene encodes DPD, and studies suggest that DPYD polymorphisms can result in DPD deficiency. Since there is not a complete consistency of how much the risk of complication is elevated, we aimed to conduct a systematic literature review and a meta-analysis to provide the risk of fluoropyrimidine-associated toxicity in patients with DPYD rs1801160 polymorphism. Methods: We searched for qualifying studies published before October 2021 from PubMed, Web of Science, and EMBASE based on Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated to evaluate the strength of the association between rs1801160 polymorphism and toxicities. A sensitivity analysis using the leave-one-out method was performed on the overall toxicity. Results: The pooled OR for overall toxicity in the patients with A allele was elevated 1.73 times higher than those with the GG genotype (95% CI 1.44–2.07). Sensitivity analysis yielded similar results, showing the robustness of the result. Subjects with variants showed a 2.37-fold increased hematological toxicity (95% CI 1.48–3.81); especially a 1.87-fold increased neutropenia compared to patients with wildtype (95% CI 1.49–2.34). Patients with A allele revealed 1.22 times higher gastrointestinal toxicity compared to those with GG genotype (95% CI 0.93–1.61), and among gastrointestinal toxicity, the risk of diarrhea was elevated 1.43 times higher in those with variants than patients with wildtype (95% CI 1.12–1.83). Conclusions: rs1801160 polymorphism is associated with elevated fluoropyrimidine-associated toxicity. Therefore, rs1801160 can be a potential candidate for DPD deficiency screening prior to fluoropyrimidine-based regimen.

Clinical course and outcome of patients developing capecitabine-induced non-neutropenic enterocolitis (NNEC): An institutional analysis.

656 Background: Non-neutropenic enterocolitis (NNEC), a potentially fatal toxicity of capecitabine (CAPE), is under-reported in the literature. An institutional review was performed to determine the incidence, clinical course, and outcome of patients developing CAPE-induced NNEC. Methods: After the institutional review board approval, a database search identified patients requiring inpatient care for CAPE-induced diarrhea over a period of 6 years (between 01/2015 and 12/2020). Among the patients requiring hospital admission, patients with radiologic features of enterocolitis were included in the analysis. Data on patient characteristics, imaging study results, clinical course, and outcomes were gathered by electronic chart review. Results: Among the 789 patients treated with CAPE, 25 patients (3%) developed grade 3 or higher diarrhea requiring hospital admission, and 13 out of these 25 patients (1.6 % of patients treated with CAPE) had evidence of enterocolitis on CT scan: ileitis in 7/13 (54%), colitis in 1/13 (8%), and both in 5/13 (38%) patients. The median age of the patient cohort was 64 years (range, 31-81), 8/13 (62%) were female, and all patients were Caucasian. CAPE was administered for the following indications: breast cancer in 6 patients, colorectal cancer in 4 patients, cholangiocarcinoma in 2 patients, and neuroendocrine tumor in 1 patient. ECOG performance status at the time of CAPE initiation was 0 in 7 patients and 1 in 6 patients. Most patients (7/13, 54%) received single-agent CAPE, and the majority (10/13, 77%) developed diarrhea with the first cycle after a median of 21 days (range, 10-50). Patients were hospitalized after a median of 27 days (range, 13-51), and the median hospital stay was 12 days (range, 4-25). None of the 13 patients demonstrated neutropenia at the time of hospital admission. The associated adverse effects at the time of admission included grade 3 abdominal pain in 8 (62%) patients, grade 3 nausea in 7 (54%) patients, and grade 3 vomiting in 3 (23%) patients. Hypokalemia and oral mucositis were present at admission in 6 (46%) and 2 (15%) patients, respectively. Stool studies performed in 11 (85%) patients ruled out infection. Testing for dihydropyrimidine dehydrogenase deficiency performed in 4 (31%) patients was negative. All patients were treated with supportive measures, and 2 (15%) patients required total parenteral nutrition. All but 1 patient recovered fully; 1 patient died due to a condition unrelated to CAPE. Intravenous infusional 5-fluorouracil (5-FU) administration in 3 patients after the recovery was tolerated well. Conclusions: CAPE-induced NNEC is uncommon and generally occurs after the first cycle of therapy. Most patients developing CAPE-induced NNEC recover fully with appropriate supportive measures. Infusional 5-FU-based regimens appear to be safe in this patient group.

Treating patients with dihydropyrimidine dehydrogenase (DPD) deficiency with fluoropyrimidine chemotherapy since the onset of routine prospective testing—The experience of a large oncology center in the United Kingdom

Fluoropyrimidine chemotherapy is used across many tumor types and settings. The incidence of severe adverse events (SAEs) is around 20%. Mortality is 0.5%-1%. Dihydropyrimidine dehydrogenase (DPD) plays a key role in fluoropyrimidine inactivation. Key DPYD mutations are linked to a high risk of SAEs. Pretreatment DPD screening was mandated by EMA guidelines in April 2020 and widely adopted thereafter. Uncertainty remains regarding optimal dosing practice. We retrospectively examined records of all 23 patients with DPYD mutation who started chemotherapy between April and November 2020. Our center tests for the mutations considered clinically actionable by Clinical Pharmacogenetics Implementation Consortium and uses the Gene Activity Score (GAS) to guide dose reduction. Most patients started on a 50% dose. One started on 100% and experienced mild diarrhea after cycle 2; DPD was tested belatedly, subsequent cycles were reduced to 50% and he remained well. Three patients receiving chemo-radiotherapy started on 76% dose; 50% was felt to be subtherapeutic. One of them had no toxicities; another had grade 2 nausea and a hospital attendance with non-neutropenic fever; the third was admitted for 6 weeks with pancolitis. Seven patients did not have toxicities above grade 1 and no hospital attendances. Five patients had further dose reductions. None had dose escalation. As our experience shows, patients with DPD deficiency are heterogeneous. Worryingly, SAEs occur despite dose reduction according to GAS. Others had minimal toxicity and may be under-dosed by GAS. There are clearly many factors at play other than the 4 DPYD variants. The DPD result must be available and inform first cycle dosing. Dose should be cautiously titrated up if tolerated; this was not done at our center due to clinician caution. Further research is needed to guide this. Patients should be reviewed frequently, counselled regarding their DPD status, and empowered to seek advice promptly when they feel unwell.

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.

SAFETY MATTERS: THE TROUBLED AND FINALLY SUCCESSFUL STORY OF DIHYDROPYRIMIDINE DEHYDROGENASE PHARMACOGENETIC TEST IN CANCER PATIENTS

Pharmacogenetics investigates the molecular basis of inter-individual differences in drug metabolism and response. Sequence variations in genes encoding for metabolic enzymes may influence drug’s pharmacokinetics and/or pharmacodynamics, resulting in reduced efficacy and/or adverse drug reactions. The dihydropyrimidine dehydrogenase (DPD) deficiency is a clear example of how gene variants may affect fluoropyrimidines metabolism, and its … Continued

Lay understandings of drug-gene interactions: The right medication, the right dose, at the right time, but what are the right words?

As pharmacogenomic (PGx) testing increases in popularity, lay concepts of drug‐gene interactions set the stage for shared decision making in precision medicine. Few studies explore what recipients of PGx results think is happening in their bodies when a drug‐gene interaction is discovered. To characterize biobank participants’ understanding of PGx research results, we conducted a focus group study, which took place after PGx variants conferring increased risk of dihydropyrimidine dehydrogenase (DPD) deficiency were disclosed to biobank contributors. DPD deficiency confers an increased risk of adverse reaction to commonly used cancer chemotherapeutics. Ten focus groups were conducted, ranging from two to eight participants. Fifty‐four individuals participated in focus groups. A framework approach was used for descriptive and explanatory analysis. Descriptive themes included participants’ efforts to make sense of PGx findings as they related to: (1) health implications, (2) drugs, and (3) genetics. Explanatory analysis supplied a functional framework of how participant word choices can perform different purposes in PGx communication. Results bear three main implications for PGx research‐related disclosure. First, participants’ use of various terms suggest participants generally understanding their PGx results, including how positive PGx results differ from positive disease susceptibility genetic results. Second, PGx disclosure in biobanking can involve participant conflation of drug‐gene interactions with allergies or other types of medical reactions. Third, the functional framework suggests a need to move beyond a deficit model of genetic literacy in PGx communication. Together, findings provide an initial evidence base for supporting bidirectional expert‐recipient PGx results communication.

A case in which TAS-102 produced disease control without severe adverse events in a patient with recurrent colorectal cancer and dihydropyrimidine dehydrogenase deficiency

Fluoropyrimidine is commonly used to treat unresectable cases of metastatic colorectal cancer or as an adjuvant therapy for colorectal cancer. Dihydropyrimidine dehydrogenase (DPD) is an enzyme encoded by the DPYD gene, which is responsible for the rate-limiting step in pyrimidine catabolism and breaks down &gt;80% of standard doses of 5-fluorouracil (5-FU). Reductions in DPD activity increase the half-life of 5-FU, resulting in excess 5-FU accumulation and toxicity, which can lead to life-threatening side effects. There have been several published case reports about DPD deficiency in colorectal cancer patients from Western countries. However, case reports of DPD deficiency in Japanese colorectal cancer patients are rare because the measurement of DPD activity is not covered by the public medical insurance system in Japan, and DPD activity is not currently measured in daily clinical practice. Furthermore, there have not been any reports about anticancer drug therapy for Japanese patients with DPD deficiency. In this report, we describe a case in which a Japanese patient with colorectal cancer was diagnosed with DPD deficiency. The DPD deficiency arose as a severe adverse effect of mFOLFOX6/CapOX treatment for recurrent colorectal cancer, and the patient was subsequently treated with TAS-102, without experiencing any severe adverse effects. We report this case along with a review of the literature.

Severe ileum bleeding following adjuvant capecitabine chemotherapy for locally advanced colon cancer: a case report and review of the literature

BackgroundCapecitabine is a prodrug that is enzymatically converted to its active form, fluorouracil (also called 5-fluorouracil), which is commonly used as adjuvant chemotherapy in colorectal cancer patients. Severe gastrointestinal bleeding induced by capecitabine is rare. Here, we are presenting the first case report of surgery specimen assisted diagnosis of this uncommon condition.Case presentationA 63-year-old Chinese male with a history of colon adenocarcinoma and right hemicolectomy presented with severe lower gastrointestinal bleeding 2 days after finishing capecitabine administration during the first cycle of XELOX adjuvant chemotherapy. Because of the negative findings of active bleeding points by digital subtraction angiography (DSA) or colonoscopy, emergency laparotomy and partial enterectomy were performed. The bloody diarrhea had resolved after surgery and a terminal ileitis was diagnosed after pathological examination of the surgical specimen.ConclusionsTerminal ileitis induced by capecitabine is likely to be underreported. It should be considered more often as a cause of severe gastrointestinal bleeding during or after treatment with capecitabine agents. Emergency surgery may achieve satisfactory outcomes if endoscopic hemostasis is ineffective.Highlights of this case1. Gastrointestinal bleeding following capecitabine treatment in colorectal cancer patients might be life-threatening.2. Terminal ileitis induced by capecitabine should always be considered in the differential diagnosis of severe gastrointestinal bleeding.3. Awareness of the risk factors such as deficiency of dihydropyrimidine dehydrogenase, advanced age, or right colectomy may aid in reducing capecitabine-related morbidity.4. When severe bleeding occurs, emergency surgery may achieve satisfactory outcomes if medical and endoscopic interventions are ineffective.

Consensus of experts from the Spanish Pharmacogenetics and Pharmacogenomics Society and the Spanish Society of Medical Oncology for the genotyping of DPYD in cancer patients who are candidates for treatment with fluoropyrimidines

5-Fluorouracil (5-FU) and oral fluoropyrimidines, such as capecitabine, are widely used in the treatment of cancer, especially gastrointestinal tumors and breast cancer, but their administration can produce serious and even lethal toxicity. This toxicity is often related to the partial or complete deficiency of the dihydropyrimidine dehydrogenase (DPD) enzyme, which causes a reduction in clearance and a longer half-life of 5-FU. It is advisable to determine if a DPD deficiency exists before administering these drugs by genotyping DPYD gene polymorphisms. The objective of this consensus of experts, in which representatives from the Spanish Pharmacogenetics and Pharmacogenomics Society and the Spanish Society of Medical Oncology participated, is to establish clear recommendations for the implementation of genotype and/or phenotype testing for DPD deficiency in patients who are candidates to receive fluoropyrimidines. The genotyping of DPYD previous to treatment classifies individuals as normal, intermediate, or poor metabolizers. Normal metabolizers do not require changes in the initial dose, intermediate metabolizers should start treatment with fluoropyrimidines at doses reduced to 50%, and poor metabolizers are contraindicated for fluoropyrimidines.

PathogenicDPYDVariants and Treatment-Related Mortality in Patients Receiving Fluoropyrimidine Chemotherapy: A Systematic Review and Meta-Analysis

Pathogenic variants of the DPYD gene are strongly associated with grade≥3 toxicity during fluoropyrimidine chemotherapy. We conducted a systematic review and meta-analysis to estimate the risk of treatment-related death associated with DPYD gene variants. We searched for reports published prior to September 17, 2020, that described patients receiving standard-dose fluoropyrimidine chemotherapy (5-fluorouracil or capecitabine) who had baseline testing for at least one of four pathogenic DPYD variants (c.1129-5923C>G [HapB3], c.1679T>G [*13], c.1905+1G>A [*2A], and c.2846A>T) and were assessed for toxicity. Two reviewers assessed studies for inclusion and extracted study-level data. The primary outcome was the relative risk of treatment-related mortality for DPYD variant carriers versus noncarriers; we performed data synthesis using a Mantel-Haenszel fixed effects model. Of the 2,923 references screened, 35 studies involving 13,929 patients were included. DPYD variants (heterozygous or homozygous) were identified in 566 patients (4.1%). There were 14 treatment-related deaths in 13,363 patients without identified DPYD variants (treatment-related mortality, 0.1%; 95% confidence interval [CI], 0.1-0.2) and 13 treatment-related deaths in 566 patients with any of the four DPYD variants (treatment-related mortality, 2.3%; 95% CI, 1.3%-3.9%). Carriers of pathogenic DPYD gene variants had a 25.6 times increased risk of treatment-related death (95% CI, 12.1-53.9; p < .001). After excluding carriers of the more common but less deleterious c.1129-5923C>G variant, carriers of c.1679T>G, c.1905+1G>A, and/or c.2846A>T had treatment-related mortality of 3.7%. Patients with pathogenic DPYD gene variants who receive standard-dose fluoropyrimidine chemotherapy have greatly increased risk for treatment-related death. The syndrome of dihydropyrimidine dehydrogenase (DPD) deficiency is an uncommon but well-described cause of severe toxicity related to fluoropyrimidine chemotherapy agents (5-fluorouracil and capecitabine). Patients with latent DPD deficiency can be identified preemptively with genotyping of the DPYD gene, or with measurement of the plasma uracil concentration. In this systematic review and meta-analysis, the authors study the rare outcome of treatment-related death after fluoropyrimidine chemotherapy. DPYD gene variants associated with DPD deficiency were linked to a 25.6 times increased risk of fluoropyrimidine-related mortality. These findings support the clinical utility of DPYD genotyping as a screening test for DPD deficiency.