Dihydropyrimidine Dehydrogenase Deficiency Research Articles

Rapid determination of uracil in biological fluids at mercury thin film electrode for early detection of potential 5-fluorouracil toxicity due to dihydropyrimidine dehydrogenase deficiency

Rapid determination of uracil in biological fluids at mercury thin film electrode for early detection of potential 5-fluorouracil toxicity due to dihydropyrimidine dehydrogenase deficiency

Can we identify patients carrying targeted deleterious DPYD variants with plasma uracil and dihydrouracil? A GPCO-RNPGx retrospective analysis.

Dihydropyrimidine dehydrogenase (DPD) deficiency is the main cause of severe fluoropyrimidine-related toxicities. The best strategy for identifying DPD-deficient patients is still not defined. The EMA recommends targeted DPYD genotyping or uracilemia (U)testing. We analyzed the concordance between both approaches. This study included 19,376 consecutive French patients with pre-treatment plasma U, UH2 and targeted DPYD genotyping (*2A, *13, D949V, *7) analyzed at Eurofins Biomnis (2015-2022). Mean U was 9.9±10.1 ng/mL (median 8.7, range 1.6-856). According to French recommendations, 7.3 % of patients were partially deficient (U 16-150 ng/mL) and 0.02 % completely deficient (U≥150 ng/mL). DPYD variant frequencies were *2A: 0.83 %, *13: 0.17 %, D949V: 1.16 %, *7: 0.05 % (2 homozygous patients with U at 22 and 856 ng/mL). Variant carriers exhibited higher U (median 13.8 vs. 8.6 ng/mL), and lower UH2/U (median 7.2 vs. 11.8) and UH2/U2 (median 0.54 vs. 1.37) relative to wild-type patients (p<0.00001). Sixty-six% of variant carriers exhibited uracilemia <16 ng/mL, challenging correct identification of DPD deficiency based on U. The sensitivity (% patients with a deficient phenotype among variant carriers) of U threshold at 16 ng/mL was 34 %. The best discriminant marker for identifying variant carriers was UH2/U2. UH2/U2<0.942 (29.7 % of patients) showed enhanced sensitivity (81 %) in identifying deleterious genotypes across different variants compared to 16 ng/mL U. These results reaffirm the poor concordance between DPD phenotyping and genotyping, suggesting that both approaches may be complementary and that targeted DPYD genotyping is not sufficiently reliable to identify all patients with complete deficiency.

Tolerance and safety of adjuvant metronomic capecitabine in Indian patients with non-metastatic triple negative breast cancer (TNBC): An institutional experience.

e12530 Background: Triple-negative breast cancer (TNBC) subtype has a high risk of recurrence and overall poorer survival after standard treatment. SYSUCC-001 study presented in ASCO 2020 reported an increased disease-free survival after one year of metronomic capecitabine in operable TNBC patients after completion of local therapy. As per our clinical experience in metastatic breast cancer, many Indian patients are not able to tolerate capecitabine for longer duration. Hence, we wanted to assess the tolerance and safety of one year of daily dosing of capecitabine in our patients with Non-Metastatic TNBC. Methods: We performed a retrospective analysis of non-metastatic TNBC patients receiving adjuvant capecitabine 650 mg /m2 twice daily continuously for one year who took treatment from June 2020 to August 2022. The data extracted included patient socio-demographics, capecitabine information, side effects, and capecitabine treatment changes (dose reductions and dose interruptions). Statistical analysis was conducted using SPSS, version 24. Results: We analyzed 90 patients, out of which majority (62%) were stage II. Median age of the cohort was 48 years. Germline data was available for 64 patients, out which 8 patients were BRCA 1 positive and 8 patients had a variant of undetermined significance. Median duration of capecitabine in our patients was 230 days (IQR: 10 - 360). Twenty-six (28.8%) patients underwent dose reduction and 15 (16.6%) had reported grade 3 toxicity. Mean dose of capecitabine received was 535 mg / m2 twice daily. Treatment was interrupted due to toxicity in 20 (22%) of patients. The most common capecitabine-induced toxicity was hand foot syndrome, which was also the most common reason for dose reduction and treatment interruption. Dihydropyrimidine dehydrogenase (DPD) mutation status was known for 38 patients out of which only one (2.6%) was found to have DPD deficiency. Incidence of grade 3 toxicity was observed to be less in patients with age less than 50 years, ECOG performance status 0-1 and absence of comorbidities. Two-year disease free survival (DFS) and overall survival (OS) was estimated to be 79.3% and 80% respectively. Most common site of metastases was reported to be brain followed by lung. Conclusions: Continuous metronomic dosing of adjuvant capecitabine for 1 year is fairly well tolerated in Indian patients with non-metastatic TNBC, but may still require dose reduction in some patients due to toxicity.

527P Systematic detection of dihydropyrimidine dehydrogenase (DPD) deficiency using UH2/U ratio in patients with digestive cancers in central Tunisia: Toxicity profile

527P Systematic detection of dihydropyrimidine dehydrogenase (DPD) deficiency using UH2/U ratio in patients with digestive cancers in central Tunisia: Toxicity profile

Unveiling Discrepant and Rare Dihydropyrimidine Dehydrogenase (DPYD) Results Using an In-House Genotyping Test: A Case Series.

Fluoropyrimidine chemotherapy is a primary component of many solid tumor treatment regimens, particularly those for gastrointestinal malignancies. Approximately one-third of patients receiving fluoropyrimidine-based chemotherapies experience serious adverse effects. This risk is substantially higher in patients carrying DPYD genetic variants, which cause reduced fluoropyrimidine metabolism and inactivation (ie, dihydropyridine dehydrogenase [DPD] deficiency). Despite the known relationship between DPD deficiency and severe toxicity risk, including drug-related fatalities, pretreatment DPYD testing is not standard of care in the United States. We developed an in-house DPYD genotyping test that detects 5 clinically actionable variants associated with DPD deficiency, and genotyped 827 patients receiving fluoropyrimidines, of which 49 (6%) were identified as heterozygous carriers. We highlight 3 unique cases: (1) a patient with a false-negative result from a commercial laboratory that only tested for the c.1905 + 1G>A (*2A) variant, (2) a White patient in whom the c.557A>G variant (typically observed in people of African ancestry) was detected, and (3) a patient with the rare c.1679T>G (*13) variant. Lastly, we evaluated which DPYD variants are detected by commercial laboratories offering DPYD genotyping in the United States and found 6 of 13 (46%) did not test for all 5 variants included on our panel. We estimated that 20.4% to 81.6% of DPYD heterozygous carriers identified on our panel would have had a false-negative result if tested by 1 of these 6 laboratories. The sensitivity and negative predictive value of the diagnostic tests from these laboratories ranged from 18.4% to 79.6% and 95.1% to 98.7%, respectively. These cases underscore the importance of comprehensive DPYD genotyping to accurately identify patients with DPD deficiency who may require lower fluoropyrimidine doses to mitigate severe toxicities and hospitalizations. Clinicians should be aware of test limitations and variability in variant detection by commercial laboratories, and seek assistance by pharmacogenetic experts or available resources for test selection and result interpretation.

Lethal Capecitabine Toxicity in Patients With Complete Dihydropyrimidine Dehydrogenase Deficiency Due to Ultra-Rare DPYD Variants.

A DPD deficiency should be considered in case of severe toxicity even in the absence of common risk variants in DPYD.

Design and Implementation of an Opt-Out, End-to-End, Preemptive DPYD Testing Program for Patients Planned for a Systemic Fluoropyrimidine.

Several allelic variants of the gene DPYD encoding dihydropyrimidine dehydrogenase (DPD) are associated with impaired metabolism of the systemic fluoropyrimidine fluorouracil (5FU) and its oral prodrug, capecitabine, which elevates the risk for severe toxicity. Following a patient death related to capecitabine toxicity in which DPD deficiency was suspected, a multidisciplinary advisory panel was convened to develop an institution-wide approach to future patients planned for a systemic fluoropyrimidine. The panel selected an opt-out testing strategy which focused on developing reliable processes to collect and report test results and targeted education. An electronic health record-based automated reminder was designed to activate when a 5FU- or capecitabine-containing chemotherapy regimen was ordered for a patient without prior exposure to either agent and without a prior DPYD sequencing test result. DPYD testing was standardized across all sites of care, and a closed loop reporting system for abnormal test results was created. Before implementation, targeted education was provided to providers, pharmacists, and nurses, and a failure mode and effects analysis was performed. Program rollout was staged over a 6-month period. At 10 months, the rate of preemptive testing increased from a baseline of 26% to a sustained rate of >90%. In the six network sites, the testing rate increased from 9% to 96%. A total of 1,043 patients have been tested preemptively; allelic variants have been identified in 43 (4.1%). Among 25 evaluable patients, dose reduction or change to a non-fluoropyrimidine-based regimen was accomplished in 96%. Preemptive DPYD testing is feasible, and high rates of testing can be achieved using an opt-out, reminder-based program. We provide the details of the implementation and encourage others to emulate it.

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.

A novel large intragenic DPYD deletion causing dihydropyrimidine dehydrogenase deficiency: a case report

BackgroundDihydropyrimidine dehydrogenase (DPD), is the initial and rate-limiting enzyme in the catabolic pathway of pyrimidines. Deleterious variants in the DPYD gene cause DPD deficiency, a rare autosomal recessive disorder. The clinical spectrum of affected individuals is wide ranging from asymptomatic to severely affected patients presenting with intellectual disability, motor retardation, developmental delay and seizures. DPD is also important as the main enzyme in the catabolism of 5-fluorouracil (5-FU) which is extensively used as a chemotherapeutic agent. Even in the absence of clinical symptoms, individuals with either complete or partial DPD deficiency face a high risk of severe and even fatal fluoropyrimidine-associated toxicity. The identification of causative genetic variants in DPYD is therefore gaining increasing attention due to their potential use as predictive markers of fluoropyrimidine toxicity.MethodsA male infant patient displaying biochemical features of DPD deficiency was investigated by clinical exome sequencing. Bioinformatics tools were used for data analysis and results were confirmed by MLPA and Sanger sequencing.ResultsA novel intragenic deletion of 71.2 kb in the DPYD gene was identified in homozygosity. The deletion, DPYD(NM_000110.4):c.850 + 23455_1128 + 8811del, eliminates exons 9 and 10 and may have resulted from a non-homologous end-joining event, as suggested by in silico analysis.ConclusionsThe study expands the spectrum of DPYD variants associated with DPD deficiency. Furthermore, it raises the concern that patients at risk for fluoropyrimidine toxicity due to DPYD deletions could be missed during pre-treatment genetic testing for the currently recommended single nucleotide polymorphisms.

Complete DPYD genotyping combined with dihydropyrimidine dehydrogenase phenotyping to prevent fluoropyrimidine toxicity: A retrospective study.

In April 2019, French authorities mandated dihydropyrimidine dehydrogenase (DPD) screening, specifically testing uracilemia, to mitigate the risk of toxicity associated with fluoropyrimidine-based chemotherapy. However, this subject is still of debate as there is no consensus on a standardized DPD deficiency screening test. We conducted a real-life retrospective study with the aim of assessing the impact of DPD screening on the occurrence of severe toxicity and exploring the potential benefits of complete genotyping using next-generation sequencing. All adult patients consecutively treated with 5-fluorouracil (5-FU) or its oral prodrug at six cancer centers between March 2018 and February 2019 were considered for inclusion. Dihydropyrimidine dehydrogenase deficiency screening included gene encoding DPD (DPYD) genotyping using complete genome sequencing and DPD phenotyping (uracilemia or dihydrouracilemia/uracilemia ratio) or both tests. Associations between each DPD screening method and (i) severe (grade ≥3) early toxicity and (ii) fluoropyrimidine dose reduction in the second chemotherapy cycle were evaluated using multivariable logistic regression analysis. Furthermore, we assessed the concordance between DPD genotype and phenotype using Cohen's kappa. A total of 551 patients were included. Most patients were tested for DPD deficiency (86%) including DPYD genotyping only (6%), DPD phenotyping only (8%), or both (72%). Complete DPD deficiency was not detected in the study population. Severe early toxicity events were observed in 73 patients (13%), with two patients (0.30%) presenting grade 5 toxicity. Despite the numerically higher toxicity rate in untested patients, the occurrence of severe toxicity was not significantly associated with the DPD screening method (p = 0.69). Concordance between the DPD genotype and phenotype was weak (Cohen's kappa of 0.14). Due to insufficient numbers, our study was not able to demonstrate any added value of DPYD genotyping using complete genome sequencing to prevent 5-FU toxicity. The optimal strategy for DPD screening before fluoropyrimidine-based chemotherapy requires further clinical evaluation.

Association of plasma uracil concentration with 5-FU pharmacokinetics, dose-limiting toxicity, and DPYD genotype in patients with gastrointestinal cancer.

751 Background: Plasma uracil concentration &gt;16 ng/mL is used in some countries as a screening test for DPD deficiency. We conducted this exploratory study to evaluate the association of uracil concentration with 5-FU exposure, toxicity, and DPYD genotype in patients without known DPD deficiency. The main hypothesis was that lower uracil concentration would be predictive of subtherapeutic 5-FU drug exposure (5-FU AUC &lt; 20 mg*h/L) in patients treated with infusional 5-FU. Methods: The study prospectively enrolled patients with GI cancer who were receiving initial chemotherapy with a regimen containing a 46-hour 5-FU infusion initially dosed at 2400 mg/m2. Study candidates were screened for the DPYD *2A, *13 and c.2846A&gt;T gene variants; variant carriers were excluded. Participants gave pretreatment fasting morning blood samples for determination of plasma uracil concentration and DPYD whole-gene sequencing. Plasma samples were collected at hour 45 of 5-FU infusion in chemotherapy cycles 1 and 2 for determination of 5-FU exposure, measured as the 5-FU AUC. We estimated a linear mixed-effects model to test the association of uracil concentration with 5-FU AUC, adjusting for cycle, sex, creatinine, and 5-FU infusion dose (in mg/m2). Results: There were 29 evaluable participants with a median age of 64 years (range 41-81); nine (31%) were female. The most common cancer sites were colorectal (n = 15) and pancreatic (10). The median (IQR) plasma uracil concentration was 10.4 ng/mL (7.2, 12.6). Data for 5-FU AUC were available for 19 subjects in cycle 1 (median = 22.0 mg*h/L) and 27 subjects in cycle 2 (median = 19.3 mg*h/L). In the mixed-effects model, male sex was significantly associated with 5-FU AUC (beta = -12.0 [95% CI -17.2, -6.7], p &lt;0.001) but plasma uracil concentration was not (beta = 0.35 [-0.16, 0.86], p=0.16). Holding other covariates constant, male sex was associated with a 29% decrease in 5-FU AUC (vs female) and plasma uracil concentration in the lowest quartile was associated with a 12% decrease in 5-FU AUC (vs highest quartile). Three of 29 participants (10%, all male) had uracil concentrations of &gt;16 ng/mL, suggestive of DPD deficiency. The subject with the highest uracil concentration (23.1 ng/mL) had severe toxicity in cycle 1 (neutropenia, mucositis) requiring 5-FU dose reduction; whole gene sequencing identified a rare DPYD missense variant in this subject (c.2185G&gt;A [p.A729T]). The other two subjects with uracil concentration &gt;16 ng/mL did not have culprit DPYD gene variants and tolerated infusional 5-FU at 2400 mg/m2 without early dose-limiting toxicity. Conclusions: Our findings suggest that male sex is more important than low pretreatment plasma uracil concentration as a predictor of risk for subtherapeutic 5-FU drug exposure. This result is consistent with prior evidence that men experience less 5-FU associated toxicity than women.

Dihydropyrimidine dehydrogenase gene variants for predicting grade 4-5 fluoropyrimidine-induced toxicity: FUSAFE individual patient data meta-analysis.

Dihydropyrimidine dehydrogenase (DPD) deficiency is the main known cause of life-threatening fluoropyrimidine (FP)-induced toxicities. We conducted a meta-analysis on individual patient data to assess the contribution of deleterious DPYD variants *2A/D949V/*13/HapB3 (recommended by EMA) and clinical factors, for predicting G4-5 toxicity. Study eligibility criteria included recruitment of Caucasian patients without DPD-based FP-dose adjustment. Main endpoint was 12-week haematological or digestive G4-5 toxicity. The value of DPYD variants *2A/p.D949V/*13 merged, HapB3, and MIR27A rs895819 was evaluated using multivariable logistic models (AUC). Among 25 eligible studies, complete clinical variables and primary endpoint were available in 15 studies (8733 patients). Twelve-week G4-5 toxicity prevalence was 7.3% (641 events). The clinical model included age, sex, body mass index, schedule of FP-administration, concomitant anticancer drugs. Adding *2A/p.D949V/*13 variants (at least one allele, prevalence 2.2%, OR 9.5 [95%CI 6.7-13.5]) significantly improved the model (p < 0.0001). The addition of HapB3 (prevalence 4.0%, 98.6% heterozygous), in spite of significant association with toxicity (OR 1.8 [95%CI 1.2-2.7]), did not improve the model. MIR27A rs895819 was not associated with toxicity, irrespective of DPYD variants. FUSAFE meta-analysis highlights the major relevance of DPYD *2A/p.D949V/*13 combined with clinical variables to identify patients at risk of very severe FP-related toxicity.

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.

Risk of Toxicity From Topical 5-Fluorouracil Treatment in Patients Carrying DPYD Variant Alleles.

Patients carrying DPYD variant alleles have increased risk of severe toxicity from systemic fluoropyrimidine chemotherapy. There is a paucity of data regarding risk of toxicity from topical 5-fluorouracil (5-FU) treatment in these patients, leading to inconsistent guideline recommendations for pretreatment testing and topical 5-FU dosing. The objective of this retrospective cohort study was to investigate whether DPYD variant allele carriers have increased risk of toxicity from topical 5-FU. Treatment and toxicity data were retrospectively abstracted from the electronic medical records. Genotypes for the five DPYD variants that are associated with increased toxicity from systemic fluoropyrimidine chemotherapy (DPYD*2A, DPYD*13, DPYD p.D949V, DPYD HapB3, and DPYD p.Y186C) were collected from a genetic data repository. Incidence of grade 3+ (primary end point) and 1+ (secondary end point) toxicity was compared between DPYD variant carriers vs. wild-type patients using Fisher's exact tests. The analysis included 201 patients, 7% (14/201) of whom carried a single DPYD variant allele. No patients carried two variant alleles or experienced grade 3+ toxicity. DPYD variant allele carriers did not have a significantly higher risk of grade 1+ toxicity (21.4% vs. 10.2%, odds ratio = 2.40, 95% confidence interval: 0.10-2.53, P = 0.19). Given the low toxicity risk in patients carrying a single DPYD variant allele, there is limited potential clinical benefit of DPYD genetic testing prior to topical 5-FU. However, the risk of severe toxicity in patients with complete DPD deficiency remains unknown and topical 5-FU treatment should be avoided in these patients.

Thymidylate Synthase Inhibition with Capped F10 Is Effective in TP53 Null Acute Myeloid Leukemia (AML)

Thymidylate Synthase Inhibition with Capped F10 Is Effective in TP53 Null Acute Myeloid Leukemia (AML)

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 &lt;2) has been detected in 5.1% of cases (28 of 553). 23 tests were performed preemptively and 5 reactively (all 5 after &gt; 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 &gt; 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.

S2373 Dihydropyrimidine Dehydrogenase Deficiency Leading to Fluorouracil Toxicity in a Patient With Colorectal Adenocarcinoma

S2373 Dihydropyrimidine Dehydrogenase Deficiency Leading to Fluorouracil Toxicity in a Patient With Colorectal Adenocarcinoma

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.

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.

Prognostic Impact of Dihydropyrimidine Dehydrogenase Germline Variants in Unresectable Non-Small Cell Lung Cancer Patients Treated with Platin-Based Chemotherapy.

Platin-based chemotherapy is the standard treatment for patients with non-small cell lung cancer (NSCLC). However, resistance to this therapy is a major obstacle in successful treatment. In this study, we aimed to investigate the impact of several pharmacogenetic variants in patients with unresectable NSCLC treated with platin-based chemotherapy. Our results showed that DPYD variant carriers had significantly shorter progression-free survival and overall survival compared to DPYD wild-type patients, whereas DPD deficiency was not associated with a higher incidence of high-grade toxicity. For the first time, our study provides evidence that DPYD gene variants are associated with resistance to platin-based chemotherapy in NSCLC patients. Although further studies are needed to confirm these findings and explore the underlying mechanisms of this association, our results suggest that genetic testing of DPYD variants may be useful for identifying patients at a higher risk of platin-based chemotherapy resistance and might be helpful in guiding future personalized treatment strategies in NSCLC patients.