MOLGEN: Detecting new DPYD variants for the safer delivery of 5FU and capecitabine.

12120 Background: Adverse drug reactions (ADRs) pose a significant challenge to healthcare systems, leading to 6.5-15% of NHS hospital admissions costing over £2.2 billion annually. Genetic factors play a crucial role in predisposing patients to ADRs. One notable example is dihydropyrimidine dehydrogenase (DPD) enzyme deficiency, which affects the metabolism of anticancer drugs like 5-fluorouracil (5FU), capecitabine and tegafur. Current genetic testing in the NHS focuses on four DPYD gene variants associated with European populations, potentially leaving non-European populations at greater risk of drug toxicity. This study aims to expand the genetic evidence base by identifying additional DPYD variants. Methods: This observational study recruited patients who experienced grade 3 or 4 toxicities after receiving 5FU and capecitabine, despite undergoing standard DPYD genetic testing. Participants include both European and non-European patients meeting specified inclusion criteria. Blood samples were collected for genetic testing using either Sanger or next generation sequencing of exons and intron-exon boundaries. Clinical data, including administered dose and toxicity grade, were recorded. Clinicians received genetic results to inform discussions with patients about future treatment. Results: Fifteen patients experienced grade 3-4 toxicity despite standard testing. Of these patients, one patient was heterozygous for c.2846A > T, and therefore predicted to have decreased DPD activity. This patient was wild-type based on NHS standard testing, and was therefore treated with full dose capecitabine, resulting in Grade 3 diarrhoea and vomiting. However, the Clinical Pharmacogenetics Implementation Consortium (CPIC) dosing guideline suggests a 50% dose reduction in the presence of this variant. Three patients were found to be heterozygous for other DPYD variants, including c.771C > A, c.2786T > C, c.2766+1G > A, and c.1757T > C. for which there are no current dosing guidelines. The functional impact of these variants requires further study, currently ongoing. All three patients had severe reactions after 1-2 cycles of capecitabine, including one patient requiring a seven-week ICU admission for Grade 4 neutropenic sepsis. Seven patients have found to be heterozygous for DPYD variants that result in normal predicted DPD enzyme activity according to current knowledge, but again further work is needed. Four patients had no DPYD variants. Conclusions: By broadening the genetic analysis of DPD deficiency and identifying new variants, opportunities exist for enhanced patient safety and treatment efficacy. Expanding the variants in DPYD testing in the future, including those found in diverse ancestral populations could lead to improved dosing strategies and reduced the risk of severe ADRs. The findings have the potential to inform future NHS genetic testing protocols and promote equitable healthcare outcomes. Clinical trial information: iras 7086 .