4CPS-070 Pharmacogenetics of fluoropyrimididine toxicity beyond DPYD variants

<h3>Background and Importance</h3> Treatment regimens based on fluoropyrimidines for colorectal cancer are associated with adverse effects such as hand-foot syndrome, diarrhoea, neutropenia, and mucositis. To date, the only gene that has been conclusively linked to fluoropyrimidine toxicity is DPYD. <h3>Aim and Objectives</h3> To analyse the association between variants in genes other than DPYD and the incidence of fluoropyrimidine-related toxicity in patients with colorectal cancer. <h3>Material and Methods</h3> This retrospective study included patients with metastatic colorectal cancer treated with fluoropyrimidine-based regimens between June 2020 and November 2021. Dose adjustments were made for patients with DPD deficiency according to established guidelines. Clinical and laboratory variables associated with toxicity were collected. The genotypes of those pharmacogenes available for analysis at our centre were determined using OpenArray technology. <h3>Results</h3> Seventy-four patients were included, 55% of whom were women. 19% received fluoropyrimidines as monotherapy, while 81% were treated with combination regimens. The median age was 73 years, and 84% had a good functional status (ECOG 0–1) prior to treatment. Four patients exhibited an intermediate metaboliser phenotype without fluoropyrimidine-related toxicity. No patients were classified as poor metabolisers. A statistically significant association was observed for the following variables: Emergency visits or hospitalisations due to toxicity in patients with the AA+AG genotype of the MTHFR gene (p-value=0.01), grade 3–4 toxicity in patients with the *1/*1 genotype of the CYP2C8 gene (p-value=0.02) and grade 2–4 diarrhoea with activity scores of 1.5 and 2 for the CYP2C9 gene (p-value=0.03). Literature evidence only supports the association between MTHFR gene variants and fluoropyrimidine treatment toxicity. In our study, 24 emergency visits or hospitalisations due to toxicity were recorded; of these, 75% involved patients with the AA+AG genotype for the MTHFR gene, compared to 25% for those with the GG genotype. No previous studies have linked CYP2C8 and CYP2C9 genes with toxicity variables, indicating the need for additional research to confirm these findings. <h3>Conclusion and Relevance</h3> There is increasing evidence that the toxicity of fluoropyrimidines is not mediated solely by the DPYD gene. Our study supports existing literature by showing an association between higher fluoropyrimidine toxicity and patients with AA and AG genotypes in the SNP rs1801133 of the MTHFR gene. <h3>References and/or Acknowledgements</h3> <h3>Conflict of Interest</h3> No conflict of interest