5074 - Dihydropyrimidine dehydrogenase (DPD) determination prior the administration of medicines containing fluorouracil: a single Spanish hospital experience.

Background

Severe toxicity as a result of Fluoropyrimidine treatments appears in up 30% of patients. The reduce activity of DPD is one of the main cause of severe adverse events. Up to 8% of the population have low levels of DPD, and up to 0.5% of the population completely lack the enzyme. We assessed the effect of prospective screening for the 4 most relevant variants (DPYD*2A [rs3918290, c.1905 + 1G>A, IVS14 + 1G>A], c.2846A>T [rs67376798, D949V], c.1679T>G [rs55886062, DPYD*13, I560S], c.1236G>A [rs56038477, E412E, in haplotype B3]) and rs34743033 TYMS, on patient safety and dose individualization in daily clinical practice.

Methods

We described our experience in a Tertiary University Hospital. We reviewed 208 patients with gastrointestinal cancer who were planned to receive fluoropyrimide treatment and we did prospective genotyping for DPYD*2A, c.2846A>T, c.1679T>G, c.1236G>A and rs34743033 TYMS. Heterozygous DPD variant allele carriers received an initial dose reduction of 25% (c.2846A>T and c.1236G>A) or 50% (DPYD*2A and c.1679T>G), and DPYD wild-type patients were treated according to the current standard of care.

Results

From April 2017 to March 2019, 208 patients were pre-tested. 8 patients (3´8%) were heterozygous DPD variant allele carriers and 200 (96´2%) were DPD wild-type patients. Overall, fluoropyrimidine-related severe toxicity was higher in DPD variant carriers (2 [25%] of 8 patients) than in wild-type patients (70 [35%] of 200 patients). 2 patients with c.1236G>A and rs34743033 TYMS heterozygous were necessary to disrupt treatment in spite of dose reduction because of severe diarrhea. However, the other 6 heterozygous have low grade toxicity with reduction preplanned.

Conclusions

Life-threatening toxicities could be presented in patients with DPD deficiency if they are treated with standar dose of fluoropyridimes. Last colorectal cancer ESMO guidelines do not recommend testing DPD deficient up front. It recommend in case of patients who experience severe toxicity, DPD levels should be tested before 5-FU is re-introduced. We suggest due to our control of potential toxicities that implementation of DPD genotype individualised dosing should be a new standard of care.

Legal entity responsible for the study: Mediano Rambla.

Clinical trial identification

Editorial acknowledgement

Funding

Has not received any funding.

Disclosure

All authors have declared no conflicts of interest.