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ORIGINAL RESEARCH article

Front. Pharmacol.

Sec. Pharmacogenetics and Pharmacogenomics

Volume 16 - 2025 | doi: 10.3389/fphar.2025.1645188

This article is part of the Research TopicGenetic and Pharmacological Frontiers in Cancer TreatmentView all 6 articles

DPYD-Guided Fluoropyrimidine Dose Adjustment in Colorectal Cancer DPYD Carriers: Start Slower to Finish Stronger

Provisionally accepted
Rocio  Rosas-AlonsoRocio Rosas-Alonso1,2*Nuria  Rodríguez SalasNuria Rodríguez Salas1Pablo  Perez WertPablo Perez Wert2Angela  HoyoAngela Hoyo2Susana  Martín-LópezSusana Martín-López2Daniel  Martínez-PérezDaniel Martínez-Pérez2Iciar  Ruiz-GutiérrezIciar Ruiz-Gutiérrez2Diego  Jiménez-BouDiego Jiménez-Bou2Jesús  PeñaJesús Peña2Pedro  AriasPedro Arias1,2Ana  CustodioAna Custodio2Itsaso  Losantos-GarcíaItsaso Losantos-García1Alberto  M BorobiaAlberto M Borobia1,2Jaime  FeliuJaime Feliu1,2Ismael  GhanemIsmael Ghanem1,2*
  • 1Instituto de Investigacion Hospital Universitario La Paz, Madrid, Spain
  • 2Hospital Universitario La Paz, Madrid, Spain

The final, formatted version of the article will be published soon.

Fluoropyrimidines (FP) are the mainstay of colorectal cancer (CRC) treatment, but can cause severe toxicity in up to 40% of patients. Variants in the DPYD gene are associated with these adverse events. A DPYD-guide dose adjustment is now recommended in Europe. This ambispective study aims to analyze the FP-related severe toxicity and the FP dose adjustment in heterozygous DPYD variant carriers with colorectal cancer, comparing a DPYD-guided FP dose adjustment (DA) approach to the non-DPYD-guided FP dose adjustment (NDA). 1.279 DPYD genotyping reports were issued. Sixty patients were identified with DPYD variants. Twenty-five CRC patients (17 in the DA cohort and 8 in the NDA cohort) were included in the analysis. Thirty-five patients were excluded from the analysis because they did not satisfy any of the study's inclusion criteria. Reasons for exclusion included having a diagnosis other than colorectal cancer, not receiving fluoropyrimidine treatment, participation in a clinical trial, or insufficient follow-up. Of the twenty-five patients included, sixteen patients (94%) started with a 50% FP dose reduction in the DA cohort while 7 out of 8 patients (87%) in the NDA cohort received 100% of dose in cycle 1. In the DA cohort, 12% of patients experienced severe fluoropyrimidines-related adverse events, compared to 50% in the NDA cohort (OR=0.13; 95%CI: 0.01-0.93; p=0.05). FP discontinuation due to severe toxicity occurred in 6% of patients in the DA cohort versus 50% in the NDA cohort (OR=0.06; 95%CI: 0.003-0.55, p=0.02). These findings suggest that DPYD-guided dose adjustment significantly reduces both the incidence of severe toxicity and the rate of treatment discontinuation in CRC patients. Initiating treatment with a 50% FP reduction allows for dose escalation in patients who exhibit good tolerance and avoid the discontinuation for those patients intolerant to higher doses thereby improving overall treatment adherence and completion.

Keywords: Fluoropyrimidines, DPYD, colorectal cancer, Toxicity, discontinuation

Received: 11 Jun 2025; Accepted: 02 Sep 2025.

Copyright: © 2025 Rosas-Alonso, Salas, Perez Wert, Hoyo, Martín-López, Martínez-Pérez, Ruiz-Gutiérrez, Jiménez-Bou, Peña, Arias, Custodio, Losantos-García, Borobia, Feliu and Ghanem. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

* Correspondence:
Rocio Rosas-Alonso, Instituto de Investigacion Hospital Universitario La Paz, Madrid, Spain
Ismael Ghanem, Hospital Universitario La Paz, Madrid, Spain

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