Pretreatment serum uracil concentration as a predictor of severe and fatal fluoropyrimidine-associated toxicity

Br J Cancer. 2017 May 23;116(11):1415-1424. doi: 10.1038/bjc.2017.94. Epub 2017 Apr 20.


Background: We investigated the predictive value of dihydropyrimidine dehydrogenase (DPD) phenotype, measured as pretreatment serum uracil and dihydrouracil concentrations, for severe as well as fatal fluoropyrimidine-associated toxicity in 550 patients treated previously with fluoropyrimidines during a prospective multicenter study.

Methods: Pretreatment serum concentrations of uracil and dihydrouracil were measured using a validated LC-MS/MS method. The primary endpoint of this analysis was global (any) severe fluoropyrimidine-associated toxicity, that is, grade ⩾3 toxicity according to the NCI CTC-AE v3.0, occurring during the first cycle of treatment. The predictive value of uracil and the uracil/dihydrouracil ratio for early severe fluoropyrimidine-associated toxicity were compared. Pharmacogenetic variants in DPYD (c.2846A>T, c.1679T>G, c.1129-5923C>G, and c.1601G>A) and TYMS (TYMS 5'-UTR VNTR and TYMS 3'-UTR 6-bp ins/del) were measured and tested for associations with severe fluoropyrimidine-associated toxicity to compare predictive value with DPD phenotype. The Benjamini-Hochberg false discovery rate method was used to control for type I errors at level q<0.050 (corresponding to P<0.010).

Results: Uracil was superior to the dihydrouracil/uracil ratio as a predictor of severe toxicity. High pretreatment uracil concentrations (>16 ng ml-1) were strongly associated with global severe toxicity (OR 5.3, P=0.009), severe gastrointestinal toxicity (OR 33.7, P<0.0001), toxicity-related hospitalisation (OR 16.9, P<0.0001), as well as fatal treatment-related toxicity (OR 44.8, P=0.001). None of the DPYD variants alone, or TYMS variants alone, were associated with severe toxicity.

Conclusions: High pretreatment uracil concentration was strongly predictive of severe, including fatal, fluoropyrimidine-associated toxicity, and is a highly promising phenotypic marker to identify patients at risk of severe fluoropyrimidine-associated toxicity.

Publication types

  • Multicenter Study

MeSH terms

  • Adult
  • Aged
  • Aged, 80 and over
  • Alleles
  • Antimetabolites, Antineoplastic / adverse effects*
  • Biomarkers / blood
  • Capecitabine / adverse effects*
  • Capecitabine / metabolism
  • Dihydropyrimidine Dehydrogenase Deficiency / complications
  • Dihydropyrimidine Dehydrogenase Deficiency / genetics
  • Dihydrouracil Dehydrogenase (NADP) / genetics*
  • Dihydrouracil Dehydrogenase (NADP) / metabolism
  • Drug-Related Side Effects and Adverse Reactions / genetics
  • Drug-Related Side Effects and Adverse Reactions / mortality
  • Female
  • Fluorouracil / adverse effects*
  • Fluorouracil / metabolism
  • Genotype
  • Hospitalization
  • Humans
  • Leukocytes, Mononuclear / enzymology
  • Male
  • Middle Aged
  • Neoplasms / blood
  • Neoplasms / drug therapy*
  • Pharmacogenomic Testing
  • Pharmacogenomic Variants
  • Phenotype
  • Predictive Value of Tests
  • Prospective Studies
  • Thymidylate Synthase / genetics*
  • Thymidylate Synthase / metabolism
  • Uracil / analogs & derivatives*
  • Uracil / blood*
  • Young Adult


  • Antimetabolites, Antineoplastic
  • Biomarkers
  • dihydrouracil
  • Uracil
  • Capecitabine
  • Dihydrouracil Dehydrogenase (NADP)
  • TYMS protein, human
  • Thymidylate Synthase
  • Fluorouracil