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

• Published in: British journal of cancer 2017-05, Vol.116 (11), p.1415-1424
• Main Authors: Meulendijks, Didier, Henricks, Linda M, Jacobs, Bart A W, Aliev, Abidin, Deenen, Maarten J, de Vries, Niels, Rosing, Hilde, van Werkhoven, Erik, de Boer, Anthonius, Beijnen, Jos H, Mandigers, Caroline M P W, Soesan, Marcel, Cats, Annemieke, Schellens, Jan H M
• Format: Article
• Language: English
• Subjects: 631/92/436/108; 692/53/2423; 692/699/67/1059; 692/700/565/2194; Adult; Aged; Aged, 80 and over; Alleles; Antimetabolites, Antineoplastic - adverse effects; Biomarkers - blood; Biomedical and Life Sciences; Biomedicine; Cancer; Cancer Research; Capecitabine - adverse effects; Capecitabine - metabolism; Chemotherapy; Dehydrogenases; Dihydropyrimidine Dehydrogenase Deficiency - complications; Dihydropyrimidine Dehydrogenase Deficiency - genetics; Dihydrouracil Dehydrogenase (NADP) - genetics; Dihydrouracil Dehydrogenase (NADP) - metabolism; Drug Resistance; Drug-Related Side Effects and Adverse Reactions - genetics; Drug-Related Side Effects and Adverse Reactions - mortality; Epidemiology; Female; Fluorouracil - adverse effects; Fluorouracil - metabolism; Genotype; Genotype & phenotype; Hospitalization; Humans; Leukocytes, Mononuclear - enzymology; Male; Middle Aged; Molecular Medicine; Neoplasms - blood; Neoplasms - drug therapy; Oncology; Pharmacogenomic Testing; Pharmacogenomic Variants; Pharmacology; Phenotype; Predictive Value of Tests; Prospective Studies; Thymidylate Synthase - genetics; Thymidylate Synthase - metabolism; Toxicity; Translational Therapeutics; Uracil - analogs & derivatives; Uracil - blood; Young Adult
• ISSN: 0007-0920; 1532-1827
• DOI: 10.1038/bjc.2017.94

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