title: 5-Fluorouracil degradation rate could predict toxicity in stages II-III colorectal cancer patients undergoing adjuvant FOLFOX.
abstract: 5-Fluorouracil is commonly used for gastrointestinal cancer treatment in an adjuvant setting; however, the toxicity can lead to a reduction, delay, or discontinuation of treatment. We retrospectively investigated the association between the 5-fluorouracil degradation rate (5-FUDR) and genetic polymorphisms of TSER, DPYD, and MHTFR with toxicity in colorectal cancer patients treated with adjuvant FOLFOX. Pretreatment 5-FUDR and MTHFR A1298T or C677T, TSER, and DPYD gene polymorphisms were characterized in stages II-III colorectal cancer patients. Patients were classified into three metabolic classes according to the 5-FUDR value. Association with toxicities was evaluated retrospectively using logistic regression analysis. Overall, 126 patients were selected (35 women, 91 men). Seven patients were poor metabolizers, 116 patients were normal metabolizers and three patients were ultra-rapid metabolizers. The median 5-FUDR was 1.53 ng/ml/10 cells/min (range: 0.42-2.57 ng/ml/10 cells/min). Severe, rate-limiting toxicities (grades 3-4) were encountered in 22.2% of patients. No associations between MTHFR or TSER polymorphisms and toxicity were detected, whereas 5-FUDR showed a statistically significant association with toxicity (P=0.0047). The DPYD heterozygous mutation was detected in only one patient, who showed grade 4 hematological toxicity and a lower 5-FUDR value. The 5-FUDR value seems not to be affected by MTHFR and TSER polymorphisms. Compared with the available pharmacogenomics tests, the pretreatment evaluation of 5-FUDR increases the proportion of identified colorectal patients at high risk for severe toxicity. Thus, it appears to be a suitable pretreatment toxicity biomarker in a subgroup of patients in whom dose-intensity maintenance is the key factor.
authors.affiliation: Departments of aClinical and Molecular Medicine bNeurosciences, Mental Health and Sensory Organs (NESMOS), 'Sapienza' University of Rome Departments of cMedical Oncology dGeneral Surgery, Sant'Andrea Hospital eIstituto Dermopatico dell'Immacolata-IRCCS, Rome, Italy.
authors.forename: Concetta E
authors.initials: CE
authors.lastname: Onesti
authors.forename: Andrea
authors.initials: A
authors.lastname: Botticelli
authors.forename: Marco
authors.initials: M
authors.lastname: La Torre
authors.forename: Marina
authors.initials: M
authors.lastname: Borro
authors.forename: Giovanna
authors.initials: G
authors.lastname: Gentile
authors.forename: Adriana
authors.initials: A
authors.lastname: Romiti
authors.forename: Luana
authors.initials: L
authors.lastname: Lionetto
authors.forename: Antonella
authors.initials: A
authors.lastname: Petremolo
authors.forename: Mario
authors.initials: M
authors.lastname: Occhipinti
authors.forename: Michela
authors.initials: M
authors.lastname: Roberto
authors.forename: Rosa
authors.initials: R
authors.lastname: Falcone
authors.forename: Maurizio
authors.initials: M
authors.lastname: Simmaco
authors.forename: Paolo
authors.initials: P
authors.lastname: Marchetti
authors.forename: Federica
authors.initials: F
authors.lastname: Mazzuca
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage* / Q000009:adverse effects*; D017024:Chemotherapy, Adjuvant; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D042943:Dihydrouracil Dehydrogenase (NADP) / Q000235:genetics / Q000378:metabolism; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D006801:Humans; D002955:Leucovorin / Q000008:administration & dosage; D008297:Male; D042965:Methylenetetrahydrofolate Reductase (NADPH2) / Q000235:genetics / Q000378:metabolism; D008875:Middle Aged; D009367:Neoplasm Staging; D009944:Organoplatinum Compounds / Q000008:administration & dosage; D020641:Polymorphism, Single Nucleotide; D012189:Retrospective Studies; D013940:Thymidylate Synthase / Q000235:genetics / Q000378:metabolism
chemical_list: D009944:Organoplatinum Compounds; D042943:Dihydrouracil Dehydrogenase (NADP); C573423:MTHFR protein, human; D042965:Methylenetetrahydrofolate Reductase (NADPH2); D013940:Thymidylate Synthase; D002955:Leucovorin; D005472:Fluorouracil