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Evaluation of 5-fluorouracil degradation rate and Pharmacogenetic profiling to predict toxicity following adjuvant Capecitabine
- Source :
- European journal of clinical pharmacology. 73(2)
- Publication Year :
- 2016
-
Abstract
- On account of the lack of predictive biomarkers of toxicity, we investigated whether polymorphisms of genes involved in fluoropyrimidine metabolism and 5-fluorouracil (5-FU) degradation rate were associated with outcomes of adjuvant capecitabine in patients with early stage gastrointestinal cancers. Genotyping of DPYD GIVS14A, MTHFR C677T and A1298C SNPs were performed by pyro-sequencing technology. PCR analysis was used for genotyping TYMS-TSER. We also evaluated the 5-FU degradation rate, which determines the amount of drug consumed by PBMC in a time unit. Association of these variables with clinical outcome was evaluated using multivariate logistic regression analysis. One hundred forty-two patients with early stage colon (39%), rectal (28%), stomach (20%) and pancreatic (13%) cancer, treated with adjuvant capecitabine, were included in this retrospective analysis. Seventy and 20% of the patients suffered from at least one G1–4 and G3–4 adverse events, respectively. According to the 5-FU degradation rate, three and 13 patients were assigned as poor ( 2.1 ng/mL/106 cells/min) metabolizers, respectively. At a multivariate logistic regression analysis, an altered 5-FU degradation rate (values 2.10 ng/mL/106 cells/min) was associated with grade 3–4 adverse events (OR = 2.09, 95% CI: 1.14–3.82, P = 0.01). No correlation was reported between toxicity and gene polymorphisms except for hand–foot syndrome that was more frequent in the MTHFR 1298CC homozygous variant genotype (OR = 2.03, 95% CI 1.04–3.96, P = 0.03). 5-FU degradation rate may be regarded as possible predictive biomarker of capecitabine toxicity in early stage gastrointestinal cancer.
- Subjects :
- 0301 basic medicine
Oncology
gene polymorphisms
Male
adjuvant capecitabine
oral fluoropyrimidines
personalized medicine
predictive biomarkers
toxicity
0302 clinical medicine
Pharmacology (medical)
Gastrointestinal Neoplasms
Aged, 80 and over
biology
General Medicine
Middle Aged
Fluorouracil
Chemotherapy, Adjuvant
030220 oncology & carcinogenesis
Toxicity
Female
medicine.drug
Adult
medicine.medical_specialty
Antimetabolites, Antineoplastic
Genotype
Polymorphism, Single Nucleotide
Capecitabine
03 medical and health sciences
Internal medicine
medicine
Humans
Gastrointestinal cancer
Adverse effect
Dihydrouracil Dehydrogenase (NADP)
Methylenetetrahydrofolate Reductase (NADPH2)
Aged
Pharmacology
business.industry
Thymidylate Synthase
medicine.disease
030104 developmental biology
Methylenetetrahydrofolate reductase
biology.protein
Leukocytes, Mononuclear
DPYD
business
Pharmacogenetics
Subjects
Details
- ISSN :
- 14321041
- Volume :
- 73
- Issue :
- 2
- Database :
- OpenAIRE
- Journal :
- European journal of clinical pharmacology
- Accession number :
- edsair.doi.dedup.....9ff686ff33379b9b1329e3e86a7d32f5