When you test for potential toxicity, you get results that help you navigate 5-FU/capecitabine therapy for sound decision making.
This information is designed for physicians with patients being tested for increased risk of toxicity to 5-FU/capecitabine–based therapies. It is meant to provide an overview of the possible test results and their implications.
Variations in 2 genes, dihydropyrimidine dehydrogenase (DPYD) and thymidylate synthetase (TYMS), are responsible for a significant portion of serious adverse reactions to 5-FU/capecitabine–based therapy.1-4
TheraGuide 5-FU™ provides comprehensive analysis of the DPYD and TYMS genes to identify high-risk individuals and help prevent toxicity in patients being considered for 5-FU/capecitabine–based therapy.
DPYD: The DPYD gene is analyzed by full sequence analysis for deleterious mutations, which are associated with up to a 7-fold increased risk of toxicity to 5-FU/capecitabine–based therapy.1
TYMS: The TYMS gene has variations in certain regions, which alter its expression and the enzyme that 5-FU/capecitabine targets, to disrupt DNA synthesis. Low levels of enzyme (2R/2R) are associated with a 1.4 - 2.5-fold risk of toxicity to 5-FU/capecitabine therapy.2-5
Overview of Results
Certain variations in the DPYD and TYMS genes are associated with up to a 60% risk of dose-limiting toxicity to 5-FU/capecitabine–based therapies. Patients carrying these variations should be managed differently, taking into account their high-risk status for adverse reactions.
Possible Test Results for TheraGuide 5-FU™
HIGH RISK- Positive result for a clinically significant variation in DPYD
| Possible Results | Overall Associated Risks |
| DPYD: Mutation detected* TYMS: 2R/2R* |
7-fold increase in 5-FU toxicity risk |
| DPYD: Mutation detected TYMS: 2R/3R or 3R/3R |
7-fold increase in 5-FU toxicity risk |
MODERATE RISK
- Positive result for a clinically significant variation in TYMS
| Possible Results | Overall Associated Risks |
| DPYD: No mutation detected TYMS: 2R/2R |
1.4 - 2.5-fold increase in 5-FU toxicity risk |
LOW RISK†
- No mutation detected
| Possible Results | Overall Associated Risks |
| DPYD: No mutation detected | No increase in 5-FU toxicity risk |
| TYMS: 2R/3R or 3R/3R variant |
INDETERMINATE RESULT
- Variant of uncertain significance detected
| Possible Results | Overall Associated Risks |
| DPYD: Variant of uncertain significance | Unknown 5-FU toxicity risk |
| TYMS: 2R/3R or 3R/3R variant |
Managing Patients at Increased Toxicity Risk
Options for reducing the risk of toxicity to 5-FU/capecitabine chemotherapy are available and should be considered when developing a patient management plan.
- Patients with certain DPYD or TYMS variants are at high risk of toxicity and may be indicated for effective alternate chemotherapeutic agents
- Patients at high risk of toxicity may be indicated for enhanced patient monitoring strategies to limit the incidence and severity of adverse reactions
*A DPYD mutation of clinical significance combined with a TYMS 2R/2R genotype is not known to present additive risk at this time.
†Risks reported are only those associated with detectable variations in the DPYD and TYMS genes. There may be other, less common factors that affect risk for toxicity.
- Sample Result TheraGuide 5-FU™ High Risk (pdf)
- Sample Result TheraGuide 5-FU™ Moderate (pdf)
- Sample Result TheraGuide 5-FU™ Indeterminate (pdf)
- Sample Result TheraGuide 5-FU™ Low Risk (pdf)
References: 1. Morel A, Boisdron-Celle M, Fey L, et al. Clinical relevance of different dihydropyrimidine dehydrogenase gene single nucleotide polymorphisms on 5-fluorouracil tolerance. Mol Cancer Ther. 2006;5:2895-2904. 2. Pullarkat ST, Stoehlmacher J, Ghaderi V, et al. Thymidylate synthase gene polymorphism determines response and toxicity of 5-FU chemotherapy. Pharmacogenomics J. 2001;1:65-70. 3. Lecomte T, Ferraz J-M, Zinzindohoué F, et al. Thymidylate synthase gene polymorphism predicts toxicity in colorectal cancer patients receiving 5-fluorouracil-based chemotherapy. Clin Cancer Res. 2004;10:5880-5888. 4. Ichikawa W, Takahashi T, Suto K, et al. Orotate phosphoribosyltransferase gene polymorphism predicts toxicity in patients treated with bolus 5-fluorouracil regimen. Clin Cancer Res. 2006;12:3928-3934. 5. Schwab M, et al. Role of genetic and non-genetic factors for fluorouracil treatment related severe toxicity; a prospective clinical trial by the German 5-FU toxicity study group. J Clin Oncol, 2008.
