Revolutionising personalised approaches to 5FU/ capecitabine treatment
5FU (5-fluorouracil)/capecitabine has been a cornerstone of chemotherapy used to treat multiple types of cancer for over 40 years.
It has been well documented that 5FU/capecitabine can lead to varying levels of toxicity in individuals, with 30-40% of patients treated experiencing severe side effects such as neutropenic sepsis, hand-foot syndrome and diarrhoea.
Furthermore, 0.5-1% of patients will suffer from lethal toxicity as a result of treatment.
The risk and effect of toxicity cannot be predicted from physiological factors alone. Due to the complicated pharmacokinetics of 5FU, the effective dose of the drug can be difficult to determine in individual patients.
ToxNav helps clinical centres identify patients who are at risk of severe toxicities before they happen.
Identifying patients most at risk from severe drug reactions before treatment with 5FU/capacitabine
ToxNav, a CE marked and approved test, is designed to identify patients most at risk from severe drug reactions before treatment with 5FU/capacitabine. By detecting the presence of over 20 genotypic variants associated with adverse toxicity, life-threatening toxicity is avoided in treated  patients and costs associated with its treatment are consequentially reduced.
Once a patient’s genotype has been determined, they are stratified into one of four clear groups:
Clinically validated and calibrated to ensure reliable performance
ToxNav has undergone robust and extensive clinical validation in colorectal cancer.
Assessment of biomarkers was carried out using data from a Phase III randomised controlled clinical study (QUASAR 2 study).
This evaluated the diagnostic accuracy of a panel of toxicity-associated variants, specifically how accurate they are at predicting risk of 5FU/capecitabine toxicity.
In order for a genetic marker to be selected for the panel, it had to meet the following criteria:
Genetic variant selection criteria
Minor allele frequency <1%, identified in patients with DPYD deficiency
Minor allele frequency >1% and associated with global capecitabine toxicity.
Methods
The genetic variants selected were then tested in 888 patients selected from the QUASAR 2 trial. The patients were included if they had DNA data and CTCAE graded toxicity data on gastrointestinal toxicities, haematological toxicities and hand-foot syndrome (HFS). 20 genetic markers were selected in total.
Clinically proven benefits and improved specificity over standard biomarker tests
Biomarker tests designed to give information on risk of 5FU-dependent toxicity commonly use single nucleotide polymorphisms (SNPs) to identify high-risk patients. Other available tests use only 4-5 SNPs to assess risk. ToxNav uses 20 SNPs to improve the specificity of the test by encompassing more genetic variants that contribute to impairment of DPYD gene function and compromise of the 5FU metabolic pathway thus directly relating these SNPs to clinical guidelines.
ToxNav has clinically superior specificity and sensitivity over other biomarker tests that measure similar toxicities, and ToxNav is currently the only test available that has robust clinical validation in a large study.
You can feel confident in the specificity of ToxNav and make clinically informed decisions to avoid toxicity or unnecessary dose change for your patients.
FAQs
References
- Church D, Kerr R, Domingo E, Rosmarin D, Palles C, Maskell K, Tomlinson I, Kerr D. ‘Toxgnostics’: an unmet need in cancer medicine. Nat Rev Cancer;14(6):440-5. 2014 Jun.
- Dan Rosmarin et al A candidate gene study of capecitabine-related toxicity identifies three new DPYD toxicity variants and a putative role for ENOSF1 rather than TYMS, Gut, Mar 19 [Epub ahead of print]
- Dan Rosmarin et al Genetic Markers of Toxicity From Capecitabine and Other Fluorouracil-Based Regimens: Investigation in the QUASAR2 Study, Systematic Review, and Meta-Analysis Dan Rosmarin, J Clinical Oncology Apr 1, 2014:1031-1039.
- Midgley R, Kerr DJ. Capecitabine: have we got the right dose? Nature Clinical Practice. Vol 6: 1, 17-24. Oct 2008.
- Chan, R and Kerr DJ. Can we individualise chemotherapy for colorectal cancer? Annals of Oncology. 15, 996-999, July 2004.
- Palles C. et al,. An evaluation of the clinical utility of a panel of variants in DPYD and ENOSF1 for predicting common capecitabine related toxicities. Annals of Oncology, 1 June 2018. 29 (Issue suppl. 5) P-213.
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