Page 34 - Personalised medicine of fluoropyrimidines using DPYD pharmacogenetics Carin Lunenburg

Chapter 2
implemented as a routine clinical test compared to the genotyping test. ‘Genetic screening does not predict DPD deficiency perfectly’;
Patients who do not carry a DPYD variant can still develop severe side-effects and patients carrying a DPYD variant do not necessarily develop toxicity. Clearly, as with other drugs, other patient and treatment characteristics also influence the risk of severe toxicity. The sensitivity and specificity shall for this reason never reach 100% as discussed above. In the USA, with a population of 300 million, there are 1,300 deaths each year due to 5-FU induced toxicity.71 More than half of the deceased patients could have been identified using genotyping according to Boisdron-Celle et al.63
Summary
Although pharmacogenomics in general has the potential to result in safer use of drugs by supporting individualised therapy, this unfortunately has not resulted in clinical implementation of DPYD screening in the oncology field. Based on the available evidence, we argue that upfront DPYD screening using a pharmacogenomic test in patients planned to be treated with a fluoropyrimidine should become the standard of care. Treatment with fluoropyrimidines has been the cornerstone chemotherapy for several oncological indications for more than 50 years, and will probably continue to stay so. With the increasing incidence of cancer the number of patients who are likely to be treated with a fluoropyrimidine drug will increase, as well as the number of patients that would be saved from 5-FU or capecitabine induced severe toxicity when using pre-treatment genetic screening. In 2010, Ciccolini et al. already pointed out that it was time to mandate the integration of systematic prospective testing for DPYD as part of routine clinical practice in oncology.10 Based on the arguments given above we truly believe it is time to add upfront DPYD genotyping to the current guidelines and to start implementation of DPYD screening without further delay. When upfront testing followed by dose adjustments is fully functional as part of routine clinical practice we can expect that grade ≥3 fluoropyrimidine-related toxicity substantially decreases without the risk of underdosing.
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