Page 323 - Personalised medicine of fluoropyrimidines using DPYD pharmacogenetics Carin Lunenburg

Introduction
Severe (grade ≥3) toxicity remains a significant problem in treatment with fluoropyrimidines such as 5-fluorouracil (5-FU) and capecitabine. Personalised medicine, specifically DPYD genotyping, is a promising strategy to predict and prevent severe fluoropyrimidine- induced toxicity. This thesis focusses on reducing the risk of severe fluoropyrimidine- induced toxicity by optimizing DPYD genotyping and improving implementation of DPYD genotyping in daily clinical care. In addition, we investigate DPD phenotyping and innovative genotyping techniques beyond current DPYD pharmacogenetics (PGx) to prevent severe fluoropyrimidine-induced toxicity.
Personalised medicine: why choose pharmacogenetics (PGx)?
Up to 30% of patients treated with fluoropyrimidines experience severe treatment-related toxicity. Besides the direct consequences of severe fluoropyrimidine-induced toxicity, it additionally can affect patients’ quality of life and efficacy of the therapy can be reduced when treatment cannot be resumed due to toxicity. A major contributor to the onset of severe fluoropyrimidine-induced toxicity is a reduced activity of the enzyme dihydropyrimidine dehydrogenase (DPD), as has been described since the eighties in several case reports.1-3 Patients with a complete deficiency for DPD are rare (~0.1%) and have shown neurological disorders, such as convulsion, seizures and epileptic attacks.4-7 Yet, there is great variation between patients. Also, patients who are partially DPD deficient generally do not show any phenotypic features. In order to predict and prevent severe fluoropyrimidine-induced toxicity, DPD deficient patients must be identified prospectively and treated individually (personalised medicine).
One way to identify DPD deficient patients, is to measure the DPD enzyme activity in peripheral blood mononuclear cells (PBMCs).2,8,9 However, the method is not widely used since feasibility in clinical practice is difficult due to substantial costs, complex sample logistics and specific equipment required for the radio assay. In addition, there is substantial intra patient variability (up to 25%) in DPD enzyme activity, possibly caused by circadian rhythm.10,11 An estimated 3─8% of the patients is DPD deficient. Therefore it is important to have inexpensive diagnostics for DPD deficiency, as all patients receiving fluoropyrimidines need to be tested while the majority of the tested patients does not require an adjusted dose or therapy. When a treatment plan has been decided, it is important to start the chemotherapy as soon as possible, thus short turn-around times of a test are essential as well.
Multiple genetic variants in DPYD, the gene encoding for DPD, lead to altered DPD enzyme activity.12 Identifying such DPYD variants can indirectly identify DPD deficient patients. There are relatively quick, easy and inexpensive methods available to perform genotyping, therefore upfront DPYD genotyping can be used successfully to apply personalised medicine of fluoropyrimidines (pharmacogenetics, PGx).13 This was shown in a prospective clinical trial by Deenen et al.14 Prospective genotyping of the variant DPYD*2A, followed by initial dose reductions in heterozygous carriers, reduced the risk of severe fluoropyrimidine-induced toxicity in these patients significantly. Also, this study showed that the genotyping approach did not increase costs, despite the fact that only 1.1% of tested patients was a carrier of the
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General discussion
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