Page 150 - Personalised medicine of fluoropyrimidines using DPYD pharmacogenetics Carin Lunenburg

Chapter 5
Abstract
Fluoropyrimidine treatment can result in severe toxicity in up to 30% of patients and is often the result of reduced activity of the key metabolic enzyme dihydropyrimidine dehydrogenase (DPD), mostly caused by genetic DPYD variants. In a prospective clinical trial, we investigated whether upfront screening for four DPYD variants and DPYD-guided dose individualization can reduce fluoropyrimidine-induced toxicity.
Prospective genotyping of DPYD*2A, c.2846A>T, c.1679T>G, and c.1236G>A was performed in adult cancer patients for which fluoropyrimidine-based chemotherapy was considered in their best interest. All patients about to start with a fluoropyrimidine regimen (capecitabine or 5-fluorouracil as single agent or in combination with other chemotherapeutic agents and/or radiotherapy) could be included in the study. Heterozygous DPYD variant allele carriers received an initial dose reduction of 25% (c.2846A>T, c.1236G>A) or 50% (DPYD*2A, c.1679T>G), DPYD wild-type patients were treated according to standard of care. The primary endpoint of the study was the incidence of severe (CTC-AE grade≥3) overall fluoropyrimidine-related toxicity. This toxicity incidence was compared between DPYD variant allele carriers and DPYD wild-type patients in the study in an intention-to-treat analysis, and relative risks for severe toxicity were compared between the current study and a historical cohort of DPYD variant allele carriers treated with full dose fluoropyrimidine- based therapy (derived from a previously published meta-analysis). This trial is registered under clinicaltrials.gov identifier NCT02324452 and is completed.
In total, 1,103 evaluable patients were enrolled, of whom 85 DPYD variant carriers (7.7%). Overall grade≥3 toxicity was higher in DPYD variant carriers than in wild-type patients (39% vs 23%, p=0.0013). The relative risk (RR) for grade≥3 toxicity was 1.31 (95% confidence interval [95%CI]:0.63–2.73) for genotype-guided dosing vs 2.87(95%CI:2.14–3.86) in the historical cohort for DPYD*2A, no toxicity vs 4.30(95%CI:2.10–8.80) in c.1679T>G, 2.00(95%CI:1.19– 3.34) vs 3.11(95%CI:2.25–4.28) for c.2846A>T, and 1.69(95%CI:1.18–2.42) vs 1.72(95%CI: 1.22–2.42) for c.1236G>A.
Upfront DPYD genotyping was feasible in routine clinical practice, and improved patient safety of fluoropyrimidine treatment. For DPYD*2A and c.1679T>G carriers, a 50% initial dose reduction seems adequate. For c.1236G>A and c.2846A>T carriers, a larger dose reduction of 50% (instead of 25%) needs to be investigated. As fluoropyrimidines are among the most commonly used anticancer agents, the findings of this study are of high clinical importance, as they endorse implementing DPYD genotype-guided dosing as the new standard of care.
Acknowledgments
All 17 participating centers are acknowledged for their contribution to patient inclusion. We thank Maarten Deenen for his input to the study, and Lida Zoetekouw and Jeroen Roelofsen for their expert analyses of the DPD enzyme activity.
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