Page 151 - Personalised medicine of fluoropyrimidines using DPYD pharmacogenetics Carin Lunenburg

Safety analysis on DPYD genotype-guided dosing
Introduction
Fluoropyrimidine anticancer drugs, including 5-fluorouracil (5-FU) and its oral prodrug capecitabine, have been widely used for over sixty years in the treatment of different
solid tumor types, such as colorectal, breast, and gastric cancer. Although these drugs are relatively well tolerated, up to 30% of patients experience severe treatment-related toxicity, including diarrhea, mucositis, myelosuppression, and hand-foot syndrome.1-3 In addition, severe fluoropyrimidine-related toxicity can lead to treatment-related death in up to 1% of patients.4,5 The occurrence of these severe side-effects can lead to treatment discontinuation
and toxicity-related hospitalization, which in addition puts a heavy burden on health-care costs. 5
Fluoropyrimidine-related toxicity is often caused by reduced activity of the enzyme dihydropyrimidine dehydrogenase (DPD), the main metabolic enzyme for fluoropyrimidine inactivation.6,7 A partial DPD deficiency (e.g. a ~50% reduced DPD activity compared to normal) is present in 3─5% of the Western population. These DPD deficient patients have a highly increased risk of developing severe treatment-related toxicity when treated with a standard dose of fluoropyrimidines.8-10 Complete DPD deficiency is much rarer, with an estimated prevalence of 0.01─0.1%.8,11,12 DPD deficiency is most often caused by genetic variants in DPYD, the gene encoding DPD. The four DPYD variants currently considered most clinically relevant and with convincingly demonstrated association with severe toxicity are DPYD*2A (rs3918290, c.1905+1G>A, IVS14+1G>A), c.2846A>T (rs67376798, D949V), c.1679T>G (rs55886062, DPYD*13, I560S), and c.1236G>A (rs56038477, E412E, in haplotype B3).10,13,14 For these variants, available evidence suggests that heterozygous carriers of these variants have an average reduction in DPD enzyme activity of approximately 25% (c.2846A>T, c.1236G>A) to 50% (DPYD*2A, c.1679T>G).14
Prospective DPYD genotyping and dose reduction in heterozygous DPYD variant allele carriers is a promising strategy for preventing severe and potentially fatal fluoropyrimidine- related toxicity without affecting treatment efficacy. In a previous study prospective genotyping and dose-individualization for one DPYD variant, DPYD*2A, in a cohort of 1,631 patients showed that severe fluoropyrimidine-related toxicity could be decreased from 73% in DPYD*2A carriers receiving a standard fluoropyrimidine dose (N=48) to 28% by genotype- guided dosing, i.e. DPYD*2A carriers receiving a 50% dose reduction (N=18, p<0.001).15 This study showed that by reducing the fluoropyrimidine dose by 50% in DPYD*2A variant allele carriers, severe toxicity was reduced to a frequency (28%) comparable to that in DPYD*2A wild-type patients treated with a standard fluoropyrimidine dose (23%).
It is expected that patient safety can be further improved by expanding the number of prospectively tested DPYD variants beyond DPYD*2A alone. The objective of the current study was to assess the impact on patient safety of prospective screening for the four most relevant DPYD variants and subsequent DPYD genotype-guided dose individualization in daily clinical care.
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