Page 162 - Personalised medicine of fluoropyrimidines using DPYD pharmacogenetics Carin Lunenburg

Chapter 5
safe in the single c.1679T>G carrier, and moderately decreased the toxicity risk in c.2846A>T carriers. For c.1236G>A carriers, a 25% dose reduction was not enough to decrease severe treatment-related toxicity. This shows that DPYD genotype-guided dose-individualization is able to improve patient safety, as toxicity risk was reduced for three of the four variants in our study. Although sample sizes of variant allele carriers were modest and not all reductions in toxicity risk were statistically significant, these findings imply high clinical relevance. Also, implementation of DPYD genotype-guided dosing resulted in similar frequencies of toxicity- related hospitalization and discontinuation of treatment due to fluoropyrimidine-related toxicity for wild-type patients and DPYD variant allele carriers.
Interestingly, for DPYD*2A carriers, the frequency of severe toxicity found in this study was 31%; drastically lower than the frequency in the historical cohort (72%). DPD enzyme activity measurements in this study showed that activity for DPYD*2A carriers was approximately 50% reduced compared to wild-type patients, which endorses the dose recommendation of 50% for this variant.
As only one carrier of the rare c.1679T>G variant was identified in our current study, this made statistical comparisons impossible. However, while a relative risk for severe toxicity of 4.30 has been reported in literature, we showed that this patient did not experience severe toxicity in a completed treatment with 50% reduced dose. The DPD enzyme activity was about 50% decreased as well in this patient, which is in line with expectations based on previous studies.24
For carriers of the c.1236G>A and c.2846A>T variant, risk of severe toxicity remained relatively high despite dose individualization based on our dosing recommendations (25% reduction). In this study, 39% of the c.1236G>A carriers experienced severe toxicity and 47% of the c.2846A>T carriers. For these two variants, an initial dose reduction of 25% was applied in this study, because these variants are considered to have a less deleterious effect on DPD activity than the non-functional variants DPYD*2A and c.1679T>G.14,16 However, the Clinical Pharmacogenetics Implementation Consortium (CPIC) mentions that evidence is limited regarding the optimal degree of dose reduction for the decreased function variants c.1236G>A and c.2846A>T, and a 25% dosing recommendation is mainly based on one small retrospective study. Therefore, they advise a 25%─50% dose reduction in heterozygous c.1236G>A and c.2846A>T carriers.13 Our current results suggest that applying 25% dose reduction might be insufficient for some patients, as toxicity risk was increased for carriers of c.1236G>A and c.2846A>T, compared to wild-type patients. In line with these findings, our pharmacokinetic analyses showed that exposure to 5-FU was markedly higher in c.2846A>T carriers than in DPYD wild-type controls. Exposure to 5-FU in the variant allele carriers was at least equal to levels observed in wild-type patients receiving standard dose, which is circumstantial evidence that the applied genotype-guided dose-reduction will not result in under-treatment. However, these pharmacokinetic results need to be interpreted with caution for some reasons. In patients with reduced DPD activity, 5-FU metabolism is affected, with 5-FU being the third metabolite derived from the parent compound capecitabine, which limits the interpretation of 5-FU exposure. Furthermore, pharmacokinetics of capecitabine and its metabolites exhibit a high inter-individual variability in exposure –even in wild- type patients– and are therefore difficult to interpret. In addition, based on the limited
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