Page 159 - Personalised medicine of fluoropyrimidines using DPYD pharmacogenetics Carin Lunenburg

Safety analysis on DPYD genotype-guided dosing
e Defined as palmar-plantar erythrodysesthesia syndrome by the common terminology criteria for adverse events (CTC-AE) version 4.03;18
f This patient (c.2846A>T carrier) was wrongly treated with a full capecitabine dose for two cycles, which resulted in fatal fluoropyrimidine-related toxicity.
Abbreviations: DPYD: gene encoding dihydropyrimidine dehydrogenase; FP: fluoropyrimidines; NA: not applicable.
Toxicity of genotype-guided dosing versus standard dosing in DPYD variant allele carriers
As another primary comparison, the relative risk for severe toxicity of DPYD variant allele carriers with genotype-guided dosing was compared with the corresponding relative risk
for severe toxicity of DPYD variant allele carriers from a historical cohort of a previously 5 performed meta-analysis.10 DPYD variant allele carriers described in the meta-analysis
were not identified prior to start of treatment and were therefore treated with a full dose. Relative risks for severe toxicity for each DPYD variant obtained in the meta-analysis10 are described in Table 3 (incidences of toxicity can be found in the Supplementary Table 2) and
were compared to calculated relative risks in the current study. This analysis showed that genotype-guided dosing reduced the relative risk for severe toxicity in DPYD*2A carriers
from 2.87 (95% confidence interval [95%CI]: 2.14─3.86)10 when treated with full dose to
1.31 (95%CI: 0.63─2.73) when treated with individualized dose, thus showing a clinically relevant reduction of toxicity risk.
Table 3. Relative risk for severe toxicity of DPYD variant carriers compared to a historical cohort
DPYD variant
c.1236G>A c.2846A>T DPYD*2A c.1679T>G
DPYD variant carriers treated with reduced dose (this study)
Relative risk overall grade≥3 toxicity (95%CI)a
1.69 (1.18–2.42) 2.00 (1.19–3.34) 1.31 (0.63–2.73) NAc
DPYD variant carriers treated with full dose (meta-analysis)
Relative risk overall grade≥3 toxicity (95%CI)b
1.72 (1.22–2.42) 3.11 (2.25–4.28) 2.87 (2.14–3.86) 4.30 (2.10–8.80)
a Relative risk for overall grade ≥3 fluoropyrimidine-related toxicity compared to non-carriers of this variant as described in Table 2;
b Relative risk for overall grade ≥3 fluoropyrimidine-related toxicity compared to non-carriers of this variant, as determined in a random-effects meta-analysis by Meulendijks et al.10 Unadjusted relative risks for the meta-analysis are depicted, as the relative risk in the current study was also calculated as an unadjusted value (as patient numbers were low);
c Relative risk cannot be calculated as only one patient who carried c.1679T>G was present. This patient did not experience severe toxicity.
Abbreviations: 95%CI: 95% confidence interval; NA: not applicable.
Interestingly, for c.1236G>A and c.2846A>T, a reduction in toxicity risk comparable to that of DPYD wild-type patients could not be demonstrated. The risk for c.1236G>A in the historical cohort was 1.72 (95%CI: 1.22─2.42),10 and in our study it was 1.69 (95%CI:
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