Page 286 - Personalised medicine of fluoropyrimidines using DPYD pharmacogenetics Carin Lunenburg

Chapter 11
Table 2. Dose advice for compound heterozygous DPYD variant allele carriers
Shown per patient are DPYD variants, phasing of the DPYD variants, GAS, retrospective DPWG dosing advice based on phasing, DPD enzyme activity, and percentage of DPD enzyme activity considered for dose advice. According to the DPWG guidelines 19 a gene activity score can be given to compound heterozygous patients when phasing is known. Fully functional/reduced functionality: gene activity score of 1.5; fully functional/inactive: gene activity score of 1; reduced functionality/reduced functionality: gene activity score of 1; reduced functionality/inactive: gene activity score of 0.5; inactive/inactive: gene activity score of 0.
Patient #
1 2 3 4 5 6 7
DPYD variants
DPYD*2A + c.1236G>A DPYD*2A + c.2846A>T c.1236G>A + c.2846A>T DPYD*2A + c.2846A>T DPYD*2A + c.2846A>T DPYD*2A + c.1236G>A DPYD*2A + c.1236G>A
Phasing
in trans in trans in trans unknown in cis unknown unknown
GAS12 DPWG dose advice
(% of regular dose)
DPD activity Percentage of (nmol/(mg*h)) DPD activitya
0.5 25% 0.9 9% 0.5 25% 6.0 60% 1 50% 4.5 45% X X 0.11 1% 1 50% 7.2 72% X X 3.8 38% X X 1.6 16%
a The reference DPD activity ranges
activity can be calculated using the average of the reference (9.9 nmol/(mg*h)). This percentage could be used as a percentage of the regular dose.
Abbreviations: DPD: dihydropyrimidine dehydrogenase; GAS: gene activity score; DPWG: Dutch Pharmacogenetic Working Group; X: could not be determined.
Preventing toxicity
Three of the seven case patients were identified as carriers of one or more DPYD variants prior to the start of therapy. For one patient, the DPD enzyme activity was determined prior to the start of therapy. Based on their genotype or phenotype, these three patients received initially reduced fluoropyrimidine dosages of 50%. They experienced limited and reversible toxicity (CTC-AE grades 0─2). The dose of one patient was increased to 70% in the second treatment cycle, after which CTC-AE grade 3 toxicity occurred.
Four of the seven case patients received a full dose, since their genotype was unknown prior to the start of therapy. These patients all experienced severe toxicity (CTC-AE grades 3─5), and three of them were admitted to the hospital for seven to 14 days. An overview of cases, including the toxicity, is shown in Table 3.
Frequencies of compound heterozygous DPYD carriers without phasing information
The ExAC and gnomAD databases revealed an average MAF for DPYD*2A, DPYD*13, c.1236G>A, and c.2846A>T of 0.55%, 0.03%, 1.43%, and 0.27%, respectively. MAFs for ExAC and gnomAD separately are summarized in Table 4. The probability of identifying a compound heterozygous DPYD patient for two variants according to these databases was ≤0.008%,
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from 5.9-14 nmol/(mg*h) 28, and therefore the percentage of DPD