Page 49 - Personalised medicine of fluoropyrimidines using DPYD pharmacogenetics Carin Lunenburg

first or second cycle the dose can be titrated according to tolerance. Wild-type patients have two fully functional alleles, are allocated the maximal gene activity score of 2 and will receive the standard starting dose. Patients heterozygous for DPYD*2A or DPYD*13 have one nonfunctional allele and one fully functional allele, will therefore have an expected DPD enzyme activity of 50% and receive a gene activity score of 1. The recommended dose reduction of capecitabine or 5-FU for those patients is 50%. Patients carrying one allele with the c.2846A>T or c.1236G>A/HapB3 variant will have one decreased activity allele and one fully functional allele, which results in DPD enzyme activity of ∼75% of normal. They are allocated a gene activity score of 1.5, for which a recommended starting dose of 75% of the standard dose applies.
Table 1. Values for activity assigned to alleles of DPYD
3
Activity Value
0
0.5
Alleles Ref.
DPYD gene activity score
DPYD*2A (rs3918290)
DPYD*13 (rs55886062) c.2846A>T (rs67376798) c.1236G>A/HapB3 (rs556038477) DPYD *1 (wild-type)
4,8,10,11,19,27,29-46 4,19,30,32,33,46,49,50 4,13,24,33,36,41,42,44,47 14,15,42,44,46,47,49,50,56
1
These values for both alleles of a patient are summed, leading to an individual gene activity score.
Table 2. Initial dose recommendation for DPYD gene activity score
Gene activity score
0 0.5 1 1.5 2
Discussion and conclusion
% of standard dose
Alternative drug 25%
50%
75%
100%
There is ample evidence that shows that DPD-deficient patients develop severe toxicities when treated with a normal dose of fluoropyrimidines. Even though this relation is widely known, there is no global systematic approach to prevent severe toxic side effects using DPYD polymorphisms as predictive markers. Upfront DPYD*2A screening has been implemented in a limited number of institutions and other SNPs are increasingly added to the standard genetic screening. Testing for an increasing number of SNPs that result in different DPD enzyme activities makes it harder to derive a dosing advice. The gene activity score is a new method for translating DPYD genotype into DPD phenotype. It can be used to standardize the process of describing DPD enzyme activity, which stimulates uniformity. In the CPIC guideline a dose recommendation of 50% is advised for DPYD*2A, DPYD*13 and c.2846A>T.19 In the gene activity score as proposed in this manuscript we adopt these recommendations
47