Page 107 - Personalised medicine of fluoropyrimidines using DPYD pharmacogenetics Carin Lunenburg

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Mutations in exon 14 of dihydropyrimi dine dehydrogenas e and 5- fluorouracil toxicity in Portuguese colorectal cancer patients. Genet Med 2004;6:102-7. ref. 32 – FU Van Kuilenburg AB et al.
High prevalence of the IVS14 + 1G>A mutation in the dihydropyrimi dine dehydrogenas e gene of patients with severe 5- fluorouracil- associated toxicity. Pharmacogen etics 2002;12:555- 8.
ref. 33 – FU, mono
Raida M et al. Prevalence of a common point mutation in the dihydropyrimi dine dehydrogenas e (DPD) gene within the 5'- splice donor site of intron 14 in patients with severe 5-
gene act. 1:CTC-AE 4
SNPs in exon 14 (n=2) versus no SNPs in exon 14: Increase in the percentage of patients with grade III- IV toxicity by 1076% (S; from 8.5% to 100%).
responsible for a significant proportion of life-threatening toxicity to 5-FU, and should therefore be excluded before its administration to cancer patients.”
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Level of evidence score: 3
gene act. 1+gene act. 0): CTC-AE 4
60 Dutch patients with grade III/IV toxicity on FU therapy (43x *1/*1, 16x *1/*2A, 1x *2A/*2A) and 54 controls, including 35 cancer patients; screening for DPD activity in peripheral mononuclear blood cells and for *2A.
- 60% of the cases had reduced DPD activity (< 70% of the average activity in controls).
- 29% of the cases had 1 or 2 *2A alleles.
- Significantly higher *2A allele frequency in the cases than in the general population (S; increase by 1548% from 0.91% to 15%).
Authors’ conclusion: “Our study demonstrates that a DPD deficiency is the major determinant of 5FU-associated toxicity. The apparently high prevalence of the IVS14 + 1G>A mutation warrants genetic screening for this mutation in cancer patients before the administration of 5FU.”
Authors’ conclusion: “Routine screening for the exon 14- skipping mutation and subsequent individual determination of the 5-FU pharmacokinetics of heterozygous patients provides a concept of individualized therapy and allows the avoidance of undesired treatment toxicity.”
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Level of evidence score: 3
gene act. 1:CTC-AE 5(2)# gene act. 0:CTC-AE 5(2)#
25 German patients (19x *1/*1, 5x *1/*2A, 1x *2A/*2A) with grade III/IV toxicity on FU monotherapy (n=20), FU chemo-radiotherapy (n=2) or FU combination therapy (n=3) and 851 controls, including 800 cancer patients; screening for *2A.
- 24% of the cases had 1 or 2 *2A alleles.
- Higher *2A allele frequency in the cases than in the controls (NS; increase by 2879% from 0.47% to 14%). - The homozygous patient and two heterozygous patients died due to toxicity.
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