Page 108 - Personalised medicine of fluoropyrimidines using DPYD pharmacogenetics Carin Lunenburg

Chapter 4
fluorouracil (5-FU)-related toxicity compared with controls. Clin Cancer Res 2001;7:2832- 9.
ref. 34 – FU, comb Yamaguchi K et al. Germline mutation of dihydropyrimi dine dehydrogenas e gene among a Japanese population in relation to toxicity to 5- fluorouracil. Jpn J Cancer Res 2001;92:337- 42.
ref. 35 – FU van Kuilenburg AB et al.
Clinical implications of dihydropyrimi dine dehydrogenas e (DPD) deficiency in patients with severe 5- fluorouracil- associated toxicity: identification of new mutations in the DPD gene. Clin Cancer Res 2000;6:4705- 12.
Level of evidence score: 3
(gene act.2+ gene act. 1,5): Clinical Relevanc e Score: AA
Level of evidence score: 3
(gene act. 1,5 + gene act. 1): CTC- AE4
69 Japanese patients (61x *1/*1, 4x *1/*9A; 1x *1/*5; 1x *1/74G, 1x *1/812delT, 1x *1/1714G); FU combination therapy or monotherapy (FU: either 800 mg/m2 by 1-hour infusion or 500 mg/m2 per day on days 1 and 5 by continuous infusion); screening by PCR and sequencing.
- The percentage of patients with grade III/IV toxicity was lower among the 8 heterozygous patients than among the *1/*1 patients (NS; decrease by 18% to 0%).
NB: *5 and *9A do not have reduced DPD activity.
37 Dutch patients with grade III/IV toxicity on FU therapy and 22 controls; sequencing of introns and intron-exon transitions.
- 59% of the cases had reduced DPD activity (< 70% of the average activity in controls).
- Weak but significant correlation between DPD activity and time to toxicity.
- Higher prevalence of grade IV neutropenia in patients with reduced DPD activity compared to those with normal DPD activity (S; increased by 323%, from 13% to 55%). No higher prevalence of other types of toxicity.
- 79% of 14 patients with reduced DPD activity had 1 or 2 allele variants (3x *1/*1, 4x *1/*2A, 1x *2A/*9A, 1x *2A/*5, 1x *9A/496G, 1x *9A/496G/c.2846A>T, 1x *1/*5, 1x *5/*9A, 1x *6/*6).
NB: *5, *6 and *9A do not have reduced DPD activity.
Authors’ conclusion: “Our observations of Japanese patients implied that the heterozygote is not associated with increased toxic response to 5FU.”
Authors’ conclusion: “Our results demonstrated that at least 57% (8 of 14) of the patients with a reduced DPD activity have a molecular basis for their deficient phenotype.”
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