Page 104 - Personalised medicine of fluoropyrimidines using DPYD pharmacogenetics Carin Lunenburg

Chapter 4
ref. 26 – FU, mono Boisdron- Celle M et al. 5- Fluorouracil- related severe toxicity: a comparison of different methods for the pretherapeuti c detection of dihydropyrimi dine dehydrogenas e deficiency. Cancer Lett 2007;249:271 -82.
Level of evidence score: 3
gene act. 1: CTC- AE4
gene act. 1,5: CTC- AE4
gene act. 0,5:CTC- AE 5(2)#
252 French patients with advanced colon cancer (163x *1/*1, 6x *1/c.2846A>T, 1x *9A/c.2846A>T, 1x *1/*2A, 1x -1590C/*2A, 1x *2A/c.2846A>T+85C, 1x *1/-1590C, 67x *1/*9A, 1x -1590C/*9A, 10x *9A/*9A) received either FU 400 mg/m2 bolus + 2500 mg/m2 by 46-hour infusion every 2 weeks (n=168) or FU 1200 mg/m2 by 4-hour infusion per week (n=84) (both regimens: plus folinic acid); dose adjustment from the second cycle based on the FU plasma concentration at the end of the previous infusion (Css); discontinuation of treatment in the event of grade IV toxicity; screening for *2A (IVS14+1G>A), c.2846A>T, *7 (295-298delTCAT), 1156G>T, *9A (85T>C), *9B (2657G>A), *10 (2983G>T), -1590T>C.
(*1/*2A + -1590C/*2A) versus *1/*1:
Clearance decreased by 80% (S; from 104.7 to 21.22 L/h per m2)
Increase in the percentage of patients with grade III- IV toxicity by 793% (S; from 5.6% to 50.0%).
(*1/c.2846A>T + 1x *9A/c.2846A>T) versus *1/*1: Clearance decreased by 40% and 58% for the two- weekly and weekly regimens respectively (both S; from 136.0 to 81.2 L/h per m2 and from 104.7 to 43.9 L/h per m2).
Increase in the percentage of patients with grade III- IV toxicity by 1175% (S; from 5.6% to 71.4%).
*2A/c.2846A>T+85T versus *1/*1:
Clearance decreased to almost 0 (NS; by almost 100%).
Increase in the percentage of patients with grade III- IV toxicity by 1686% (NS; from 5.6% to 100%).
The patient had grade IV multi-organ toxicity and died after 40 days in Intensive Care.
(1x *9A + 2x *9A) versus *1/*1:
No difference in clearance and incidence of toxicity (NS).
1x -1590C versus *1/*1:
No difference in clearance and incidence of toxicity (NS).
Analysis of relevant SNPs had a high specificity (98.3%), but a low sensitivity (47.1%) for detecting DPD deficiency.
21 Korean colon cancer patients with grade III-IV toxicity on FU therapy (500 mg/m2 by continuous infusion on days 1-5, plus folinic acid) and 100 healthy volunteers; screening by sequencing all exons and flanking introns.
Authors’ conclusion: “Except in cases where alternative treatment is recommended because the 5-FU metabolism is close to zero, IVS14 + 1G>A or 2846A>T heterozygote are not strict contra- indications to 5-FU treatment, provided that the physician is aware of it and that added precautions are taken, such as an initial 5-FU dose reduction and an individual dose adjustment based on a close clinical and pharmacokinetic follow-up.”
“In the case of a homozygous status for a relevant SNP, with a uracil plasma level higher than 100 lg/L or a UH2/U ratio below 1, then fluoropyrimidine administration must be discussed and an alternative treatment proposed.”
Clearance versus gene activity 2: gene act.1.5: 55% gene act.1: 20% gene act.0.5: almost 0%
Authors’ conclusion: “The findings, from Korean patients with colon cancer, suggest that polymorphisms of the DPYD gene are
table continues
ref. 27 – FU, mono
Cho HJ et al. Thymidylate synthase (TYMS) and
Level of evidence score: 3
gene act. 1,5:
102