Page 106 - Personalised medicine of fluoropyrimidines using DPYD pharmacogenetics Carin Lunenburg

Chapter 4
Mol Cancer Ther 2006;5:2895- 904.
(*1/*2A + *2A/*2A + *1/c.2846A>T + *1/*13) versus *1/*1:
Clearance decreased by 43% (S; from 132.3 to 74.9 L/h per m2)
Increase in the percentage of patients with grade III- IV toxicity by 838% (S; from 6.6% to 61.9%).
One *1/*2A patient died due to toxicity.
The *2A/*2A patient developed grade IV diarrhoea, neutropenia and mucositis a few days after initiation of low-dose bolus FU in combination with epirubicin and cyclophosphamide. She was treated in Intensive Care for 15 days.
Patients with SNPs: treatment was discontinued in 40% of the patients with severe toxicity and continued with a 25-50% dose reduction and pharmacokinetic follow-up in the other 60%.
(*1/*2A + *1/*13) versus *1/*1:
Clearance decreased by 54% (NS; from 132.5 to 60.8 L/h per m2)
*1/c.2846A>T versus *1/*1:
Clearance decreased by 45% (NS; from 132.5 to 72.3 L/h per m2)
(*1/*9A + *9A/*9A + *1/-1590C) versus *1/*1:
No difference in clearance (NS, increased by 3%).
No significant difference in the percentage of patients with grade III-IV toxicity (NS).
None of the homozygous patients had grade III/IV toxicity.
The sensitivity and specificity of the analysis of the 3 most important SNPs for predicting toxicity were 0.31 and 0.98 respectively.
105 French patients with advanced breast cancer received capecitabine monotherapy; screening for *2A (IVS14+1G>A).
1 patient was *1/*2A. This patient died due to haematological toxicity after treatment with capecitabine 1820 mg/m2 per day for 12 days.
73 Portuguese colon cancer patients (71x *1/*1, 1x *1/*2A, 1x *1/1845T), including 8 with grade III/IV toxicity; various FU regimens; sequencing of exon 14.
dehydrogenase deficiency, 5-FU administration often can be safely continued with an individual dose adjustment.”
Clearance versus gene activity 2: gene act.1.5: 55% gene act.1: 46%
ref. 30 – CAP, mono Largillier R et al. Pharmacogen etics of capecitabine in advanced breast cancer patients.
Clin Cancer Res 2006;12:5496 -502.
ref. 31 – FU, mono Salgueiro N et al.
Level of evidence score: 3
gene act. 1:CTC-AE 5(2)#
Level of evidence score: 3
Authors’ conclusion: “Our case report clearly identifies DPD deficiency as a source of life- threatening toxicity under capecitabine treatment.”
Authors’ conclusion: “We conclude that mutations in exon 14 of DPYD gene are
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