Page 101 - Personalised medicine of fluoropyrimidines using DPYD pharmacogenetics Carin Lunenburg

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5-Fluorouracil toxicity- attributable IVS14 + 1G > A mutation of the dihydropyrimi dine dehydrogenas e gene in Polish colorectal cancer patients. Pharmacol Rep 2008;60:238- 42.
ref. 21 – FU, mono Schwab M et al.
Role of genetic and nongenetic factors for fluorouracil treatment- related severe toxicity: a prospective clinical trial by the German 5-FU Toxicity Study Group.
J Clin Oncol 2008;26:2131 -8.
gene act. 1:CTC-AE 4(2)#
population and is responsible for a significant proportion of life-threatening toxicity of 5-FU.”
4
Level of evidence score: 3
gene act. 1: CTC- AE4
683 German patients (670x *1/*1, 13x *1/*2A), of whom 110 with grade III/IV toxicity; FU monotherapy with folinic acid or levamisole; screening for *2A (IVS14+1G>A) and also sequencing of exons and exon/intron transitions in 28 patients with grade IV toxicity, grade III toxicity or grade 0-II toxicity.
*1/*2A versus *1/*1:
Increased risk of grade III/IV toxicity: OR = 4.67 [95% CI = 1.54-14.2].
Significantly increased risk of grade III/IV leukopenia and mucositis (OR = 10.19 [95% CI = 3.0-35.1] and OR = 5.8 [95% CI = 1.71-19.4] respectively), but not of grade III/IV diarrhoea.
Significantly increased risk of grade III/IV toxicity in men (OR = 41.8 [95% CI = 9.2-190]), but not in women.
The sensitivity of *2A genotyping for overall toxicity was 5.5% [95% CI = 0.02-0.11] with a positive predictive value of 0.46 [95% CI = 0.19-0.75].
Sequencing of 3x 28 patients with different toxicity classes:
12 additional SNPs, including 4 new ones.
5 variants (623G>A, *4 (1601G>A), *6 (2194G>A), c.2846 A>T and 2585G>C) further investigated in 3 250 patients.
2585G>C was found in 1 patient with grade IV mucositis, but not in other patients (NS).
The percentage of patients with toxicity was increased for c.2846A>T (60% versus 16.1% in the overall population) (NS).
All other variants did not show a significant association with toxicity.
Authors’ conclusion: “DPYD, TYMS, and MTHFR play a limited role for FU related toxicity but a pronounced DPYD gene/sex-interaction increases prediction rate for male patients.”
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