Page 93 - Personalised medicine of fluoropyrimidines using DPYD pharmacogenetics Carin Lunenburg

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732) (NS; p=0.0075, whilst this should be less than 0.0048 due to multiple testing)
- No significant association with grade III-V toxicity for 5-FU bolus injection, but increased risk of grade III-V neutropenia (OR = 12.9; 95% CI: 3.13-53.3) (1 study, n = 338) (S)
Variant c.2846A>T:
- No meta-analysis for capecitabine, 5-FU infusion and 5-FU bolus injection (1 study each time)
Variant 496G>A:
- No meta-analysis for capecitabine and 5-FU infusion (in both cases only 1 study)
- No association with grade III-V toxicity for 5-FU bolus injection (2 studies, n = 379) (NS)
Variant c.1236G>A:
- No meta-analysis for capecitabine, 5-FU infusion and 5-FU bolus injection (1 study each time)
Variant c.2846A>T and/or *2A:
- No meta-analysis for capecitabine (only 1 study)
- There was a significant association (p=0.05) with grade III-V toxicity for 5-FU infusion and 5-FU bolus injection (S)
NOTE: No association was found for the gene variants *4, *5, *6 and *9A. However, associations with severe toxicity have never been found in studies concerning these gene variants.
Meta-analysis of 15 studies investigating patients treated with fluorouracil, capecitabine or tegafur- uracil (1 study). Data on *2A (IVS14+1G>A) were derived from 15 studies including a total of 4,094 patients and 60 carriers of *2A. Data on c.2846A>T were derived from 7 studies including a total of 2,308 patients and 34 carriers of c.2846A>T. These 15 studies include 8 studies that have also been included separately in this risk analysis: Salgueiro 2004, Morel 2006, Largillier 2006, Boisdron-Celle 2007, Schwab 2008, Sulzyc-Bielicka 2008, Kristensen 2010 and Deenen 2011.
*2A versus (no *2A):
Increased risk of grade III-V toxicity (OR = 5.42; 95% CI: 2.79-10.52; increase in the percentage of patients with grade III-V toxicity from 39% to 68%) (S) Exclusion of each of the studies from the meta- analysis did not lead to substantially different results (OR = 4.05 - 7.32 (S)).
The risk was increased in studies in which the percentage of patients with grade III-V toxicity was less than 40% (OR = 8.31; 95% CI: 3.63-19.06) (S).
4
ref. 12 – FU/CAP, mono/comb Terrazzino S et al. DPYD IVS14+1 G>A and c.2846A>T genotyping for the prediction of severe fluoropyrimidi ne-related toxicity: a meta- analysis. Pharmacogen omics 2013;14:1255 -72. PubMed PMID: 23930673.
Level of evidence score: 4
gene act. 1: CTC- AE 4
gene act. 1,5: CTC- AE 4
Authors’ conclusion: “The results of this meta-analysis confirm clinical validity of DPYD IVS14+1 G>A and 2846A>T as risk factors for the development of severe toxicities following fluoropyrimidine treatment.”
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