Page 84 - Personalised medicine of fluoropyrimidines using DPYD pharmacogenetics Carin Lunenburg

Chapter 4
- 1875x *1/*1
- 77x *1/c.1236A>G
- 1x c.1236A>G/c.1236A>G
Results:
Risk of grade ≥ 3 adverse event for c.1236A>G/c.1236A>G versus *1/c.1236A>G versus *1/*1:
any adverse event
diarrhoea neutropenia
pain
fatigue nausea/vomiting stomatis/mucositis dehydration leukopenia
NS, trend for an increase (p=0.082)
ORadj for (*1/c.1236A>G + c.1236A>G/c.1236A>G) compared to *1/*1 also showed a trend for an increase (NS, p=0.127). NS
S for an increase NS
NS
NS
NS NS NS
ref. 8 – FU/CAP, mono/comb Deenen MJ et al. Upfront genotyping of DPYD*2A to individualize fluoropyrimidi ne therapy: a safety and cost analysis. J Clin Oncol 2016;34:227- 34. PubMed PMID: 26573078.
Level of evidence score: 3
gene act. 1: Clinical Relevanc e Score A
NOTE: Results were reported for 1129-5923C>G, which was in complete linkage disequilibrium with the also genotyped c.1236G>A.
1631 patients received genotype-guided therapy with capecitabine (90% of patients) or 5-FU (10% of patients), either as combined chemotherapy (different combinations) or as monotherapy (with or without radiotherapy). Genotyping was for *2A. For *1/*2A, dose reduction in the first two cycles was ≥ 50% and was followed by dose titration based on tolerance. Initial dose was not reduced for *1/*1. Patients with the *1/*2A genotype were compared with 48 patients with this genotype, treated with the full initial dose in published cohorts studies without genotype-guided dosing. Of these 48 patients, 79% was treated with 5-fluorouracil, 19% with capecitabine and 2% with tegafur combined with uracil. In addition, patients with the *1/*2A genotype were compared to patients with the *1/*1 genotype. For 16 *1/*2A-patients, 5-fluorouracil AUC in blood plasma after the first capecitabine dose was compared with that of 25 unselected patients from two studies (n = 11 and n = 14 per study).
For 15 *1/*2A-patients, DPD enzyme activity in peripheral mononuclear blood cells was determined and compared with the mean Caucasian DPD enzyme activity (mainly *1/*1-patients).
The study had 100% power to detect a reduction of the incidence of grade ≥ 3 toxicity in *2A-carriers from 85% to 20%.
Authors’ conclusion: ‘DPYD*2A genotype- guided dosing results in adequate systemic drug exposure and significantly improves safety of fluoropyrimidine therapy for the individual patient. On a population level, upfront genotyping seemed cost saving.’
AUC versus gene activity 2:
gene activity 1: 203%
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