Page 82 - Personalised medicine of fluoropyrimidines using DPYD pharmacogenetics Carin Lunenburg

Chapter 4
ref. 6 – FU/CAP, mono/comb Lunenburg CA et al. Evaluation of clinical implementati on of prospective DPYD genotyping in 5- fluorouracil- or capecitabine- treated patients. Pharmacogen omics 2016;17:721- 9. PubMed PMID: 27181275.
Level of evidence score: 3
gene act. 1.5:CTC- AE 4(2)#
gene act. 1:CTC-AE 4(2)#
gene act. 0.5:CTC- AE 4(2)#
patient with genotype c.1236A>G/c.1236A>G, who developed fatal toxicity during the first cycle with full dose 5-FU plus cisplatin.
NOTE: Patients were genotyped for c.1129-5923C>G and checked for the presence of c.1236G>A and c.959-51T>G, which are in complete linkage disequilibrium with c.1129-5923C>G in haplotype B3. The results of routine prospective genotyping and genotype-guided dosing were retrospectively evaluated in patients receiving capecitabine or 5- fluorouracil, either as combined chemotherapy (different combinations) or as monotherapy (with or without radiotherapy). Genotyping was originally only for *2A (275 patients), but from approximately 30% of the total study time genotyping for *13 and 2846A>T was added (214 patients) and from 65% of the total study time genotyping for c.1236G>A was added (n = 109). Recommended dosing reductions were 50% of the normal dose per *2A- and *13- variant and 25% per c.1236A>G-variant. Recommended dosing reduction per c.2846A>T- variant was 50% (change to a recommendation of 25% reduction was only after the study), but was not applied. 14 patients with gene variants were identified.
Due to the low number of patients with DPD variants the study was not powered to formally test the effect of genotype-guided dosing on fluoropyrimidine- induced toxicity and only explorative analyses could be performed.
Genotyping:
- 8x *1/c.1236A>G
- 5x *1/*2A
- 1 carrier of both *2A and c.2846A>T (either *2A/c.2846A>T (on separate alleles) or *1/(*2A+c.2846A>T) (variants on the same allele))
Results:
- 8 patients (5x *1/c.1236A>G and 3x *1/*2A) received the recommended initial dose reduction and did not develop toxicity grade 3-4 in cycle 1. The dose of 4 patients was subsequently increased. Two patients (1x *1/c.1236A>G with a dose increase to 100% of the normal dose and 1x *1/*2A with a dose increase to 60% of the normal dose) did not develop toxicity grade 3-4. A patient with genotype *1/*2A developed diarrhoea grade 3 and enteritis after dose increase to 80% of the normal dose. Another patient with this genotype developed hand-foot-syndrome grade 2-3 after multiple cycles with the normal dose.
Authors’ conclusion: ‘Prospective DPYD screening can be implemented successfully in a real world clinical setting, is well accepted by physicians and results in low toxicity.’
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