Page 100 - Personalised medicine of fluoropyrimidines using DPYD pharmacogenetics Carin Lunenburg

Chapter 4
ref. 19 – FU, mono Capitain O et al.
The influence of fluorouracil outcome parameters on tolerance and efficacy in patients with advanced colorectal cancer. Pharmacogen omics J 2008;8:256- 67.
Level of evidence score: 3
(gene act. 1 + gene act. 1,5):CTC- AE 4(2)#
capecitabine-based chemotherapy. Chemotherapy was discontinued in 2 of these.
The association seems stronger with combination therapy than with monotherapy.
Variant IVS10-15T>C:
Association with grade III and IV toxicity: OR = 3.38 [95% CI = 1.71-8.78] for 39 patients with toxicity.
The association was significant in patients with breast and gastro-oesophageal cancer (n=46 and n=146), but was non-significant in colon cancer patients (n=58).
Variant *2A (IVS14+1G>A):
Low allele frequency in these groups (0.03 in patients with severe toxicity; 0 in healthy people and patients without severe toxicity) (NS difference).
16 other variants identified:
No significant association with severe toxicity.
76 French patients with advanced colon cancer received weekly or two-weekly FU plus folinic acid (initial FU dose 1200 and 2500 mg/m2 respectively; by continuous infusion, two-weekly regimen partially using a bolus (400 mg/m2); dose adjustments based on a target AUC of 25 mg.h/L; dose reduction of 10% in the event of significant grade II toxicity, discontinuation and dose decrease of 25% in the event of grade III toxicity and discontinuation of therapy in the event of grade IV toxicity), screening for *2A (IVS14+1G>A), c.2846A>T, *13 (1679 T>G) and 464T>A and for DPD-deficient patients and also for 19 other variants.
- 11.8% of the patients (n=9) displayed abnormally low clearance of FU associated with abnormal dihydrouracil/uracil plasma ratio prior to therapy. An SNP was found in 3 of these (2x c.2846A>T, 1x *2A).
- Despite pharmacological dose adjustments, the incidence of grade III and IV toxicity was higher in the group with reduced DPD activity (n=9) than in the group with normal DPD activity (33.3% versus 7.5%; S by 347%; OR = 6.20 [95% CI = 1.18-32.56]).
- The incidence of grade III and IV toxicity was higher in the group with SNPs (n=3) than in the group without SNPs (66.7% versus 8.2%; S by 711%).
- The authors indicated that the increased toxicity in DPD-deficient patients may have been prevented by reduced initial doses followed by pharmacokinetic dose adjustments.
252 Polish colon cancer patients received FU chemotherapy and screening for *2A (IVS14+1G>A).
- 1 patient was heterozygous. This patient was 1 of the 4 patients with grade III-IV neutropenia.
Authors’ conclusion: “Toxicity was linked to low UH2/U ratio, c.2846 A>T, IVS14+1 G>A for DPD.”
ref. 20 – FU Sulzyc- Bielicka V et al.
Level of evidence score: 3
Authors’ conclusion: “We conclude that IVS14 + 1G > A DPYD (DPYD*2A) variant occurs in the Polish
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