Page 99 - Personalised medicine of fluoropyrimidines using DPYD pharmacogenetics Carin Lunenburg

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ref. 17 – FU/CAP, mono/comb Kristensen MH et al. Variants in the dihydropyrimi dine dehydrogenas e, methylenetet rahydrofolate reductase and thymidylate synthase genes predict early toxicity of 5- fluorouracil in colorectal cancer patients.
J Int Med Res 2010;38:870- 83. PubMed PMID: 20819423. ref. 18 – FU/CAP, comb
Gross E et al. Strong association of a common dihydropyrimi dine dehydrogenas e gene polymorphis m with fluoropyrimidi ne-related toxicity in cancer patients.
PLoS ONE 2008;3:e4003 .
Level of evidence score: 3
gene act. 1,5: CTC- AE4
NOTE: No associations were found for gene variants *4 (1601 G>A), *5 (1627A>G) and *9A (85T>C). However, associations with severe toxicity have never been found in studies concerning these gene variants. 68 patients with advanced colorectal cancer were given adjuvant or palliative treatment with fluoropyrimidine-based therapy. Therapy consisted of either a 5-FU bolus injection 500 mg/m2 every 2 weeks plus folinic acid (n=24) or fluorouracil (400 mg/m2 bolus plus 600 mg/m2 by infusion every 2 weeks) plus folinic acid and oxaliplatin (n=27) or capecitabine 1250 mg/m2 twice daily for 14 days every 3 weeks (n=17). There was no significant difference between incidences of grade I-IV toxicity in the first 2 cycles caused by the different chemotherapies. However, the proportion of grade III-IV toxicity did differ (67%, 33% and 0% respectively).
Results:
- Higher frequency of 1896C>T in the group with grade I-IV toxicity than in the group without toxicity (13% versus 2% 1896T heterozygotes; there were no homozygotes; RR = 6) (S)
- Of the 4 1896T heterozygotes, 2 developed grade III- IV toxicity, 1 developed grade I toxicity and 1 did not develop toxicity; the number of patients with toxicity was 24, the number of patients without was 44.
This is equivalent to 8.3% 1896T heterozygotes in the group with grade III-IV toxicity and 4.5% in the group with < grade III toxicity. This is equivalent to an RR of 1.8 for grade III-IV toxicity.
128 Caucasian patients including 39 with poor tolerance to FU combination therapy (grade III or IV toxicity). 2 of the patients with poor tolerance died as a result of FU-associated toxicity. Independent group of 53 patients with poor tolerance to FU (n=39) or capecitabine combination therapy (n=14). The presence of variants was investigated by fully sequencing the DPD alleles.
Variant 496A>G:
Strongest association with grade III and IV toxicity: OR = 4.42 [95% CI = 2.12-9.23] for 92 patients with toxicity.
The polymorphism attributable risk was 56.9%.
The association was significant in patients with breast and gastro-oesophageal cancer (n=56 and n=158), but was non-significant in colon cancer patients n=128).
1 of the fatalities was heterozygous.
All 3 homozygotes had grade III or IV toxicity.
Grade III and IV toxicity (especially diarrhoea and hand-foot syndrome) also occurred in carriers using
Authors’ conclusion:
“Patients with the
genetic variant
IVS14+1 G/A or
c1896 C/T in the 4 DPYD gene had a
statistically significant increased risk of experiencing toxicity (RR 2 and 6, respectively), both having a high specificity (0.97 and 0.98, respectively) and low sensitivity (0.04 and 0.13, respectively). It is concluded that pre- treatment detection of genetic variants can help to predict early toxicity experienced by patients receiving 5- FU-based chemotherapy.”
Authors’ conclusion: “Our results show compelling evidence that, at least in distinct tumour types, a common DPYD polymorphism strongly contributes to the occurrence of fluoropyrimidine- related drug adverse events. Carriers of this variant could benefit from individual dose adjustment of the fluoropyrimidine drug or alternate therapies.”
table continues
Level of evidence score: 3
gene act. 1,5: CTC- AE5 gene act. 1: CTC- AE4
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