Page 96 - Personalised medicine of fluoropyrimidines using DPYD pharmacogenetics Carin Lunenburg

Chapter 4
resistance associated protein-1 (ABCC1/ MRP1) predicts hematological toxicity in breast cancer patients receiving (neo- )adjuvant chemotherap y with 5- fluorouracil, epirubicin and cyclophospha mide (FEC). Ann Oncol 2013;24:1513 -25. PubMed PMID: 23396606. ref. 15 – FU, mono/ comb van Kuilenburg AB et al. Evaluation of 5-fluorouracil pharmacokin etics in cancer patients with a c.1905+1 G>A mutation in DPYD by means of a Bayesian limited sampling strategy.
Clin Pharmacokine t 2012;51:163- 74. PubMed PMID: 22339448.
Relevanc e Score AA
Variant *2A (c.1905+1G>A, rs3918290):
No significant association with serious adverse events (febrile neutropenia, prolonged grade III-IV neutropenia or severe neutropenia, grade III-IV anaemia, grade III-IV thrombocytopenia or grade III-IV non-haematological toxicity) (NS)
The authors indicated that the lack of association is likely due to the fact that 5-FU toxicity is not common among breast cancer patients treated with this combination therapy. The 5-FU dose in this combination therapy is much lower than the dose in combination therapies used for colorectal cancer.
NOTE: Associations were also not found for gene variants *5 (1627A>G), *6 (2194G>A) and *9A (85T>C). However, associations with severe toxicity have never been found in studies concerning these gene variants.
Clinical aspects were determined in 20 patients who had been genotyped as *1/*2A beforehand and were treated with 5-FU. Kinetics were determined in 30 *1/*2A (c.1905+1G>A) and 18 *1/*1, who received a 5-FU bolus injection of 300 mg/m2 and/or 450 mg/m2. Treatment regimens were not given.
Clinical
- All 7 *1/*2A receiving a standard dose of 5-FU showed grade III-V toxicity, of which 3 showed grade IV neutropenia
The severe toxicity occurred in the first cycle each time and 1 patient died.
- Among 13 *1/*2A receiving low-dose 5-FU, 4 had grade III toxicity and none had grade IV toxicity
The patients with grade III toxicity received on average 74% of the standard dose, and those with grade II or lower toxicity received 61% of the dose.
Kinetics
*1/*2A versus *1/*1:
- The 5-FU AUC increased by 52% for the 300 mg/m2 dose (from 6.0 to 9.1 mg.hour/L) and by 32% for the 450 mg/m2 dose (from 13.4 to 17.7 mg.hour/L) (S) The dose-corrected AUC increased by 32% (from 0.026 to 0.034 mg.hour/L per mg/m2; 45 and 25 patient/dose combinations respectively) (S).
The AUC seems to be predictive of the first 2 hours after the injection and may therefore cause an
a significant association with IVS14+1 G>A probably relates to the fact that 5-FU toxicity is not frequent in breast cancer patients treated with FEC due to a much lower 5-FU dose in breast compared with colorectal cancer patients.”
Level of evidence score: 3
gene act. 1: CTC- AE5
Authors’ conclusion: “Profound differences in the elimination of 5FU could be detected between DPD- deficient patients and control patients. Furthermore, treatment of DPD- deficient patients with standard 5FU- containing chemotherapy was associated with severe (lethal) toxicity.”
Maximum clearance (Vmax for 300 mg/m2) versus EM:
gene activity 1: 54%
AUCt versus EM: gene activity 1: 132%
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