Page 77 - Personalised medicine of fluoropyrimidines using DPYD pharmacogenetics Carin Lunenburg

OR Teysuno) AND ("Dihydropyrimidine Dehydrogenase Deficiency"[Mesh] OR
Search performed in 2017: (“Tegafur”[Mesh] OR “S 1 (combination)” [Supplementary
Concept] OR “tegafur-gimeracil-oteracil” [Supplementary Concept] OR tegafur OR
S1eaOrcRhS-1peOrRfo“rmS e1d” ORinTe2ys0u1n7o:) A(N"TDeg(“aDfuihry"d[rMouersahc]il DOeRhydr"oSgen1ase(c(oNmADbPin)”a[tMioensh)"]
OR “Dihydropyrimidine Dehydrogenase Deficiency”[Mesh] OR “Dihydropyrimidine
[Supplementary Concept] OR "tegafur-gimeracil-oteracil" [Supplementary
Dehydrogenase Deficiency” OR “Dihydropyrimidine Dehydrogenase” OR DPYD OR DPD) Concept] OR tegafur OR S1 OR S-1 OR “S 1” OR Teysuno) AND ("Dihydrouracil
AND (English[lang] OR German[lang] OR Dutch[lang])
Supplementary Table 1. Literature review of DPYD-[5-FU/capecitabine] interactions to support the therapeutic dose guidelines to optimize dose
Dehydrogenase (NADP)"[Mesh] OR "Dihydropyrimidine Dehydrogenase
4
Supplement
Reference
ref. 1 – CAP/FU, mono/comb Henricks LM et al. Treatment algorithm for homozygous or compound heterozygous DPYD variant allele carriers with low-dose capecitabine. JCO Precis Oncol 2017 Oct 8.
Code
Level of evidence score: 2
gene act. 1: Clinical Relevanc e Score A
gene act. 0: Clinical Relevanc e Score A
Effect
5 patients, being either homozygous for a gene variant or having two different gene variants, received capecitabine or 5-FU treatment with doses based on the pre-treatment DPD activity in peripheral blood mononuclear cells. Pre-treatment DPD activity was also determined in a patient with genotype c.2846A>T/c.2846A>T, who did not receive treatment, because she was disease free after surgery. For 3 patients, the AUC of 5-FU after the first dose of capecitabine was determined, normalised to a dose of 850 mg/m2 and compared to 22 patients from another study receiving combined chemotherapy with capecitabine 850 mg/m2.
Genotyping:
- 2x c.1236A>G/c.1236A>G
- 2x c.2846A>T/c.2846A>T
- 1x *2A/*2A
- 1 carrier of both c.1236A>G and c.2846A>T (either c.1236A>G/c.2846A>T (on separate alleles) or *1/(c.1236A>G+c.2846A>T) (variants on the same allele))
Results:
- Of the four patients with gene activity score 1, the two patients with genotype c.1236A>G/c.1236A>G had respectively 79% and 42% of the normal DPD activity. The first was treated with 75% of the normal capecitabine dose in cycle 1 and with 100% in cycle 2. The second was treated with 50% of the normal 5-FU dose. The patients did not have severe toxicity on the reduced doses.
The two patients with genotype c.2846A>T/c.2846A>T had respectively 29% and 10% of the normal DPD activity. The first was treated with 17% of the normal capecitabine dose (278 mg/m2 once daily in combination with radiotherapy as neoadjuvant treatment) and the second was the patient who did not need treatment. The first patient tolerated treatment
Comments
Authors’ conclusion: ‘We showed that fluoropyrimidine treatment in homozygous or compound heterozygous DPYD variant allele carriers is feasible and that therapy does not have to be withheld. Additional DPD phenotyping tests, such as measurement of DPD activity in PBMCs, are recommended to compose an individualized treatment. After an initial dose reduction, tolerability in patients should be monitored closely, and the dose should be individually titrated according to tolerance.’
Dose-corrected AUC versus gene activity 2:
gene act. 1: 546% gene act. 0: 13812%
Tolerated dose compared to gene activity 2:
gene act. 1: 55% gene act. 0: 0.43%
table continues
75