Page 324 - Personalised medicine of fluoropyrimidines using DPYD pharmacogenetics Carin Lunenburg

Chapter 13
DPYD*2A variant. In chapter 5 and chapter 6, we have shown similar results, i.e. increasing patient safety without increasing treatment costs, for prospective genotyping of four DPYD variants (DPYD*2A, rs3918290, c.1905+1G>A, IVS14+1G>A; c.1679T>G, DPYD*13, rs55886062, I560S; c.1236G>A/HapB3, rs56038477, E412E; and c.2846A>T, rs67376798, D949V).15,16
Feasibility of DPYD genotyping in daily clinical care was shown in chapter 8 of this thesis.17 DPYD genotyping at the Leiden University Medical Center (LUMC) was investigated, starting with the introduction as routine care in April 2013 until the end of the observation period in December 2014. This study showed that the implementation of DPYD genotyping was first characterised by a learning or acceptance curve, but was feasible thereafter in a real world clinical setting with 90-100% of the patients treated with fluoropyrimidines being genotyped. The dose adherence in this study was 90% instead of 100%, due to concerns of oncologists to reduce the dose in a DPYD variant allele carrier about to start chemoradiation therapy. The doubt was caused by the fact that fluoropyrimidine dosages in chemoradiation therapy are already lower compared to fluoropyrimidine dosages in other treatment regimens, and further reduction of the fluoropyrimidine dose could result in underdosing. To remove the uncertainty on fluoropyrimidine dose reductions in DPYD variant allele carriers who will receive chemoradiation therapy, we investigated this specific group in chapter 7.18 DPYD variant allele carriers treated with regular fluoropyrimidine doses in chemoradiation therapy experienced more severe toxicity compared to DPYD variant allele carriers treated with reduced fluoropyrimidine doses in chemoradiation therapy, showing dose reductions are required as well in this treatment regimen.
The abovementioned studies show that DPYD genotyping to reduce severe fluoropyrimidine-induced toxicity is a useful strategy for all patients starting treatment with fluoropyrimidines. Both implementation of DPYD genotyping and adherence to a dose advice is feasible in a real world clinical setting.
Resistance and acceptance in implementation of DPYD genotyping
Despite substantial evidence on the association between DPYD variants and the onset of severe fluoropyrimidine-induced toxicity,19-26 implementation of DPYD genotyping in clinical practice remained limited.27,28 To improve uptake of genotyping an opinion review (chapter 2) was written, in which arguments for and against genotyping were discussed.29 One of these arguments against genotyping was that a randomized clinical trial (RCT) is necessary to obtain the required evidence on DPYD genotyping prior to implementation. As described in chapter 2, there was one attempt to perform such an RCT. Dose adjustments were applied based on the prospectively determined DPYD genotype and DPD phenotype of patients in arm A, compared to patients in arm B who were retrospectively analysed and treated with full dose. This trial was stopped prematurely due to ethical reasons, and was later published in 2017.30 Patients were in fact not randomized, as inclusion in either study arm was dependent on current practice of each participating institution and some patients were thus predestined to receive treatment in the control arm. However, this large trial of the group of Boisdron-Celle et al. was closest to the set-up of an RCT thus far performed and results were long awaited for. Unfortunately, significant differences in the frequency of DPD
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