Page 326 - Personalised medicine of fluoropyrimidines using DPYD pharmacogenetics Carin Lunenburg

Chapter 13
including information on DPYD genotyping and the associated risk of severe fluoropyrimidine- induced toxicity.35 An updated SPC, including a paragraph on DPYD genotyping, is attached to the European Public Assessment Report (EPAR) for capecitabine on the EMA website.36 They state that genotyping of four variants is recommended, and variant carriers should be treated with extreme caution. Yet, it cannot be excluded that patients with a negative result can experience severe toxicity. The European Society for Medical Oncology (ESMO) explicitly states that they do not recommend upfront routine testing for DPD deficiency,37 which was publicly questioned.38,39 In October 2018, the results of chapter 5 were presented at the ESMO conference and the presenter suggested to ESMO to update their guidelines. In the Netherlands, updated guidelines (September 2017) for colorectal carcinoma from the Dutch Society of Medical Oncology clearly state that DPYD genotyping is recommended prior to treatment with fluoropyrimidines.40 These updated guidelines were of assistance in the uptake of prospective DPYD genotyping in the Netherlands, which implies that the lack of official recommendations on pre-therapeutic genotyping is limiting the process of implementation of DPYD genotyping in other countries.
Dosing recommendations for DPYD genotyping
There are several pharmacogenetic dosing guidelines available for the use of fluoropyrimidines in DPYD variant allele carriers published by the Clinical Pharmacogenetics Implementation Consortium (CPIC), the Dutch Pharmacogenetics Working Group (DPWG) established by the Royal Dutch Pharmacists Association (KNMP), the French Network of Pharmacogenetics (RNPGx) and the Italian Association of Medical Oncology (AIOM-SIF, unpublished guidelines, edited by the AIOM-SIF Working Group).41-43 In addition to dosing guidelines, the DPWG also describes an implication score in which DPYD genotyping is considered ‘essential’, directing DPYD genotyping prior to treatment with fluoropyrimidines (chapter 4). Both CPIC and DPWG guidelines recommend to treat carriers of the DPYD*2A and DPYD*13 variants with a 50% dose reduction. CPIC recommended to treat carriers of the c.2846A>T and c.1236G>A variants with a 25─50% dose reduction due to limited evidence for these variants, compared to the DPWG who recommended a 25% dose reduction. These dose reductions are based on the functional effect of a variant on the DPD enzyme activity and represent an expected remaining DPD enzyme activity, as described in chapter 3.44 However, after publication of chapter 5, both groups discussed the results of this study and the possibility to adjust the recommendation from a 25% dose reduction to a 50% dose reduction for variants c.2846A>T and c.1236G>A/HapB3. This has resulted in an update from CPIC published online November 2018, in which dose reductions of 50% are recommended for all four DPYD variants.45 An update from the DPWG is expected soon and will be implemented in the guideline.
In chapter 5 we indeed describe that a 25% dose reduction seems inadequate to reduce the risk of severe toxicity in carriers of c.2846A>T and c.1236G>A to the risk of severe toxicity for DPYD wild-type patients. We could not provide evidence that a 50% dose reduction is the best option for these patients. In fact, for carriers of c.2846A>T a 35% dose reduction seems more logical, which is based on the median DPD enzyme activity (67% of DPYD wild-type patients) and the additional dose reductions made by physicians in carriers of c.2846A>T (average dose titration from 73 to 64% during treatment) in our clinical trial (unpublished
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