DPYD genotype-guided dose individualisation of fluoropyrimidine therapy

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Published: 24 Oct 2018
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Dr Linda M. Henricks - Netherlands Cancer Institute, Amsterdam, Netherlands

Dr Linda M. Henricks speaks with ecancer at ESMO 2018 in Munich about results from of a study into the DPYD genotype-guided dose individualisation of fluoropyrimidine therapy.

Dr Henricks states that 5% of the population has a deficiency in the DPYD enzyme, therefore they are at increased risk of treatment related toxicity when treated with a standard dose.

She found that the reduced dose does reduce toxicity risk yet also providing a similar exposure level to the control patients, meaning they were not under-dosed.

ecancer's filming has been kindly supported by Amgen through the ecancer Global Foundation. ecancer is editorially independent and there is no influence over content.

DPD is an enzyme also called dihydropyrimidine dehydrogenase and it’s the main metabolic enzyme for a class of anti-cancer drugs called fluoropyrimidines which includes 5FU and capecitabine. This metabolic enzyme, DPD, is responsible for the inactivation of these drugs which means that there’s only a small proportion available for conversion to the active metabolites that result in the anti-tumour effect. However, around 5% of the population has a deficiency in this DPD enzyme so when those patients are treated with standard doses of fluoropyrimidine drugs they are at highly increased risk of developing severe treatment related toxicity as their exposure to these drugs will be highly increased due to the low DPD activity that these patients have.

Which is where the individualisation of doses comes in.

Yes, that’s exactly right.

How have you been approaching the individualisation process?

What we did in our study is that we genotyped all patients about to start with fluoropyrimidine-based chemotherapy and we screened for four genetic DPYD variants because these are the variants for which clinical relevance has been established. When patients carried one of these four variants they received initial dose reductions of the fluoropyrimidine drugs which was a 25% or 50% dose reduction. The amount of dose reduction dependent on the variant that was identified because these variants have a slightly different effect on the remaining amount of DPD enzyme activity.

How is that affecting the tolerability and adverse events?

What we found out in our study, we screened over 1,100 patients for these variants and those patients that carried one of these four variants, that was 85 patients, were treated with a reduced dose, as I already mentioned. We saw that indeed this dose reduction reduced the toxicity risk so patients have less chance of developing severe side effects; there were no patients that died due to severe toxicity so that’s a really positive outcome. What we also saw is that the patients who received a 25% dose reduction still were at increased risk of developing toxicity so this amount of dose reduction that we applied seems to be a little bit too low for reducing the risk of toxicity to the background risk in wildtype patients.
How is that being weighed against the risk of disease progression by limiting the amount of chemotherapy?
It is true that a lot of physicians are afraid of under-dosing when you apply these dose reductions but we showed by pharmacokinetic analysis that the drug exposure in those patients that received the dose reduction was comparable to control patients without a DPD variant. So this suggests that indeed these patients are not under-dosed as the exposure of the drug is similar to control patients.

Could that then also be used to reduce the amount of drugs required for non-DPD deficient patients as well?

Yes, that will be a next step in our research, yes.

Speaking of next steps, where else do you plan to take this?

With this genotyping you can identify a large part of the DPD deficient patients but not all of them so more research is needed on other ways to investigate or to identify patients with DPD deficiency. So that can either be a more elaborate genetic screening or maybe phenotyping methods which are also being investigated for DPD deficiency.

What is really interesting about this project is that it was a nationwide study in the Netherlands in which 17 different hospitals participated and we were very happy with that because it shows that this genotyping strategy is feasible in clinical practice because all these hospitals participated and also continued with the screening after finishing the trial and made it standard of care. That’s eventually the aim of our project, to make DPYD genotyping standard of care.