Is Genotype Screening Needed Before Fluoropyrimidines?

David J. Kerr, CBE, MD, DSc, FRCP, FMedSci


March 15, 2018

Hello. I'm David Kerr, professor of cancer medicine from the University of Oxford.

One of the major challenges we oncologists face is delivering a treatment as safely and effectively as we can. Chemotherapy safety has become a huge issue in the United Kingdom. Every patient who dies within 30 days of having received chemotherapy is discussed at our morbidity and mortality meetings by the whole consultant body, so that we can learn and better understand what may underlie some of these toxic deaths. This is a useful exercise.

We've had a recent run of fluoropyrimidine-associated toxic deaths, and some articles have again appeared in the Annals of Oncology [related to this topic]. Jan Schellens' group from the Netherlands [published a review article],[1] and there was also a very useful accompanying editorial from another friend, Josep Tabernero,[2] from Barcelona, that posed the question: Should we be routinely testing for dihydropyrimidine dehydrogenase (DPD) deficiency in patients before we embark on treating them with fluoropyrimidine? Jan Schellens' group would argue yes.

Case for Preemptive Screening

There are four relatively common single nucleotide polymorphisms (SNPs) associated with an increased risk of dying in someone. They are relatively rare, but one could argue that there is a health economic case to be put forward for doing these tests before we embark on treatment with fluoropyrimidine. Josep Tabernero and his colleagues in the corresponding editorial in Annals are approximately agreeing, but they are narrowing it down to one very potent mutation that is very, very rare.

I take the middle ground. I think that we can do better. Rather than just identifying some relatively rare SNPs, which are strongly associated with the risk of dying, I think there is a wider pattern of work that's emerging in some of our own research and others', suggesting that there are more contributory SNPs, which would allow us to make sensible dose modifications rather than avoiding treatment altogether.

In fact, a fantastic geneticist in our group, Claire Palles, has made some brilliant progress in terms of identifying SNPs associated with the cardiotoxicity of fluoropyrimidines, but it is as yet unpublished. This is a really important piece of work because, to me, the cardiotoxicity associated with 5-fluorouracil (5-FU), capecitabine, and others remains clinically serious and rather mysterious. If we had markers that would allow us to predict which patients might be at risk of these significant and serious side effects, then we would be able to dose-modify or even possibly exchange drugs and consider using [raltitrexed] rather than 5-FU.

This is a really well-argued case by Jan Schellens and colleagues which I think doesn't go quite far enough. There are better tests out there looking not only at DPD but at some other SNPs that contribute to 5-FU toxicity. This is also a really nicely worded editorial from Josep and colleagues, which I think is a little narrow.

Again, I would say that toxicity testing for fluoropyrimidines is ready for inclusion at least in international treatment guidelines. Whether we should modify the drug label to insist on DPD testing before we use these drugs awaits further discussion.

All of this work is about helping to deliver efficacious drugs but with an improved safety profile, which is something all of us oncologists would sign up for.

Have a look at the articles. Tell me what you think by posting any comments. I'd be really, really interested. But I do think these are ready for primetime.

Thanks for listening. Medscapers, ahoy.


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