The Case for Mandatory Germline DPD Testing

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


February 27, 2019

This transcript has been edited for clarity.

Hello. I'm David Kerr, professor of cancer medicine at the University of Oxford. There are a couple of nice articles that have popped up recently in Lancet Oncology looking at another field that's quite close to my heart, which is germline testing for variants of dihydropyrimidine dehydrogenase (DPD).

I've talked about this a couple of times before, but there are now clear emerging data about the clinical utility of taking this approach. Conventionally, people look at four of the single nucleotide polymorphism (SNP) variants in DPD—although, as we and others have shown, there are more variants, which I think could improve the specificity and sensitivity of the test if taken into account.

Nevertheless, this recent report suggests that by using a DPD test, by making a 25% dose reduction [in fluoropyrimidine] in those patients who are heterozygotes, then you can reduce grade 4 toxicity and hospital admission rates.[1]

So, for 20 years now, we've known about the effects of mutations in the enzyme DPD, which is responsible for the most important catabolic step in the metabolism of 5-fluorouracil. But still, we haven't managed to incorporate this into routine guidelines, and this must change.

Interestingly, this issue was picked up by a major national newspaper in the United Kingdom. A patient died acutely after the first dose of fluoropyrimidine therapy. The patient's family and his medics have gone to the public press with this. We have 20 years of science, quality publications, and good studies; however, what may make the difference in the United Kingdom is an anecdote of an individual patient who didn't have the DPD test who died on first treatment.

Perhaps he was homozygous and a carrier, or perhaps he had lost a gene. This single anecdote, because it was so highly publicized, has been carried up to our Department of Health. It may be the pivotal point that forces our regulatory authorities to mandate clinical testing for DPD and the various SNPs.

There are different tests out there, and we need to do that which is best. Empirically, what do we do if we discover someone with a germline defect in DPD?

In the study published in Lancet Oncology, the dose reduction is 25%. Some patients still suffered significant toxicity, so perhaps a safer way would be to take a dose reduction of 50%. In those patients who are dose-reduced, assuming they tolerate the treatment with no toxicity, you could consider some dose-adapted guideline or possibly small increments in dose.

My feeling is that in those who we find have significant defects in DPD in germline genetic testing, we should make a 50% dose reduction in fluoropyrimidine and follow those patients carefully. Perhaps through prospective trials, we can determine the best means of dose-adapting, if needed, for those patients. There is more good clinical evidence of the utility of DPD testing.

In the United Kingdom, there has been quite a debate precipitated by the sad loss of an individual to fluoropyrimidine toxicity. Perhaps a mixture of good signs and public pressure may lead us to mandate this germline testing in patients who are receiving capecitabine and fluoropyrimidine-based chemotherapy.

I'd be really interested in your comments, both around the science and this nice paper in Lancet Oncology, and also what you think are the drivers that can cause changes in public attitude to lead health departments, peers, and others to actually adopt the test.

What is it that sometimes pushes a test from the realm of scientific certainty on the pages of Lancet Oncology on to the front pages of national newspapers, and how do these issues affect governmental policy?

Thanks for listening. Over and out, I'm David Kerr. Thank you.

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