It's Time to Cast a Wider Net With DPD Testing

David J. Kerr, CBE, MD, DSc


September 09, 2020

This transcript has been edited for clarity.

I'm David Kerr, professor of cancer medicine at the University of Oxford. One of my abiding interests has been to apply my old training in clinical pharmacology to how I deliver cancer medicine. I've been a cancer doc for 30 years and one of the recent roads I've traveled has been trying to incorporate pharmacogenetics into my clinical decision pathway. I'm a gastrointestinal oncologist; I treat patients predominantly with colorectal, gastric, and pancreatic cancers. Therefore, the fluoropyrimidines — 5-fluorouracil (5-FU) and capecitabine — are a central part of my therapeutic armamentarium.

I've talked before about the relevance of the pharmacogenomics of fluoropyrimidines and dihydropyrimidine dehydrogenase (DPD). This is a rate-limiting catabolic enzyme which is responsible for breaking down and destroying fluoropyrimidines. Therefore, it's terribly important. If we find genetic variance which reduces the activity of the enzyme, you get a concomitant increase in the plasma concentration of the 5-FU, and consequently much worse toxicity — even to the point of death in some situations or extremely bad toxicity. This is compounded by the fact that 5-FU has nonlinear pharmacokinetics; that means for a small increase in dose you can get a very large increase in plasma concentration. It's a very complicated kinetic situation to be in.

We've instituted DPD testing in our institute in Oxford, I think successfully, and we're seeing a very significant change in reduction in the number of patients being admitted to wards with severe toxicity. I think DPD tests are very good at predicting life-threatening myelosuppression and risk of death, but they're not so good at fluoropyrimidine-induced diarrhea and mucositis.

One thing that interests me, and this is perhaps a more philosophical than scientific question, is how widely do we cast the ethnic net when we build a pharmacogenetic test? I do a lot of work in China. The single nucleotide polymorphisms (SNPs) we've discovered, based on our Western databases, don't apply as readily to our patients who are citizens of Eastern Asian countries.

I have many friends in the Middle East, having worked in Qatar, and I have very strong associations with colleagues in Saudi Arabia and the Middle East. We know that the Arab genome looks significantly different. Also, I work in sub-Saharan Africa, and the SNPs we see in DPD again have different frequencies and prevalences in the African population.

All of us live within a multiethnic society. Although patients in my hospital are predominantly Caucasian, it still seems to me important that we incorporate SNPs, which allow us to detect the possibility of these variants if we're seeing patients from Africa or from other ethnic groups. Rather than focusing and narrowing down in a very small SNP set, as is sometimes recommended, I would rather we had an expanded SNP set, especially in the time of next-generation sequencing when it's relatively easy to expand the SNP signature algorithm to include these different ethnic groups.

We have had a couple of Eastern African patients where, if we had not done the wider SNP that we helped to develop, we would have missed the possibility of being able to dose-reduce somebody who would undoubtedly have had life-threatening toxicity if we'd gone ahead with conventional treatment.

Why is that a philosophical question? So far, pharmacogenomics has been predominantly driven from the West in Caucasian populations. With precision medicine, of course, we understand that we can shape, change, or alter the SNP panel to suit one's local population — an Arab SNP test, a Chinese SNP test, and so on. But if we live in a multiethnic society in which we serve a population of patients of many different ethnicities, shouldn't we have a pan test to cover the spectrum of these so that if we do have patients coming from different ethnic backgrounds, a single test with the appropriately wide SNP signature would serve all rather than some? Something to think about.

I would be very interested in your comments and I'd be very happy to engage in discussion about this. For the time being, Medscapers, over and out.

David J. Kerr, CBE, MD, DSc, is a professor of cancer medicine at the University of Oxford. He is recognized internationally for his work in the research and treatment of colorectal cancer and has founded three university spin-out companies: COBRA Therapeutics, Celleron Therapeutics, and Oxford Cancer Biomarkers. In 2002, he was appointed Commander of the British Empire by Queen Elizabeth II.

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