Pharmacogenetic Testing for 5-FU Saves Lives and Money

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


February 05, 2016

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Hello. I'm David Kerr, professor of cancer medicine at the University of Oxford. As you know, I have a life-standing interest in the treatment of colorectal cancer and metabolism pharmacokinetics of fluoropyrimidines. One of the key enzymes involved is dihydropyrimidine dehydrogenase (DPD), which is responsible for catabolizing the drug. Therefore, if the enzyme is deficient, you get higher levels of 5-FU in the bloodstream, which can cause life-threatening toxicity. There are polymorphisms that are well recognized in DPD that are strongly associated with a risk for death from these drugs.

A big debate is going on about whether this enzyme should be encoded in routine clinical practice. A lovely study[1] was just published in the Journal of Clinical Oncology by Jan Schellens' group from The Netherlands. They looked at the impact of genotyping for the high-risk variant of DPD, the impact in terms of reducing toxicity and toxic deaths. They did a health economic analysis, too.

It was a clever study design. Approximately 2000 patients were prospectively genotyped and compared retrospectively with patients who had been genotyped and who had received conventional-dose chemotherapy. They showed that patients who were genotyped prospectively and who had received a 50% dose reduction in 5-FU had much lower levels of grade 3 and grade 4 toxicity compared with controls. There was a reduction from 73% to 28%. The toxic death rate in this particular group was reduced from 10% to 0%, a big impact. Moreover, in terms of total treatment cost, even though you have to screen everybody to detect the 1% of patients with this particular polymorphism, they showed that it was still a cost-effective thing to do.

The evidence is mounting.[2] I have no doubt about that. We have been at the foothills of pharmacogenetics. Pharmacogenetically driven dose reductions are logical and rational. Here, we can show that they save morbidity, they save lives, and they are cost-effective. Surely, by bringing these three elements together, we have a compelling argument for upfront genotyping of patients who are going to receive fluoropyrimidines for gastrointestinal cancer[3]—and for breast cancer, too. It is the same metabolic pathway. I think the case has been made, and I think it is something that we should do.

I should say that I am somewhat conflicted in that I do sit on a spin-out company from the University called Oxford Cancer Biomarkers, which has a genotypic test in this field. I say that openly and honestly.

These data have been produced by other excellent groups,[4,5] and I think that the time has come for us to consider it virtually mandatory. At a time when there is an increasing focus on chemotherapy safety and chemotherapy morbidity and mortality, here is a simple step that we can take with a well-validated genetic test that saves lives and saves money. It seems logical.

Thanks for listening. I would be interested in any comments that you have about this. Medscapers, over and out.


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