JCO Article Insights: DYPD-Guided Dose Individualization and Survival Outcomes

In this episode of JCO Article Insights, host Dr. Soldato discussed with Dr. Knikman and Dr. Cats the findings of a study that assesses the influence of fluoropyrimidine dosing based on DYPD genotype on both progression-free and overall survival. The article, featured in the December edition of JCO, presents groundbreaking and reassuring data. Furthermore, it highlights emerging research challenges aimed at refining the prescription practices of one of the most widely utilized chemotherapy agents, striking a delicate balance between safety and efficacy.

TRANSCRIPT

The guest on this podcast episode has no disclosures to declare.

Davide Soldato: Welcome to this JCO Article Insights episode for the December issues of the Journal of Clinical Oncology. This is Davide Soldato, and today I will have the pleasure of interviewing Dr. Knikman and Dr. Cats, respectively first and corresponding authors of the manuscript titled "Survival of Patients with Cancer with the DPYD Variant Alleles and Dose Individualized Fluoropyrimidine Therapy: A Matched-Pair Analysis."

Dr. Knikman is a clinical pharmacologist and assistant professor at the UMC Utrecht, while Dr. Cats is a gastroenterologist specializing in gastrointestinal oncology at the NKI in the Netherlands.

Welcome, Dr. Knikman and Dr. Cats, and thank you for accepting our invitation today.

Dr. Annemieke Cats: Thank you so much for the invitation.

Davide Soldato: So I just wanted to start by discussing the manuscript that you published. But before delving into the results of the manuscript that was published in the JCO, I just wanted to ask if you could give a brief overview of the DPD polymorphism and explain a little its relevance in the clinical practice.

Dr. Annemieke Cats: The DPD polymorphism is very important in the metabolism of fluoropyrimidines. Fluoropyrimidines have been in practice for over seven decades now in the world and more than 2 million people received fluoropyrimidines in the beginning of this millennium. The indications for fluoropyrimidines have only been extended since then, so a lot of people are receiving this fluoropyrimidines. But with the good side of that there’s also another side and that is that there are a lot of side effects encountered by this chemotherapeutic drug. In the 1990s, it became clear that DPD was a key enzyme in the metabolism of fluoropyrimidines.

Dr. Jonathan Knikman: To better understand the toxicity associated which fluoropyrimidines are accompanied by, we have to take a closer look at the metabolism of fluoropyrimidines, and more specifically at the key metabolic enzyme which is dehydropyrimidin dehydrogenase, DPD in short. This enzyme breaks down the main active metabolite into inactive metabolites because 5-fluorouracil is the main active metabolite which is metabolized into inactive metabolites. However, if this enzyme does not function properly, this could lead to higher exposures of the active metabolites and subsequently more toxicity. This can be caused by mutations in the gene encoding for the DPD enzyme, which is the DPYD gene, and single nucleotide polymorphisms, so mutations in this gene can lead to less functional DPYD enzymes, subsequently can lead to more toxicity.

Davide Soldato: So basically, patients that are harboring these SNPs in the gene encoding for the enzyme have a higher risk of toxicities. I think what is really important about the manuscript you published is that, apart from looking at the toxicities, side effects and pseudo profile among these patients who harbor these SNPs you also wanted to check whether this was associated with some reduction or at least with inferior clinical outcomes. The endpoints you selected were progression-free survival and overall survival. But I was really interested, and I think our readers and listeners would be interested in understanding a little bit the methods of the study. What was the cohort of patients that was selected? Was this a cohort composed only of patients with gastrointestinal malignancy or also different types of malignancies? And in this second case, if you included the patients with different types of malignancies, did you have any methods to be sure that there was not any differences among these patients at the very beginning? So basically, how you handled all the confounding factors that could potentially impact the analysis of clinical outcomes.

Dr. Annemieke Cats: To start your question, we have to go back to a previous study we performed, which was a prospective, multicenter study we performed in the Netherlands in 17 centers in which 1100 patients that had an indication for fluoropyrimidine therapy were included. In these 1100 patients, there were about 85 patients that were heterozygous carriers of a DPYD variant. What we did, we compared these two g...