'Call to Action' for DPYD Testing Before Fluorouracil Chemo

Liam Davenport

December 01, 2022

The debate over whether or not to test for DPYD gene variants before administering fluoropyrimidine (FP) chemotherapy has erupted again among experts in the United States, where such testing is not recommended at present, unlike in Europe.

Testing for DPYD variants and subsequent dose adjustment should be offered to US patients who are due to receive fluoropyrimidine chemotherapy, says Daniel L. Hertz, PharmD, PhD, Department of Clinical Pharmacy, University of Michigan College of Pharmacy, Ann Arbor, Michigan.

Such testing does not affect treatment efficacy, and it would reduce unnecessary toxicities, he maintains.

FP chemotherapy, which includes fluorouracil and its prodrug capecitabine (Xeloda), can cause significant, and occasionally fatal, toxicity.

The risk is greatest among patients with reduced activity polymorphisms in the DPYD gene, which encodes the dihydropyrimidine dehydrogenase enzyme responsible for fluoropyrimidine degradation.

"Approximately 7% of patients carry one of four confirmed pathogenic germline DPYD variants," Hertz noted.

Although precise estimates are lacking, approximately 0.5% of patients carry two DPYD variants. These patients "have even greater increases in severe and fatal toxicity risk."

In practice, this means that an "estimated 250,000 patients receive FP, and 1300 experience fatal toxicity in the United States annually," he said.

Hertz recently issued a "call to action" to clinicians and US clinical guidelines committees to reevaluate the clinical utility of pretreatment DPYD testing. He outlines his arguments in an article published on November 20 in the Journal of Clinical Oncology.

"Clinical guideline recommendations for pretreatment DPYD testing would increase adoption of this lifesaving strategy to ensure that all patients receive maximally safe and effective FP treatment," he maintains.

However, leading expert and guideline author Alan Venook, MD, pushed back at the suggestion and reiterated previous concerns over introducing these pretreatment genetic tests. One argument is that toxicity rates to that form of chemotherapy are higher among US patients than among patients elsewhere, and so US patients already receive lower doses.

Vennok, a medical oncologist at the University of California, San Francisco (UCSF), Helen Diller Family Comprehensive Cancer Center and vice-chair of the National Cancer Centers Network (NCCN) Guidelines Version 2.2022 Colon Cancer, also told Medscape Medical News that the guidelines panel will look at "any and all data, any information" when deciding how to proceed with their recommendations.

"In fact, we're going to meet over this article," he added.

Already Recommended in Europe

Pretreatment DYPD testing and tailored FP dosing are already recommended in European oncology guidelines and have been adopted across the continent to reduce toxicity and associated healthcare costs.

In the US, however, pretreatment testing has not been recommended by the US Food and Drug Administration (FDA), the NCCN, or the American Society of Clinical Oncology, Hertz noted.

"The lack of recommendation from clinical practice guidelines is a major reason medical oncologists in the United States do not order pretreatment DPYD testing," he said.

In his analysis, Hertz singled out the chairs of the NCCN colon cancer guidelines. He underlined their concerns over whether reducing the dose of FU chemotherapy would affect its efficacy, as well as concerns about how the dosing, particularly that of capecitabine, should be adjusted following the discovery of a DPYD variant.

To examine whether fears around DPYD testing are unfounded, Hertz performed an analysis of all the available data. He found that treatment efficacy appears to be unaffected by the testing of patients when DYPD-guided dose adjustment is used rather than standard-of-care dosing. Moreover, DPYD-guided dosing approximates the maximum tolerated dose of FP chemotherapy.

In his article, Hertz calls on US clinical guidelines committees "to re-evaluate the clinical utility of pre-treatment DPYD testing, and, if applicable, describe what additional evidence is needed to demonstrate clinical utility."

In an interview with Medscape Medical News, Hertz said that he would like to see a statement from the NCCN and added, "We have not heard anything from the FDA in over 5 years.

"Last we heard from them [the FDA], they were concerned about the availability and accuracy of testing, and reimbursement," he said. "If we can convince insurance companies that they should be reimbursing for testing, that would overcome one of the major barriers to clinicians actually ordering testing.

"The clinical communities are sort of waiting on the FDA, and FDA is waiting on the insurance companies, and the insurance companies are waiting on the clinical communities," Hertz commented.

"In some way, everyone's sort of looking at each other to decide that evidence is there for this to be standard of care. And I'm hoping that this paper demonstrates that the evidence is there and someone will take that first step," he added.

Some Agree, Others Don't

Approached for comment, Gabriel A. Brooks, MD, associate professor of the Dartmouth Institute, Geisel School of Medicine, Dartmouth, New Hampshire, said he agrees with Hertz's analysis.

Brooks said that for him, the urgency of the need to make DPYD testing more widely available in the US became apparent when he was a fellow in 2010.

"I saw a patient in the intensive care unit, and he died after one treatment with adjuvant chemotherapy. He was not tested, but I presume he had DPD deficiency with perhaps a homozygous condition, where he had complete loss of function of the DPYD gene."

Throughout his training, other patients had less severe toxicity, but toxicity still impaired their quality of life, and that "could have been avoided with a simple test."

He suggested that the difference in uptake of DPYD testing between Europe and the US is partly due to the fact that the tests have only become widely available in the past 5 years or so.

"Chemotherapy requires a rapid turnaround, unlike some other uses of pharmacogenetic testing," Brooks said. "Up to this point, there's been limited access to rapid turnaround genomic testing, but the dam has been breaking in the last 5 years."

He also believes that there could be differences in the prevalence of genetic variants between the two populations, which could mean that the issue of DPYD testing is "more salient" in Europe.

Venook from UCSF agreed that the turnaround time for DPYD testing "is such that in many cases, you'd be hard-pressed to get the information in time."

However, Venook also told Medscape Medical News that, while there are four "well-established, well-known" risk variants that affect toxicity risk with FU chemotherapy, the dose adjustments to reduce that risk are "entirely empirical."

Venook also noted that in Europe, doses of FU chemotherapy are approximately 25% higher than in the US. For example, in the UK, a total daily dose of 2500 mg/m2 is used, while the equivalent dose in the US would be 2000 mg/m2.

The reason for the lower dose in the US is that past studies have shown that rates of grade 3/4 adverse events with FU chemotherapy are from 47% to 77% higher among US patients than among those treated elsewhere, with the result that rates of treatment discontinuation are as much as twice as high.

As to why US patients appear to experience higher rates of toxicity with FU chemotherapy, "the reason is not clear," Venook said. "There's a fair bit of debate that it's because of the different folate supplements in the diet of people in the US.... I'm not sure that that's true."

Whatever the cause of the increased toxicity, he asked: "How do we extrapolate that out if we also going to be adjusting based on [DPYD] variants?"

The dose in the US is "already reduced," he continued, and so "we have no idea how we would incorporate the information from the variants," given that the dose reduction associated with those variants is an "empirical decision."

Venook emphasized, "You have to think of the implications" of DPYD testing and recognize that there are "other issues" beyond those of simply adjusting the dose to avoid toxicity. He noted that in a formal health technology assessment, which concluded that pretreatment DPYD testing would save healthcare dollars per patient, the "key factor that made it economically viable" was the inclusion of the antidote for toxicity, uridine triacetate, which has been shown to markedly increase the chances of recovery.

The assessment included some patients hospitalized for toxicity, "which is one thing," said Venook, "but they also included the cost of the antidote, which cost about US$75,000 per patient."

In his article, Hertz emphasizes that the clinical utility of tumor biomarker tests "is dependent on the clinical context, particularly as it affects the potential risk of efficacy reduction."

He notes that in "clinical contexts in which standard of care FP treatment is more efficacious, for example, curative rather than palliative treatment, the maximum potential efficacy reduction is larger, and thus the net clinical benefit of DPYD testing is smaller.

"The potential efficacy reduction also depends on the alternative treatment strategy," he added.

Hertz has relationships with Disarm Therapeutics, Advocates for Universal DPD/DPYD Testing (AUDT), PEPID, and Saladax Biomedical.

J Clin Oncol. Published online September 15, 2022. Abstract

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