Response to the FDA Decision Regarding DPYD Testing Prior to Fluoropyrimidine Chemotherapy

Abstract

Fluoropyrimidine (FP) chemotherapy is associated with severe, life‐threatening toxicities, particularly among patients who carry deleterious germline variants in the DPYD gene. Pretreatment DPYD testing is standard of care throughout most of Europe; however, it has not been recommended in clinical practice guidelines in the United States. Due to increased risk of severe toxicity, a Citizen's Petition asked the US Food and Drug Administration (FDA) to update language in FP drug labels to recommend DPYD testing as part of a boxed warning and recommend FP dose reduction in patients carrying deleterious germline variants. In response, the FDA updated the capecitabine package insert to inform patients about the toxicity risk and test availability and consider DPYD testing. However, the FDA did not include a testing recommendation or requirement, or a boxed warning. Additionally, the FDA did not recommend FP dose adjustment in DPYD variant carriers. This review provides a critical assessment of the DPYD‐FP pharmacogenetic association using the FDA's previously published Pharmacogenetic Pyramid, demonstrating that the evidence is compelling for recommending DPYD testing prior to FP treatment. Additionally, the FDA's stated concerns about recommending DPYD testing and DPYD‐guided FP dose adjustment are addressed and discussed in the context of the FDA's other genetic testing and dose adjustment recommendations. We call on the FDA to follow our European counterparts in recommending DPYD testing and genotype‐based dose adjustment to ensure patients with cancer receive safe and effective FP chemotherapy.

Updated DPYDHapB3 haplotype structure and implications for pharmacogenomic testing

“…Given the severity of toxicity, pre‐emptive testing is a powerful tool to identify DPD deficiency before treatment initiation 8 , 23 and, thus, future considerations should include universal recommendations for DPD deficiency testing. 3 , 24 , 25 Additionally, current guidelines need to be updated to reflect that c.1236G>A may not be a reliable variant to detect decreased DPD activity. Tests predicting DPD activity using only c.1236G>A should contain explicitly clear language stating that this tagSNP is not in complete LD with the underlying causal variant, which in rare cases may lead to a false‐positive prediction of decreased DPD activity, which may trigger an inappropriate dose reduction.…”

Strategies for DPYD Testing Prior to Fluoropyrimidine Chemotherapy in the United States

“…Other bene ts of outsourcing to a commercial lab include less upfront cost and time to launch testing [38]. On the other hand, in-house testing has bene ts including greater control over interpretation (e.g., using activity score or metabolic phenotype), EMR integration (e.g., ordering and results return), and inclusion of alleles of interest, such as DPYD variants carried by non-Europeans [39] to increase testing equity [24,[39][40][41]. At the time of our survey all sites were currently using genotyping and one site was in the planning stages of using DPYD sequencing.…”

“…A survey conducted in Europe found that the number of DPYD genotyping tests doubled from 2019 to 2021 [17], primarily due to the European Medicine Agency (EMA) recommendation for pre-treatment DPD testing in 2020 [18] and consistent testing reimbursement [17]. Pharmacogenetic (PGx) testing to optimize treatment is rapidly expanding within the US [19,20] across a number of therapeutic areas and drugs [21,22]; however, DPYD testing prior to FP treatment is not currently recommended by any US-based clinical oncology guidelines or the FDA [23][24][25]. According to a 2017 survey, only 20% of US medical oncologists had ever ordered pre-treatment DPYD testing, despite 98% agreeing that patients with DPD de ciency have increased FP toxicity risk [26].…”

Binding Pattern and Structural Interactome of the Anticancer Drug 5-Fluorouracil: A Critical Review

“…The enzyme represents the rate-limiting step responsible for the rapid breakdown of the chemotherapeutic drug 5-FU. Deficiency in dihydropyrimidine dehydrogenase activity can lead to severe and potentially fatal toxicity, with nearly 30% of patients with reduced activity experiencing severe toxicity during chemotherapy [ 9 , 11 , 23 ]. The co-crystal structure of dihydropyrimidine dehydrogenase from pig liver ( Sus scrofa ) has been resolved at a 1.9 Å resolution (PDB ID 1H7X) [ 24 ].…”

“…In the catabolic pathway, 5-FU is converted into dihydrofluorouracil by dihydropyrimidine dehydrogenase, with most of it being degraded in the liver [ 11 , 12 ]. This leads to the formation of α-fluoro-β-alanine and α-fluoro-β-ureido propionic acid, which are excreted through the kidneys.…”