Assessment of the Clinical Utility of PretreatmentDPYDTesting for Patients Receiving Fluoropyrimidine Chemotherapy

Abstract

PURPOSE Patients who carry pathogenic variants in DPYD have higher systemic fluoropyrimidine (FP) concentrations and greater risk of severe and fatal FP toxicity. Pretreatment DPYD testing and DPYD-guided FP dosing to reduce toxicity and health care costs is recommended by European clinical oncology guidelines and has been adopted across Europe, but has not been recommended or adopted in the United States. The cochairs of the National Comprehensive Cancer Network Guidelines for colon cancer treatment explained their concerns with recommending pretreatment DPYD testing, particularly the risk that reduced FP doses in DPYD carriers may reduce treatment efficacy. METHODS This special article uses previously published frameworks for assessing the clinical utility of cancer biomarker tests, including for germline indicators of toxicity risk, to assess the clinical utility of pretreatment DPYD testing, with a particular focus on the risk of reducing treatment efficacy. RESULTS There is no direct evidence of efficacy reduction, and the available indirect evidence demonstrates that DPYD-guided FP dosing results in similar systemic FP exposure and toxicity compared with standard dosing in noncarriers, and is well calibrated to the maximum tolerated dose, strongly suggesting there is minimal risk of efficacy reduction. CONCLUSION This article should serve as a call to action for clinicians and clinical guidelines committees in the United States to re-evaluate the clinical utility of pretreatment DPYD testing. If clinical utility has not been demonstrated, further dialogue is needed to clarify what additional evidence is needed and which of the available study designs, also described within this article, would be appropriate. Clinical guideline recommendations for pretreatment DPYD testing would increase clinical adoption and ensure that all patients receive maximally safe and effective FP treatment.

Confirmatory DPYD Testing in Patients Receiving Fluoropyrimidines Who are Suspected DPYD Variant Carriers Based on a Genetic Data Repository

“…We have demonstrated, for the first time to our knowledge, the feasibility of creating such a program, using confirmatory DPYD testing prior to FP treatment as the case study. In 2 years since activation, we prevented one DPYD carrier from receiving standard FP dosing that has an unacceptably high risk of severe toxicity 10 and have passively monitored ~ 3,000 other patients, for minimal cost and effort. Expansion of this efficient approach to other drugs and institutions will dramatically increase the number of patients who could benefit from PGx‐guided treatment.…”

“…Fluoropyrimidine (FP; 5‐fluorouracil or capecitabine) chemotherapy is metabolized by the dihydropyrimidine dehydrogenase (DPD) enzyme, which is encoded by DPYD . DPYD testing to identify patients with cancer who are at unacceptably high risk of severe FP toxicity is among the most clinically useful PGx associations 10 . Despite the clinical benefits of DPYD testing, 11 which led to pretreatment testing recommendations in Europe, 12 testing is not recommended in clinical practice guidelines in the United States 13 or the US Food and Drug Administration (FDA) drug labels, partially due to low carrier frequency and costs 14 …”

Routine DPYD Genetic Testing

“…In his article published in JCO , Dr Hertz 1 correctly pointed out that DPYD is a germline indicator of toxicity risk, yet fails to include many aspects of DPYD genetic testing in the clinic. Despite his title, he fails to address the main issues that actually influence the clinical logistics and realities of DPYD testing as a potential standard of care.…”

Reply to H.S. Hochster

“…Dr Hochster 1 raises concerns about my recommending DPYD genetic testing before fluoropyrimidine treatment. 2 He points out that the proposed DPYD -guided dosing recommendations were not evaluated for efficacy in prospective randomized trials. As I noted in my article, direct efficacy comparisons in randomized trials may be unethical, implausible, and unnecessary.…”

“…Finally, I explained that if direct efficacy comparisons are necessary, these could be made within nonrandomized trials or by use of real-world data. 2…”