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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., Competing Interests: Daniel L. HertzResearch Funding: Disarm TherapeuticsOther Relationship: Advocates for Universal DPD/DPYD Testing (AUDT)Uncompensated Relationships: PEPID, Saladax BiomedicalNo other potential conflicts of interest were reported.