CurrentCapital BluecrossPolicy MP 2.354

Laboratory and Genetic Testing for Use of 5‑Fluorouracil in Patients with Cancer

This policy governs coverage for laboratory assays measuring 5‑FU plasma exposure (AUC) and genetic testing for DPYD and TYMS variants to guide 5‑FU dosing or treatment selection for patients with cancer under certain Capital Blue Cross products.

Policy Summary

PayerCapital Bluecross

PolicyLaboratory and Genetic Testing for Use of 5‑Fluorouracil in Patients with Cancer

Policy CodePolicy MP 2.354

Change TypeNo material change

Effective Date

Next Review Date

Key ActionCheck member product/program benefit details before ordering; coverage varies by Capital Blue Cross product.

SourceLink

POLICY UPDATE CHANGES

No material clinical or coverage changes in this revision.

2genes mentioned for testing (DPYD, TYMS)

2procedures considered investigational

2codes removed

No changeno policy statement changes

Coverage determinations

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Investigational services

Covered status and primary determinations

Investigational determinations: Assay testing to determine 5‑fluorouracil (5‑FU) area under the curve (AUC) to adjust 5‑FU dose and genetic testing for DPYD or TYMS variants to guide 5‑FU dosing or treatment choice are considered investigational.

There is insufficient evidence to support a general conclusion concerning the health outcomes or benefits associated with these procedures.

Procedures assigned CPT codes 81232 and 81346 are listed in this policy as investigational; therefore, not covered and may be denied when billed for assessment of 5‑fluorouracil exposure or for genetic testing to guide 5‑FU dosing or treatment selection.

The commercially marketed assay My 5-fluorouracil™ was removed from this policy because it is no longer commercially available in the United States.

Available evidence is insufficient to demonstrate that laboratory assays measuring 5‑FU area under the curve (AUC) or genetic testing for DPYD and TYMS variants lead to improved health outcomes. Randomized trials and observational studies have not shown consistent benefits in overall or progression‑free survival, and systematic reviews and technology assessments have found limited prognostic capacity and methodological limitations in the literature. Therefore, these tests are considered investigational.

Covered indications and uses

DPYD genotype-guided dose individualization and pharmacokinetic monitoring

Covered indications (note: supported evidence summarized but policy classifies these approaches as investigational)

DPYD genotype-guided dosing and pharmacokinetic monitoring: DPYD genotype-guided dose individualization and pharmacokinetic monitoring to predict or reduce 5‑FU toxicity in patients receiving fluoropyrimidine chemotherapy have been evaluated in guideline and research literature (for example, CPIC guideline and multiple trials/meta-analyses).

Despite guideline discussion and studies (see references), the policy concludes insufficient evidence for routine coverage.

Services considered not covered

Genetic testing for DPYD and TYMS variants to guide 5‑fluorouracil dosing or treatment selection is considered investigational and is not covered. Procedures specifically identified as investigational in the coding section include CPT codes 81232 and 81346.

My 5-fluorouracil™ is no longer commercially available in the U.S. and was therefore removed from this policy; it is not an available testing option for members.

Provider actions and operational guidance

Note

Product / program-specific coverage

This policy is applicable only to certain Capital Blue Cross programs and products; benefit variations exist and providers should verify member-specific benefits and program applicability prior to ordering tests or submitting claims.

Applies only to certain Capital Blue Cross programs and products.
Providers should check member benefits and program-specific coverage before testing or billing.

Denial Risk

Investigational procedures not covered

The procedures listed below are considered investigational and are not covered by this policy. Claims for these procedures may be denied as not medically necessary.

Investigational / Not covered procedure codes: 81232, 81346

Note

Policy history and administrative notes

Policy history documents consensus reviews and administrative updates. Review the history for coding updates, removals, and administrative changes that may affect billing or authorization.

See policy history for multiple consensus reviews and administrative updates (dates include: 02/04/2020; 01/14/2021; 04/15/2022; 04/20/2023; 06/19/2024; 11/19/2024; 07/11/2025; 09/24/2025).
Recent administrative and consensus updates removed codes and edited policy statements; providers should confirm current coding when submitting claims.

Billing Rule

Removed codes — provider billing action

Codes S3722 and 84999 have been removed from the policy. Providers should not use these codes for billing under this policy and should verify current billing codes prior to claim submission.

Removed codes: S3722, 84999 (effective per policy history updates).
Confirm alternative coding with payer if these were previously used.

Documentation Required

Genetic counseling recommended

Recommend formal genetic counseling by qualified individuals for patients at risk for inherited disorders who are considering genetic testing; counseling can affect testing decisions and interpretation.

Genetic counseling should be performed by individuals with experience in genetic medicine/testing.
Counseling may reduce inappropriate testing and assist with result interpretation and family risk implications.

Background and context

5‑Fluorouracil (5‑FU) is an antineoplastic agent used for a variety of solid tumors (for example, colorectal and head and neck cancers) that exerts cytotoxic effects in part by inhibiting thymidylate synthase (TYMS). Higher systemic exposure to 5‑FU is associated with increased risk of severe toxicities (such as neutropenia, diarrhea, mucositis, and hand‑foot syndrome). Pharmacokinetic monitoring has been studied to target AUC for dose adjustment, and genetic variants in DPYD and TYMS have been evaluated as potential predictors of 5‑FU toxicity; however, evidence is insufficient to support routine clinical use of these assays to improve patient outcomes.

Definitions and terminology

Variant nomenclature and classification — definitions

Variant classification termsACMG-AMP recommended standard terminology: pathogenic; likely pathogenic; variant of uncertain significance; likely benign; benign.

Nomenclature standardHuman Genome Variation Society (HGVS) nomenclature is the recommended international standard for reporting DNA variants.

Scope of recommendationsACMG-AMP standards apply to clinical laboratory genetic tests including single-gene tests, panels, exomes, and genomes.

PurposeUse HGVS for consistent variant reporting and ACMG-AMP terms for interpretation to support clinical decision-making and documentation.

DPYD genotyping / therapeutic drug monitoring — methods

DefinitionDPYD genotyping: testing for dihydropyrimidine dehydrogenase (DPYD) gene variants to identify patients at increased risk for fluoropyrimidine toxicity.

DefinitionTherapeutic drug (pharmacokinetic) monitoring: measurement of 5‑fluorouracil plasma exposure (AUC) to guide dose adjustments to reduce toxicity risk.

Guideline supportCPIC guideline (2017 update) provides recommendations for DPYD genotype-guided fluoropyrimidine dosing.

Evidence contextMultiple clinical trials and meta-analyses have evaluated DPYD variants and 5‑FU toxicities; results inform but do not establish routine use per policy evidence summary.