ModifiedUnitedHealthcarePolicy LABORATORY 032.4

FDA Cleared or Approved Companion Diagnostic Testing

Defines medical necessity and coverage rationale for FDA-cleared or approved oncology companion diagnostic tests (tissue and liquid biopsy), including repeat and concurrent testing rules, and lists applicable procedure codes. Affects providers ordering CDx tests and payers adjudicating coverage.

Policy Summary

PayerUnitedHealthcare

PolicyFDA Cleared or Approved Companion Diagnostic Testing

Policy CodePolicy LABORATORY 032.4

Change TypeCoding update — CPT 0543U added

Effective DateApr 1, 2025

Next Review DateN/A

Key ActionWhen ordering companion diagnostic or genomic tests, follow payer prior-authorization processes and verify applicable procedure codes per member benefit.

SourceLink

POLICY UPDATE CHANGES

Applicable CPT codes list was updated to reflect quarterly edits and CPT code 0543U was added.

up to 3Repeat tests allowed

30 daysConcurrent testing window

NCApplicable state(s)

multipleProcedure code list

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Coverage Criteria

inv-01: FDA-listed Companion Diagnostic Tests

Covered when ALL of the following are met:

Core CDx alignment: The companion diagnostic is listed on the FDA List of Cleared or Approved Companion Diagnostic Devices and the use is consistent with the CDx label and aligns with the drug's FDA-approved indication and appropriate tissue/specimen.

inv-02: Repeat CDx Testing

Repeat Companion Diagnostic Testing on a new tissue or liquid biopsy specimen is considered medically necessary when ALL are met:

Repeat testing conditions: The companion diagnostic criteria are met AND there is clinical justification for repeat testing (one or more of the following): cancer progression or lack of response to the most recent systemic therapy; disease recurrence; or other clinical need to select therapy.Up to three times annually

Repeat testing allowed up to three times annually when criteria are met.

inv-03: Concurrent Tissue and Liquid Biopsy CDx Testing

Concurrent tissue-based and liquid biopsy companion diagnostic testing (ordered within 30 days of each other) is considered medically necessary for the following cancer types when CDx criteria are met:

Eligible cancers for concurrent testing: Advanced or metastatic (stage IV) non-small cell lung cancer OR advanced or metastatic (stage IV) breast cancer.Tests ordered within 30 days of each other

Concurrent testing allowed within a 30-day window for these cancer types.

inv-04: Coverage criteria for genomic profiling

Covered when test is an FDA-approved companion diagnostic used per its labeled indication; non-FDA-approved broad molecular profiling tests require demonstration of clinical validity and utility:

FDA CDx used per label: Test is an FDA-approved companion diagnostic and is used for the tumor type, biomarker, and specimen consistent with the FDA product labeling.

Supported by validation and labeling information for tests such as FoundationOne CDx.

Non-FDA CGP consideration: Non-FDA-approved broad CGP or expanded profiling assays may be considered only when peer-reviewed evidence demonstrates analytical validity, clinical validity, and clinical utility for the specific indication.

Hayes assessments reported insufficient evidence for several non-FDA assays (examples: Guardant360 TissueNext, MI Profile).

inv-05: Contexts with reported clinical utility

Contexts supported by cited studies and assessments (not an administrative coverage rule in the provided text):

Supported clinical contexts: Liquid biopsy/comprehensive ctDNA profiling may be clinically useful for: identifying actionable genomic alterations in advanced/metastatic solid tumors to guide targeted therapy; when tissue biopsy is infeasible or insufficient; to shorten time to treatment initiation by providing early genotyping; for longitudinal monitoring or detection of resistance mutations after therapy; and when tumor fraction in plasma is adequate (higher tumor fraction increases assay sensitivity).See tumor fraction thresholds in analytical validity considerations

Based on multiple prospective, retrospective, and validation studies and Hayes assessments.

inv-06: Analytical validity considerations

Analytical performance characteristics summarized from validation studies:

Analytical validation highlights: Published validation studies report limits of detection and performance metrics for liquid CDx assays: e.g., FoundationOne Liquid CDx reported 95% LOD ~0.40% VAF for select substitutions and 0.37% for rearrangements, reproducibility 99.59%, false positive rate ~0.013%; InVisionFirst reported >99% sensitivity for SNVs and >92% for indels. Sensitivity depends on variant class and tumor fraction.LOD values as reported

These analytical characteristics inform interpretation of negative results and need for reflex tissue testing when tumor fraction is low.

inv-07: Clinical outcome observations

Clinical impact and outcome evidence in specific studies:

Observed clinical impacts: Studies report that broad ctDNA or tissue CGP identifies actionable targets in a substantial proportion of individuals (e.g., 64% actionable targets in a FoundationOne Liquid CDx cohort), can increase detection of therapeutically targetable mutations compared with tissue alone, may shorten time to treatment initiation when performed early, and in some cohorts is associated with higher rates of matched targeted therapy and improved treatment-related outcomes.N/A

Quality of evidence varies across studies and assessments.

inv-08: Guideline-supported Coverage Criteria

Covered when the following guideline-supported clinical contexts are met

Guideline-aligned advanced/metastatic testing: Patient has advanced or metastatic solid tumor and testing is intended to identify genomic biomarker-linked, approved therapy or to inform tumor-agnostic therapy selection, consistent with guideline recommendations (ASCO, ESMO, NCCN).

Supported by ASCO, ESMO, and NCCN guidance.

When tissue unavailable: ctDNA/plasma-based testing is acceptable when tumor tissue is not available or new biopsy is not feasible, or when rapid results are clinically necessary.

Supported by ASCO, ESMO, and IASLC statements.

Tumor type–specific recommendations: Testing for specified alterations (for example, PIK3CA in HR+/HER2- breast cancer; MET exon 14 in NSCLC; FGFR2/NTRK/IDH/BRAF/MSI in biliary tract cancers) is appropriate when the individual meets disease-stage criteria and results will inform targeted therapy selection.

Supported by tumor-specific NCCN recommendations.

inv-09: General tumor-type agnostic coverage criteria

Covered when ALL of the following are met (per NCCN guidance excerpts in this section):

General coverage conditions

Specimen preference: Tissue testing preferred; ctDNA acceptable when tissue unavailable or for monitoring indications.
Repeated guidance across tumor-specific sections.

inv-10: NSCLC and progression-specific criteria

Additional coverage considerations for NSCLC and situations of progression:

NSCLC / progression: (1) Broad panel-based NGS is preferred to identify guideline-listed biomarkers; (2) In progression on targeted therapy, repeat broad genomic profiling (tissue preferred) may be appropriate to detect resistance mechanisms; (3) ctDNA is useful in metastatic disease but should not replace histologic diagnosis or be used for early-stage disease.

Based on NCCN NSCLC guidance.

inv-11: Selected tumor-specific covered indications

Tumor-specific testing recommendations (examples captured here):

Breast/PIK3CA: PIK3CA mutation testing may be performed on tumor tissue or ctDNA to identify candidates for alpelisib plus fulvestrant; a negative ctDNA should prompt tissue testing.

NCCN breast cancer guidance.

Ovarian/HRD and BRCA: Tumor molecular analysis including BRCA1/2 and HRD status is recommended upfront and at recurrence; testing should be performed on the most recent tumor tissue available, with ctDNA when tissue is not feasible.

NCCN ovarian cancer guidance.

Pancreatic and Fusion Detection: Tumor/somatic profiling including RNA-based assays for fusion detection is recommended for locally advanced/metastatic disease; tissue preferred, cfDNA acceptable if tissue infeasible.

NCCN pancreatic adenocarcinoma guidance.

inv-12: NCCN-aligned testing recommendations

Covered when aligned with NCCN recommendations and member benefit plan:

Small Cell Lung Cancer: Consider comprehensive molecular profiling (CMP) using blood, tissue, or both in selected extensive-stage/relapsed small cell lung cancer cases (e.g., minimal smoking history or diagnostic/therapeutic dilemmas) or at relapse if not previously done.

NCCN v2.2025.

Anaplastic Thyroid Carcinoma: Molecular testing should include BRAF, NTRK, ALK, RET, MSI, dMMR, and TMB; BRAF IHC may be used for faster turnaround when indicated to guide systemic therapy or trial eligibility.

NCCN Thyroid Carcinoma v4.2024.

Uterine Neoplasms: Comprehensive molecular evaluation of endometrial carcinoma to identify clinically significant subgroups is recommended; include at minimum NTRK, MSI, and TMB for metastatic uterine sarcoma and consider CGP early.

NCCN Uterine Neoplasms v2.2024.

Coverage is limited to Companion Diagnostic (CDx) tests listed on the U.S. FDA List of Cleared or Approved Companion Diagnostic Devices and when the test use is consistent with the CDx label and the corresponding drug's FDA-approved indication and specified specimen type. If no cancer/test match is found on the FDA list, providers should refer to the Clinical Policy titled "Molecular Oncology Testing for Solid Tumor Cancer Diagnosis, Prognosis, and Treatment Decisions" or the corresponding hematologic cancer policy and follow the member-specific benefit terms when determining coverage.

Repeat CDx testing on a new tissue or liquid biopsy specimen for therapy selection is considered medically necessary up to three times annually when the CDx criteria above are met and there is clinical justification (for example, disease progression, lack of response to the most recent systemic therapy, or disease recurrence).

Concurrent tissue-based and liquid biopsy CDx testing ordered within a 30-day window may be considered medically necessary for specified cancers (for example, advanced/metastatic non–small cell lung cancer and advanced/metastatic breast cancer) when all other CDx criteria are satisfied.

This FDA list is provided for informational use only; FDA approval alone is not a basis for coverage and coverage decisions must be reconciled with the member-specific benefit plan and any applicable mandates.

Broad molecular profiling tests that are not FDA-cleared/approved CDx assays require peer-reviewed evidence of analytical and clinical validity and demonstrated clinical utility for the intended indication before routine coverage is supported. Hayes assessments cited in the policy identified insufficient peer-reviewed evidence for several non-FDA CGP assays (examples include Guardant360 TissueNext and the MI Profile), and FoundationOne Heme was noted as having insufficient evidence for hematologic malignancies and sarcomas.

Evidence summaries cited in the policy show variable clinical impact from broad profiling: some cohorts report identification of actionable variants and occasional matched therapy use, but larger studies and reviews (including Hayes assessments) concluded that evidence for improved clinical outcomes from undirected broad profiling is limited or insufficient in many settings.

When non-FDA CGP testing is requested for coverage consideration, clinical documentation should demonstrate the test's analytical validation and peer-reviewed evidence supporting clinical validity and utility for the specific cancer type and therapeutic decision.

Although FoundationOne Liquid CDx is an FDA-approved circulating tumor DNA assay and is FDA-cleared as a CDx for specific tumor–drug pairs, the policy notes that only 12 of the 324 genes in the panel are included in FDA CDx indications and that FoundationOne Liquid CDx is not approved for assessment of TMB or MSI in FDA labeling despite manufacturer statements of validation for those biomarkers. Hayes assessments found poor-quality evidence for broad tumor mutational profiling using the assay and did not demonstrate that comprehensive testing conclusively improves clinical outcomes compared with more-limited testing.

When ordering or adjudicating coverage for FoundationOne Liquid CDx, confirm that the requested use aligns with the FDA-labeled CDx indications and the member's benefit plan; uses outside those labeled CDx indications require supporting evidence of analytical and clinical validity and documented clinical utility for the intended purpose.

Use of circulating tumor DNA (ctDNA) assays for population-level cancer screening is not supported by the evidence summarized in this policy. Systematic reviews and guideline statements cited (for example ASCO/CAP reviews) found insufficient evidence of clinical validity and utility for the majority of ctDNA assays in screening contexts, and the policy concludes that ctDNA-based population screening is not recommended.

Any proposed use of ctDNA assays for screening should be considered investigational in the absence of high-quality evidence demonstrating benefit and should not be covered as routine screening under the standard policy.

ctDNA testing is generally not recommended for non-advanced (stage I–III) disease and should not replace histologic tissue diagnosis. The policy cites guideline guidance indicating tissue-based testing is preferable in early-stage disease and that ctDNA has limited sensitivity in many such settings.

Both ctDNA and tissue assays have high specificity but can have considerable false-negative rates; when a liquid biopsy is negative for actionable alterations and a treatment decision depends on biomarker status, tissue testing should be pursued when feasible.

FDA information is provided for reference, but FDA approval alone does not constitute coverage; clinicians and reviewers must follow member-specific benefit terms and applicable mandates when considering ctDNA in non-advanced disease.

The policy emphasizes that FDA approval or clearance by itself is informational only and is not sufficient to guarantee coverage. Coverage decisions must be made in the context of the member-specific benefit plan and any applicable federal or state mandates.

Providers and adjudicators should confirm that the proposed test use aligns with the member's benefit terms and with any applicable regulatory or contractual requirements before authorizing payment.

Use of a companion diagnostic that is not consistent with the test labeling, the corresponding drug labeling, or that is not listed on the FDA List of Cleared or Approved Companion Diagnostic Devices may not meet the policy's medical necessity criteria and is subject to denial. The policy requires consistency between the CDx labeling, the drug's FDA-approved indication, and the specimen type.

When a requested CDx use falls outside the test or drug labeling or is not found on the FDA list, coverage should be determined by applying the relevant molecular oncology clinical policies and by reviewing member-specific benefit terms and available evidence of analytical and clinical validity and clinical utility.

Broad molecular profiling performed as an undirected screening approach to match patients to off‑label targeted therapies without evidence of clinical outcome benefit is not supported. Hayes assessments and clinical studies cited in the policy report low to insufficient-quality evidence that such undirected profiling improves patient outcomes and therefore caution against routine use for this purpose.

Tests requested to support off‑label therapy selection should be accompanied by documentation of analytical and clinical validity as well as peer‑reviewed evidence of clinical utility for the specific off‑label indication to be considered for coverage.

The policy notes limited or low‑quality evidence that comprehensive ctDNA testing or broad CGP universally improves clinical outcomes compared with more limited, focused testing. Hayes assessments and study evidence found variable clinical impact; some cohorts had identification of actionable alterations and subsequent targeted therapy, but randomized or high-quality outcome data demonstrating improved survival or other patient-centered outcomes were generally lacking.

When considering comprehensive ctDNA or broad CGP testing, documentation of a clear intended clinical action based on potential results (for example, eligibility for an FDA‑approved targeted therapy or clinical trial) and supporting evidence of clinical utility should be provided to support coverage.

Routine adoption of many ctDNA assays is not supported because published evidence of clinical validity and clinical utility is insufficient for most tests. ASCO/CAP and other reviews concluded that while some ctDNA tests demonstrate validity and utility in specific advanced-stage contexts, the majority lack robust evidence to support routine use across indications.

Tests without demonstrated clinical utility for the intended indication should be considered not medically necessary unless convincing, indication‑specific evidence is provided and the member's benefit plan allows coverage.

Routine molecular profiling is not established for hepatocellular carcinoma because, to date, no treatments have been shown to provide differential benefit for molecularly defined subgroups in this disease. The policy states profiling may be considered on a case‑by‑case basis and encourages clinical trial participation where appropriate.

For hepatocellular carcinoma, testing decisions should be individualized and supported by clinical rationale; routine reflex profiling is not indicated in the absence of actionable, evidence‑supported therapies for molecular subgroups.

The policy does not include explicit not‑medically‑necessary (NMN) statements for every test or indication in these excerpts; instead, it directs reviewers to align determinations with the member‑specific benefit language, applicable guidelines, and the available evidence of clinical validity and utility for the requested test and indication.

When there is uncertainty, adjudicators should reference the member's benefit plan, applicable clinical policies, and the FDA List of Cleared or Approved Companion Diagnostic Devices for guidance in coverage decisions.

Covered Indications

inv-69: Identification of individuals with cancer likely to benefit when an FDA-cleared/approved CDx exists for that drug and sample type

Identification via FDA CDx: Identification of individuals with cancer most likely to benefit from, at increased risk of side effects from, or requiring monitoring related to a particular FDA-labeled oncology therapeutic when an FDA-cleared/approved CDx exists for that drug and sample type.

Leverages FDA List of Cleared or Approved Companion Diagnostic Devices.

inv-70: FDA-labeled companion diagnostic testing to identify individuals likely to benefit from a specific FDA-approved therapy (examples and study citations)

FDA-labeled CDx to guide therapy: FDA-labeled companion diagnostic testing is indicated to identify individuals likely to benefit from a specific FDA-approved therapy when the test and drug labeling are aligned (example: FoundationOne CDx used as CDx for multiple drug therapies; genomic testing identifying BRCA in mCRPC to inform PARP inhibitor use per TRITON2 evidence).

Supported by clinical and analytical validation data and clinical trial results.

Coding

Covered CPT/HCPCS/PLA codes (listed)mixed

0022U	Targeted genomic sequence analysis panel, non-small cell lung neoplasia, DNA and RNA analysis, 23 genes, interrogation for sequence variants and rearrangements, reported as presence or absence of variants and associated therapy(ies) to consider.
0037U	Targeted genomic sequence analysis, solid organ neoplasm; DNA analysis of 324 genes, interrogation for sequence variants, gene copy number amplifications, gene rearrangements, microsatellite instability and tumor mutational burden.
0179U	Oncology (non-small cell lung cancer), cell-free DNA, targeted sequence analysis of 23 genes (single nucleotide variations, insertions and deletions, fusions without knowledge of partner/breakpoint; copy number variations), with report of significant mutation(s) prior.
0239U	Targeted genomic sequence analysis panel, solid organ neoplasm, cell-free DNA, analysis of 311 or more genes, interrogation for sequence variants, including substitutions, insertions, deletions, select rearrangements, and copy number variations.
0242U	Targeted genomic sequence analysis panel, solid organ neoplasm, cell-free circulating DNA analysis of 55-74 genes, interrogation for sequence variants, gene copy number amplifications, and gene rearrangements.
0473U	Oncology (solid tumor), NGS of DNA from formalin-fixed paraffin-embedded (FFPE) tissue with comparative sequence analysis from a matched normal specimen (blood or saliva), 648 genes, interrogation for sequence variants, insertion and deletion alterations, copy number variants, rearrangements, microsatellite instability, and tumor-mutation burden.
0543U	Oncology (solid tumor), next-generation sequencing of DNA from formalin-fixed paraffin-embedded (FFPE) tissue of 517 genes, interrogation for single-nucleotide variants, multi-nucleotide variants, insertions and deletions from DNA, fusions in 24 genes and splice variants in 1 gene from RNA, and tumor mutation burden.

Additional laboratory/molecular CPT codesCPT

81445	Solid organ neoplasm, genomic sequence analysis panel, 5-50 genes, interrogation for sequence variants and copy number variants or rearrangements, if performed; DNA analysis or combined DNA and RNA analysis.
81449	Solid organ neoplasm, genomic sequence analysis panel, 5-50 genes, interrogation for sequence variants and copy number variants or rearrangements, if performed; RNA analysis.
81450	Hematolymphoid neoplasm, genomic sequence analysis panel, 5-50 genes, interrogation for sequence variants, and copy number variants or rearrangements, or isoform expression or mRNA expression levels, if performed; DNA analysis or combined DNA and RNA analysis.
81451	Hematolymphoid neoplasm, genomic sequence analysis panel, 5-50 genes, interrogation for sequence variants, and copy number variants or rearrangements, or isoform expression or mRNA expression levels, if performed; RNA analysis.
81455	Solid organ or hematolymphoid neoplasm; 51 or greater genes, genomic sequence analysis panel, interrogation for sequence variants and copy number variants or rearrangements, or isoform expression or mRNA expression levels, if performed; DNA analysis or combined DNA and RNA analysis.
81456	Solid organ or hematolymphoid neoplasm; 51 or greater genes, genomic sequence analysis panel, interrogation for sequence variants and copy number variants or rearrangements, or isoform expression or mRNA expression levels, if performed; RNA analysis.
81479	Unlisted molecular pathology procedure.
81599	Unlisted multianalyte assay with algorithmic analysis.

Covered CPT Codesmixed

No codes listed

Applicable CPT Codes UpdatedCPT

0543U

CPT code added to applicable codes list (no further description in this section)

ctDNA tumor fraction (1% threshold)

ctDNA tumor fraction (threshold used in studies)1% — used as a prevalence and sensitivity threshold in cited analyses (prevalence and sensitivity drop markedly below this level)

Context of useApplied in cohort analyses comparing detection rates by tumor fraction (e.g., liquid vs tissue comparisons)

Implication for reflex testingAuthors recommend reflex tissue biopsy when ctDNA tumor fraction is below the 1% threshold due to lower detection prevalence in plasma

ctDNA tumor fraction and assay sensitivity

Sensitivity at high tumor fractionSensitivity near or at 100% when ctDNA tumor fraction ≥ 10% (concordance with tissue-based detection in F1LCDx cohort)

Provider Actions & Prior Authorization

Billing Rule

Applicable codes referenced

Applicable procedure and diagnosis codes are provided for reference only and may not be exhaustive. Listing a code does not guarantee coverage or reimbursement; providers must follow payer prior authorization and billing guidance and verify member benefit plan terms.

Verify prior authorization requirements and billing guidance with UnitedHealthcare before ordering or performing testing.
Updated applicable codes may include new CPT/HCPCS additions (e.g., 0543U); confirm current code lists prior to submission.

Prior Authorization

Prior authorization for non‑FDA‑approved CGP

Prior authorization may be required for non–FDA‑approved comprehensive genomic profiling (CGP) assays or broad NGS tests. Non‑FDA‑approved CGP tests (including some commercial multicancer or broad profiling assays) currently have limited peer‑reviewed evidence supporting clinical validity and utility for broad profiling indications; coverage decisions may require demonstration that testing will impact management.

Frequency Limits

Repeat companion diagnostic testing (frequency)

Repeat companion diagnostic testing — allowanceUp to three times annually (repeat testing on a new tissue or liquid biopsy specimen is considered medically necessary when CDx criteria are met and clinical need exists)

Clinical triggers for repeat testingCancer progression, lack of response to most recent systemic therapy, or disease recurrence

Specimen requirementRepeat testing must be performed on a new tissue or liquid biopsy specimen

Example frequency: personalized ctDNA RaDaR assay

Example assay — personalized RaDaR ctDNAMonitoring performed every 6–12 months in the cited prospective MRD study (personalized RaDaR assay)

Study contextUsed for surveillance in high‑risk, early‑stage HR+ breast cancer with serial plasma collections

Ordering Requirements

Prior Authorization

Request CDx consistent with drug label and specimen; supply records if requested

Ordering providers must request companion diagnostics consistent with the drug label and specimen; be prepared to supply medical records documenting the clinical criteria when requested.

Policy requires CDx use consistent with the drug label and specimen; records may be requested to document clinical criteria and benefit applicability.
If no FDA‑listed CDx exists for the drug/indication, follow the referenced molecular oncology policies for guidance.

Documentation Required

Order and interpret testing via an oncology specialist; consider molecular tumor board review

Have an oncologist or other appropriate specialist order and interpret genomic testing; consider molecular tumor board review for complex cases or when interpreting broad CGP/ctDNA results.

Consensus and guideline statements recommend involvement of oncology specialists and molecular tumor boards for interpretation and treatment selection.
Document the specialist ordering the test on the requisition and in the medical record.

Not Covered / Limitations

Companion diagnostic testing that is not consistent with the FDA‑cleared or approved CDx labeling, or that is used outside the labeled drug/indication/specimen, is categorized as not covered under this policy unless supporting evidence of analytical and clinical validity and clinical utility is provided and the member's benefit plan allows coverage.

Additionally, broad, non‑FDA‑cleared profiling tests that lack sufficient peer‑reviewed evidence of clinical validity or utility (for example, Guardant360 TissueNext, MI Profile, and certain other non‑FDA CGP assays identified by Hayes) are considered not covered for routine use in the absence of compelling indication‑specific evidence.

Non‑FDA‑cleared broad profiling assays and expanded panels without robust peer‑reviewed evidence of analytic and clinical validity or demonstrated clinical utility are listed as not covered for routine use. The policy references Hayes molecular test assessments that identified insufficient evidence for several named assays (for example, Guardant360 TissueNext and the MI Profile).

Requests for these assays must be supported by indication‑specific evidence of validity and utility and by documentation showing that results would directly inform an FDA‑labeled therapy decision or an evidence‑based off‑label plan supported by clinical data and the member's benefit provisions.

The document excerpts do not provide an exhaustive list of explicitly excluded tests or indications; rather, they describe categories with limited or low‑quality evidence and reference specific non‑FDA assays evaluated by Hayes as examples. The practical effect is that many non‑FDA‑approved broad CMP tests and some uses of ctDNA lack sufficient evidence to support routine coverage.

Coverage determinations for particular tests or panels not explicitly described should be made on the basis of the available peer‑reviewed evidence, FDA indications when applicable, and the member‑specific benefit language.

Background

Companion Diagnostic (CDx) tests are in vitro assays that provide information necessary for the safe and effective use of specific oncology therapeutic drugs by detecting biomarkers associated with treatment response, adverse effect risk, or monitoring needs. The policy uses the FDA List of Cleared or Approved Companion Diagnostic Devices to define approved CDx use and aligns coverage to the CDx labeling and the corresponding drug indication, specimen type, and intended clinical purpose.

Because treatment decisions and patient safety depend on test accuracy and appropriate use, the policy requires that CDx testing be consistent with test labeling and drug labeling and that testing be performed and interpreted in the clinical context of the member's disease and benefit coverage.

Definitions

Companion Diagnostic Test — definition

Definition — Companion Diagnostic TestA test that provides important information for the safe and effective use of a corresponding therapeutic drug (FDA; 2024)

PurposeIdentifies individuals most likely to benefit from or at increased risk of side effects from a specific FDA‑labeled oncology therapeutic

Link to labelingMust be used consistent with the CDx and drug labeling and appropriate specimen type per FDA list

Liquid Biopsy — definition

Definition — Liquid BiopsyMinimally invasive testing performed on bodily fluids (most commonly blood) to analyze tumor-derived biomolecules including ctDNA/cfDNA, RNA, circulating tumor cells, proteins, and extracellular vesicles

UsesMay be used for detection of tumor alterations, treatment selection, monitoring, and when tissue biopsy is infeasible

Revision History

2025-04-01coding_updateLatest

Applicable CPT codes list updated to reflect quarterly edits; CPT code 0543U was added.

Billing Rule

Verify PA and edits for newly added code 0543U

Following the policy revision adding CPT code 0543U, verify whether prior authorization or other utilization edits apply to the newly listed code before submitting claims or PA requests.

Policy history notes the applicable codes list was updated to include 0543U on 04/01/2025.
Confirm payer coding edits and PA requirements for 0543U with the member’s plan.

Policy Summary

PayerUnitedHealthcare

PolicyFDA Cleared or Approved Companion Diagnostic Testing

Policy CodePolicy LABORATORY 032.4

Change TypeCoding update — CPT 0543U added

Effective DateApr 1, 2025

Next Review DateN/A

Key ActionWhen ordering companion diagnostic or genomic tests, follow payer prior-authorization processes and verify applicable procedure codes per member benefit.

SourceLink

On This Page

Laboratory certification: Testing is performed in an appropriately certified laboratory and, when available and applicable, using clinically validated or FDA-cleared/approved assays.

ASCO/CAP and guideline recommendations.

Vaginal Cancer: NGS and CMP profiling is recommended for recurrent or persistent disease to guide systemic therapy selection; tissue preferred but ctDNA CGP acceptable if tissue unavailable.

NCCN Vaginal Cancer v2.2025.

inv-71: Use of liquid biopsy as complementary or alternative to tissue testing in advanced NSCLC, especially when tissue is insufficient or to detect acquired resistance

Liquid biopsy in advanced NSCLC: Use of liquid biopsy (cfDNA/ctDNA) is acceptable as complementary or alternative to tissue testing in advanced NSCLC, particularly when tissue is insufficient or to detect acquired resistance; negative liquid results should be confirmed on tissue when feasible.

Consensus recommendations and studies support complementary or alternative use of liquid biopsy in advanced NSCLC.

inv-72: Advanced or metastatic solid tumors where detection of actionable genomic alterations will inform targeted therapy selection

Advanced/metastatic solid tumors: Advanced or metastatic solid tumors (e.g., NSCLC, breast, colorectal, prostate, pancreatic, RCC) where detection of actionable genomic alterations will inform selection of targeted therapy; testing may be performed on tissue or validated ctDNA assays when appropriate.

Multiple studies and test assessments report utility in advanced/metastatic settings.

inv-73: Advanced or metastatic solid tumors where identification of actionable genomic alterations will direct use of targeted therapies (disease-specific examples)

Disease-specific examples: Advanced or metastatic solid tumors where identification of actionable genomic alterations will direct targeted therapies, with examples including breast, NSCLC, biliary tract, bladder, bone tumors, and ampullary adenocarcinoma; RNA sequencing or tissue testing may be preferred for fusion detection.

NCCN recommends tumor NGS and/or plasma ctDNA in these settings.

inv-74: Advanced, metastatic, recurrent, or unresectable solid tumors where results could inform targeted therapy decisions (examples)

Broad advanced/recurrent indications: Advanced, metastatic, recurrent, or unresectable solid tumors where results could inform targeted therapy decisions (examples: breast, NSCLC, CRC, ovarian, pancreatic); tissue-based NGS is preferred, but ctDNA is acceptable when tissue is unavailable or for certain monitoring indications.

NCCN and guideline-aligned recommendations.

inv-75: Selected advanced or recurrent cancers where NCCN recommends molecular profiling (small cell lung, anaplastic thyroid, uterine, vaginal)

Selected NCCN-recommended cancers: Selected advanced or recurrent cancers where NCCN recommends molecular profiling include small cell lung cancer, anaplastic thyroid carcinoma, uterine neoplasms, and recurrent/persistent vaginal cancer; testing may inform systemic therapy selection and clinical trial eligibility, with tissue preferred when feasible.

NCCN tumor-specific guidance.

Sensitivity at lower tumor fraction

Sensitivity ranged from ~58% to 86% in samples with tumor fraction <10%

Analytical validation contextFoundationOne Liquid CDx validation reported limits of detection and tumor-fraction–dependent performance metrics that underpin these sensitivity observations

Prior authorization should be obtained when ordering non‑FDA‑approved CGP or broad molecular profiling assays.
Hayes assessments cited limited or insufficient peer‑reviewed evidence for several non‑FDA‑approved broad CGP assays; expect additional documentation requests to justify medical necessity.

Prior Authorization

Prior authorization for tumor genomic testing

Prior authorization may be required for tumor genomic testing used to guide targeted therapy. For many tumor types (e.g., NSCLC, bladder, breast, ovarian), guidelines recommend early genomic testing; when testing will inform use of a labeled companion diagnostic or targeted agent, documentation supporting the indication and intended treatment should be available.

Obtain prior authorization when the test is intended to select or exclude a specific targeted therapy unless an FDA‑cleared/approved companion diagnostic is used in accordance with the drug label.
When testing is performed to identify biomarkers prior to targeted therapy initiation, include rationale that results will change management.

Prior Authorization

Prior authorization for broad NGS in advanced disease

Prior authorization should confirm that broad NGS or comprehensive profiling is clinically indicated — for example in advanced/metastatic disease, when results will alter therapy selection, or when tissue is limited and CGP is appropriate. Broad NGS in early‑stage disease or for screening is generally not supported.

For advanced/metastatic disease, document how broad molecular profiling will affect treatment decisions (e.g., eligibility for targeted agents or clinical trials).
Broad NGS for screening or non‑advanced disease is unlikely to meet criteria; prior authorization may be denied without clear clinical justification.

Denial Risk

Non‑FDA‑approved CGP tests have limited evidence

Non–FDA‑approved CGP tests have limited peer‑reviewed evidence for clinical utility as broad profiling tools. Expect stricter prior authorization review and requirements for clinical documentation when ordering these assays.

Tests without FDA approval for the intended use may be considered experimental for broad profiling absent high‑quality evidence; include supporting literature if available.
If the assay is being used to detect specific FDA‑linked biomarkers for which analytic validity is established, specify those biomarkers and evidence.

Note

No explicit administrative authorization lists provided

No explicit administrative authorization or denial triggers are listed in these excerpts; however, coverage is determined by the member‑specific benefit plan and by clinical evidence. Providers should anticipate individualized review.

Absence of an explicit code list in this section does not preclude PA requirements — always check current UnitedHealthcare PA policies and plan documents.
Third‑party tools (e.g., InterQual) may be used to assist benefit administration; results can affect authorization decisions.

Denial Risk

Evidence‑based denial risk

Tests lacking sufficient evidence of clinical validity or utility, tests used outside guideline‑recommended settings (e.g., ctDNA in non‑advanced disease), or tests ordered without demonstrating impact on management are at higher risk for denial.

ctDNA assays used for screening or in early stage disease are generally unsupported and may be denied.
Broad CGP without evidence that results will change therapy or without validated analytical performance may be subject to denial.

Denial Risk

ctDNA use outside advanced/metastatic settings

Use of circulating tumor DNA (ctDNA) testing is generally recommended for advanced or metastatic disease; ctDNA testing outside that setting (e.g., screening or routine early‑stage use) is not typically recommended and may not be covered.

If ordering ctDNA for non‑advanced disease, provide strong justification and supporting evidence; anticipate review or denial.
Prefer tissue‑based testing for stage I–III disease; ctDNA may complement or be used when tissue is unobtainable.

Documentation Required

Medical records may be requested

Medical records and other documentation may be requested to assess whether the member meets clinical criteria for coverage. Submission of complete clinical records does not guarantee coverage; member plan terms govern the final determination.

Be prepared to submit relevant medical records, prior test results, staging, prior therapies, and treatment plans upon request.
Documentation requests may be used to establish medical necessity and alignment with FDA labeling or guideline recommendations.

Documentation Required

Required clinical documentation

Required clinical documentation should include tumor type and stage, indication for testing, prior systemic therapies, prior biomarker or molecular testing results, and how the test result will impact management or treatment selection.

Include tumor histology, stage (e.g., advanced/metastatic), performance status, prior targeted or systemic therapies, and any prior molecular test reports.
If tissue is unavailable and ctDNA is used, document why tissue sampling is not feasible and how ctDNA results will guide therapy.

Documentation Required

Analytical validation and tumor fraction information

Analytical validation metrics (including limit of detection, tumor fraction/ctDNA fraction, and assay sensitivity/specificity) and prior test results may be requested to support the reliability of the assay and interpretation of negative results.

Provide assay validation data where applicable (e.g., limit of detection, positive/negative percent agreement) and, for liquid biopsies, report ctDNA tumor fraction when available.
If a liquid biopsy is negative and ctDNA tumor fraction is low, document plans for reflex tissue testing or justification for foregoing tissue testing.

Documentation Required

Laboratory certification and documentation

Testing must be performed in appropriately certified laboratories and results should be reported with sufficient detail to support clinical decision making. CLIA certification and, when applicable, FDA approval/clearance status should be documented.

Specify the performing laboratory, CLIA certification status, and whether the assay is FDA‑cleared/approved (e.g., FoundationOne CDx, Guardant360 CDx).
Results should include method, genes/biomarkers tested, analytic performance, and interpretation relevant to treatment decisions.

Note

Member benefit plan governs

Member‑specific benefit plan documents govern coverage determinations. In case of conflict between this policy and the member's plan, the member plan controls. Check for applicable federal or state mandates that may alter coverage.

Before ordering, verify member benefits and any plan‑specific prior authorization requirements or mandates.
In the event of discrepancies between this policy and the member plan, follow the member‑specific benefit plan.

Note

Testing sequence considerations

Testing sequence considerations: tissue testing at initial diagnosis is preferred for many tumor types; liquid biopsy can be complementary or used when tissue is unobtainable. Sequential strategies (tissue first then liquid, or liquid first with reflex tissue if negative or low ctDNA) are acceptable when justified.

Consider tissue CGP at initial diagnosis when feasible; use liquid biopsy to identify acquired resistance or when tissue is insufficient.
When liquid biopsy is performed first and is negative or has low ctDNA fraction, plan reflex tissue testing before excluding actionable biomarkers.

Documentation Required

Sequencing before targeted therapy

Detecting actionable biomarkers prior to initiating targeted therapy is recommended. Document that testing is being used to guide selection of targeted agents and include evidence that results will impact treatment.

Order appropriate companion diagnostic or validated test prior to starting targeted therapy when required by drug labeling.
If a companion diagnostic is used, ensure its use aligns with the specific drug label and specimen requirements.

Documentation Required

Sequential testing when liquid biopsy is negative

When a liquid biopsy is negative for actionable biomarkers, follow‑up tissue testing is recommended before excluding targeted therapy — especially when ctDNA tumor fraction is low or clinical suspicion is high.

If liquid biopsy is negative and ctDNA tumor fraction is below validated detection thresholds, obtain tissue testing if feasible to confirm absence of actionable alterations.
Document rationale for foregoing reflex tissue testing if tissue biopsy is not performed.

Step Therapy

No explicit step therapy requirements stated

No step therapy or step‑edit requirements are described in the provided excerpts. Providers should follow any plan‑specific step therapy rules if present in the member's benefit documentation.

If the member's plan includes step therapy or other utilization management, those rules must be followed; check plan documents and PA requirements prior to ordering.

Clinical outcome observedctDNA detection preceded distant metastatic recurrence by a median of 12.4 months in positive cases

Frequency limits (unspecified)

Frequency limits — unspecifiedNo explicit frequency limits provided in the cited sections for this test type (not specified in provided chunks)

InterpretationFrequency should be guided by clinical indication and available evidence; document justification when frequent/serial testing is ordered

Action for providersIf using repeated ctDNA/NGS for monitoring, document clinical rationale and alignment with guideline-recommended contexts

NGS / ctDNA — repeat testing (general)

NGS/ctDNA repeat testing — general policyRepeat genomic testing is permitted as clinically indicated, particularly when initial testing used a limited panel or when acquired resistance is suspected

ASCO guidanceASCO suggests repeat testing may be justified after progression or when initial sequencing used a limited panel

DocumentationDocument prior panel size and clinical reason for repeat testing (e.g., suspected resistance) to support medical necessity

Broad genomic profiling / NGS — repeat testing

Broad genomic profiling allowed at progressionRepeat broad genomic profiling/NGS is allowed when clinically indicated, such as at disease progression to assess resistance mechanisms

Specimen preferenceTissue biopsy preferred for resistance evaluation when feasible; ctDNA acceptable if tissue not available

Clinical rationaleBroad profiling may detect mechanisms of resistance that inform next-line targeted therapy choices

CGP / NGS — frequency (not specified)

CGP/NGS frequency — not specifiedFrequency limits for CGP/NGS are not specified in this section of the policy

Clinical guidanceRepeat testing decisions should be based on clinical context, guideline recommendations, and prior testing scope

RecommendationWhen frequency is not specified, document clinical justification and adherence to member benefit terms

Note

No explicit provider‑type restrictions stated — document ordering clinician

No explicit ordering provider restrictions are stated in the provided excerpts; nonetheless, document the clinical responsible provider when ordering tests.

Studies describe tests being used in routine oncology practice and at initial clinic visits to expedite genotyping.
Verify any payer‑specific ordering provider requirements prior to submission.

Documentation Required

Order testing for advanced/metastatic cases and use certified labs; document indication

Ensure tests are ordered by clinicians managing individuals with advanced or metastatic cancer and that testing is performed in certified laboratories; include clinical indication and intended use in the request.

ASCO guidance and NCCN recommend testing for individuals with advanced/metastatic cancer; testing should be done in certified/validated labs.
Include why testing is clinically indicated and how results will influence management on the requisition and in records.

Documentation Required

Document why tissue is unavailable when ordering ctDNA

If ctDNA is used because tissue is unavailable, document the clinical rationale and why tissue sampling is not feasible; this justification should accompany the test order and any PA request.

NCCN and study authors recommend documenting why tissue is unavailable when preferring ctDNA.
Include prior biopsy attempts, inadequate tissue notes, or clinical risks that preclude tissue sampling.

Note

Align ordering and coverage decisions with the member’s benefit plan

Ensure ordering and coverage decisions align with the member‑specific benefit plan and applicable mandates; check the plan for any additional ordering or authorization requirements.

This policy is informational and assistance for standard plans; member‑specific benefit plans govern coverage.
Confirm any federal or state mandates that may affect authorization or coverage.

ctDNA assays submitted for routine cancer screening or for indications that lack demonstrated clinical validity and utility are designated not covered. ASCO/CAP and other systematic reviews cited in the policy reported insufficient evidence to support the use of ctDNA assays for population screening.

Requests for ctDNA testing for screening purposes should be denied in the absence of high‑quality evidence and appropriate benefit coverage, and such use is not supported by the policy.

Routine molecular profiling for hepatocellular carcinoma and use of ctDNA testing in early‑stage (stage I–III) disease are categorized as not covered under routine circumstances because no differential treatment benefits by molecular subgroup have been established for hepatocellular carcinoma, and ctDNA lacks sufficient validity and utility in early‑stage disease.

Case‑by‑case consideration is permitted for HCC when clinical circumstances or clinical trial participation justify testing, but routine coverage is not supported.

The policy does not provide an explicit enumerated list of tests that are categorically not covered in every circumstance. Importantly, the policy reiterates that FDA listing or approval alone does not guarantee coverage; adjudicators must also consider the member‑specific benefit plan and the clinical evidence of validity and utility for the requested use.

Providers and reviewers should follow the processes described in the policy to document clinical indication, alignment with test labeling or evidence, and member benefit provisions when evaluating coverage for any specific assay.

SpecimensCommon specimens include blood (plasma), urine, cerebrospinal fluid, pleural fluid, and other aspirates

Comprehensive Genomic Profiling (CGP) / NGS — definition

Definition — Comprehensive Genomic Profiling (CGP) / NGSNext‑generation sequencing approaches that detect multiple classes of genomic alterations across many genes from a single sample (broad panels may cover hundreds of genes)

ExampleFoundationOne CDx uses NGS‑based CGP to analyze 324 genes in solid tumor tissue

Intended useDetects short variants, copy number alterations, rearrangements, and biomarkers such as TMB and MSI to guide targeted therapy selection

Advanced Cancer — definition

Definition — Advanced CancerCancer that is unlikely to be cured or controlled with treatment; may also be called end‑stage

Coverage relevancePolicy generally prioritizes genomic testing in advanced or metastatic disease where results may inform targeted therapy selection

Guideline alignmentASCO, ESMO, and NCCN recommend tumor NGS or ctDNA in many advanced cancer contexts

Liquid biopsy — short definition

Liquid biopsy (short)Minimally invasive testing of bodily fluids to detect tumor‑derived biomarkers (e.g., ctDNA)

AdvantageFaster turnaround and less invasive than tissue biopsy

LimitationMay have reduced sensitivity when tumor fraction is low

Companion diagnostic — CDx definition / note

Companion diagnostic (CDx) — regulatory definitionAn FDA‑approved or cleared test used to identify individuals likely to benefit from a specific therapy per product labeling; use the FDA List of Cleared or Approved Companion Diagnostic Devices for reference

Coverage noteFDA listing is informational; coverage requires alignment with member benefit terms and the CDx/drug label

Specimen alignmentCDx must be used with the specimen type specified in the FDA listing and drug label

Tumor fraction — definition

Definition — Tumor fractionProportion of circulating cell‑free DNA in plasma derived from tumor cells; influences sensitivity of ctDNA assays and detection of actionable alterations

Measured impactMedian tumor fraction reported (e.g., 2.2% in a large F1LCDx cohort) and TF thresholds strongly affect detection sensitivity

Clinical implicationLow tumor fraction may necessitate reflex tissue testing due to reduced plasma sensitivity

Comprehensive molecular profiling (CMP) — definition

Definition — Comprehensive Molecular Profiling (CMP)Broad NGS panels of multiple cancer‑related genes performed on tissue or ctDNA to identify actionable genomic alterations for targeted therapies

IncludesDetection of mutations, amplifications, fusions, MSI/MMR status, and TMB depending on assay design

Use caseRecommended in advanced/metastatic disease where results may change systemic therapy selection

ctDNA — definition

Definition — ctDNA (circulating tumor DNA)Tumor‑derived fragments of cell‑free DNA in plasma used to detect tumor genomic alterations via liquid biopsy

RoleEnables noninvasive genotyping, monitoring, and detection of resistance alterations when tissue is unavailable

LimitationSensitivity depends on tumor fraction and variant type

ESCAT — definition

Definition — ESCATESMO Scale for Clinical Actionability of molecular Targets; a framework to classify genomic alterations by level of clinical evidence for actionability

Use in guidanceReferenced by ESMO when recommending tumor NGS for advanced cancers and to prioritize alterations ready for routine use

Clinical implicationESCAT levels help determine which alterations should drive routine therapeutic decisions versus trial enrollment

circulating tumor DNA (ctDNA) / cell-free DNA (cfDNA) — definition

Definition — circulating tumor DNA (ctDNA) / cell‑free DNA (cfDNA)Fragments of tumor‑derived DNA (ctDNA) within the total pool of cell‑free DNA (cfDNA) in plasma used for liquid biopsy assays

Analytical considerationsAssay LOD, tumor fraction, and variant type affect detection performance

Clinical useUsed for genotyping, monitoring, and when tissue biopsy is infeasible

CGP / NGS — definition

Definition — CGP / NGSComprehensive genomic profiling via next‑generation sequencing capable of detecting mutations, amplifications, MSI/MMR status, TMB, and fusions across large gene panels

Panel sizesPanel sizes vary widely (examples include ~55, 83, and 324 genes across different assays)

Preferred specimenTissue‑based NGS is preferred when feasible; ctDNA acceptable if tissue unavailable

FDA‑approved/cleared companion diagnostic devices — informational

FDA‑approved or cleared CDx — informational noteThe FDA list of Cleared or Approved Companion Diagnostic Devices is provided for informational purposes only; FDA approval alone is not a basis for coverage and testing must align with member benefit plan and CDx labeling

Laboratory regulationLaboratories performing genetic tests are regulated under CLIA; links to FDA regulatory information are provided in policy

Coverage implicationUse of an FDA‑listed CDx must still meet policy criteria and member benefit terms to be covered