ModifiedUnitedHealthcarePolicy CS373NE.E

FDA Cleared or Approved Companion Diagnostic Testing (for Nebraska Only)

Policy governing coverage of FDA-cleared or approved companion diagnostic molecular oncology tests for members in Nebraska, specifying which CDx tests and indication/drug pairings are considered medically necessary and conditions for subsequent or concurrent testing.

Policy Summary

PayerUnitedHealthcare

PolicyFDA Cleared or Approved Companion Diagnostic Testing (for Nebraska Only)

Policy CodePolicy CS373NE.E

Change TypeMaterial updates (coverage, concurrent testing, coding)

Effective DateMar 1, 2026

Next Review Date

Key ActionCheck and verify applicable CPT codes and prior authorization requirements when ordering FDA-cleared or approved CDx tests (0211U and 0523U were added).

SourceLink

POLICY UPDATE CHANGES

This policy applies to tests that have been granted approval as FDA cleared or approved Companion Diagnostic (CDx) tests.

FoundationOne CDx and FoundationOne Liquid CDx are proven and medically necessary for specific indication/drug pairings listed in the policy.

Concurrent testing using an FDA cleared tissue-based CDx and a liquid biopsy-based CDx is considered proven and medically necessary for advanced/metastatic (stage IV) breast cancer and NSCLC when criteria are met.

Added CPT codes 0211U and 0523U and removed several older CPT codes (0179U, 81445, 81449, 81450, 81451, 81455, 81456, 81599).

Subsequent use of an FDA cleared or approved CDx test on a new specimen to assist therapy selection is proven and medically necessary when the patient has recurrence or progression and the CDx criteria are met.

NebraskaApplies only to

MultipleNamed CDx assays

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Coverage Criteria

Medically necessary coverage criteria

Covered when ALL of the following are met for FDA-cleared or approved CDx tests listed or for tests with FDA CDx designation:

Primary conditions: Test is FDA cleared or approved as a Companion Diagnostic (CDx) and is listed in the FDA List of Cleared or Approved Companion Diagnostic Devices or has an approval order in the FDA Premarket Approval (PMA) Database designating it as a CDx for the intended therapeutic product/indication.

Policy requires FDA CDx status or PMA approval order

Test characteristics: The CDx is a molecular oncology test that detects alterations in five or more genes in tumor tissue or in circulating tumor DNA (liquid biopsy).>=5 genes

Policy limits CDx to tests detecting five or more genes (see policy summary)

Named FDA-cleared/approved CDx tests and indication/drug pairings: Use of specifically listed CDx tests (for example, FoundationOne CDx, FoundationOne Liquid CDx, Guardant360 CDx, MI Cancer Seek, Oncomine Dx tests, oncoReveal CDx, TruSight Oncology Comprehensive, xT CDx) is considered proven and medically necessary when used to inform management for the listed cancer types and companion therapeutic product pairings in the policy.

See policy lists for exact indication/drug pairings

FDA CDx for unlisted tests: For FDA-cleared/approved CDx tests not explicitly named in the policy, coverage is proven and medically necessary when the test results will be used to inform use of a targeted oncology therapeutic for the corresponding indication and the test appears in FDA's CDx table or has an approval order in the FDA PMA database for that intended use.

Two recognition pathways: FDA table listing or PMA approval order

Subsequent testing: Subsequent use of an FDA cleared or approved CDx on a new specimen is covered when the CDx criteria above are met and the individual has disease recurrence or the cancer has progressed or did not respond to the most recent systemic therapy.

Allows repeat testing on progression/recurrence

Concurrent tissue and liquid CDx: Concurrent testing (tissue-based and liquid biopsy CDx) is considered medically necessary for advanced/metastatic (stage IV) breast cancer and advanced/metastatic (stage IV) non-small cell lung cancer when the CDx criteria above are met.within 30 days for concurrent definition

Concurrent Testing defined in policy and explicitly allowed for these two cancer types

Coverage when clinically indicated and specimen-adequate

Tests and use cases summarized in this excerpt are supported when device labeling, specimen adequacy, and clinical context are met:

General coverage conditions: Use of FDA-cleared/approved CDx or validated comprehensive genomic profiling (CGP) assays (tissue or liquid) is appropriate when results will be used to inform selection of an FDA-approved targeted therapy per product labeling or for enrollment in a relevant clinical trial.

Supported by clinical-validation and FDA indications

Specimen adequacy and tumor fraction: For plasma-based (liquid) assays, an adequate circulating tumor DNA (ctDNA) tumor fraction (TF) is required for reliable detection; consider reflex tissue biopsy when TF is < 1% or when reported sensitivity is insufficient.TF >= 1% preferred; TF < 1% may require reflex tissue biopsy

Studies report markedly reduced detection prevalence and sensitivity when TF < 1%

Use consistent with device labeling: Testing must be used in accordance with the device labeling and intended clinical indication (e.g., tumor type and therapeutic pairing specified in the FDA approval).

Guideline-recommended indications (by tumor type)

NCCN and other guideline recommendations list the following tumor‑type indications as options for use of FDA‑approved or validated NGS/CDx testing:

Ampullary adenocarcinoma: Testing for actionable somatic findings (fusions, mutations, amplifications, MSI/MMR deficiency, or TMB) using an FDA-approved and/or validated NGS assay is recommended as an option for locally advanced/metastatic disease candidates for anticancer therapy.

NCCN recommendation (2025a)

Bone cancers: Consideration of comprehensive genomic profiling (CGP) with a validated and/or FDA-approved assay is an option for metastatic chondrosarcoma, recurrent chordoma, metastatic Ewing sarcoma, or metastatic osteosarcoma; TMB and MMR/MSI testing may be considered for select patients.

NCCN recommendation (2025b)

Cervical cancer: TMB testing by an FDA-approved assay is an option for progressed tumors with no satisfactory alternatives; consider plasma ctDNA CGP if tissue is not feasible and CGP for systemic therapy selection in distant metastases.

NCCN recommendation (2025c)

FDA Cleared/Approved CDx — general coverage

Covered when ALL of the following are met for an FDA cleared or approved CDx test:

Core CDx coverage conditions: (1) The test results will be used to inform the use of a targeted oncology therapeutic product or group of products in an individual with the corresponding clinical indication; AND (2) The test appears in the FDA's Cleared or Approved Companion Diagnostic Devices Table for use with the intended targeted therapeutic product and clinical indication, OR the test has an FDA approval order designating it as a CDx for that use in the FDA PMA database.

From policy: CDx coverage requires FDA table listing or PMA approval order

Named assays with specified indication/drug pairings

Certain named FDA-cleared/approved CDx assays are explicitly listed as proven and medically necessary for specified indication/drug pairings:

Named CDx tests and indicated pairings: Named assays such as FoundationOne CDx, FoundationOne Liquid CDx, Guardant360 CDx, MI Cancer Seek, Oncomine Dx Express/Target tests, oncoReveal CDx, TruSight Oncology Comprehensive, and xT CDx are proven and medically necessary when used to inform management for the specific cancer type and therapeutic product pairings enumerated in the policy (see test-specific lists).

Policy provides explicit indication/drug pairings for each named test

Concurrent tissue and liquid CDx testing

Concurrent testing (tissue CDx + liquid biopsy CDx) is allowed when ALL of the following are met:

Concurrent testing for specific cancers: The CDx criteria above are met AND the cancer type is either advanced/metastatic (stage IV) breast cancer OR advanced/metastatic (stage IV) non-small cell lung cancer; when these conditions are met, concurrent tissue and liquid CDx testing is considered proven and medically necessary.concurrent defined as within 30 days

Concurrent testing explicitly permitted for these two cancer types

Subsequent use on new specimen

Subsequent use of an FDA cleared or approved CDx on a new specimen is considered proven and medically necessary when ALL of the following are met:

Subsequent use criteria: The original CDx coverage criteria are met AND the individual is experiencing disease recurrence OR the individual's cancer has progressed or did not respond to the most recent systemic therapy.

Allows repeat CDx testing on new specimen at recurrence or progression

All uses of FDA-cleared or FDA-approved companion diagnostic (CDx) tests that are not explicitly supported by the policy’s listed indications, device labeling, or the FDA CDx listings are considered unproven and not medically necessary. This includes any clinical scenarios or indication/drug pairings that do not meet the policy criteria or are not enumerated in the policy lists.

Available studies assessing some claims of clinical benefit (for example, clinical utility of comprehensive cfDNA or broad CGP panels) were judged to be of low to very poor quality. The evidence summarized in assessment reports and small cohort studies did not conclusively demonstrate that comprehensive testing consistently improves clinical outcomes compared with more limited testing, and important study limitations (small size, retrospective design, lack of randomization) reduce confidence in generalized clinical benefit.

The excerpt does not list explicit policy exclusions beyond the general not-medically-necessary statements; however, cited studies have limitations including retrospective designs, lack of treatment outcome data, mixed cancer populations, and potential confounding (e.g., clonal hematopoiesis). These limitations should be considered when interpreting test performance and utility.

All uses of FDA-cleared or FDA-approved CDx tests that do not meet the policy’s stated criteria or are for indication/drug pairings not listed in the policy are considered unproven and not medically necessary and are subject to denial.

Use of companion diagnostics for indications that are not listed in the policy or that fail to meet the defined CDx criteria should be treated as not covered (off-label/not supported). Ordering clinicians should confirm that the CDx device and indication align with policy criteria or FDA CDx listings before proceeding.

When considering substituting a blood-based CGP or liquid biopsy CDx for a tissue-based biopsy, clinicians should account for circulating tumor DNA tumor fraction (TF). The policy and supporting analyses note substantially reduced detection sensitivity at low ctDNA burdens; reflex tissue biopsy is recommended or required when ctDNA < 1% or when an adequate tissue specimen is obtainable to ensure reliable detection of actionable alterations.

No specific conditions that would render a test explicitly not medically necessary are provided in this section of the policy; this block serves as a placeholder where such NMN conditions would be documented if specified.

Ordering a CDx for an indication or indication/drug pairing not listed in the policy or not meeting the stated criteria carries a risk of denial because such uses are considered unproven and not medically necessary under this policy.

Covered Indications and Tests

Specific cancer types and associated therapeutic pairings listed per CDx test

See each listed test section for exact indication/drug pairings; examples below summarize covered pairings per test:

FoundationOne CDx / Liquid CDx pairings: FoundationOne CDx and FoundationOne Liquid CDx are listed as proven and medically necessary for multiple cancer type / drug pairings (examples include breast cancer with trastuzumab/ado-trastuzumab emtansine/pertuzumab/alpelisib/capivasertib+fulvestrant; NSCLC with alectinib and multiple TKIs; colorectal cancer with EGFR inhibitors), as enumerated in the policy test lists.

See chunks 2,4,5,6 for full pairing lists

Guardant360 CDx pairings: Guardant360 CDx is proven and medically necessary for listed pairings including NSCLC (targeted TKIs and antibody-drug conjugates) and select breast cancer indications as listed in the policy.

See policy test list for exact drugs

Other named CDx pairings: MI Cancer Seek, Oncomine Dx Express/Target Tests, oncoReveal CDx, TruSight Oncology Comprehensive, xT CDx and other listed assays are proven and medically necessary for the specific indication/drug pairings provided in the policy sections for each test.

Coding

Applicable Procedure/CPT CodesCPT

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.
0211U	Oncology (pan-tumor), DNA and RNA by next-generation sequencing, utilizing formalin-fixed paraffin-embedded tissue, interpretative report for single nucleotide variants, copy number alterations, tumor mutational burden, and microsatellite instability, with therapy association.
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), next-generation sequencing (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.
0523U	Oncology (solid tumor), DNA, qualitative, next-generation sequencing (NGS) of single-nucleotide variants (SNV) and insertion/deletions in 22 genes utilizing formalin-fixed paraffin-embedded tissue, reported as presence or absence of mutation(s), location of mutation(s), nucleotide change, and amino acid change.
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.
81479	Unlisted molecular pathology procedure

Covered CPT Codesmixed

No codes listed

Test names listed (no billing codes provided in this section)mixed

	Oncomine Dx Express Test - qualitative IVD using targeted NGS to detect substitutions, insertions, and deletions in 42 genes; copy number variants in 10 genes; fusions/splice variants in 18 genes from FFPE tumor samples.
	Oncomine Dx Target Test - qualitative IVD to detect SNVs, deletions, and insertions in 23 genes and selected fusions from RNA isolated from FFPE tumor tissue (NSCLC and other indicated tumor types).
	oncoReveal CDx - qualitative NGS-based IVD using amplicon-based target enrichment for detection of SNVs, insertions and deletions in 22 genes from FFPE tumor tissue.
	TruSight Oncology Comprehensive - qualitative IVD using targeted NGS to detect variants in 517 genes, fusions in 24 genes, splice variants in 1 gene, and reports TMB from FFPE tumor tissue.
	xT CDx - qualitative NGS-based IVD for detection of substitutions and insertion/deletions in 648 genes and MSI status from FFPE tumor tissue with matched normal specimen when required.

Added CPT CodesCPT

0211U	CPT code added to policy (exact description provided in Applicable Codes section).
0523U	CPT code added to policy (exact description provided in Applicable Codes section).

Removed CPT CodesCPT

0179U	Removed from policy
81445	Removed from policy
81449	Removed from policy
81450	Removed from policy
81451	Removed from policy
81455	Removed from policy
81456	Removed from policy
81599	Removed from policy

TMB-high cutoff

TMB-high cutoff>= 10 mut/Mb

ContextUsed for pembrolizumab approval and FoundationOne CDx TMB-high indication

Clinical implicationTMB determined by an FDA-approved test; used to identify patients for pembrolizumab when progressed and no satisfactory alternatives

TMB-high threshold used in cited pembrolizumab study

Study TMB-high threshold>= 10 mut/Mb

StudyKEYNOTE-158 used prespecified FoundationOne CDx cutpoint of >=10 mut/Mb

Provider Actions and Administrative Requirements

Prior Authorization

Reflex Tissue Biopsy When ctDNA TF Is Low

When liquid biopsy (ctDNA) testing is used, consider the circulating tumor DNA (ctDNA) tumor fraction (TF). If ctDNA TF is < 1%, reflex tissue biopsy for comprehensive genomic profiling is recommended because detection prevalence for actionable variants is substantially lower at low TF.

Reflex tissue biopsy recommended when ctDNA TF < 1%
Low ctDNA tumor fraction may require reflex tissue testing

Denial Risk

Non‑Listed Indications and Coverage Limits

Uses of FDA-cleared or -approved companion diagnostic (CDx) tests that are not listed in this policy or that do not meet the criteria specified in the policy may be considered unproven and may be denied.

Non-listed indications may be denied

Frequency Limits

Any FDA cleared or approved CDx — Subsequent testing

Policy statementAny FDA cleared or approved CDx: subsequent testing allowed when criteria are met

ScopeApplies to FDA cleared/approved molecular oncology CDx tests listed in FDA tables or with approval orders in the PMA database

Trigger for repeat testingDisease recurrence, progression, or lack of response to most recent therapy

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Action

Ordering Requirements

Documentation Required

Order supported by medical record documentation demonstrating medical necessity

Ordering clinicians must document medical necessity in the patient's record when requesting CDx testing; no specific clinician-type restriction is stated, but the treating clinician typically places the order.

Include indication, prior treatments, and how results will inform therapy selection.
Ensure documentation is legible and available for review.

Note

Consider clinical context (stage, prior therapy, tissue feasibility) when ordering

Consider clinical context when ordering CDx testing — advanced/metastatic disease status, prior lines of therapy, and feasibility of tissue biopsy should guide whether to order tissue-based CGP, plasma ctDNA testing, or both.

If tissue is feasible, tissue-based NGS is generally preferred; plasma ctDNA may be complementary or initial in select situations.
Document disease stage and prior therapy lines to support test choice.

Not Covered

Companion diagnostic tests used outside their listed FDA-cleared/approved indications or without meeting the policy’s coverage conditions are treated as not covered; clinicians should verify that the test, specimen type, and clinical indication align with the policy before ordering.

The policy does not support routine use of commercial CGP or plasma-based liquid CDx tests as a substitute for tissue biopsy when a tissue specimen is obtainable and ctDNA tumor fraction is low (1%), because low TF substantially reduces sensitivity for actionable alterations.

The excerpt does not explicitly enumerate individual tests or indications that are categorically excluded beyond the general policy statements; this entry is a placeholder reflecting that no additional not-covered items are listed in this section.

FDA-cleared or FDA-approved CDx tests used in a manner that does not meet the policy criteria or that are applied to unlisted indication/drug pairings are considered unproven and not medically necessary and are therefore not covered.

Background

Companion diagnostics provide essential information for the safe and effective use of corresponding therapeutic drugs. This policy covers FDA-cleared or FDA-approved molecular oncology CDx tests that detect alterations in multiple genes in tissue or plasma and limits coverage to uses that align with FDA CDx device listings, approval orders, and the specific indication/drug pairings enumerated in the policy.

Definitions

Companion Diagnostic definition

DefinitionCompanion Diagnostic: a tool essential for the safe and effective use of a corresponding therapeutic drug; for this policy, an FDA cleared or approved test for use with a specific drug or group of drugs

Regulatory contextEligible to be listed in FDA's Cleared or Approved Companion Diagnostic Devices table or have an approval order in FDA PMA database

Policy implicationCoverage applies only to FDA cleared/approved CDx tests detecting >=5 genes per policy scope

Concurrent Testing definition

DefinitionConcurrent Testing: tissue-based testing and liquid biopsy ordered for the same clinical indication within a 30-day period

Policy allowanceConcurrent tissue + liquid CDx is explicitly allowed for advanced/metastatic (stage IV) breast cancer and NSCLC when CDx criteria are met

Revision History

2026-03-01policy_updateLatest

Revised Coverage Rationale to specify that the policy applies to tests granted approval as FDA cleared or approved Companion Diagnostic (CDx) tests and listed FoundationOne CDx as proven and medically necessary for multiple indication/drug pairings; effective date 03/01/2026.

2026-03-01summary_of_changes

Added multiple indication/drug pairings across tumor types (including additions such as Perjeta, Piqray, Truqap combinations, pemigatinib, cetuximab, panitumumab, osimertinib, and others) and listed FoundationOne Liquid CDx indications.

Policy Summary

PayerUnitedHealthcare

PolicyFDA Cleared or Approved Companion Diagnostic Testing (for Nebraska Only)

Policy CodePolicy CS373NE.E

Change TypeMaterial updates (coverage, concurrent testing, coding)

Effective DateMar 1, 2026

Next Review Date

Key ActionCheck and verify applicable CPT codes and prior authorization requirements when ordering FDA-cleared or approved CDx tests (0211U and 0523U were added).

SourceLink

On This Page

Coverage contingent on using test per its FDA-cleared/approved indication

Analytical performance considerations: For liquid CDx assays, analytic limits of detection and tumor-fraction performance characteristics (e.g., FoundationOne Liquid CDx LOD ~0.40% VAF; copy number TF limits reported) should be considered when interpreting results and determining specimen adequacy.LOD ~0.40% VAF for select variants; TF limits for CNAs reported

See assay validation data for performance (Woodhouse et al. 2020)

Testing strategy to shorten time to treatment: Simultaneous or initial liquid NGS plus tissue genotyping may shorten time to treatment initiation for suspected advanced NSCLC and may be considered based on clinical context and tissue availability.

Supported by studies showing shorter time to treatment with combined testing

Cutaneous melanoma: Testing BRAF mutational status using an FDA-approved test is an option for selection of dabrafenib and trametinib therapy.

NCCN recommendation (2025d)

Neuroendocrine and adrenal tumors: Consideration of MSI, MMR, and TMB testing by an FDA-approved test is an option for adrenocortical carcinoma.

NCCN recommendation (2025e)

Non-small cell lung cancer (NSCLC): NCCN recommends testing for individual biomarkers and supports use of clinically validated NGS platforms or plasma ctDNA as complementary or initial approaches in appropriate situations.

NCCN (2025f) and IASLC guidance

Occult primary: Determination of TMB by a validated and/or FDA-approved assay is a Category 2B option for cancer of unknown primary.

NCCN (2025g)

Ovarian/fallopian/peritoneal cancers: An FDA-approved CDx test is an option for selection of patients for PARP inhibitor therapy (niraparib, olaparib, rucaparib).

NCCN (2025h)

Pancreatic adenocarcinoma: Testing for actionable somatic mutations (fusions, mutations, amplifications), MSI/MMR deficiency, or TMB via FDA-approved/validated NGS assay is an option for locally advanced/metastatic disease candidates for therapy.

NCCN (2025i)

Uterine neoplasms: Comprehensive molecular profiling via a validated/FDA-approved assay is an option in initial evaluation; testing for NTRK, MSI, RET fusions, and TMB in metastatic disease is recommended as informative options.

NCCN (2025j)

Breast cancer (HR+, HER2-): ASCO recommends routine testing for activating mutations in PIK3CA, AKT1, or PTEN to guide targeted/endocrine therapy choices based on trial evidence and approvals.

ASCO 2024; CAPItello-291 supports CDx use

Refer to test-specific sections for complete pairing lists

Detection of actionable genomic alterations and complex biomarkers (TMB, MSI) to inform targeted therapy

FDA-approved/cleared assays and validated NGS-based tests detect actionable genomic alterations and complex biomarkers used to inform targeted therapy:

Detection of actionable genomic alterations: NGS-based CDx assays detect substitutions, indels, rearrangements/fusions, and copy-number alterations that are actionable for targeted oncology therapeutics and are FDA-cleared/approved for specific tumor types and companion drugs.

Examples: FoundationOne Liquid CDx (311 genes), Guardant360 CDx (55 genes)

Complex biomarkers (TMB, MSI): Some FDA-cleared/approved CDx assays report complex biomarkers such as tumor mutational burden (TMB) and microsatellite instability (MSI) which are used to inform immune checkpoint inhibitor therapy where FDA indications exist (e.g., pembrolizumab for TMB-high ≥10 mut/Mb assessed by FoundationOne CDx).TMB-high >= 10 mut/Mb

Clinical studies used TMB cutoff >=10 mut/Mb (see pembrolizumab data)

Use in advanced solid tumors: Assays are used to inform targeted therapy selection in patients with advanced or metastatic solid tumors when aligned with FDA indications or guideline recommendations.

NCCN recommends validated/FDA-approved NGS assays as options in advanced/metastatic settings

Use of FDA-cleared/approved or validated NGS-based assays on FFPE tissue to guide therapy

Use of FDA-cleared/approved or otherwise validated NGS-based assays on FFPE tumor tissue to guide therapy is supported per tumor-type guideline recommendations:

Assay types and specimen: Use of listed FDA-cleared/approved or validated NGS-based assays on formalin-fixed, paraffin-embedded (FFPE) tumor tissue specimens is appropriate to detect actionable genomic alterations to guide therapy selection per tumor-type guideline recommendations.

Some assays also require or allow matched normal blood/saliva or RNA for fusion detection (see test descriptions)

Examples of validated assays: Examples include Oncomine Dx Express/Target Tests, oncoReveal CDx, TruSight Oncology Comprehensive, and xT CDx; some assays report TMB and require matched normal specimens for certain analyses.

See chunks 36-40 for assay gene content and specimen requirements

Advanced or metastatic solid tumors

In advanced or metastatic solid tumors, validated or FDA-approved NGS/CDx testing is an option to identify actionable alterations and biomarkers to inform therapy selection:

Advanced/metastatic pancreatic adenocarcinoma: Testing for actionable somatic mutations, fusions, amplifications, MSI/MMR deficiency, or TMB via a validated and/or FDA-approved NGS assay is recommended as an option for patients with locally advanced or metastatic pancreatic adenocarcinoma who are candidates for anticancer therapy.

NCCN recommendation (2025i)

Gynecologic and uterine neoplasms: Comprehensive molecular profiling and testing for MSI/MMR, TMB, and NTRK fusions via validated or FDA‑approved assays is an option for uterine, vaginal, and vulvar cancers to identify rare pan‑tumor targeted therapy opportunities.

NCCN recommendations (2025j, 2025k, 2025l)

Use to inform targeted therapy selection: Validated/FDA-approved NGS assays can detect actionable somatic alterations and biomarkers (fusions, mutations, amplifications, MSI/MMR, TMB) to inform targeted therapy selection in advanced/metastatic solid tumors.

Guideline-supported option in advanced disease settings

Reported outcomeObjective response 29% in TMB-high group vs 6% in non-TMB-high group

Analytical limit of detection (FoundationOne Liquid CDx)

Analytical limit of detection0.40% variant allele fraction (95% limit of detection for select substitutions/indels)

Rearrangements LOD0.37% variant allele fraction for select rearrangements

Validation sizeValidation included >7,500 tests and >=30,000 individual variants across >300 genes

Copy number amplification TF limit (FoundationOne Liquid CDx)

Copy number amplification TF limit21.7% tumor fraction

Copy number loss TF limit for comparison30.4% tumor fraction (reported for copy number losses)

Assay performance noteValidation reported high reproducibility (99.59%) and PPA/NPA of 96.3% and >99.9% respectively

Copy number loss TF limit (FoundationOne Liquid CDx)

Copy number loss TF limit30.4% tumor fraction

Related metricCopy number amplification TF limit 21.7% TF

Validation contextDerived from clinical and analytical validation reported by Woodhouse et al. (2020)

Gene panel size (Tempus xT CDx)

Gene panel size648 genes

Assay targetsDetects substitutions (SNVs and multi-nucleotide variants), insertions/deletions, and MSI status

Specimen typesDNA from FFPE tumor tissue and matched normal blood or saliva when required

Gene panel size (TruSight Oncology Comprehensive)

Gene panel size517 genes

Assay capabilitiesDetects SNVs, multi-nucleotide variants, insertions/deletions (DNA) and fusions from RNA; reports TMB

Specimen typeNucleic acids extracted from FFPE tumor tissue samples

Subsequent use on new specimen

Policy allowanceSubsequent use on a new specimen is allowed when the CDx criteria are met and the individual has disease recurrence or cancer progression (or did not respond to most recent systemic therapy)

ConditionsOriginal CDx coverage criteria must be met and the new specimen is for therapy selection

ReferenceSummary of Changes and FoundationOne Liquid CDx policy language specify recurrence/progression as triggers for subsequent testing

Coverage limited to listed CDx uses or meeting listed criteria

Documentation Required

Medical Record Documentation Requirement

The patient’s medical record must contain documentation that fully supports the medical necessity for the requested testing. Documentation may be required to assess whether the member meets clinical criteria for coverage and must be made available upon request. Records should include relevant medical history, physical examination findings, diagnostic test results, and any other information supporting the use of the specific CDx/NGS test.

Medical records required to support medical necessity
Medical record documentation (history, exam, diagnostics)

Billing Rule

Specify Exact FDA‑Cleared/Approved Test and Specimen

Specify the exact FDA-cleared or FDA-approved test name and the specimen type when ordering and documenting testing (for example: FFPE tumor tissue; matched normal blood/saliva when required by the test). Testing that does not align with the intended FDA-cleared/approved assay or validated NGS-based assay for the actionable alteration may not be supported.

Specify exact FDA-cleared/approved test name and specimen type
Testing alignment with FDA-cleared/validated NGS-based assays

Note

Check Benefit Plan and Contractual Requirements

Use this policy alongside federal, state, and contractual benefit terms. Always check the member’s benefit plan requirements, as plan-specific coverage mandates or exclusions govern in the event of a conflict.

Check benefit plan requirements
Policy is interpretive guidance — plan terms govern

Prior Authorization

Prior Authorization and Administrative Checks

Prior authorization may be required for some FDA-cleared or validated NGS-based companion diagnostic tests per payer-specific requirements. Verify prior authorization and any other administrative requirements before ordering.

Prior authorization may be required for CDx/NGS testing
Verify applicable CPT/HCPCS/code requirements and prior auth processes

Note

Concurrent Testing to Shorten Time to Treatment

Concurrent or simultaneous testing strategies (for example, ordering liquid NGS and tissue genotyping together, or initial liquid NGS with reflex tissue testing guided by TF) can shorten time to treatment and reduce need for repeat biopsies in selected clinical contexts (e.g., suspected advanced NSCLC). Consider local capabilities and benefit requirements when planning testing strategy.

Testing strategy to shorten time to treatment: concurrent or initial liquid + tissue genotyping

Verify against full policy source if needed

Frequency limits

Frequency limitsNo frequency limits specified in this excerpt

ImplicationPolicy allows subsequent testing per criteria but does not set routine time-based limits in the excerpt

RecommendationFollow clinical criteria and documentation requirements when ordering repeat CDx testing

FDA cleared/approved CDx — Subsequent testing on new specimen

AllowanceSubsequent testing on a new specimen is allowed for FDA cleared/approved CDx when criteria are met

Required conditionsOriginal CDx criteria must be met and the patient has recurrence or progression (or non-response)

Where documentedPolicy language and Summary of Changes describe this allowance

Note

Order by treating clinician; prefer tissue-based NGS when feasible

Orders should be placed by the treating clinician; consider tissue-based NGS as the primary test when tissue is available and plasma ctDNA as complementary or as an initial approach in select settings (e.g., oncogene-addicted NSCLC).

Treating clinician should document rationale for choosing tissue vs plasma testing.
When using plasma-first strategies, document plan for reflex tissue testing if results are negative or TF is low.

Prior Authorization

Ensure documentation and verify benefit/prior authorization requirements

Before ordering, ensure documentation supports medical necessity and verify federal, state, or contractual benefit plan requirements and prior authorization rules that may affect coverage.

Check the member's benefit plan for applicable coverage rules and prior authorization requirements.
Provide required documentation with authorization requests to minimize denials.

Practical noteUsed to shorten time to treatment in selected settings (see ordering guidance) and must meet CDx criteria

Liquid Biopsy definition

DefinitionLiquid Biopsy: testing on bodily fluid to identify tumor-derived cells or circulating tumor DNA/RNA

Specimen typeTypically plasma-derived circulating cell-free DNA isolated from peripheral whole blood

Use caseComplementary to tissue-based testing; specimen adequacy (tumor fraction) affects sensitivity

Tumor Mutational Burden (TMB)-high

TMB-high definitionTMB-high defined as >= 10 mut/Mb

Regulatory useDefinition used for pembrolizumab approval and FoundationOne CDx TMB-high indication

Clinical implicationTMB must be determined by an FDA-approved test and applied to patients who progressed and have no satisfactory alternatives per labeling

Tumor fraction (TF)

DefinitionTumor fraction (TF): proportion of circulating tumor DNA in plasma; higher TF increases sensitivity of ctDNA assays

Assay thresholdsFoundationOne Liquid CDx reports TF thresholds relevant for copy number calls (e.g., 21.7% for amplifications, 30.4% for losses)

Clinical actionReflex tissue biopsy recommended when TF < 1% due to reduced detection sensitivity

Tumor mutational burden (TMB)

DefinitionTumor mutational burden (TMB): a quantitative biomarker reported as mutations per megabase (mut/Mb)

UseUsed by some assays (e.g., FoundationOne CDx) to predict response to immune checkpoint inhibitors in certain settings

Measurement noteCutpoints (e.g., >=10 mut/Mb) are assay-specific and used in regulatory approvals/studies

CGP

DefinitionComprehensive Genomic Profiling (CGP): broad NGS-based genomic profiling to detect multiple alteration types across many genes

ExamplesTests referenced include TruSight Oncology Comprehensive (517 genes) and Tempus xT CDx (648 genes)

Policy contextCGP/NGS assays may be used when results will inform targeted therapy selection per labeling and guidelines

CDx — Companion diagnostic definition

DefinitionCDx: an FDA-cleared or approved in vitro diagnostic test used to detect specific biomarkers to guide therapy selection for a defined cancer indication

Regulatory noteCoverage applies to CDx tests listed in FDA's CDx table or with approval orders in the PMA database

Clinical implicationTest labeling and therapeutic product labeling jointly specify intended use

Concurrent Testing (policy-specific)

DefinitionConcurrent Testing (policy-specific): use of both an FDA cleared/approved tissue-based CDx and a liquid biopsy-based CDx test concurrently

Allowed casesExplicitly allowed for advanced/metastatic (stage IV) breast cancer and advanced/metastatic (stage IV) NSCLC when CDx criteria are met

TimingConcurrent defined as tests ordered for same clinical indication within 30 days

coverage_clarification

Clarified that subsequent use of an FDA cleared/approved CDx on a new specimen is proven and medically necessary for therapy selection when criteria are met and the patient has recurrence or progression or lack of response to recent therapy.

2026-03-01coverage_clarification

Added explicit concurrent testing coverage: concurrent tissue-based CDx and liquid biopsy CDx considered medically necessary for advanced/metastatic (stage IV) breast cancer and advanced/metastatic (stage IV) NSCLC when criteria are met.

2026-03-01coding_update

Updated applicable codes list: added CPT codes 0211U and 0523U and removed older CPT codes 0179U, 81445, 81449, 81450, 81451, 81455, 81456, and 81599.

2026-03-01documentation_requirement

Added and clarified medical records documentation requirements: records may be required to assess clinical criteria, must fully support medical necessity, and be made available upon request.