CurrentUnitedHealthcarePolicy 202570653F

FDA Cleared or Approved Companion Diagnostic Testing

Defines coverage criteria for FDA-cleared or approved companion diagnostic tests for oncology indications under UnitedHealthcare Commercial and Individual Exchange benefit plans, including repeat and concurrent testing rules for specific cancers.

Policy Summary

PayerUnitedHealthcare

PolicyFDA Cleared or Approved Companion Diagnostic Testing

Policy CodePolicy 202570653F

Change TypeTemplate update / no material clinical changes

Effective DateMay 1, 2025

Next Review DateN/A

Key ActionDocument testing rationale and supporting clinical documentation (tumor histology, prior therapies, specimen source, assay and biomarker thresholds) when requesting coverage.

SourceLink

POLICY UPDATE CHANGES

No material clinical or coverage changes in this revision.

up to 3Repeat CDx tests allowed annually for therapy selection

30 daysConcurrent tissue/liquid testing window

324 genesF1CDx gene panel size

29%KEYNOTE-158 TMB-H response

0.40%FoundationOne Liquid CDx LOD (select)

Trek Health ingests and normalizes Transparency in Coverage data and payer policy updates to give provider organizations a clear view of how commercial reimbursement behaves across markets, payers, and services. Our platform transforms raw payer disclosures into structured intelligence that supports contract evaluation, payer negotiations, and service line strategy. By combining market benchmarks with ongoing policy visibility, Trek helps teams identify variability, risk, and opportunity in commercial reimbursement. The result is faster insight, stronger negotiating positions, and more informed financial decisions.

Coverage Criteria for Companion Diagnostics

Coverage Criteria — Tumor-type Specific Molecular Testing

Covered when ALL of the following are met:

The request is for comprehensive genomic profiling (CGP) or targeted molecular testing for a specific tumor type as described below and consistent with guideline recommendations (e.g., NCCN, ASCO, ESMO) for that tumor type.

Testing is performed using an FDA-cleared/approved companion diagnostic where the test and intended therapeutic match an FDA-labeled indication, or testing is performed in a CLIA-certified laboratory when an FDA-approved CDx is not available but guideline recommendations support testing.

Tissue-based testing is preferred when guideline statements indicate tissue is the preferred specimen; plasma (ctDNA) may be used when tissue is unavailable or unsafe to obtain, recognizing limitations of sensitivity and the potential need for reflex tissue testing if ctDNA is negative and a tissue result would change management.

Procedure and Molecular Codes

Referenced Proprietary/PLA 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.
0179U	Oncology (non-small cell lung cancer), cell-free DNA, targeted sequence analysis of 23 genes (single nucleotide variations, insertions and deletions, fusions without prior knowledge of partner/breakpoint; copy number variations), with report of significant mutation(s).
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.

Additional CPT and Molecular CodesCPT

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 FFPE tissue with comparative sequence analysis from a matched normal specimen, 648 genes, interrogation for sequence variants, insertions/deletions, copy number variants, rearrangements, microsatellite instability, and tumor-mutation burden.
0543U	Oncology (solid tumor), NGS of DNA from FFPE tissue of 517 genes, interrogation for single-nucleotide variants, multi-nucleotide variants, insertions/deletions from DNA, fusions in 24 genes and splice variants in 1 gene from RNA, and tumor mutation burden.
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 or disorder, 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 or disorder; 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 or disorder; 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 or disorder; 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.

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Tumor mutational burden (TMB) high — threshold ≥ 10 mut/Mb as used in F1CDx/pembrolizumab approval

TMB-high threshold≥ 10 mutations per megabase (mut/Mb) — cut-point used by FoundationOne CDx and in the KEYNOTE-158/FDA pembrolizumab approval

Alternate study threshold~175 mutations/exome reported in some retrospective analyses (Cristescu et al.)

Assay contextTMB reported by an FDA-approved CDx (e.g., FoundationOne CDx) using the prespecified cut-point informs eligibility for pembrolizumab in TMB-H tumors

Variant allele fraction limit of detection — 0.40% for select substitutions/indels

Limit of detection (select substitutions/indels)95% limit of detection: 0.40% variant allele fraction (VAF) for select substitutions/indels (FoundationOne Liquid CDx validation)

Rearrangements LODSelect rearrangements 95% LOD: 0.37% VAF

Copy-number LODCopy number amplifications 95% tumor fraction LOD: 21.7%; copy number losses TF LOD: 30.4%

Provider Actions, Prior Authorization & Documentation

Prior Authorization

Prior Authorization Required

Prior authorization may be required by the member's plan for comprehensive genomic profiling (CGP) or companion diagnostic testing. Verify member benefits and obtain any payer-specific prior authorization before ordering when plan documents or prior authorization portals indicate a requirement.

Medical records may be requested to assess coverage criteria and prior authorization requests (see documentation list below).
No payer-level PA code lists are specified in this excerpt; follow the payer's current PA portal and plan documents.

Prior Authorization

Prior Authorization & Rationale for Broad NGS Panels

When ordering broad NGS panels (commonly >50 genes), providers should document clinical rationale for choosing a broad panel over targeted testing. Rationale may include need to detect multiple potential actionable biomarkers, limited tissue, or alignment with guideline recommendations (e.g., NCCN/ASCO).

Document why a broad panel is needed (e.g., multiple potential biomarkers, referral to clinical trials, prior negative single-gene tests).

Biomarker and Assay Requirements

Tumor mutational burden (TMB) — ≥10 mut/Mb threshold used in FoundationOne CDx / KEYNOTE-158

Actionable cut-pointTMB ≥ 10 mut/Mb as defined by FoundationOne CDx and used in KEYNOTE-158 and FDA labeling for pembrolizumab

Evidence sourceKEYNOTE-158 reported objective response rate of 29% in TMB-high tumors (n=102) supporting pembrolizumab approval

Assay referenceFoundationOne CDx (F1CDx) is the FDA-approved CDx reporting TMB with the prespecified ≥10 mut/Mb cut-point

TMB — ≥10 mut/Mb per FoundationOne CDx cut-point

FoundationOne CDx cut-point≥ 10 mut/Mb (prespecified F1CDx cut-point) used to define TMB-high for pembrolizumab eligibility

Regulatory noteF1CDx received FDA premarket approval to include a CDx indication for TMB-high solid tumors using the ≥10 mut/Mb cut-point

Therapies Linked to CDx Results

Regimen	Indication / Context	Coverage status
Pembrolizumab 200 mg IV every 3 weeks
Tumor-agnostic treatment for TMB-high (TMB ≥10 mut/Mb by an FDA-approved CDx such as FoundationOne CDx) in individuals with advanced or metastatic solid tumors who have progressed following prior treatment and have no satisfactory alternative treatment options; regimen/dosing as used in KEYNOTE-158 (maximum cycles per protocol)

Regimen	Indication / Context	Coverage status
Rucaparib oral (dosing per clinical trials; twice daily in TRITON2 context)
Metastatic castration‑resistant prostate cancer (mCRPC) with deleterious BRCA1/2 (germline or somatic) or other HR‑DDR alterations after progression on next‑generation androgen receptor‑directed therapy and taxane chemotherapy; regimen supported by TRITON2 single‑arm trial evidence

Regimen	Indication / Context	Coverage status
Alectinib 600 mg orally twice daily
Advanced or metastatic NSCLC with ALK rearrangement detected by blood‑based NGS (BFAST trial used Foundation ACT/blood NGS to identify ALK‑positive patients treated with alectinib); regimen and dosing per BFAST trial context

Regimen	Indication / Context	Coverage status
Sotorasib (dose per FDA label/clinical protocol)
KRAS p.G12C‑mutant NSCLC identified by Guardant360 CDx (liquid biopsy); Guardant360 CDx has demonstrated clinical validity for identification of KRAS p.G12C to select individuals for sotorasib in reported cohorts

Definitions

Companion Diagnostic Test definition (FDA)

Companion diagnostic (CDx) definitionA CDx is an FDA-cleared or approved test used to identify biomarkers necessary for safe and effective use of a corresponding therapeutic drug

FDA listProviders may reference the FDA List of Cleared or Approved Companion Diagnostic Devices to confirm CDx–drug pairings (informational only)

Laboratory regulationGenetic tests must be performed in laboratories regulated under CLIA; lack of certification may affect coverage

Liquid Biopsy definition

DefinitionLiquid Biopsy: minimally invasive testing of bodily fluids (commonly blood) to analyze circulating tumor DNA (ctDNA)/cell-free DNA and other tumor-derived biomarkers

UsesMay be used for detection of actionable genomic alterations, assessing resistance mechanisms, monitoring, and research MRD applications

Line of Therapy Considerations

salvage

Salvage‑line testing considerations (single top‑level node):

Salvage-line (tumor-agnostic TMB) testing: For individuals who have progressed following prior systemic therapy and have no satisfactory alternative treatment options, CDx testing reporting TMB using an FDA‑approved cut‑point (e.g., F1CDx TMB ≥10 mut/Mb) may identify candidates for pembrolizumab per FDA labeling and KEYNOTE‑158 evidence.TMB ≥10 mut/Mb

Context: salvage setting; ECOG 0–1 in KEYNOTE‑158; used to identify tumor‑agnostic pembrolizumab candidates

first-line

First‑line testing considerations (single top‑level node):

First-line tissue CGP at diagnosis: Perform comprehensive tumor biomarker testing (NGS/CGP) at initial diagnosis for advanced non‑squamous NSCLC and other cancers where detection could impact first‑line therapy; consider simultaneous or reflex liquid biopsy when tissue is insufficient or to shorten time to treatment initiation.

Background Evidence and Assay Performance

up to 3Repeat CDx tests allowed annually

30 daysWindow for concurrent tissue+liquid testing

324Genes in FoundationOne CDx panel

0.40%95% LOD (select substitutions/indels) F1LCDx

94%Detectable ctDNA rate in large F1LCDx series

29%KEYNOTE-158 ORR in TMB‑high tumors

~43.5%TRITON2 confirmed ORR in BRCA‑altered mCRPC

Companion diagnostics (CDx) are intended to identify biomarkers that are necessary for the safe and effective use of a corresponding therapeutic agent. CDx tests must align with the FDA List of Cleared or Approved Companion Diagnostic Devices and be used consistent with the labeled indication for the associated drug. The FDA list is provided for informational use; laboratories performing these tests are regulated under CLIA and coverage determinations require that testing meet the policy’s criteria and the member’s benefit plan requirements.

Policy Revision History

2025-05-01policy_revisionLatest

Template update and creation of a shared policy version to support application to Rocky Mountain Health Plans; removed prior language excluding Colorado and archived previous policy version 2025T0653E.

Policy Summary

PayerUnitedHealthcare

PolicyFDA Cleared or Approved Companion Diagnostic Testing

Policy CodePolicy 202570653F

Change TypeTemplate update / no material clinical changes

Effective DateMay 1, 2025

Next Review DateN/A

Key ActionDocument testing rationale and supporting clinical documentation (tumor histology, prior therapies, specimen source, assay and biomarker thresholds) when requesting coverage.

SourceLink

On This Page

Many NGS assays exceed the CPT 50-gene convention; panels >50 genes may be clinically appropriate per guidelines.

Note

Coding Inclusion Is Not Coverage

Listing of a code in this policy (or in any coding appendix) is for reference only and does not guarantee coverage or payment. Benefit coverage is determined by the member-specific benefit plan and applicable law.

Codes provided in the policy are informational — inclusion does not imply coverage or reimbursement rights.
Verify member benefit plan and PA requirements prior to ordering or billing.

Denial Risk

Non–FDA-Approved CGP — Evidence Risk

Some commercial CGP assays that are not FDA-approved or cleared may have limited peer-reviewed evidence for clinical validity or utility. When using non–FDA-approved tests, document the evidence supporting the test's use and consider whether clinical decisions will be driven by the results.

Non–FDA-approved tests (example: certain tissue or ctDNA CGP offerings) may lack robust published data; note this risk in records.
Prefer validated, CLIA-certified assays with published analytical and clinical validation when possible.

Step Therapy

Step Therapy — Not Specified in This Excerpt

This excerpt does not state an explicit step therapy sequence or step-therapy requirements at the payer level. Clinical pathway sequencing (if any) should be confirmed via the member's benefit plan or utilization management program.

No explicit step therapy rules are provided in the policy excerpt.
Confirm any step-therapy requirements or sequencing through the payer's clinical policy or pharmacy/program portals.

Denial Risk

ctDNA Cannot Replace Histologic Diagnosis

ctDNA (liquid biopsy) testing should not be used as a substitute for a required histologic tissue diagnosis. Use ctDNA as a complementary test or when tissue biopsy is unsafe or unobtainable, and interpret negative ctDNA results cautiously.

Do not replace diagnostic histology with ctDNA testing.
ctDNA may be appropriate when biopsy is unsafe, or to complement tissue testing in metastatic disease; document why tissue is not feasible if relying on ctDNA.

Documentation Required

Molecular Tumor Board Documentation

When cases are reviewed by a Molecular Tumor Board (MTB) or multidisciplinary panel, document the MTB review and its treatment recommendations in the medical record to support the clinical decision-making process.

Preserve MTB notes, recommendations, and rationale in the record for prior authorization or medical necessity reviews.
MTB documentation can support use of broader panels or off-label targeted therapies when appropriate.

Documentation Required

Purpose and Timing Documentation

Document the purpose and timing of testing in the medical record — specifically how results will guide a particular targeted therapy decision or clinical management, and the timing relative to diagnosis or progression.

Include tumor histology, prior therapies, progression status, and intended therapeutic action based on results.
Indicate whether testing is initial (at diagnosis), at progression, or for recurrence to justify clinical necessity.

Documentation Required

Test Method and Specimen Documentation

Document the test method, specimen source, assay name and version, and laboratory certification (e.g., CLIA). Include specimen collection date and whether tissue or plasma (ctDNA) was used.

Specify CLIA-certified laboratory and assay (e.g., F1CDx, FoundationOne Liquid CDx) when available.
Record specimen type (tumor tissue, metastatic site, plasma), collection date, and any pre-analytic limitations.

Documentation Required

Testing Strategy When Tissue Is Limited

When tissue is available but limited, consider a CGP approach (validated NGS assay) rather than sequential single-biomarker testing to preserve tissue and maximize detection of actionable alterations. If tissue is insufficient, reflex to ctDNA or alternative validated methods per guideline recommendations.

Document tissue limitations and rationale for choosing CGP over sequential single-gene tests.
If ordering ctDNA due to limited tissue, document why tissue biopsy is infeasible and note plan for confirmatory testing when appropriate.

Documentation Required

Testing Sequence Recommendation

Recommended testing sequence for many advanced solid tumors: perform tissue-based comprehensive genomic profiling (CGP) at diagnosis when feasible; reflex to liquid biopsy (ctDNA) to detect acquired resistance or when tissue is unavailable. Simultaneous tissue and plasma testing may be appropriate in selected advanced/metastatic settings to shorten time to actionable results.

Tissue CGP at diagnosis with reflex to ctDNA for acquired alterations or when tissue is insufficient.
Concurrent tissue and liquid testing (within ~30 days) may be medically necessary in certain cancers (e.g., advanced/metastatic breast cancer, NSCLC) per guideline context.

Documentation Required

Re-evaluation at Progression

Re-evaluation with repeat NGS testing may be considered at disease progression because tumor molecular profiles can change after treatment; document progression and prior therapies to justify repeat testing.

Repeat NGS/CtDNA testing at progression can identify resistance mechanisms and guide subsequent targeted therapies.
Policy permits repeat companion diagnostic testing up to three times annually when criteria for medical necessity are met and progression or recurrence is documented.

Clinical contextCut-point was prespecified and blinded in KEYNOTE-158 which formed the basis for approval

BRCA1/2 (germline or somatic) — biomarker for PARP inhibitor selection

BiomarkerBRCA1/2 (germline or somatic) — used to select patients for PARP inhibitor therapy in mCRPC (e.g., rucaparib in TRITON2 context)

Clinical evidenceTRITON2 reported confirmed ORR ~43.5% in measurable mCRPC with BRCA alterations supporting PARP use

Specimen/assayTumor or germline testing (tissue or validated assay) can identify BRCA1/2 alterations for therapy selection; perform in CLIA-approved lab

KRAS (ctDNA) — listed as a biomarker requirement for certain targeted therapies

BiomarkerKRAS (ctDNA) — ctDNA assays can detect KRAS mutations (including in NSCLC) and guide targeted therapy selection or trial eligibility

Diagnostic performancePooled cfDNA sensitivity for KRAS ~0.71 and specificity ~0.93 per systematic review (Palmieri et al.)

Clinical usectDNA KRAS testing may be used when tissue is unavailable or to shorten time to treatment; negative ctDNA may require tissue confirmation

ctDNA (MRD assays) — listed under biomarker considerations for MRD testing

MRD ctDNA definitionPersonalized ctDNA MRD assays track tumor-specific somatic variants in plasma to detect minimal residual disease and recurrence earlier than clinical diagnosis

Clinical findingsProspective HR+ breast cancer study (RaDaR) detected ctDNA median lead time ~12.4 months before distant metastasis in a small cohort

Coverage contextMRD ctDNA is evolving; further high-quality studies needed before routine coverage — may be considered in selected/research contexts

Actionable genomic alterations (ALK, EGFR, KRAS p.G12C, ROS1, BRAF, MET, RET, etc.) — biomarkers for targeted agents

Actionable alterations listActionable genomic alterations include ALK, EGFR, KRAS p.G12C, ROS1, BRAF, MET, RET and others used to match patients to targeted agents

Assay capabilityCommercial CDx/liquid NGS assays (e.g., FoundationOne Liquid CDx, Guardant360 CDx) detect substitutions, indels, rearrangements, CNVs, fusions, MSI and TMB relevant to therapy selection

Clinical examplesBlood-based CDx has been used prospectively (BFAST) and for therapies such as alectinib (ALK) and sotorasib (KRAS p.G12C) when detected by validated assays

Tumor fraction (ctDNA) — >= 10% tumor fraction associated with near 100% sensitivity

Tumor fraction sensitivity>= 10% tumor fraction in plasma associated with near 100% sensitivity for detecting tissue-identified driver alterations

Assay implicationsLower tumor fraction reduces sensitivity; interpret negative ctDNA results cautiously and consider tissue testing if clinical suspicion remains

SourceFoundationOne and pooled study data indicate sensitivity is highly dependent on ctDNA tumor fraction

PIK3CA — biomarker for breast cancer targeted therapy

PIK3CA indicationPIK3CA mutations are used to identify candidates for alpelisib plus fulvestrant in HR+ HER2- metastatic breast cancer per guideline recommendations

Specimen optionsPIK3CA testing may be performed on tumor tissue or plasma-based ctDNA; tissue preferred for sensitivity but ctDNA acceptable when tissue unavailable

Guideline supportASCO and NCCN guidance support routine testing for activating PIK3CA alterations in appropriate clinical contexts

ESR1 — biomarker referenced for certain breast therapy decisions

ESR1 clinical roleESR1 mutation testing is recommended at recurrence or progression on endocrine therapy in ER+ HER2- metastatic breast cancer to inform therapy selection

Testing contextESR1 alterations can be assessed via tissue or ctDNA assays; results should guide targeted endocrine strategies when present

Evidence basisASCO guideline updates and retrospective cohort analyses support testing ESR1 in endocrine-resistant settings

KRAS p.G12C — specific actionable biomarker

KRAS p.G12C actionable biomarkerKRAS p.G12C is a specific actionable biomarker used to identify candidates for sotorasib in NSCLC when detected by validated assays (e.g., Guardant360 CDx)

Clinical validationGuardant360 CDx clinical validation and trial analyses demonstrated ORR and DOR in KRAS p.G12C-positive cohorts supporting therapeutic use

Testing noteDetection by blood-based CDx can guide therapy when tissue is unavailable; confirmatory testing per clinical context may be recommended

FGFR3 — biomarker referenced in bladder/urothelial contexts

FGFR3 roleFGFR3 alterations (e.g., detected by FGFR RGQ RT-PCR or NGS) are recommended for testing in stages IVA/IVB bladder cancer to guide targeted therapy considerations

Testing preferenceNCCN recommends early testing (ideally at diagnosis of advanced bladder cancer) in a CLIA-approved laboratory

Assay examplesBoth targeted PCR (FGFR RGQ RT-PCR) and broad NGS panels can detect FGFR3 alterations; choose assay appropriate to clinical need

BRCA1/2 — reiterated across tumor types as actionable biomarker

BRCA1/2 recurrenceBRCA1/2 alterations are repeatedly cited across tumor types (ovarian, pancreatic, prostate) as actionable biomarkers informing PARP inhibitor eligibility and genetic counseling

Testing recommendationTumor molecular analysis should include BRCA1/2 assessment in upfront and recurrent settings for ovarian cancer and in metastatic pancreatic and prostate contexts where relevant

Specimen guidanceUse most recent tumor tissue when feasible; ctDNA acceptable if tissue not available; perform testing in CLIA-approved/validated assays

KRAS/NRAS — biomarkers for colorectal and other cancers

KRAS/NRAS in CRCKRAS and NRAS mutation testing is required for colorectal cancer workup and is commonly included in NGS panels to guide anti-EGFR therapy decisions

Testing preferenceNGS panels preferred for metastatic CRC to simultaneously assess KRAS/NRAS, BRAF, HER2, and MMR/MSI status

Repeat testing noteRepeat testing generally not recommended after standard cytotoxic chemotherapy but may be considered after targeted therapy if resistance is suspected

BRAF — biomarker across multiple tumor types

BRAF roleBRAF alterations (e.g., V600E) are actionable across multiple tumor types including melanoma, CRC, and NSCLC to inform targeted therapy selection

Assay considerationsNGS and specific IHC or PCR assays may be used depending on tumor type and urgency (e.g., BRAF IHC recommended for thyroid for faster turnaround)

Tumor contextsBRAF testing recommended in melanoma and considered in CRC, gastric/esophageal and other advanced cancers per guidelines

HER2 — biomarker referenced in multiple tumor contexts

HER2 actionable biomarkerHER2 overexpression/amplification is an actionable biomarker in multiple tumors (breast, gastric, colorectal, ovarian, pancreatic) and should be assessed to guide targeted therapy

Testing methodsIHC and ISH are commonly used for HER2; NGS panels can also detect amplifications when appropriate

TimingNCCN recommends early testing in advanced disease to support therapeutic decision-making

MMR/MSI — biomarker requirement for immunotherapy selection in some tumors

MMR/MSI requirementMMR/MSI testing is recommended universally in newly diagnosed colorectal cancer and for other tumors when immunotherapy selection is considered

Assay guidanceUse validated NGS or IHC methods appropriate to tumor type; consider NGS when TMB or tumor-agnostic indications are relevant

Clinical rationaleMMR/MSI status informs eligibility for immune checkpoint inhibitors and is emphasized in multiple guidelines (NCCN, ASCO, ESMO)

NTRK/RET fusions — fusion biomarkers with tumor-agnostic therapies

NTRK/RET fusion testingNTRK and RET fusions are fusion biomarkers with tumor-agnostic therapies; testing should be included in panels when TRK- or RET-directed therapy is a consideration

Assay preferenceRNA sequencing is preferred for fusion detection when feasible; ensure selected panel includes fusions of interest

Clinical useInclude fusion testing in metastatic disease or when tumor-agnostic targeted therapy may be indicated; reference NCCN/ESMO guidance

ALK, ROS1, RET, MET exon 14 skipping — biomarkers for lung cancer targeted therapies

Lung cancer fusions and alterationsALK, ROS1, RET rearrangements and MET exon 14 skipping are key biomarkers for NSCLC targeted therapies and are detectable by tissue and ctDNA NGS assays

Clinical examplesBlood-based NGS has been used prospectively (BFAST) to detect ALK rearrangements guiding alectinib therapy when detected in plasma

Testing notectDNA sensitivity varies; negative plasma results may require reflex tissue testing

BRAF (melanoma) — specific melanoma biomarker

Melanoma BRAF testingBRAF (e.g., V600) is a specific melanoma biomarker used to select BRAF-directed targeted therapies in stage IV or recurrent disease

Testing preferenceTumor tissue NGS preferred; liquid biopsy acceptable if tissue unavailable but negative ctDNA should prompt tissue testing

Clinical recommendationBroader genomic profiling recommended for initial stage IV or recurrence to identify targetable mutations and trial eligibility

MSI — microsatellite instability reporting

MSI reportingMSI (microsatellite instability) should be reported as part of tumor profiling when relevant; MSI status informs immunotherapy eligibility

Assay capabilityF1CDx and other validated NGS assays report MSI and TMB alongside sequence variants and CNVs

Regulatory noteMSI testing and CDx indications are referenced in FDA-cleared assays and professional guidelines

BRAF (IHC) — IHC testing noted as acceptable modality in some contexts

BRAF (IHC) useBRAF IHC is noted as an acceptable, faster-turnaround modality in some contexts (e.g., thyroid carcinoma) to assess BRAF status

When to useIHC may be preferred when rapid results are needed, but confirmatory molecular testing may be required depending on context

Guideline mentionNCCN recommends BRAF IHC in thyroid carcinoma for faster turnaround compared to genetic testing

NTRK — NTRK biomarker reporting

NTRK testingNTRK fusions are recommended for testing when TRK-inhibitor therapy is a potential option; include in initial CGP panels for advanced disease

Assay guidanceUse NGS panels that include RNA-based fusion detection or reflex to RNA sequencing when DNA-only panels are negative but suspicion remains

Tumor-agnostic relevanceNTRK fusions are tumor-agnostic biomarkers used to guide TRK inhibitor therapy across tumor types

TMB — reiterated as biomarker requirement in multiple contexts

TMB reiteratedTMB is reiterated as a biomarker requirement for pembrolizumab tumor-agnostic use when reported by an FDA-approved CDx (≥10 mut/Mb)

Clinical evidenceKEYNOTE-158 and supporting FDA review underpin the role of TMB measured by F1CDx in selecting patients for pembrolizumab

Testing recommendationWhen TMB may influence immunotherapy decisions, use validated large-panel NGS or whole exome methods as appropriate per guidelines

LimitationsHigh specificity but variable sensitivity with false-negative risk at low tumor fraction; negative results may require tissue confirmation

Next Generation Sequencing (NGS) definition

NGS definitionNext-generation sequencing (NGS): sequencing techniques that quickly analyze multiple DNA regions simultaneously to detect genomic alterations

Clinical roleNGS enables broad panel-based molecular testing to detect mutations, CNVs, fusions, MSI and TMB relevant to targeted therapy selection

Assay typesNGS may be performed on tumor tissue or plasma (ctDNA); assay selection should match the alterations of interest (RNA for fusions)

Comprehensive Genomic Profiling (CGP) definition

CGP definitionComprehensive Genomic Profiling (CGP): an NGS approach that detects multiple classes of genomic alterations across hundreds of genes to inform targeted therapy selection

Panel size exampleFoundationOne CDx analyzes 324 genes in tumor tissue; FoundationOne Liquid CDx assesses >300 genes in plasma

Use caseCGP is preferred when broad biomarker detection (including rare fusions or tumor-agnostic markers) is needed per guideline recommendations

Advanced Cancer definition (NCI)

Advanced cancer definitionAdvanced Cancer: cancer unlikely to be cured or controlled with treatment; may be referred to as end-stage or terminal cancer (NCI)

Clinical implicationMolecular profiling is often prioritized in advanced/metastatic disease where targeted therapies or trials are being considered

Guideline tie-inProfessional guidelines recommend tumor NGS for many advanced cancers to identify actionable alterations

Tumor mutational burden (TMB) definition — mut/Mb and common cut-points

TMB unit and cut-pointsTumor mutational burden (TMB) reported as mutations per megabase (mut/Mb); common CDx cut-point: ≥10 mut/Mb (F1CDx)

Alternative thresholdsSome whole-exome analyses report different thresholds (e.g., ~175 mutations/exome) corresponding to TMB-high in retrospective studies

Clinical applicationValidated assay reporting of TMB (e.g., F1CDx) is required to apply the ≥10 mut/Mb cut-point for pembrolizumab eligibility

CDx / companion diagnostic definition

CDx / companion diagnosticAn FDA-cleared/approved test tied to a specific therapeutic product to identify patients likely to benefit from that therapy

Informational useFDA approval/listing of a CDx is informational in this policy; FDA approval alone is not a basis for coverage

Laboratory requirementTesting should be performed in appropriately certified (CLIA) laboratories for clinical use

MRD (ctDNA) definition

MRD (ctDNA) definitionMinimal residual disease (MRD) ctDNA assays: personalized plasma assays tracking tumor-specific variants to detect recurrence earlier than clinical diagnosis

Clinical evidenceSmall prospective studies show lead times (e.g., ~12 months) for ctDNA-detected recurrence; impact on outcomes requires further study

Coverage stanceMRD testing remains investigational for routine use and may be considered in research or selected clinical contexts

ctDNA/liquid biopsy definition — cfDNA assayed from plasma and its clinical uses/limitations

ctDNA / cfDNA testing definitionPlasma-based ctDNA testing assays cell-free tumor-derived DNA to infer tumor genomic alterations when tissue is unavailable or biopsy unsafe

StrengthsRapid results and ability to reflect tumor heterogeneity; high specificity for many alterations

LimitationsVariable sensitivity with false-negative risk at low tumor fraction and potential for CHIP-related false-positives; negative results may need tissue confirmation

Tumor NGS / CGP definition

Tumor NGS / CGP definitionComprehensive tumor genomic profiling performed on tumor tissue using NGS to identify actionable genomic alterations, MSI, TMB and fusions

Preferred specimenTissue is preferred when feasible; ctDNA is acceptable when tissue unavailable or rapid results needed

Panel considerationsEnsure assay includes necessary analytic methods for the alterations of interest (e.g., RNA for fusions, sufficient coverage for CNVs)

Broad molecular profiling / CGP definition

Broad molecular profiling definitionNGS-based assays or combinations that detect a wide range of biomarkers (mutations, amplifications, MSI/MMR, TMB, fusions) often spanning >50 genes

Use casePreferred for advanced NSCLC and other cancers where multiple guideline-listed biomarkers must be assessed simultaneously

Evidence cautionBroad profiling intended solely for treatment selection without FDA-labeled indications may have insufficient evidence of clinical utility

ctDNA / cfDNA testing definition — plasma-based alternative when tissue unavailable

ctDNA as alternativectDNA/cfDNA testing: plasma-based ctDNA testing used as an alternative when tumor tissue is unavailable or biopsy is unsafe; appropriate for advanced/metastatic disease

Clinical caveatctDNA testing should not replace histologic tissue diagnosis; use in conjunction with tissue when possible

Laboratory requirementTesting to inform clinical care must be performed in appropriately certified/validated laboratories (CLIA)

ctDNA / cfDNA used as plasma-based assay when tissue biopsy is unsafe or not feasible

ctDNA when tissue unsafeCirculating tumor DNA (ctDNA) may be used as a plasma-based assay when tissue biopsy is unsafe or not feasible; preference for collection during biochemical or radiographic progression to maximize yield

Interpretation cautionInterpret ctDNA-only results cautiously because of potential interference from clonal hematopoiesis (CHIP) and lower sensitivity at low tumor fraction

Regulatory noteLaboratories performing genetic tests are regulated under CLIA

CLIA — laboratory regulation note

CLIA regulationClinical Laboratory Improvement Amendments (CLIA): laboratories performing genetic tests are regulated under CLIA

Coverage implicationTesting performed outside appropriately certified laboratories may trigger denial or limited coverage

ReferencePolicy references CLIA as a laboratory regulation for genetic testing

Clonal hematopoiesis of indeterminate potential (CHIP) — source of false-positives in ctDNA-only evaluations

CHIP caveatClonal hematopoiesis of indeterminate potential (CHIP) can be a source of false-positive findings in ctDNA-only evaluations and should be considered when interpreting plasma-only results

Clinical impactCHIP-related variants may lead to inappropriate therapy selection if not recognized; consider matched normal or orthogonal testing where relevant

GuidanceNCCN and other guidelines urge caution interpreting ctDNA-only results due to CHIP potential

Reflects consensus and prospective trial data showing blood‑first approaches shorten time to treatment

subsequent-line

Subsequent‑line testing considerations (single top‑level node):

Subsequent-line liquid biopsy for resistance: Use liquid biopsy as the preferred initial step when disease has progressed after targeted therapy to identify acquired resistance mechanisms; confirm negative liquid results with tissue biopsy when clinically indicated.

Consensus and guideline recommendations for resistance assessment

first-line | second-line

Considerations that apply to both first‑ and second‑line settings (single top‑level node):

First-line and second-line combined considerations: Blood‑based NGS can be used prospectively to identify actionable alterations in treatment‑naïve advanced NSCLC (e.g., BFAST) and to shorten time to treatment; it is also useful to inform therapy at progression. When performed early, concurrent tissue and liquid testing can improve detection of actionable alterations.

Supported by BFAST and randomized/observational studies showing shorter time to treatment and complementary detection

first-line

First‑line guideline‑driven testing considerations (single top‑level node):

Guideline-driven first-line testing: Professional guidelines recommend genomic testing for individuals with advanced or metastatic disease to inform targeted therapy selection at diagnosis or at progression; testing should be performed in appropriately certified laboratories and include biomarkers relevant to therapy selection.

ASCO and guideline recommendations