CurrentUnitedHealthcarePolicy CS152TN.AF

Molecular Oncology Testing for Solid Tumor Cancer Diagnosis, Prognosis, and Treatment Decisions (Tennessee Medicaid / CoverKids)

Policy governs coverage of molecular and gene expression profiling tests used for diagnosis, prognosis, and treatment decisions for solid tumor cancers for Tennessee Medicaid and CoverKids.

Policy Summary

PayerUnitedHealthcare

PolicyMolecular Oncology Testing for Solid Tumor Cancer Diagnosis, Prognosis, and Treatment Decisions (Tennessee)

Policy CodePolicy CS152TN.AF

Change TypeNo material change

Effective DateFeb 1, 2026

Next Review Date

Key ActionObtain prior authorization and document clinical rationale when ordering molecular tests that will alter management (e.g., to guide adjuvant therapy or avoid diagnostic surgery).

SourceLink

POLICY UPDATE CHANGES

No material clinical or coverage changes in this revision.

50+listed CPT/PLA/U codes referenced

≤50 genesNSCLC multigene panel limit

Multiplemajor breast GEPs named

Manytests listed as unproven

6693MINDACT participants

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Coverage Criteria and Indications

Covered with policy criteria (billing/coding guidance)

Note: Applicable CPT/PLA/U-code listings for molecular oncology tests are provided below for billing reference. Inclusion of a code here does not imply coverage for all uses — coverage is determined by the clinical criteria stated elsewhere in this policy (see individual criteria groups).

0069U — Oncology (colorectal), microRNA, RT-PCR expression profiling of miR-31-3p; algorithm reported as expression score.

0089U — Oncology (melanoma), gene expression profiling by RTqPCR, PRAME and LINC00518, superficial collection using adhesive patch(es).

0090U — Oncology (cutaneous melanoma), mRNA gene expression profiling by RT-PCR of 23 genes, FFPE tissue, algorithm reported as categorical result.

0091U — Oncology (colorectal) screening, cell enumeration of circulating tumor cells, whole blood, algorithm reported as positive/negative.

0113U — Oncology (prostate), measurement of PCA3 and TMPRSS2-ERG in urine and PSA, algorithm reported as risk score.

0153U — Oncology (breast), mRNA GEP by NGS of 101 genes, FFPE tissue; TNBC subtype/immune information reported.

0179U — Oncology (non-small cell lung cancer), cfDNA targeted sequence analysis of 23 genes, report of significant mutations.

0211U — DNA and RNA by NGS, FFPE tissue, interpretative report for SNVs, CNAs, fusions, TMB, and MSI with therapy associations.

0239U — Targeted genomic panel, solid organ neoplasm, cfDNA, analysis of ≥311 genes.

0242U — Targeted genomic cfDNA panel, 55-74 genes.

0244U — Comprehensive genomic profiling, 257 genes, FFPE tissue, includes TMB/MSI.

0245U — Oncology (thyroid), mutation analysis of 10 genes and 37 RNA fusions with mRNA markers using NGS, fine needle aspirate.

0250U — Targeted genomic sequence DNA analysis of 505 genes, interrogation for somatic alterations, MSI and TMB.

0262U — Gene expression profiling by RT-PCR of 7 gene pathways, FFPE, reported as pathway activity scores.

0287U — Oncology (thyroid), DNA and mRNA NGS analysis of 112 genes, fine needle aspirate, algorithmic analyses to determine tumor-recurrence risk score.

0611U/0612U — Oncology (liver), cfDNA methylation region analyses, quantitative result.

0613U — Oncology (urothelial), DNA methylation and mutation analysis, urine, probability index report.

81445 — Solid organ neoplasm, genomic sequence analysis panel, 5-50 genes.

Covered Indications by Tumor Type

Provider Actions, Prior Authorization & Documentation

Note

Provider Actions — Not Specified

Provider action: Not provided in this excerpt. No explicit prior authorization procedures or provider actions are listed here. Providers should be aware that the policy text in this section does not specify prior authorization, step therapy, or procedural documentation requirements.

No step therapy rules are specified in this segment.
No step therapy requirements are described.
No explicit procedural or documentation actions are provided in this excerpt.
Denial triggers are not provided in this excerpt.

Denial Risk

Denial Risk — Not Explicitly Defined

Denial triggers and explicit provider action steps are not described in the presented excerpts. Where coverage is limited (e.g., tests labeled unproven or not medically necessary), standard operational expectations apply: documentation demonstrating clinical indication, test selection rationale, and relevant pathology/clinical data should be included with any authorization or claim. However, the policy excerpts do not provide a discrete list of denial criteria or required forms.

Applicable Billing Codes and Coding Notes

Applicable PLA/CPT/MLC Codes (part 1)mixed

0005U	Oncology (prostate) gene expression profile by real-time RT-PCR of 3 genes (ERG, PCA3, SPDEF), urine, algorithm reported as risk score.
0011M	Oncology, prostate cancer, mRNA expression assay of 12 genes (10 content and 2 housekeeping), RT-PCR test utilizing blood plasma and urine, algorithms to predict high-grade prostate cancer risk.
0012M	Oncology (urothelial), mRNA, gene expression profiling by real-time quantitative PCR of five genes (MDK, HOXA13, CDC2 [CDK1], IGFBP5, CXCR2), utilizing urine, algorithm reported as a risk score for having urothelial carcinoma.
0013M	Oncology (urothelial), mRNA, gene expression profiling by real-time quantitative PCR of five genes (MDK, HOXA13, CDC2 [CDK1], IGFBP5, CXCR2), utilizing urine, algorithm reported as a risk score for having recurrent urothelial carcinoma.
0016M	Oncology (bladder), mRNA, microarray gene expression profiling of 219 genes, utilizing formalin-fixed paraffin-embedded tissue, algorithm reported as molecular subtype.
0018U	Oncology (thyroid), microRNA profiling by RT-PCR of 10 microRNA sequences, utilizing fine needle aspirate, algorithm reported as a positive or negative result for moderate to high risk of malignancy.
0019U	Oncology, RNA, gene expression by whole transcriptome sequencing, formalin-fixed paraffin embedded tissue or fresh frozen tissue, predictive algorithm reported as potential targets for therapeutic agents.
0020M	Oncology (central nervous system), analysis of 30000 DNA methylation loci by methylation array.

Applicable PLA/CPT/MLC Codes (part 2)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.
0026U	Oncology (thyroid), DNA and mRNA of 112 genes, next-generation sequencing, fine needle aspirate of thyroid nodule, algorithmic analysis reported as a categorical result ("Positive, high probability of malignancy" or "Negative, low probability of malignancy").
0036U	Exome (i.e., somatic mutations), paired formalin-fixed paraffin-embedded tumor tissue and normal specimen, sequence analyses.
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.
0045U	Oncology (breast ductal carcinoma in situ), mRNA, gene expression profiling by real-time RT-PCR of 12 genes (7 content and 5 housekeeping), utilizing formalin-fixed paraffin-embedded tissue, algorithm reported as recurrence score.
0047U	Oncology (prostate), mRNA, gene expression profiling by real-time RT-PCR of 17 genes (12 content and 5 housekeeping), utilizing formalin-fixed paraffin-embedded tissue, algorithm reported as a risk score.
0048U	Oncology (solid organ neoplasia), DNA, targeted sequencing of protein-coding exons of 468 cancer-associated genes, including interrogation for somatic mutations and microsatellite instability, matched with normal specimens, utilizing formalin-fixed paraffin-embedded tumor tissue, report of clinically significant mutation(s).
0069U	Oncology (colorectal), microRNA, RT-PCR expression profiling of miR-31-3p, formalin-fixed paraffin-embedded tissue, algorithm reported as an expression score.
0089U	Oncology (melanoma), gene expression profiling by RTqPCR, PRAME and LINC00518, superficial collection using adhesive patch(es).
0090U	Oncology (cutaneous melanoma), mRNA gene expression profiling by RT-PCR of 23 genes (14 content and 9 housekeeping), utilizing formalin-fixed paraffin-embedded (FFPE) tissue, algorithm reported as a categorical result (benign, intermediate, malignant).

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1/3

Applicable CPT/PLA/HCPCS Codes and descriptionsmixed

0069U	Oncology (colorectal), microRNA, RT-PCR expression profiling of miR-31-3p, FFPE tissue, algorithm reported as an expression score.
0089U	Oncology (melanoma), gene expression profiling by RT-qPCR, PRAME and LINC00518, superficial collection using adhesive patch(es).
0090U	Oncology (cutaneous melanoma), mRNA gene expression profiling by RT-PCR of 23 genes, FFPE tissue, algorithm reported as a categorical result (benign, intermediate, malignant).
0091U	Oncology (colorectal) screening, cell enumeration of circulating tumor cells, whole blood, positive/negative result.
0113U	Oncology (prostate), measurement of PCA3 and TMPRSS2-ERG in urine and PSA in serum following prostatic massage, RNA amplification, algorithm reported as risk score.
0153U	Oncology (breast), mRNA, gene expression profiling by NGS of 101 genes, FFPE, reports triple negative breast cancer clinical subtype(s).
0179U	Oncology (NSCLC), cell-free DNA, targeted sequence analysis of 23 genes, report of significant mutation(s).
0211U	Oncology (pan-tumor), DNA and RNA by NGS, FFPE, report for SNVs, CNVs, TMB, MSI with therapy associations.
0239U	Targeted genomic sequence analysis panel, cfDNA, analysis of 311+ genes.
0242U	Targeted genomic sequence analysis panel, cfDNA analysis of 55-74 genes.

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Applicable CPT/Unlisted assay codesCPT

81529	Oncology (cutaneous melanoma), mRNA, gene expression profiling by real-time RT-PCR of 31 genes (28 content and 3 housekeeping), FFPE, algorithm reported as recurrence risk, including likelihood of sentinel lymph node metastasis.
81540	Oncology (tumor of unknown origin), mRNA, gene expression profiling by real-time RT-PCR of 92 genes (87 content and 5 housekeeping) to classify tumor into main cancer type and subtype, FFPE, algorithm reported as a probability of a predicted main cancer type and subtype.
81541	Oncology (prostate), mRNA gene expression profiling by real-time RT-PCR of 46 genes (31 content and 15 housekeeping), FFPE, algorithm reported as a disease-specific mortality risk score.
81542	Oncology (prostate), mRNA, microarray gene expression profiling of 22 content genes, FFPE, algorithm reported as metastasis risk score.
81546	Oncology (thyroid), mRNA, gene expression analysis of 10,196 genes, utilizing fine needle aspirate, algorithm reported as a categorical result (e.g., benign or suspicious).
81551	Oncology (prostate), promoter methylation profiling by real-time PCR of 3 genes (GSTP1, APC, RASSF1), FFPE, algorithm reported as a likelihood of prostate cancer detection on repeat biopsy.
81552	Oncology (uveal melanoma), mRNA, gene expression profiling by real-time RT-PCR of 15 genes (12 content and 3 housekeeping), FNA or FFPE, algorithm reported as risk of metastasis.
81599	Unlisted multianalyte assay with algorithmic analysis.

Applicable HCPCS codesHCPCS

G0327

Colorectal cancer screening; blood-based biomarker.

No specific CPT/HCPCS/ICD codes listed in this excerptmixed

No codes listed

NGS / multigene tests referenced (no explicit codes in excerpt)mixed

No codes listed

Gene expression recurrence signatures (e.g., 12-gene, 15-gene, Oncotype DX)mixed

No codes listed

Blood-based SEPT9 tests (Epi proColon / ColoHealth)mixed

No codes listed

NGS panel size limit for NSCLC

NGS panel size limit for NSCLCPermitted panel size: no more than 50 genes; panels >50 genes allowed only when used consistent with FDA-cleared/approved companion diagnostic policy.

Sample typesTumor tissue or liquid biopsy (cfDNA/ctDNA) as specified for NSCLC molecular profiling.

Preferred methodologyMultiplexed NGS panels preferred over multiple single-gene tests when available.

Gene count thresholds

Small panels

Not Covered / Investigational Tests

The policy lists numerous tests and indications considered unproven or not medically necessary. Examples include: large NGS/CGP panels (>50 genes) unless otherwise specified; multi‑cancer early detection tests (e.g., Galleri); MRD assays (tumor‑informed or tumor‑naïve such as Signatera, Guardant Reveal); CancerTYPE ID; PancraGEN; a variety of melanoma and cutaneous lesion assays (DecisionDx‑Melanoma, DermTech PLA, myPath); select prostate urine/tissue tests with low evidence (ExoDx, MyProstateScore, ConfirmMDx, SelectMDx); and whole‑exome/genome/transcriptome profiling for routine decision making. These uses are considered unproven and not medically necessary due to insufficient evidence of clinical utility.

This excerpt does not list a separate short catalogue of additional ‘not covered’ items beyond the broader unproven list; the policy’s not‑medically‑necessary section enumerates specific assays and contexts that lack evidence and should be interpreted against the full unproven list.

Evidence is insufficient to support routine use of BluePrint in conjunction with MammaPrint to determine clinical management; the policy notes that combined MP/BluePrint clinical utility is not established at this time.

Studies have reported limited concordance between molecular subtyping (BluePrint/MammaPrint) and pathological subtyping for some luminal subgroups, highlighting surrogate limitations of BluePrint and the need for additional validation before routine clinical reliance.

Other breast GEPs and DCIS assays (e.g., Theros H/I alone, 41‑gene signatures, DCISionRT, Oncotype DX DCIS) have low‑quality or insufficient evidence for clinical utility. Hayes assessments found limited or low‑quality data for DCISionRT and Oncotype DX DCIS, and the policy treats these uses as unproven/not medically necessary.

Definitions and Test Descriptions

Comprehensive Genomic Profiling (CGP)

DefinitionComprehensive Genomic Profiling (CGP) is an NGS-based test able to detect all classes of genomic alterations (SNVs, indels, CNAs, rearrangements, MSI/TMB) from a single sample.

Typical specimen typesPerformed on tumor tissue (FFPE/fresh/frozen) and may be reported from paired normal specimens when applicable.

Use casesUsed to identify actionable alterations, guide targeted therapy selection, and match patients to molecularly targeted trials; broad panels may exceed 50 genes.

Liquid Biopsy definition

DefinitionLiquid biopsy: testing of bodily fluid (commonly plasma) to identify tumor-derived material (cfDNA/ctDNA) for detection, treatment selection, or monitoring.

Clinical contexts

Eligibility Requirements (placeholders / references)

ELIGIBILITY REQUIREMENTS: The excerpt provided does not specify separate eligibility requirement nodes in this segment. Coverage determinations depend on meeting the clinical criteria described in the coverage sections (for example, receptor/HER2 and node status for breast GEP; Bethesda III/IV cytology and decision impact for thyroid molecular testing; biopsy‑proven localized prostate cancer and documented life expectancy >10 years where applicable).

ELIGIBILITY REQUIREMENTS: No additional eligibility elements were listed in this excerpt; ordering and prior‑authorization expectations are tied to whether the test result is likely to change management and to the specific clinical criteria enumerated per tumor type.

ELIGIBILITY REQUIREMENTS: The policy does not list family history, prior‑testing, or other distinct eligibility checklists in the provided excerpt; clinical documentation demonstrating how results will affect care is required for coverage decisions where noted.

ELIGIBILITY REQUIREMENTS: For tests covered under tumor‑specific criteria, routine prerequisites include standard pathology information (e.g., ER/PR and HER2 status for breast assays; cytology Bethesda category for thyroid assays) as noted in the respective sections.

ELIGIBILITY REQUIREMENTS: The policy emphasizes that tests must be ordered and interpreted in clinical contexts where results will be integrated with clinicopathologic factors and will plausibly change management; absence of such rationale may affect coverage.

ELIGIBILITY REQUIREMENTS: The excerpt does not provide discrete step‑by‑step eligibility checklists for every named assay; readers should consult the coverage criteria per tumor type for the required clinical elements.

Background and Policy Scope

BACKGROUND: Molecular and gene expression profiling assays can provide prognostic and, for some tests, predictive information that helps tailor treatment decisions in selected solid tumors. This policy defines which assays and clinical contexts are considered proven and medically necessary (for example, specific breast GEPs in early ER+, HER2– disease), and identifies many tests and indications judged unproven or not medically necessary based on current evidence assessments.

Revision History

2026-02-01Policy effective / codes updatedLatest

Policy effective date set to February 1, 2026 and applicable CPT/PLA/HCPCS code list updated (added codes including 0611U, 0612U, 0613U, and 81524).

Policy Summary

PayerUnitedHealthcare

PolicyMolecular Oncology Testing for Solid Tumor Cancer Diagnosis, Prognosis, and Treatment Decisions (Tennessee)

Policy CodePolicy CS152TN.AF

Change TypeNo material change

Effective DateFeb 1, 2026

Next Review Date

Key ActionObtain prior authorization and document clinical rationale when ordering molecular tests that will alter management (e.g., to guide adjuvant therapy or avoid diagnostic surgery).

SourceLink

On This Page

Policy notes multiple tests and indications as “unproven and not medically necessary” (see Unproven Molecular Tests) — these situations may lead to claim denial.
Applicable CPT/HCPCS/PLA codes are listed elsewhere in the policy (Applicable Codes) but no code-specific prior authorization requirements are stated in this excerpt.
When a test is explicitly deemed “proven and medically necessary” the policy describes clinical criteria; when tests are “unproven” or “not medically necessary” the excerpted text does not enumerate clinic-level denial workflow or appeals steps.

Documentation Required

Documentation — Provider Responsibilities (No Formal Checklist Provided)

Documentation requirements are not explicitly enumerated in this excerpt. The clinical sections reference guideline-based indications and specify clinical criteria for when particular assays are considered proven and medically necessary; however, no standalone procedural or documentation checklist (e.g., required fields for authorization requests) is provided in the shown text.

Clinical indication and correlation with pathology are described throughout (e.g., criteria for GEP in breast cancer, molecular testing for indeterminate thyroid nodules, prostate GEP) and should be documented.
Although the policy emphasizes clinical criteria for coverage decisions, this excerpt does not present an explicit provider documentation checklist or required forms.
Providers should include clinical rationale, staging/biomarker status, and intended management impact when ordering tests — the excerpt recommends documenting how results will affect management but does not prescribe a formal submission set.

Defined panels commonly covering 5–50 genes (CPT codes for 5-50 gene panels such as 81445/81449).

Large/broad panelsBroad/comprehensive panels range to 51+ genes and up to several hundred genes (CPT codes 81455/81456 and many PLA codes for larger panels).

Whole-exome/genomeWhole exome, whole genome or whole-transcriptome sequencing described separately and not supported for routine decision-making in many contexts.

Definition threshold for multi-gene panel

Multi-gene panel definition>= 5 genes constitutes a multi-gene panel for this policy (with noted exceptions).

Exceptions noteSpecific policy sections may specify different thresholds for particular assays or coding categories.

Implication for codingCPT panel codes correspond to gene-count ranges (e.g., 5-50 genes vs 51+ genes) used in coverage and coding guidance.

Tumor thickness thresholds noted in uveal melanoma prognostication

Class 2 tumor thickness thresholdClass 2 uveal melanoma with thickness >= 7.0 mm associated with higher metastasis risk.

Class 1 tumor thickness observationClass 1 tumors with thickness >= 9.0 mm were also associated with increased metastasis risk in analyses.

Clinical implicationTumor thickness adds prognostic value independent of GEP class and should be considered when interpreting results.

Recurrence Score risk group thresholds

Oncotype DX Recurrence Score thresholds (study usage)Low: < 30; Intermediate: 30–40; High: >= 41 (as used in referenced validation/analysis).

Use with clinicopathologic factorsRecurrence score should be integrated with clinical/pathologic staging to estimate individualized recurrence risk and guide therapy decisions.

Application contextsUsed in colon and breast recurrence score contexts in studies to stratify recurrence risk and inform treatment choices.

Consistent with guideline statements, assays are not recommended for HER2‑positive or triple‑negative breast cancer; the policy lists these breast‑subtype non‑recommendations among not‑covered or non‑recommended uses.

TMB should not be used in isolation to guide immune checkpoint inhibitor selection in advanced NSCLC; tests such as TMB lack sufficient evidence as a standalone predictive biomarker and therefore are considered unsupported when used without other validated indicators.

Routine substitution of cfDNA/liquid biopsy testing for tissue‑based testing in NSCLC (outside advanced/metastatic or tissue‑insufficient situations) is not supported. Liquid biopsy may be appropriate when tissue is unavailable or the patient is unfit for invasive sampling, but tissue testing remains the preferred standard when feasible.

Several prostate assays intended to refine biopsy or screening decisions (e.g., SelectMDx, ConfirmMDx, ExoDx/EPI, MyProstateScore) have been judged by evidence assessments to have low‑quality or insufficient data to demonstrate clinical utility for many proposed indications; these assays are listed among those not medically necessary without stronger outcome data.

Guideline panels emphasize that molecular biomarkers and genomic classifiers should be used selectively rather than routinely; routine use without documentation that results will affect management is not supported and therefore considered not medically necessary in many contexts.

Hayes concluded evidence is insufficient in some assessments to support certain ThyroSeq v3 uses for preoperative assessment, and tests without demonstrated outcome improvement may be considered not medically necessary in those contexts.

Pigmented Lesion Assay (PLA) and several melanoma prognostic tests have low‑quality evidence for diagnostic accuracy or impact on outcomes; systematic reviews and HTAs flagged high risk of bias, inconsistent performance, and insufficient evidence of benefit, so routine coverage is not supported.

Assays such as PLA, myPath Melanoma, and DecisionDx‑UM lack sufficient high‑quality evidence demonstrating clinical utility to support routine coverage as prognostic tools or to drive treatment decisions outside defined clinical contexts or research.

CancerTYPE ID and similar GEP approaches for identifying tissue of origin in CUP have not demonstrated consistent clinical utility to direct site‑specific therapy; Hayes assessments and guideline reviews conclude evidence is insufficient to support routine use for this purpose.

The American College of Gastroenterology recommends against using Septin 9 blood testing for colorectal cancer screening due to low sensitivity and very low–quality evidence; such tests are therefore not endorsed for screening indications.

PancraGEN and multi‑cancer detection (MCD/MCED) tests are not supported for routine clinical use or population screening because of insufficient evidence of analytic/clinical validity and unproven impact on outcomes; prior‑authorization denial risk is noted for these indications.

Routine use of tumor‑informed or tumor‑naïve ctDNA MRD assays for early‑stage cancer screening, routine monitoring to guide therapy changes, or directing MRD‑targeted treatment is not supported by current evidence; whole exome/genome/transcriptome approaches likewise lack sufficient evidence for routine clinical decision‑making.

May be used when tissue is insufficient or patient unfit for invasive sampling; not recommended to routinely replace tissue-based testing in non-advanced settings.

LimitationscfDNA results may be heterogeneous; negative plasma results should prompt tissue-based analysis when feasible if no driver is identified.

Gene Expression Profiling (GEP)

DefinitionGene Expression Profiling (GEP): laboratory tests that analyze mRNA patterns to determine gene activity and produce prognostic or predictive information (scores, classifiers, risk categories).

Specimen typesTypically performed on tumor tissue (FFPE, fresh, or frozen) and in some platforms on FNA samples or other materials.

Examples of useUsed in breast (Oncotype DX, MammaPrint, Prosigna, EndoPredict, BCI), prostate, melanoma, uveal melanoma, and other tumor contexts for prognosis or treatment decisions.

Formalin-fixed paraffin-embedded tissue (FFPE)

Definition/abbreviationFormalin-fixed paraffin-embedded tissue (FFPE): standard tissue preservation method commonly used as specimen input for molecular assays and GEP.

Use in assaysMany commercial GEP and NGS assays are validated on FFPE material; CNB and surgical resection FFPE concordance supports using CNB for some assays (e.g., MammaPrint/BluePrint).

Specimen considerationsDNA/RNA quantity and quality from FFPE influence analytic validity; laboratories should use validated methods for FFPE-derived nucleic acids.

ctDNA / cfDNA definition

DefinitionctDNA / cfDNA: circulating tumor-derived DNA or cell-free DNA in plasma used for molecular profiling (liquid biopsy) to detect tumor alterations or monitor disease.

ApplicationsUsed for mutation detection, methylation assays, MRD monitoring, and multi-cancer detection in investigational and select clinical contexts.

LimitationsSensitivity varies by tumor type and stage; negative ctDNA does not rule out a tumor alteration and may require tissue testing follow-up.

Multi-gene analysis threshold (policy definition)

Policy thresholdMulti-gene analysis generally refers to gene panels containing five or more genes for the purposes of this policy.

Coding implicationPanel size determines applicable CPT panel codes (e.g., 5-50 gene vs 51+ gene codes) used for billing and coverage mapping.

ExceptionsSpecific policy sections may define different thresholds for certain tests or indications.

Expression signature/classifier

DefinitionExpression signature/classifier: combined pattern of gene expression reported as a score, classifier, or risk category to inform diagnosis, prognosis, or treatment.

ExamplesSignatures include MammaPrint (70-gene), Oncotype DX Recurrence Score (21-gene), EndoPredict (EPclin), Prosigna ROR (PAM50), BCI (H/I + MGI).

Clinical useReported classifier results are intended to be integrated with clinicopathologic factors to guide management decisions.

MammaPrint definition

DefinitionMammaPrint: a 70-gene expression assay (Amsterdam Signature) that classifies tumors as low or high risk of distant recurrence using fresh, frozen, or FFPE tumor tissue.

Companion testOften considered with BluePrint molecular subtyping; evidence supports prognostic use and use in trials (e.g., MINDACT) to inform chemotherapy decisions in select patients.

LimitationsNot recommended for certain populations per NICE guidance; combined utility with BluePrint remains under evaluation.

BluePrint definition

DefinitionBluePrint: an 80-gene expression assay used complementarily with MammaPrint to assign molecular subtype (Luminal A/B, HER2-type, Basal) to help predict behavior and therapy response.

Evidence noteBluePrint may refine subtype classification and influence neoadjuvant treatment decisions, but combined clinical utility evidence is limited and concordance with pathological subtyping can vary.

Current stanceEvidence insufficient to support BluePrint combined utility for routine adoption beyond research or specific contexts.

Prosigna (PAM50) definition

DefinitionProsigna (PAM50): a PAM50-based assay yielding a risk-of-recurrence (ROR) score and intrinsic molecular subtype for prognostic assessment in HR+ breast cancer.

Intended useProvides 10-year distant recurrence risk categorization for postmenopausal women with HR+ N0 or selected N+ disease; not intended for N2 disease.

Coding/assay noteReported as a 50-gene PAM50 ROR result; NCCN classifies prognostic value though predictive value for chemo is not determined.

EPclin Risk Score (EndoPredict)

DefinitionEPclin (EndoPredict): combined molecular score incorporating tumor gene expression and clinical factors (nodal status, tumor size) reported as an EPclin risk score to estimate recurrence risk.

Gene contentEndoPredict evaluates a 12-gene signature including eight disease-relevant genes plus normalization and reference genes.

Clinical noteEPclin incorporates clinicopathologic data and may estimate 10-year distant recurrence risk; prospective validation is limited.

DCISionRT Decision Score

DefinitionDCISionRT Decision Score (DS): a score from 0 to 10 combining expression of seven genes and clinicopathologic factors to estimate ten-year DCIS recurrence risk and potential radiotherapy benefit.

Scoring interpretationScores 0–3 considered low risk; higher scores indicate elevated recurrence risk per test design.

Evidence noteHayes assessment and other reviews cite limited quality evidence on impact for long-term outcomes; additional studies needed.

MammaPrint (70-gene signature)

DefinitionMammaPrint (70-gene signature): expression-based assay using 70 content genes to classify genomic risk of distant recurrence in early-stage breast cancer.

SpecimenPerformed on fresh, frozen, or FFPE tumor tissue; provides binary low/high risk categorization.

Clinical evidenceEvaluated in large trials (e.g., MINDACT) supporting prognostic utility in select populations.

GEAs / GEP general list

DefinitionGene expression assays (GEAs)/GEP: multi-gene tests (e.g., Oncotype DX, MammaPrint, Prosigna, EndoPredict, BCI) that provide prognostic and sometimes predictive information to inform adjuvant therapy decisions in breast cancer.

Common usesEstimate recurrence risk, predict chemo benefit (Oncotype DX), and inform adjuvant endocrine or chemotherapy decisions when integrated with clinical factors.

LimitationsPredictive evidence is strongest for Oncotype DX; other assays often provide prognostic but limited predictive evidence.

ctDNA / cfDNA (liquid biopsy) entry

DefinitionctDNA / cfDNA (liquid biopsy): circulating tumor-derived DNA in blood used for molecular profiling as an alternative or adjunct to tissue testing; can detect mutations or methylation signals.

Clinical applicationsUsed for mutation detection, prognostic assessment, MRD monitoring, and multi-cancer detection research; may be used when tissue is insufficient or patient is unfit for biopsy.

LimitationsSensitivity varies by stage/type; negative plasma findings should prompt tissue testing when feasible; routine substitution for tissue not recommended in many settings.

cfDNA shorthand

ShorthandcfDNA: circulating cell-free DNA often used interchangeably with ctDNA when tumor-derived fragments are described.

Clinical notecfDNA assays are developing; NCCN and ASCO recommend cfDNA use in select situations (e.g., insufficient tissue, medically unfit for biopsy) with follow-up tissue testing if negative for drivers.

Assay typesIncludes targeted mutation panels, methylation assays, and broader cfDNA sequencing approaches.

Broad panel NGS definition

DefinitionBroad panel NGS: NGS-based panels often including >50 genes used to achieve comprehensive genotyping in cancers (e.g., NSCLC) and to detect SNVs, indels, CNAs, rearrangements, MSI/TMB.

Typical codingBroad panels map to CPT/PLA codes for 51+ genes (e.g., 81455/81456) or to numerous PLA codes for large gene-content assays listed in the policy.

Usage guidancePreferred when feasible per NCCN for NSCLC to capture multiple actionable alterations; panels >50 genes permitted when consistent with companion diagnostic policy.

Clinical Cell-Cycle Risk (CCR) score

DefinitionClinical Cell-Cycle Risk (CCR) score: combined score using cell cycle progression (CCP/Prolaris) results and clinical data (e.g., CAPRA) to predict prostate cancer risk and guide surveillance selection.

Use caseApplied to risk stratification in localized prostate cancer to inform decisions about active surveillance vs definitive therapy.

Evidence noteEvidence includes observational and validation studies; prospective outcome data remain limited.

EPI (ExoDx Prostate IntelliScore)

DefinitionEPI (ExoDx Prostate IntelliScore): urine exosome gene expression assay designed to stratify risk for high-grade prostate cancer and inform biopsy decisions.

Performance noteProspective studies reported high sensitivity and NPV at predefined thresholds with potential to reduce biopsies, though further validation and comparison with MRI-based workflows is ongoing.

SpecimenFirst-void urine (no prior DRE in some studies) used for exosome RNA analysis.

Genomic Classifier (GC) definition

DefinitionGenomic Classifier (GC): a multigene expression or sequencing-based assay (e.g., Decipher, ThyroSeq) used to stratify recurrence risk or probability of malignancy based on tumor tissue or FNA samples.

ExamplesDecipher (22-gene GC), Oncotype DX Prostate (GPS), Prolaris (CCP) are used in prostate cancer risk stratification contexts.

Clinical noteUse is recommended selectively when results will affect management; routine use without demonstrated impact is discouraged.

Indeterminate Thyroid Nodule (ITN)

DefinitionIndeterminate Thyroid Nodule (ITN): thyroid FNA cytology classified as Bethesda III or IV where cytology alone does not clearly indicate benignity or malignancy.

ImplicationMolecular testing (ThyroSeq v3, Afirma GSC/XA) may be used to avoid diagnostic surgery when results and surveillance strategy are acceptable.

Evidence noteMeta-analyses report high pooled sensitivity and variable specificity across platforms; TSv3 and GSC show high rule-out performance in many studies.

miRNA-based diagnostic tests

DefinitionmiRNA-based diagnostic tests: assays measuring microRNA expression differences between benign and malignant thyroid nodules to improve diagnostic sensitivity/NPV when combined with mutation panels.

ExamplesThyraMIR is an example of a miRNA classifier used in conjunction with other molecular data for ITN evaluation.

Evidence noteReported sensitivity/specificity vary by study; often used as adjunct to other molecular tests rather than standalone.

Whole transcriptome RNA-sequencing (Afirma XA)

DefinitionWhole transcriptome RNA-sequencing (e.g., Afirma XA): RNA-seq approach to detect gene variations and fusions from a large panel of genes in FNA samples for molecular classification and fusion detection.

Analytic performanceAfirma XA reported analytical reproducibility and inter-lab accuracy; variant/fusion detection differs by VAF and methodology.

Clinical roleXA may add genomic insight when used after Afirma GSC or in specific diagnostic workflows but standalone sensitivity can be limited in some cohorts.

PLA (Pigmented Lesion Assay)

DefinitionPLA (Pigmented Lesion Assay): adhesive patch (tape-stripping) noninvasive assay measuring gene expression of markers (e.g., LINC00518, PRAME, TERT) to help triage pigmented lesions.

LimitationsReported analytic failure rates and discordance with histopathology in real-world studies; evidence for clinical utility is limited and additional prospective data needed.

Use contextIntended as adjunct to dermatologic evaluation to reduce unnecessary biopsies, but routine adoption is not supported due to limited outcome data.

31-GEP definition

Definition31-GEP: a 31-gene expression profile classifier that stratifies cutaneous melanoma into risk classes correlated with recurrence and metastasis outcomes.

Prognostic performanceStudies report class-specific differences in 5-year RFS (e.g., Class1 88% vs Class2 52%) and association with sentinel node and metastasis outcomes when combined with clinicopathologic factors.

Evidence limitationsMost data from retrospective/prospective observational cohorts; further prospective outcome studies needed to confirm impact on management and survival.

DecisionDx-UM / 15-GEP definition

DefinitionDecisionDx-UM / 15-GEP: a quantitative RT-PCR-based 15-gene expression profile for prognostication in uveal melanoma classifying tumors (Class 1 vs Class 2) to predict metastatic risk.

Clinical findingsClass 2 associated with substantially higher metastasis and lower metastasis-free survival; evidence includes prospective registry and meta-analytic cohorts but quality noted as low to very low in HTA reviews.

Interpretation cautionGEP prognostication should be considered with tumor size/thickness and clinical context; some HTA assessments found insufficient evidence for outcome benefit.

40-GEP definition

Definition40-GEP: a 40-gene expression profile (DecisionDx-SCC) developed to stratify localized high-risk cutaneous squamous cell carcinoma into three risk classes (Class 1, 2A, 2B) with differing metastasis-free survival estimates.

Risk classesClass 1 (low risk), Class 2A (high risk), Class 2B (highest risk) with 3-year MFS estimates reported differing markedly across classes in validation cohorts.

Clinical contextMay inform adjuvant radiation therapy decisions in multidisciplinary settings; evidence mainly retrospective/validation with potential for bias and need for further prospective data.

40-GEP (risk classes)

Risk classes summary40-GEP stratifies patients into three risk classes (Class 1, Class 2A, Class 2B) with differing 3-year metastasis-free survival and PPV/NPV estimates used to inform management.

Clinical implicationHigh-risk classes (2A/2B) identify patients with substantially higher metastatic risk who may be considered for intensified surveillance or adjuvant therapy discussions.

Evidence limitationsValidation derived from retrospective cohorts and prospective validation with potential selection bias; guideline endorsement limited.

CUP definition

DefinitionCUP (Cancer of Unknown Primary): clinical scenario where metastatic cancer is identified but the primary tumor site cannot be determined using standard clinicopathologic methods.

Role of testingComprehensive genomic profiling (NGS/CGP) and GEP can be used to identify actionable alterations or suggest tissue of origin, but evidence that GEP-guided site-specific therapy improves outcomes is limited.

Guideline contextNCCN/ESMO recommend case-by-case, collaborative use of IHC, GEP and NGS for CUP; randomized trials have not established routine GEP-directed site-specific therapy benefit.

MSI/MMR testing definition and uses

Definition and usesMSI/MMR testing: evaluation of mismatch repair deficiency or microsatellite instability used for Lynch syndrome identification, immunotherapy decisions in metastatic disease, and informing some stage II adjuvant decisions.

Testing methodsPerformed by IHC for MMR proteins or by molecular MSI testing; recommended universally in colorectal cancer per NCCN.

Clinical impactResults guide eligibility for immunotherapy and hereditary cancer evaluation; should be included with tumor genotyping where relevant.

mSEPT9 / Epi proColon definition

DefinitionmSEPT9 / Epi proColon: plasma methylated SEPT9 assay intended as a blood-based CRC screening test for average-risk adults who have not completed screening.

PerformancePooled sensitivity ~0.69 and specificity ~0.92 in meta-analyses; sensitivity increases with cancer stage and is lower for advanced precancerous lesions.

Guideline stanceACG recommends against SEPT9 testing for routine CRC screening; test may be used for individuals otherwise noncompliant with screening in some contexts but does not replace standard screening.

TTNB definition

DefinitionTTNB: through-the-needle biopsy—EUS-guided tissue sampling technique for pancreatic cystic lesions to obtain tissue for molecular and histologic analysis.

Diagnostic yieldTTNB-derived NGS shows sensitivity ~83.7% and specificity ~81.8% for mucinous cyst diagnosis in prospective studies; adverse event risk ~9.9% noted.

Clinical roleTTNB may improve diagnostic accuracy for pancreatic cyst subtyping when combined with molecular testing versus cyst fluid alone.

MCD / MCED definition

DefinitionMCD / MCED: multi-cancer detection tests that detect cancer-specific signals (often cfDNA methylation patterns) in blood to screen for multiple cancer types.

Performance overviewStudies report high specificity (often >=95% and up to 99%+) with variable sensitivity that increases with cancer stage; stage I-III pooled sensitivity ~67% for selected cancer types in validation cohorts.

Policy stanceCurrent evidence does not support routine population screening with MCED tests; professional societies have not recommended routine use pending prospective outcome data.

Tumor-informed MRD assay

DefinitionTumor-informed MRD assay: personalized ctDNA assay designed from a patient’s tumor sequence (e.g., Signatera) to monitor molecular residual disease after definitive treatment.

MethodologyInitial tumor sequencing identifies patient-specific mutations to create a bespoke panel for longitudinal plasma monitoring (codes 0306U/0307U describe MRD baseline and subsequent assessments).

Clinical evidenceRetrospective and cohort studies show prognostic associations but evidence that MRD-guided therapy improves outcomes is currently insufficient; routine use not established.

Multi-cancer detection test definition

DefinitionMulti-cancer detection test: blood-based cfDNA methylation assays aiming to detect multiple cancer types and predict tissue of origin (example: Galleri).

Performance noteValidation studies report high specificity (e.g., 99.3%) and tissue-of-origin prediction rates up to 96% among samples with cancer-like signals; sensitivity varies by cancer type and stage.

Policy cautionProspective population-level outcome data are lacking; routine screening with MCED is not supported by current guidelines and may be denied without investigational context.

TTMV-HPV DNA / NavDx definition

DefinitionTTMV-HPV DNA / NavDx: assay detecting tumor tissue-modified viral HPV DNA in plasma intended for HPV-related cancer genotyping, surveillance, and MRD detection.

Reported performanceMeta-analyses report pooled sensitivity ~86% for ctHPV and ~96% for TTMV-HPV, with pooled specificity ~96%; some cohort studies report high specificity (near 100%).

Policy stanceEvidence promising for earlier detection of recurrence in HPV+ OPSCC but methodologies require standardization and further prospective validation before routine implementation.

Limit on Multiple GEP Tests (policy statement crossref)

Policy limitUse of more than one predictive GEP for the same breast tumor is unproven and not medically necessary; exception: BCI may be used once for extended endocrine therapy decisions even if prior GEP used for chemo decision.

Implication for orderingOrdering multiple predictive GEPs for a single tumor is generally not supported and may be denied; document clinical rationale if exceptions are considered.

DocumentationProviders should document indication, tumor receptor/HER2 status, nodal status, and how the assay result will affect management when ordering GEP tests.

ELIGIBILITY REQUIREMENTS: Where panels or tests are limited by gene count (e.g., NSCLC panels limited to ≤50 genes unless aligned with FDA‑cleared companion diagnostics), eligibility to use larger panels depends on adherence to those exceptions.

ELIGIBILITY REQUIREMENTS: For cancers of unknown primary, molecular profiling may be considered after initial histology determination and when the findings could identify actionable alterations or trial eligibility; tumor tissue testing is preferred when feasible.

ELIGIBILITY REQUIREMENTS: For pancreatic cyst fluid targeted NGS, documentation should show that results would change management (e.g., clarify mucinous vs non‑mucinous cyst or detect markers of advanced neoplasia).

ELIGIBILITY REQUIREMENTS: For MRD or WGTA/WES/WGS orders, prior authorization or detailed clinical justification may be expected given limited evidence for routine clinical utility.

ELIGIBILITY REQUIREMENTS: The provided excerpt contains no explicit numeric or administrative eligibility thresholds beyond the tumor‑specific clinical criteria already described.

ELIGIBILITY REQUIREMENTS: In all cases, documentation should include the specimen type, intended test, and how the assay result will be used to inform treatment decisions; this supports medical‑necessity review.

ELIGIBILITY REQUIREMENTS: When cfDNA testing is used as an alternative due to insufficient tissue or an unfit patient, tissue‑based analysis should be pursued when feasible if an actionable driver is not identified.

ELIGIBILITY REQUIREMENTS: For prostate genomic classifiers, life expectancy documentation (e.g., >10 years) and clinical risk grouping are relevant eligibility elements cited in guideline‑aligned recommendations.

ELIGIBILITY REQUIREMENTS: The excerpt does not include an exhaustive list of covered CPT/PLA/HCPCS codes tied to each eligibility rule; coding sections in the full policy provide the mapping.

ELIGIBILITY REQUIREMENTS: Where NICE or other national programs require laboratory QA participation for programmatic use, similar quality and documentation expectations may be relevant for institutional implementation.

ELIGIBILITY REQUIREMENTS: In the absence of explicit local PA rules in this excerpt, providers should follow payer prior‑authorization processes and document clinical rationale when ordering tests that the policy limits to actionable situations.

ELIGIBILITY REQUIREMENTS: The policy’s effective application requires correlating the named assay’s intended use with the documented clinical scenario (e.g., Oncotype DX for premenopausal node‑negative ER+/HER2– patients per ASCO guidance).