RetiredUnitedHealthcarePolicy CS152LA.AA

Molecular Oncology Testing for Solid Tumor Cancer Diagnosis, Prognosis, and Treatment Decisions (Louisiana)

State-specific UnitedHealthcare medical policy for molecular and genetic testing to diagnose, prognose, or guide treatment of solid tumor cancers in Louisiana, including coverage criteria, required genetic counseling, and lists of proven and unproven tests.

Policy Summary

PayerUnitedHealthcare

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

Policy CodePolicy CS152LA.AA

Change TypeRetirement/No material change

Effective DateFeb 1, 2026

Next Review DateN/A

Key ActionDocument pre- and post-test genetic counseling in the medical record including structured family history, genetic risk assessment, and counseling about diagnosis, prognosis, and treatment.

SourceLink

POLICY UPDATE CHANGES

No material clinical or coverage changes in this revision.

State-specificApplies only to Louisiana

RequiredGenetic counseling

≤50 genesNGS panel limit

RetiredStatus

~140

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Coverage Criteria and Evidence-Based Use

Breast Cancer Gene Expression Profiling (GEP)

Covered when ALL of the following are met for newly diagnosed or currently on adjuvant hormonal therapy scenarios

Newly diagnosed invasive breast cancer: Newly diagnosed (within the last 6 months); lymph node negative (including micrometastases ≤2 mm) or 1-3 positive ipsilateral axillary lymph nodes; no distant metastases; hormone receptor–positive; HER2 negative; adjuvant chemotherapy not precluded by other factors (e.g., advanced age/comorbidities).

Currently receiving adjuvant hormonal therapy: Hormone receptor–positive; HER2 negative; individual and treating physician have discussed potential results and will use results to guide a decision regarding extended adjuvant hormonal therapy.

Lung Cancer - NSCLC molecular profiling

Non-small cell lung cancer multigene profiling covered when:

NSCLC molecular profiling: Multigene molecular profiling performed on tumor tissue or via liquid biopsy (cfDNA/ctDNA); panel size ≤50 genes unless used consistent with FDA‑cleared/approved companion diagnostic testing policy or guideline-endorsed broader NGS when clinically indicated.<= 50 genes (unless companion diagnostic policy applies)

Testing may be performed on tissue or plasma per clinical circumstance; cfDNA should not replace tissue when tissue is available.

Prostate Cancer Gene Expression Profiling (GEP)

Prostate cancer GEP covered when ALL of the following are met

Biopsy-proven, untreated localized adenocarcinoma: Test ordered by a physician specializing in organ‑confined prostate cancer (urology/surgical oncology, radiation oncology, or medical oncology); results will assist treatment decision-making when the individual is a candidate for active surveillance or definitive therapy; life expectancy > 10 years; risk group appropriate to the assay (very low, low, favorable intermediate for some tests; unfavorable intermediate/high considered for select assays per guideline).>= 10 years

Assays include GPS (Oncotype DX Prostate), Prolaris, Decipher as described in policy.

Thyroid Cancer / Indeterminate Thyroid Nodule Testing

Thyroid nodule molecular testing covered when ALL of the following are met

Indeterminate thyroid cytology (Bethesda III/IV): Fine‑needle aspiration cytology is indeterminate (AUS/FLUS or follicular neoplasm/suspicious for follicular neoplasm — Bethesda III or IV); and test results will be used to inform decisions about further surgery (avoidance of diagnostic thyroidectomy or extent of surgery).

Preferred assays include Afirma GSC, ThyroSeq v3 when results will affect management.

Anaplastic thyroid cancer CGP: Comprehensive genomic profiling (CGP) is medically necessary for confirmed anaplastic thyroid cancer when results will inform targeted therapy or trial selection.

Genomic profiling does not replace histopathology for ATC diagnosis.

Uveal Melanoma GEP

Uveal melanoma GEP covered when ALL of the following are met

Primary localized uveal melanoma: Individual has primary, localized uveal melanoma; no evidence of metastatic disease; individual has not previously had DecisionDx‑UM (or equivalent) testing for the current diagnosis; results will inform prognosis and follow‑up planning.

Discuss biopsy risks and intended use; testing is prognostic to inform surveillance intensity.

Breast gene-expression assay coverage context

Assay-specific contexts and population limits for breast gene-expression assays

Oncotype DX (21‑gene) uses: Oncotype DX RS estimates ten‑year distant recurrence risk and assists adjuvant chemotherapy decisions in early‑stage ER+/HER2‑ disease; validated for node‑negative and selected 1–3 node‑positive patients per trials and guideline recommendations.RS numeric categories per cited studies

See TAILORx and related analyses for predictive utility.

MammaPrint / BluePrint: MammaPrint (70‑gene) classifies low vs high distant recurrence risk and, together with BluePrint (80‑gene), may inform neoadjuvant vs adjuvant chemotherapy decisions and de‑escalation in select high clinical/low genomic risk discordant cases (MINDACT and other studies).

Evidence includes MINDACT and prospective observational studies.

Prosigna (PAM50): Prosigna (50‑gene PAM50) provides a 10‑year distant recurrence risk (ROR) in postmenopausal women with HR+, stage I–II N0 or selected N1 disease; not intended for N2 disease and is prognostic but not established predictive for radiotherapy benefit.

Prosigna (PAM50) coverage context

Prosigna (PAM50) clinical context and limits

Prosigna intended population: Prosigna provides a 10‑year distant recurrence risk score for postmenopausal women with HR+, stage I–II N0 or selected N1 (stage II) breast cancer; not intended for N2 disease.ROR score cutoffs as per assay

Prognostic for recurrence risk; not predictive for radiotherapy benefit in available analyses.

Evidence summaries

Evidence summaries and reported utilities:

Prosigna utility: Prosigna measures expression of 50 genes to provide a 10‑year distant recurrence risk score in postmenopausal HR+ N0/N1 invasive breast cancer; not intended for N2 disease.

Prosigna prognostic but not predictive for radiotherapy: PAM50 ROR score is prognostic for local recurrence risk but was not predictive of radiotherapy benefit in the ABCSG‑8 subgroup analyses; retrospective design limits inference.

MammaPrint prognostic/predictive context: MammaPrint (70‑gene) classifies tumors as low or high distant recurrence risk; secondary/ exploratory analyses (e.g., NSABP B‑42) suggest possible predictive signal for extended endocrine therapy in some subgroups but primary hypotheses were not uniformly confirmed.

MammaPrint/BluePrint influence on treatment: Prospective and observational studies (DETERMIND, WSG‑PRIMe, MINDACT) report clinician treatment‑recommendation changes and use to de‑escalate chemotherapy in select patients.

Assay-specific evidence summaries

Assay-specific evidence summaries:

MammaPrint / BluePrint: Multiple randomized (MINDACT) and prospective/observational studies demonstrate MammaPrint/BluePrint influence on chemotherapy and neoadjuvant decisions and identify patients who may avoid chemotherapy; concordance between core biopsy and surgical specimen reported in concordance studies.

EndoPredict (EPclin): EndoPredict (12‑gene EPclin) provides prognostic information for 10‑year distant recurrence in ER+, HER2‑ early breast cancer and has shown impact on treatment decisions in prospective studies though prospective randomized outcome data are limited.

Breast Cancer Index (BCI): BCI gives prognostic information for late distant recurrence and may predict benefit from extended endocrine therapy in meta‑analyses; evidence stronger in postmenopausal N0 populations, limited for N1.

DCIS assays: DCISionRT and Oncotype DX DCIS provide individualized decision scores associated with ipsilateral breast event risk; evidence on impact of score‑guided management on clinical outcomes is limited and Hayes assessments judged evidence insufficient for routine outcome‑driven use.

Guideline-based coverage context

Guideline-based coverage context (selected recommendations)

ASCO 2022 guidance (breast): Oncotype DX, MammaPrint, BCI, and EndoPredict may be used to guide adjuvant endocrine and chemotherapy decisions in postmenopausal (or >50) individuals with early‑stage ER+, HER2‑ disease with 0–3 nodes; Oncotype DX may be used in premenopausal node‑negative ER+ disease; no assays recommended for HER2+ or triple‑negative disease.

NCCN breast guidance: Oncotype DX (21‑gene) preferred for prognosis and prediction of chemotherapy benefit (pN0 and selected pN1); other GEAs provide prognostic information with variable predictive utility.

NICE recommendations: EndoPredict, Oncotype DX, or Prosigna may be used with clinical risk factors to guide adjuvant chemotherapy in postmenopausal ER+/HER2‑ early BC with 1–3 positive nodes; specific access and QA conditions apply.

DCIS assay evidence

DCIS assay evidence — key points

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Oncotype DX DCIS evidence: Oncotype DX DCIS (12‑gene) provides a DCIS score (0–100) estimating ten‑year recurrence risk; Hayes assessment found overall low‑quality evidence and no studies demonstrating clinical outcome benefit from score‑guided treatment decisions.

NSCLC molecular testing evidence

Lung cancer molecular testing evidence and utility

Percepta GSC evidence is low quality with insufficient data to establish clinical benefit for risk reclassification in bronchial specimens.

ctDNA prognostic data: Baseline negative ctDNA and early ctDNA clearance after therapy are associated with improved PFS/OS in NSCLC in meta‑analyses, but heterogeneity limits certainty; serial testing studies are recommended.

Specimen-dependent success of multi-gene tests: Assay success rates vary by specimen type (e.g., Oncomine Dx success ~80% overall; higher for surgical resection vs bronchoscopic biopsy); specimen adequacy affects results and turnaround time can be reduced using fresh biopsy protocols in selected settings.

Broad NGS utility: Broad, hybrid capture‑based NGS can detect actionable alterations missed by non‑NGS methods (e.g., Drilon et al.), supporting use when comprehensive genotyping is needed.

NSCLC testing criteria

Guideline-informed testing approach for NSCLC

Panel-based NGS preferred when feasible: NCCN recommends broad panel‑based NGS testing to identify multiple actionable alterations; panels larger than 50 genes are commonly used to achieve full genotyping when clinically appropriate.panel size typically >50 genes for comprehensive genotyping

Use of cfDNA: Plasma cfDNA/ctDNA testing may be used when tissue is insufficient or the patient is unfit for invasive sampling; cfDNA should not replace tissue diagnosis when tissue is available and negative cfDNA should prompt tissue testing if feasible.advanced/metastatic or insufficient tissue

PD‑L1 and TMB guidance: Use validated PD‑L1 IHC assays for immune checkpoint inhibitor selection; do not use TMB alone to select patients for immunotherapy.

Prostate genomic classifier evidence and coverage considerations

Prognostic associations: Decipher, GPS/Oncotype, and Prolaris show associations with biochemical recurrence, metastasis, and prostate cancer‑specific mortality across multiple studies and systematic reviews, though evidence certainty is low to very low in many contexts.

Clinical utility uncertainty: While genomic classifiers may improve risk stratification beyond standard models in select settings, evidence is insufficient to demonstrate consistent improvement in long‑term clinical outcomes; routine use is not recommended without clear management‑impact rationale.

Use cases with supportive data: Decipher has shown prognostic value in post‑prostatectomy and biopsy settings (ancillary analyses of randomized trials and large cohorts) and may inform adjuvant/salvage therapy discussions when results will change management.

Coverage considerations by evidence level

Coverage considerations by evidence level — summary statements

Tests with supportive evidence: Decipher (biopsy and post‑RP), Oncotype DX Prostate (GPS), and Prolaris have studies demonstrating prognostic associations and may be considered in select men when results will influence management decisions.

Tests with insufficient evidence: Other assays evaluated by independent assessments (e.g., Select mdx, Confirm mdx, some ExoDx assessments) have insufficient evidence of clinical utility and are not supported for routine clinical decision‑making.

Urine‑based biopsy decision assays: MyProstateScore and ExoDx/EPI show high sensitivity/NPV in prospective studies to reduce unnecessary biopsies but have limitations and need longer‑term outcome data.

Prostate cancer — selective use

Covered when ALL of the following are met

Prostate molecular testing — selective use: Commercial tissue‑based molecular biomarker tests (e.g., Oncotype DX Prostate/GPS, Prolaris, Decipher, ProMark) may be offered when the assay result, combined with routine clinical factors, is likely to affect management decisions (e.g., active surveillance vs definitive treatment) and ordering clinician documents intended management impact; routine ordering is not recommended.life expectancy >= 10 years

Ordering physician should be specialist in organ‑confined prostate cancer.

Prostate cancer — post-prostatectomy testing

Covered when ALL of the following are met

Post‑prostatectomy Decipher use: Decipher post‑prostatectomy genomic classifier may be considered when assay results, together with clinical factors (adverse pathologic features or PSA persistence/recurrence), will influence decisions regarding adjuvant versus salvage radiation or additional systemic therapy; routine use without clear management impact is not supported.

NCCN categorizes Decipher for post‑RP use (category 2B) to inform adjuvant therapy discussions.

Thyroid nodules — indeterminate cytology

Covered when ALL of the following are met

Thyroid indeterminate nodules — rule‑out testing: For Bethesda III/IV indeterminate thyroid nodules, second‑generation molecular classifiers (e.g., Afirma GSC, ThyroSeq v3) may be used to rule out malignancy when results will affect the decision to avoid diagnostic surgery; tests with high sensitivity and NPV are preferred and results must be considered with clinical and sonographic features and patient preference.

CGP is medically necessary for confirmed anaplastic thyroid cancer when actionable alterations are sought.

Thyroid indeterminate cytology

Use of molecular testing in thyroid nodules

Indeterminate nodules adjunctive testing: Molecular testing may supplement malignancy risk assessment for nodules categorized as Bethesda III (AUS/FLUS) or Bethesda IV (follicular neoplasm/suspicious for follicular neoplasm) after consideration of clinical and sonographic features; informed patient preference should guide decision‑making.

Testing should be selected based on the clinical question (diagnostic vs predictive for targeted therapy).

Anaplastic / Suspicious for malignant cytology

Use of molecular testing in anaplastic and suspicious/malignant cytology

ATC and suspicious/malignant cytology: Genomic profiling may aid differential diagnosis in selected cases (e.g., atypical presentations) but cannot replace histopathology for anaplastic thyroid cancer; mutational testing (eg, BRAF, limited multigene panels) may be considered when results would change surgical or systemic therapy decisions.

Melanoma prognostic/triage tests

Cutaneous melanoma molecular testing — contexts where testing may be considered

31‑GEP for SLNB decisionmaking: 31‑GEP may be used in select T1‑T2 cutaneous melanoma patients to inform sentinel lymph node biopsy (SLNB) decisions and risk stratification when results will change management; evidence shows reduced SLNB rates in some prospective studies but longer‑term outcome data remain limited.

Ancillary molecular techniques for equivocal lesions: Ancillary techniques (CGH, FISH, GEP) may be used as adjuncts for diagnostically equivocal melanocytic neoplasms in conjunction with expert dermatopathology.

AAD and NCCN recommend adjunctive use for equivocal cases.

Pigmented lesion adhesive patch (PLA): Adhesive patch assays (e.g., PRAME/LINC00518) have variable diagnostic performance and current evidence is insufficient to support routine standalone use; may be considered adjunctive where appropriate.

Coverage stance and criteria per indication

Coverage stance and criteria per indication — guideline reflections

Cutaneous melanoma prognostic GEP: Routine prognostic GEP testing for cutaneous melanoma is discouraged until clinical utility is established; GEP should not be used routinely to direct management outside clinical studies or multidisciplinary decision making.

AAD and NCCN statements discourage routine prognostic use.

Uveal melanoma prognostic testing: When biopsy is performed for uveal melanoma, molecular/chromosomal testing may provide prognostic stratification and is preferred over cytology alone; biopsy risks and intended impact on follow‑up should be documented.

NCCN recommends stratification if biopsy is performed.

cSCC 40‑GEP testing: 40‑GEP may stratify metastatic risk in localized high‑risk cSCC and could inform adjuvant radiation decisions in multidisciplinary contexts; evidence is promising but not definitive and documentation aligning test result with treatment rationale is advised.

Coverage-relevant evidence summaries

Coverage‑relevant evidence summaries — selected syntheses

CUP — molecular testing: Molecular testing (GEP, NGS/CGP) can aid diagnosis and identify actionable alterations in a subset of CUP cases and may support clinical trial enrollment; randomized trials have not demonstrated improved survival with GEP‑guided site‑specific therapy and guideline panels do not recommend routine use for site identification alone.

Document clinicopathologic correlation and how results will inform therapy or trials.

MCD tests and cfDNA screening: Multi‑cancer detection (methylation‑based cfDNA) tests show high specificity but variable sensitivity by cancer and stage; current evidence insufficient to support population screening outside study contexts.

MRD ctDNA assays: Tumor‑informed MRD assays (e.g., Signatera) demonstrate prognostic association with recurrence in several studies but lack prospective evidence demonstrating that testing and subsequent management changes improve long‑term patient outcomes; routine surveillance use is not established.

Coverage stance and criteria

Coverage stance and criteria — guideline‑aligned recommendations across indications

CRC — universal MMR/MSI testing: Universal testing for MMR/MSI is recommended for any individual with colon or rectal cancer to identify Lynch syndrome, inform immunotherapy decisions in metastatic disease, and assist stage II adjuvant decisions.

NCCN/ASCP/CAP/AMP/ASCO guidance.

Advanced/metastatic CRC biomarker testing: Testing for KRAS/NRAS, BRAF and HER2 (and MSI/MMR) is recommended for advanced/metastatic CRC to guide targeted therapies; testing may be done by individual assays or NGS panels, with NGS preferred.

Pancreatic cyst and TTNB NGS: Targeted NGS of pancreatic cyst fluid or TTNB samples may be used to evaluate for mucinous cysts and advanced neoplasia when results will affect management; combine molecular results with cytology and clinical data.

Reported sensitivities/specificities in cohort studies support adjunctive use.

Coverage summary for tests discussed

Coverage summary for tests discussed — synthesis

Pancreatic cyst/TTNB molecular testing: Molecular analysis of pancreatic cyst fluid or TTNB samples may be considered when results will change management; some commercial tests lack sufficient validation and evidence quality varies across platforms.

Document lesion size, sampling method, and intended clinical impact.

NavDx / TTMV‑HPV DNA: TTMV‑HPV DNA assays show high specificity and promising sensitivity for HPV‑positive OPSCC diagnosis and surveillance in some studies, but evidence is limited and clinical utility for surveillance‑driven management remains unproven.

Hayes and ECRI assessments indicate limited evidence for routine use.

WGTA/WES/WGS: Whole exome/genome/transcriptome approaches identify many potentially actionable findings but lack prospective evidence demonstrating improved clinical outcomes when used routinely; routine coverage is not supported pending further data.

Overall coverage conclusions

General coverage logic: Tests with demonstrated analytic validity, clinical validity, and evidence that results will affect management decisions and outcomes are considered medically necessary for specified indications; tests lacking such evidence (including many MRD, multi‑cancer detection and very large WG/WES/WTS applications) are considered investigational or not medically necessary for routine use.

Policy lists specific covered indications and enumerates tests considered unproven.

Context‑dependent ctDNA use: ctDNA/MRD and other liquid biopsy applications have prognostic associations in research settings but routine use for surveillance or to guide therapy is not established and may require enrollment in trials or prior authorization documentation of intended management impact.

Comprehensive sequencing conclusions: WGTA/WES/WGS identify many actionable alterations in advanced cohorts but evidence that routine use improves outcomes is insufficient; use is generally limited to research, clinical trials, or when documented to inform therapy selection and trial eligibility.

All other molecular testing for solid tumors (tissue or liquid biopsy) using any method is considered unproven and not medically necessary. This includes, but is not limited to, NGS panels of >50 genes or comprehensive genomic profiling (unless otherwise specified), tumor‑informed or tumor‑naïve MRD assays, multi‑cancer early detection tests, and the additional proprietary assays listed in the policy.

The policy lists numerous applicable CPT, HCPCS and proprietary (Category III/U) codes for reference. Presence of a code in these lists indicates the procedure or test is recognized by the policy for billing/reference purposes, but inclusion in the code list alone does not imply coverage for all clinical scenarios; coverage depends on meeting the clinical criteria specified elsewhere in the policy.

Some CPT codes in the applicable code lists are marked with an asterisk (*): these codes are not on the State of Louisiana Medicaid Fee Schedule and therefore may not be covered by the Louisiana Medicaid program.

Per the Prosigna (PAM50) assay intended use, Prosigna is not intended for individuals with N2 disease; ordering or using Prosigna outside this population is outside the assay’s indicated use and may not be supported.

Other breast cancer profiling assays (for example, Breast Cancer Gene Expression Ratio/Th eros H/I, DCISionRT, Oncotype DX DCIS, and several historical or alternative signatures) are described in the evidence review as having insufficient evidence of clinical utility for routine use and therefore are considered unproven for most treatment‑decision indications.

ASCO guidance states that no genomic assays are recommended to guide adjuvant systemic therapy for individuals with HER2‑positive or triple‑negative breast cancer.

Cell‑free circulating tumor DNA (cfDNA) or liquid biopsy testing may be used in specific clinical circumstances (for example, advanced/metastatic disease or when tissue is unavailable), but cfDNA testing should not routinely replace tissue‑based diagnostic testing; when cfDNA does not identify an actionable driver, tissue testing should be pursued.

Independent assessments (e.g., Hayes) have judged several tests to have insufficient evidence to support clinical validity or utility. Examples include urine and tissue assays such as Select mdx and Confirm mdx, for which available evidence was rated low or very low and was inadequate to conclude effectiveness for guiding clinical decisions.

Other molecular biomarkers and commercially marketed assays that lack adequate analytic validation, clinical validity, or peer‑reviewed evidence are not recommended for routine clinical decision‑making and should not be offered as standard of care until sufficient validation is available.

For anaplastic thyroid cancer (ATC), genomic profiling of tumor tissue alone is not sufficient for diagnosis; molecular testing may aid differential diagnosis but histopathology remains the diagnostic standard.

Pigmented lesion adhesive patch assays (PLA) have variable diagnostic accuracy and low quality evidence. Systematic reviews and technology assessments conclude the impact on patient outcomes and cost‑effectiveness is uncertain; evidence is inadequate to support routine replacement of standard clinical and dermatopathologic assessment.

Professional guidelines (AAD, NCCN) discourage routine prognostic gene‑expression profiling (GEP) for cutaneous melanoma because current platforms have not demonstrated added, clinically actionable prognostic value beyond established clinicopathologic factors; use should be limited to research or cases where multidisciplinary documentation justifies how results will alter management.

Gene expression profiling tests intended to identify tissue of origin in cancers of unknown primary (for example, CancerTYPE ID) have insufficient evidence to demonstrate improved clinical outcomes with site‑specific therapy; guideline panels do not endorse routine GEP‑guided site‑directed therapy and recommend case‑by‑case consideration.

Septin 9 (mSEPT9) blood‑based tests are not recommended by the ACG as optimal colorectal cancer screening modalities due to limited sensitivity and insufficient comparative and long‑term outcome data; such tests do not replace established screening methods.

Commercially available tests for pancreatic cyst risk stratification (e.g., PancraGEN) and tumor‑derived HPV DNA assays for oropharyngeal cancer surveillance (e.g., NavDx) currently lack sufficient high‑quality evidence of analytic validity, clinical validity, or demonstrated clinical utility; available assessments conclude evidence is inadequate to support routine use.

Routine use of whole exome sequencing (WES), whole genome sequencing (WGS), whole transcriptome analysis, or combined WGTA approaches to inform routine clinical decisions is not supported by sufficient peer‑reviewed evidence and therefore is not endorsed for routine coverage; these technologies may be considered investigational for standard clinical decision‑making.

Evidence for use of gene‑expression profiling (GEP) assays in breast cancer is assay‑ and indication‑specific. While validated assays (e.g., Oncotype DX, MammaPrint, Prosigna, EndoPredict, BCI) are used to estimate distant recurrence risk and guide adjuvant systemic therapy in ER+/HER2‑ early breast cancer per guideline‑based populations, use of GEP for other breast indications (including DCIS and certain other profiling assays) is considered unproven and not medically necessary due to insufficient evidence of impact on clinical outcomes.

Indications Considered Medically Necessary

Not Medically Necessary / Not Covered Tests

Tests and categories explicitly identified as not covered include NGS panels >50 genes (unless otherwise specified), MRD assays for routine surveillance, multi‑cancer detection platforms, whole exome/genome/transcriptome profiling to inform routine decisions, and other listed proprietary tests lacking sufficient evidence.

The policy’s applicable code lists are informational; some sections enumerate codes without an accompanying explicit clinical exclusion statement — presence of a code does not on its own define coverage or noncoverage.

CPT codes annotated with an asterisk (*) are not present on the State of Louisiana Medicaid Fee Schedule and thus may not be covered under Louisiana Medicaid.

Prosigna use for N2 disease is outside the assay’s intended population and therefore is not supported for coverage in that setting.

Other breast profiling assays (e.g., Breast Cancer Gene Expression Ratio, DCISionRT, Oncotype DX DCIS) lack sufficient evidence of clinical utility and therefore are identified as tests that would not be routinely covered.

ASCO guidance indicates genomic assays are not recommended to guide therapy in individuals with HER2‑positive or triple‑negative breast cancer; such uses would not be supported under routine coverage.

Oncotype DX DCIS and DCISionRT have limited evidence; use of these assays to direct therapy in DCIS without stronger outcome data is not supported and may be considered not covered.

Applicable Procedure and Proprietary Codes

CPT/PLA / Proprietary (U) codes (selected list)mixed

0005U	Oncology (prostate) gene expression profile, urine, algorithm reported as risk score
0011M	Oncology, prostate cancer, mRNA expression assay of 12 genes, blood plasma and urine
0012M	Oncology (urothelial), mRNA, gene expression profiling, urine, risk score
0018U	Oncology (thyroid), microRNA profiling by RT-PCR of 10 microRNA sequences, fine needle aspirate
0179U	Oncology (NSCLC), cell-free DNA targeted sequence analysis of 23 genes
0239U	Targeted genomic sequence analysis panel, solid organ neoplasm, cfDNA, 311+ genes
0242U	Targeted genomic sequence analysis panel, cfDNA, 55-74 genes
0306U	Oncology (MRD) initial baseline, cfDNA patient-specific panel
0307U	Oncology (MRD) subsequent assessment, cfDNA patient-specific panel
0313U	Oncology (pancreas), DNA and mRNA NGS of 74 genes and CEA expression, pancreatic cyst fluid

1–10 of 41

1/5

HCPCS / Othermixed

G0327

Colorectal cancer screening; blood-based biomarker

Prior Authorization

Provider action: Prior authorization for tests with limited/ evolving evidence

Provider action: Prior authorization is recommended or required for many molecular tests, particularly for tests with limited or evolving evidence, large-panel NGS (>50 genes), comprehensive cfDNA panels, MRD assays, whole exome/genome/transcriptome, and tests not on the State fee schedule. Prior authorization expectations for NSCLC molecular testing: tumor tissue-based multigene profiling (≤50 genes) is considered proven and medically necessary for NSCLC; cfDNA (liquid biopsy) may be used when tissue is unavailable or to identify specific actionable mutations per guideline-based indications, but prior authorization and documentation of clinical context are expected. Evidence-based prior authorization considerations include demonstration of intended clinical use, test-specific clinical utility, and that results will inform management decisions. Selective prior authorization may be applied to tests with uncertain or limited evidence (e.g., MRD assays, multi-cancer early detection tests, NavDx, many proprietary gene panels).

* Prior authorization recommended/required for large NGS panels (>50 genes), comprehensive cfDNA panels, MRD testing, whole exome/genome/transcriptome, and tests not on the State fee schedule.
* NSCLC molecular testing: tissue-based multigene profiling (≤50 genes) is proven and medically necessary; cfDNA may be authorized when tissue is unavailable or to guide therapy per guidelines.
* Evidence-based prior authorization review will assess clinical utility, intended use, and whether results will change management.

Provider Actions, Documentation, and Prior Authorization

Documentation Required

Document pre- and post-test genetic counseling

Document that pre-test and post-test genetic counseling occurred and include a structured family genetic history, genetic risk assessment, and counseling about diagnosis, prognosis, and treatment in the medical record.

Record a structured family genetic history.
Document genetic risk assessment and counseling content (diagnosis, prognosis, treatment).

Note

Ordering providers: reference listed procedure codes

Ordering providers should reference the policy's listed procedure codes when requesting tests and be aware that some codes may trigger prior-authorization review per payer rules.

Codes in the policy are for reference and may be subject to prior authorization.

Key Definitions and Test Descriptions

CGP — definition

Comprehensive Genomic Profiling (CGP)A next-generation sequencing approach that detects all classes of genomic alterations (SNVs, indels, CNAs, rearrangements, MSI/TMB) in a sample to inform diagnosis and therapy

Common use-casesIdentification of actionable somatic alterations, trial matching, and pan-tumor profiling when results will affect treatment selection

Specimen requirementTypically performed on tumor tissue (FFPE) and may be paired with normal specimen for somatic/constitutional subtraction

Liquid Biopsy — definition

Liquid biopsy — definitionTesting of bodily fluid (commonly plasma) to detect tumor-derived cells or circulating nucleic acids (cfDNA/ctDNA) for detection, treatment selection, or monitoring

Applications

Eligibility Requirements by Indication

Documentation for genetic testing must include pre‑ and post‑test genetic counseling recorded in the medical record, including a structured family genetic history, genetic risk assessment, and counseling about diagnosis, prognosis, and treatment implications as required by the Louisiana MCO Genetic Counseling and Testing rules.

Eligibility and coverage depend on the specific indication and whether the individual and treating clinician will use the test results to guide management. Tests identified as proven for specific indications (e.g., select breast, prostate, thyroid, uveal melanoma, and NSCLC indications) have defined clinical inclusion criteria; by contrast, tests listed as unproven are not eligible for routine coverage.

For NSCLC, multigene molecular profiling is supported when performed as a panel approach consistent with guideline recommendations; the policy limits routine somatic multigene panels to those with ≤50 genes unless use is consistent with FDA‑cleared/approved companion diagnostic testing or specifically addressed in the policy.

Prostate genomic classifier testing is covered selectively when results are expected to influence management decisions (for example, choice between active surveillance and definitive therapy, or post‑prostatectomy adjuvant decisions), and ordering clinicians should document how results will change management; routine ordering is not recommended.

For pancreatic cyst fluid or TTNB specimens, targeted NGS testing may be considered when results would influence surveillance or surgical management; required documentation should include lesion characteristics, sampling method, and correlation with cytology and imaging.

Documentation Needed with Test Orders and Claims

Documentation Required

Document specimen type and test description for multi-gene analyses

When a multi-gene analysis is ordered, document specimen and test details: multi-gene panels generally contain five or more genes and assays may use FFPE, fresh/frozen tissue, or other specimen types as specified by the assay.

Specify specimen type (FFPE, CNB, SR, plasma, etc.) in the order and documentation.

Documentation Required

Document CNB vs SR specimen details for MammaPrint/BluePrint

For MammaPrint/BluePrint, document whether the specimen is core needle biopsy (CNB) or surgical resection (SR); studies show high concordance but documentation of specimen type and matching may be relevant for claims.

Record whether CNB or SR specimen was used and include concordance notes if applicable.

Documentation Required

Include supporting trial evidence and assessments with test claims

Background and Scope

This policy addresses molecular and genomic testing modalities including gene expression profiling (GEP), comprehensive genomic profiling (CGP), next‑generation sequencing (NGS), and liquid biopsy (cfDNA/ctDNA) for the purposes of diagnosis, prognosis, and treatment selection in solid tumor cancers; it distinguishes assays and indications with established evidence from those considered investigational or not medically necessary.

Covered test modalities discussed in the policy include assay types used for estimating recurrence risk (gene‑expression assays), identifying actionable genomic alterations for targeted therapy (NGS/CGP), noninvasive tumor profiling (cfDNA/ctDNA), and specialized applications such as tumor‑of‑origin classification, MRD detection, and whole exome/genome/transcriptome profiling — with coverage determined by assay‑specific evidence and indication.

Revision History and Policy Status

2026-02-01policy_effective_date

Policy effective date for this Louisiana-specific molecular oncology testing coverage policy (CS152LA.AA).

2026-04-01policy_retirementLatest

Policy retired (no longer in effect) as of April 1, 2026 per header notice.

Policy number: CS152LA.AA; Effective date: February 1, 2026. This is a Louisiana‑specific UnitedHealthcare medical policy addressing molecular and genetic testing for solid tumor cancers; the policy was retired April 1, 2026 as noted in the header.

Policy Summary

PayerUnitedHealthcare

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

Policy CodePolicy CS152LA.AA

Change TypeRetirement/No material change

Effective DateFeb 1, 2026

Next Review DateN/A

Key ActionDocument pre- and post-test genetic counseling in the medical record including structured family history, genetic risk assessment, and counseling about diagnosis, prognosis, and treatment.

SourceLink

On This Page

ROR score cutoffs per assay

Intended population limited to postmenopausal HR+ N0/N1 as described.

Tumor mutational burden (TMB) alone is not supported as a sole criterion to select patients for immune checkpoint inhibitor therapy; routine use of TMB alone for immunotherapy selection is not covered.

Tests judged by independent assessments (e.g., Hayes) to have insufficient analytic validity or clinical utility — such as Select mdx, Confirm mdx, and some assessments of ExoDx — are identified as unlikely to be supported for coverage absent stronger evidence.

Molecular biomarkers that lack sufficient validation or are not commercially available (for example, certain thyroid panel permutations like ThyGeNEXT/ThyraMIR when inadequately validated) are not recommended for routine clinical use and are effectively not covered.

Pigmented lesion (PLA) testing lacks evidence demonstrating improved patient outcomes or reliable diagnostic accuracy when compared to standard care and therefore is not supported for routine coverage.

Routine prognostic GEP testing for cutaneous melanoma to guide management is discouraged by guideline panels and is therefore not supported for routine coverage outside clinical studies or well‑documented exceptional circumstances.

CancerTYPE ID and similar tumor‑of‑origin GEP assays lack sufficient evidence that GEP‑guided site‑specific therapy improves survival; routine coverage for site‑of‑origin testing to direct therapy in CUP is not supported.

Septin 9 (mSEPT9) testing is not recommended by ACG for colorectal cancer screening and is not included in USPSTF recommendations due to limited evidence; such blood‑based tests are not supported as optimal screening alternatives.

Commercial tests lacking adequate analytic or clinical validation (e.g., PancraGEN for pancreatic cyst risk) and tests with limited evidence of clinical utility (e.g., NavDx per Hayes/ECRI assessments) are unlikely to be covered for routine clinical use.

Routine coverage for whole exome, whole genome, or whole transcriptome sequencing to inform clinical decision‑making is not supported by sufficient evidence and therefore is not covered as standard practice.

Use of tumor‑informed MRD ctDNA assays (for example, Signatera) for routine surveillance or therapy monitoring across solid tumors is not established and is therefore considered not covered for routine clinical surveillance.

Documentation Required

Provider action: Clinical-population documentation requirement

Documentation is essential to support medical necessity. Providers must submit clinical and specimen documentation with test claims or prior authorization requests. Missing or insufficient documentation may lead to denial. Required clinical-population documentation typically includes diagnosis, stage, prior relevant testing (e.g., immunohistochemistry, single-gene tests), intended clinical use of the test (how results will change management), and life expectancy when relevant (e.g., prostate molecular assays per NCCN). Specimen and test description (type of specimen, collection date, adequacy) and prior testing results must be provided. Genetic counseling documentation is expected when germline testing or hereditary cancer implications exist.

Clinical-population documentation requirement: diagnosis, stage, and rationale for testing (how result will inform treatment).
Specimen documentation: specimen type (FFPE, FNA, plasma), collection date, tumor content/adequacy, and chain-of-custody if applicable.
Supporting documentation to submit with test claims: prior molecular/pathology reports, IHC results, imaging or tumor markers if relevant, and prior therapies.
Genetic counseling documentation: include when germline testing or hereditary implications are possible.

Denial Risk

Provider action: Insufficient evidence may lead to denial

Provider action: Evidence-based prior authorization considerations — tests without demonstrated clinical utility, limited evidence, or those intended for screening rather than diagnostic/therapeutic decision-making are likely to be denied. Examples include MRD assays for solid tumors, multi-cancer early detection tests, and many proprietary assays listed as unproven. NavDx and certain ctDNA-based screening or surveillance tests have limited evidence and may be noncovered. Tests marked as unproven in this policy are considered not medically necessary.

* Insufficient evidence may lead to denial for assays such as MRD (tumor-informed or tumor-naïve) in solid tumors, multi-cancer early detection tests (e.g., Galleri®), and listed proprietary assays (see Unproven Molecular Tests).
* Limited evidence for NavDx and select cfDNA screening assays may result in noncoverage.
* Tests without demonstrated clinical utility or that do not change management may be considered not medically necessary.

Prior Authorization

Provider action: Prior authorization expectations for NSCLC molecular testing

Provider action: Prior authorization expectations for NSCLC molecular testing — document the clinical indication (e.g., advanced non-small cell lung cancer), prior tissue testing if performed, and whether tissue is unavailable necessitating cfDNA. Provide evidence that test results will guide targeted therapy selection. Prior authorization reviewers will evaluate panel size (≤50 genes preferred unless companion diagnostic rules apply) and the analytical and clinical validity of the assay.

* Provide documentation of tumor histology, stage, prior testing, and clinical plan contingent on results.
* cfDNA use limited: recommended when tissue is unavailable or insufficient, or to detect resistance mutations; not routinely for screening or surveillance without evidence.
* Panel gene count: NGS panels ≤50 genes are the standard for NSCLC unless FDA-cleared/companion diagnostic use justifies larger panels.

Note

Provider action: Test selection guidance

Provider action: Test selection guidance — order tests with demonstrated clinical utility for the clinical question (diagnosis, prognostic stratification, therapeutic selection). Limit use of multiple overlapping GEP tests for the same tumor (e.g., performing more than one GEP for prognostic assessment) as multiple GEPs are generally discouraged; prior authorization may limit repeat or duplicate testing. For pancreatic cysts, uveal melanoma, cutaneous melanoma prognostic GEP, and MRD/ctDNA use, provide specific clinical and clinicopathologic correlation and intended clinical use documentation.

* Limit on multiple GEP tests: avoid ordering more than one prognostic GEP for the same indication; prior authorization may deny redundant testing.
* Prior authorization recommended for prognostic GEP in cutaneous melanoma; document clinical impact on management (e.g., sentinel node decisions or adjuvant therapy plans).
* Required clinical documentation for pancreatic cyst testing: cyst imaging characteristics, cyst fluid CEA when available, and how results will alter management.

Documentation Required

Provider action: Specimen and test description & documentation

Provider action: Specimen and test documentation — adequate specimen information and test-specific details must accompany test orders and claims. For cfDNA/ctDNA or MRD testing, include timing relative to therapy, baseline (pre-treatment) tumor sequencing if MRD is tumor-informed, and imaging/standard markers before ctDNA surveillance. For uveal melanoma GEP testing, document clinicopathologic correlation and intended clinical use. For MCD (molecular cancer diagnostics) and other specialized tests, include pathology correlation and rationale.

Specimen adequacy documentation: tumor content estimate, percent tumor nuclei for tissue, plasma volume and processing details for cfDNA.
Prior testing and clinical context: submit prior somatic/germline testing reports used to design patient-specific MRD panels or to interpret results.
Suggested documentation for ctDNA/MRD tests: baseline tumor NGS, dates of surgery/therapy, imaging status, and intended surveillance interval and action thresholds.

Billing Rule

Provider action: Potential denial for asterisked CPT codes and billing expectations

Provider action: Potential denial risks and billing rules — codes marked with an asterisk (*) may not be covered by State Medicaid. Use of unlisted codes (81479, 81599) requires narrative justification and supporting documentation. Tests deemed experimental, lacking clinical utility, or ordered without appropriate clinical context or documentation are at risk for denial.

* Potential denial for asterisked CPT codes: may not be covered by Louisiana Medicaid — verify fee schedule and obtain prior authorization where required.
* This portion of the policy provides codes for reference only; coverage determinations depend on medical necessity and state program rules.
* Diagnostic sufficiency: tests ordered without adequate or appropriate specimens or without clinical indication may be denied.

Note

Provider action: Patient counseling, testing sequence preference, and sequencing notes

Provider action: Additional guidance — document patient counseling regarding test purpose and potential impact on management. For tests with hereditary implications, include genetic counseling notes. Management sequencing notes: molecular testing should follow initial histologic evaluation and standard biomarker/imaging assessments. There is no mandated step therapy or sequencing specified in this section, but prior authorization may require documentation that standard diagnostic steps were performed prior to advanced molecular testing.

* Patient counseling and clinical context should be documented in the medical record.
* Molecular testing after initial histologic evaluation: ensure standard markers and imaging were considered prior to advanced panels.
* No step therapy specified in this section; however, prior authorization may require evidence of prior standard workup.

Denial Risk

Provider action: Guideline and evidence-based denial risk

Provider action: Tests with uncertain utility or limited evidence (e.g., CUP site-of-origin assays, many multi-cancer early detection tests, MRD assays, NavDx) are subject to guideline-based denial risk when clinical utility is not established. Prior authorization reviewers will consider published guideline recommendations (NCCN, specialty societies) and peer-reviewed evidence when adjudicating requests. When evidence is insufficient or clinical utility is not demonstrated, tests may be noncovered.

* Guideline-based denial risk for CUP site-of-origin testing and other assays lacking demonstrated impact on outcomes.
* Uncertain utility tests may be denied; provide high-quality evidence when requesting authorization.

Billing Rule

Align documentation with listed billing codes

When submitting claims, use the CPT and Category III (U) codes specified in the policy and ensure clinical documentation aligns with the billed codes; prior authorization may be required by the payer.

Billing Rule

Use the policy's enumerated CPT and HCPCS codes

Order and bill using the specific CPT and HCPCS codes enumerated (policy lists codes such as 81520–81525, 81529, 81540 and HCPCS G0327); verify prior-authorization requirements for these codes with the payer.

Documentation Required

Document clinical population when ordering assay (Prosigna/MammaPrint/BluePrint)

When ordering tests such as Prosigna, MammaPrint, or BluePrint, document the patient's clinical population and that the individual meets the assay’s intended indications (for example, Prosigna is intended for postmenopausal HR+, stage I–II N0 or selected N1 and is not intended for N2 disease).

For Prosigna document postmenopausal status, HR+ disease, and nodal stage (not N2).
For MammaPrint/BluePrint document ER/HER2 status and clinical stage as applicable.

Prior Authorization

PA may be required for multigene assays guiding adjuvant therapy

Prior authorization may be required for multigene assays used to guide adjuvant chemotherapy or radiation; justification should reference clinical/genomic risk discordance and relevant assay results.

Provide documentation showing how results will influence adjuvant chemotherapy or radiation decisions.

Prior Authorization

PA likely required for tests with limited/evolving evidence

Tests with limited or evolving evidence (for example, Oncotype DX DCIS or emerging ctDNA prognostic assays) may require prior authorization and demonstration that results will influence management.

Include evidence or rationale that testing will change patient management when requesting authorization.

Prior Authorization

PA expectations for NSCLC molecular testing (tissue preferred; cfDNA limited use)

For NSCLC, prior authorization expectations reflect guideline recommendations: broad panel NGS is preferred when feasible; cfDNA (liquid biopsy) should not replace tissue diagnosis and may be reserved for advanced/metastatic disease or when tissue is insufficient or patient unfit.

If using cfDNA, document why tissue testing is not feasible and plan for follow-up tissue testing if no driver is identified.

Prior Authorization

Provide evidence distinguishing established vs unproven tests for PA

Prior-authorization determinations may distinguish tests with established prognostic associations (e.g., Decipher, GPS/Oncotype, Prolaris) from tests with insufficient evidence (e.g., Select mdx, Confirm mdx, ExoDx) — include supporting evidence when requesting coverage.

Attach pertinent studies or assessments (e.g., Hayes reports) when ordering to support clinical utility.

Prior Authorization

Obtain PA when insurer requires demonstration of management impact

If insurer criteria require demonstration that test results will influence management, obtain prior authorization before ordering tissue-based genomic assays and document the management-impact rationale.

Document how assay results will affect choices such as active surveillance vs definitive therapy or adjuvant treatment decisions.

Prior Authorization

PA recommended for prognostic GEP in cutaneous melanoma

Given guideline discouragement of routine prognostic GEP in cutaneous melanoma and incomplete evidence of clinical utility, prior authorization is likely required and orders should justify how results will change management.

Document intended use (e.g., influence on SLNB decision or surveillance) when requesting authorization.

Documentation Required

Justify CUP molecular testing with clinicopathologic correlation

Before ordering molecular profiling for CUP, document clinicopathologic correlation and prior IHC results, and justify how genomic findings would inform site-specific therapy or clinical trial eligibility given limited evidence for improved outcomes.

Include prior pathology/IHC and rationale that results could change treatment or enable clinical trial enrollment.

Prior Authorization

PA may be required for multigene/NGS tests with uncertain utility

Prior authorization may be required for certain multigene/NGS tests with uncertain evidence (e.g., Immunoscore, post-surgical ctDNA); document indication and how testing aligns with guidelines or evidence when requesting authorization.

Attach guideline citations or trial evidence supporting the proposed test use.

Prior Authorization

PA may be required for tumor profiling and germline testing in pancreatic cancer

For advanced/metastatic pancreatic cancer, prior authorization may be required for tumor profiling or germline testing when results would affect anti-cancer therapy selection; follow NCCN guidance and document potential treatment impact.

Document that results could change systemic therapy or clinical trial eligibility.

Prior Authorization

PA recommended for MRD and WGTA/WES/WGS tests

Prior authorization is recommended for tumor‑informed MRD assays (e.g., Signatera) and for whole‑exome/genome/transcriptome testing because current evidence is insufficient to support routine clinical use; document prior testing and intended impact on management.

Include prior tumor sequencing and a management plan tied to assay results when requesting authorization.

Denial Risk

Limit use of multiple predictive breast GEPs for the same tumor

Using more than one predictive breast cancer GEP for the same tumor is not medically necessary; do not order multiple predictive GEPs for a single tumor (BCI exception for use to evaluate extended endocrine therapy is noted).

BCI may be ordered once to evaluate need for extended endocrine therapy even if prior GEP was used for adjuvant chemotherapy decisions.

Step Therapy

Step therapy: none specified

No step therapy requirements are stated in this policy segment; clinicians should follow clinical judgment and guideline-based pathways when sequencing tests or therapies.

Note

MammaPrint/BluePrint can inform neoadjuvant vs adjuvant chemo decisions

Evidence supports use of MammaPrint/BluePrint to inform neoadjuvant versus adjuvant chemotherapy decisions and to de-escalate or escalate therapy based on genomic risk classification; document how results will influence therapy selection.

Reference MINDACT and DETERMIND results when documenting expected management impact.

Note

Consider Ki67 or IHC4 as alternatives when genomic assays unavailable

When genomic assay access is limited, consider alternative assessments such as Ki67 or an IHC4 score combined with clinical parameters to assist adjuvant therapy decisions per ASCO guidance.

Document rationale for using alternatives when genomic testing is unavailable.

Note

Prefer multiplexed panels over multiple single-gene tests

Prefer multiplexed gene panels over sequential single-gene tests for comprehensive genotyping; single-gene testing (e.g., RET, KRAS, MET) is not recommended as routine standalone testing.

Use broad NGS panels to improve turnaround and detection of actionable alterations.

Step Therapy

Obtain imaging and standard markers before ctDNA surveillance

Before relying on ctDNA surveillance, consider standard imaging and tumor markers (e.g., CEA in CRC); imaging and markers should precede or be used alongside ctDNA given variable sensitivity and comparative performance.

Document imaging and tumor marker results when ordering ctDNA surveillance.

Documentation Required

Document genetic counseling, including family history and risk assessment

Document pre- and post-test genetic counseling including structured family history, genetic risk assessment, and counseling content (diagnosis, prognosis, treatment) in the medical record for genetic testing.

Record family history and the counseling discussion in the chart before testing.

Denial Risk

Denial risk for unproven or not medically necessary tests

Tests categorized as unproven and not medically necessary (for example, NGS panels >50 genes except where specified, MRD assays, multi-cancer detection tests, and listed proprietary assays) are at risk for denial; avoid billing those tests without clear supporting documentation of medical necessity.

Examples: whole exome/genome/transcriptome sequencing, Signatera and other MRD assays, Galleri, NavDx, PancraGEN.

Denial Risk

Asterisked CPT codes may not be covered by LA Medicaid

Some CPT codes shown with an asterisk (*) in the policy are not on the Louisiana Medicaid Fee Schedule and therefore may not be covered by Louisiana Medicaid; confirm state Medicaid coverage before billing.

Denial Risk

Population limitation for Prosigna; ordering outside indicated population risks noncoverage

Ordering Prosigna outside its intended population (postmenopausal HR+, Stage I–II N0 or selected N1) — for example, for N2 disease — may risk noncoverage; document that the patient matches the assay’s intended population.

Prosigna is not intended for individuals with N2 disease.

Denial Risk

Oncotype DX DCIS — evidence limitations may lead to denial

Oncotype DX DCIS has low-quality evidence and no demonstrated clinical outcomes from DCIS-score–based treatment decisions; coverage for decisions based solely on DCIS score may be denied without stronger evidence.

Denial Risk

cfDNA testing should not substitute for tissue diagnosis; misuse risks denial

Plasma/cell-free circulating tumor DNA testing should not replace tissue diagnosis; cfDNA testing is generally reserved for advanced/metastatic disease or when tissue is unavailable or patient is unfit — using cfDNA in place of tissue may risk denial.

If cfDNA is used, document why tissue testing was not feasible and plan for confirmatory tissue testing if needed.

Denial Risk

Insufficient evidence for WG/WES/WTS to inform clinical decisions — denial risk

Whole genome, whole exome, or whole transcriptome sequencing (WG/WES/WTS) currently lack sufficient evidence to inform clinical decisions; claims for these tests to guide routine patient care may be denied without strong justification.

Used for noninvasive genotyping, MRD surveillance, and when tissue is insufficient or risky to obtain

LimitationsSensitivity varies by tumor type, stage, and assay; not a substitute for tissue diagnosis in most settings

Prostate risk group definitions

Very low and low riskDefined by NCCN criteria (e.g., very low: cT1c, Grade Group 1, PSA <10, <3 cores positive, PSA density <0.15); low: similar but not meeting very-low specifics)

Favorable/unfavorable intermediateFavorable intermediate: 1 intermediate risk factor, Grade Group 1–2, <50% cores positive; Unfavorable intermediate: Grade Group 3 or ≥50% cores positive or 2–3 intermediate risk factors

High / very high riskHigh: one high-risk feature (e.g., cT3a, Grade Group 4–5, PSA >20); Very high: multiple features (cT3b–T4, Grade Group 4–5, PSA >40)

Panel sizes — definition & examples

Panel size categoriesDefined ranges include 5–50 genes (small targeted panels), 51+ genes (larger panels/CGP), up to hundreds of genes (80–600+), and whole exome/genome/transcriptome

Coding examplesCPT 81445/81449 cover 5–50 gene panels; 81455/81456 describe 51+ gene panels; numerous U-codes represent 22–600+ gene panels

Implication for coveragePanels >50 genes are generally considered CGP and are subject to exception language or investigational review per policy

Multi-gene analysis — general definition

Multi-gene analysis — definitionA gene panel containing five or more genes that may report expression signatures, scores, or classifiers to inform diagnosis, prognosis, or therapy selection

Specimen typesTypically performed on FFPE tumor tissue but may use blood, urine, saliva, cyst fluid, or other biospecimens depending on assay

Report outputsCan report gene-level variants, copy-number changes, fusion events, expression scores, risk categories, or decision-support recommendations

Oncotype DX Recurrence Score — definition

Oncotype DX Recurrence Score (RS)A 21-gene mRNA expression assay that generates a numeric Recurrence Score estimating ten-year risk of distant recurrence in ER+/HER2- breast cancer

Intended applicationUsed to inform adjuvant chemotherapy decisions in early-stage ER+/HER2- disease (node-negative and selected 1–3 node-positive patients)

OutputNumeric RS with study-specific cutoffs used to define low/intermediate/high risk groups in clinical trials and guidance

Distant recurrence (DR) — definition

Distant recurrence (DR) — definitionRisk of distant (metastatic) recurrence within specified time horizon (commonly ten years) as used in breast prognostic assays

Assay linkageDR estimates are the key prognostic outputs for assays such as Oncotype DX, MammaPrint, Prosigna, EndoPredict

Clinical useDR estimates inform adjuvant systemic therapy decisions and long-term surveillance planning

BluePrint molecular subtype — definition

BluePrint molecular subtype — definitionAn 80-gene expression test that classifies breast tumors into molecular subtypes (Luminal A, Luminal B, HER2-type, Basal) to refine prognosis and treatment selection

Coupled assayOften reported alongside MammaPrint (70-gene) to provide subtype and chemosensitivity insights

SpecimenPerformed on tumor tissue (fresh/frozen or FFPE)

EndoPredict EPclin — definition

EndoPredict EPclin — definitionA 12-gene expression test (EndoPredict) combined with clinical features to produce an EPclin risk score estimating 10-year distant recurrence risk

Genes includedIncludes eight disease-relevant genes (e.g., BIRC5, UBE2C, DHCR7, RBBP8, IL6ST, AZGP1, MGP, STC2) plus normalization and reference genes

Clinical integrationEPclin incorporates nodal status and tumor size into risk calculation

DCISionRT DS — definition

DCISionRT Decision Score (DS)A molecular-clinicopathologic index combining seven genes with clinical factors to generate a DS (0–10); 0–3 = low risk, 3–10 = elevated risk for DCIS recurrence

Intended useDesigned to estimate ten-year risk of ipsilateral breast events and potential radiotherapy benefit after breast-conserving surgery

Evidence limitsStudies report prognostic associations but prospective clinical outcome impact remains limited

Oncotype DX DCIS score — definition

Oncotype DX DCIS score — definitionA 12-gene RT-PCR assay producing a DCIS score (0–100) estimating ten-year recurrence risk in ductal carcinoma in situ

Clinical noteHayes assessment found overall low-quality evidence and no studies demonstrating clinical outcomes from DCIS-score–based treatment decisions

Use considerationMay be correlated with treatment changes but utility for outcome improvement is unproven

Decision Score (DS) — general definition

Decision Score (DS) — generalA numeric risk estimate generated by molecular assays (e.g., DCISionRT, Oncotype DX DCIS) representing individualized risk over a specified time (commonly ten years)

Range/examplesDCISionRT DS: 0–10 (0–3 low risk); Oncotype DX DCIS score: 0–100; used to stratify recurrence risk

Clinical implicationUsed alongside clinicopathologic factors to guide consideration of radiotherapy or other local management decisions

ctDNA / cfDNA — definition (repeated)

ctDNA / cfDNA — definition (repeated)Circulating tumor-derived cell-free DNA in plasma used for noninvasive genomic profiling, prognostic assessment, MRD detection, or multi-cancer signal detection

Assay modalitiesIncludes targeted mutation panels, hybrid-capture NGS, methylation assays, and personalized tumor-informed MRD assays

Clinical caveatSensitivity and clinical utility depend on tumor burden, timing, and technology; negative results do not rule out disease

Broad hybrid-capture NGS — definition

Broad hybrid-capture NGS — definitionLarge-panel NGS (hybrid-capture) assays targeting hundreds of exons and introns (e.g., FoundationOne) to detect SNVs, indels, CNAs, and gene rearrangements across many cancer-related genes

Use-caseUsed to detect actionable alterations missed by non-NGS methods and to comprehensively genotype tumors for targeted therapy or trial matching

LimitationsMay detect many variants of uncertain significance; requires validated lab workflows and sufficient tissue/DNA quality

Decipher genomic classifier — definition

Decipher genomic classifier (GC)A whole-transcriptome–derived classifier that outputs a score associated with risk of metastasis, biochemical recurrence, and prostate cancer–specific mortality in biopsy or post-prostatectomy specimens

VersionsBiopsy-based and post-RP versions exist to inform initial risk stratification and adjuvant/salvage therapy decisions

EvidenceLarge retrospective cohorts and RTOG ancillary studies demonstrate prognostic associations though prospective outcome-improving evidence is limited

Decipher GC — additional reference

Decipher GC — additional noteValidated in multiple cohorts with association to distant metastasis and PCa-specific mortality; may inform adjuvant therapy discussions post-RP (NCCN category 2B contexts)

LimitationsSample QC failures and retrospective designs limit some analyses; manufacturer involvement noted in several studies

Clinical documentationOrdering clinicians should document how results will affect management decisions

Prolaris / CCP — definition

Prolaris / CCP — definitionCell Cycle Progression (CCP) / Prolaris: a gene expression test measuring cell cycle-related genes combined with clinical data to create a Clinical Cell-Cycle Risk (CCR) score for prostate cancer prognosis

UseProvides prognostic information to aid active surveillance vs definitive therapy decisions

Evidence notesPrognostic value demonstrated in validation studies though limitations include older cohorts and variable sample QC

ExoDx Prostate IntelliScore (EPI) — definition

ExoDx Prostate IntelliScore (EPI)Urine exosome-based three-gene expression assay intended to discriminate high-grade from low-grade or benign prostate disease to aid biopsy decisions

PerformanceProspective validation studies report high NPV and reduction in unnecessary biopsies at validated cut-points

SpecimenFirst-void urine sample collected prior to DRE/biopsy per study protocols

NCCN risk groups (prostate) — definition

NCCN prostate risk groups — definitionRisk groups (Very Low, Low, Intermediate [favorable/unfavorable], High, Very High) defined by combinations of clinical T stage, Grade Group, PSA, percent positive cores, and PSA density per NCCN guidance

Clinical applicationRisk groups used to guide suitability for active surveillance, definitive therapy, and potential use of genomic classifiers

Reference guidanceNCCN Prostate Cancer v1.2025 cited in policy text

Indeterminate thyroid nodule — definition

Indeterminate thyroid nodule — definitionFine-needle aspiration cytology categorized as Bethesda III (AUS/FLUS) or Bethesda IV (follicular neoplasm/suspicious for follicular neoplasm) where malignancy risk is uncertain and molecular testing may aid decision-making

Clinical useMolecular testing considered to avoid unnecessary diagnostic surgery when results would change management

ExamplesTests evaluated include Afirma GSC, ThyroSeq v3, Afirma XA; performance varies by assay

XA whole-transcriptome panel — definition

XA whole-transcriptome panelA whole-transcriptome RNA-sequencing test detecting gene variations and fusions from a panel of >500 genes in thyroid FNA samples (Afirma XA)

Analytic performanceReported intra-/inter-plate reproducibility 86–94% and inter-lab accuracy ~90%; sensitivity as standalone was low in one cohort (49% in Bethesda III/IV)

Intended rolePotential adjunct after Afirma GSC suspicious results to provide additional genomic insight; clinical utility requires further validation

ThyraMIR — definition

ThyraMIR — definitionA commercial miRNA classifier analyzing miRNA (and parallel mRNA sequencing) to improve diagnostic accuracy for indeterminate thyroid nodules

Performance noteSmall cohorts reported sensitivity ~85% and specificity ~95% in limited evaluations; used alongside mutation panels to raise NPV

Clinical roleMay be used in combination with mutation testing to reduce residual cancer risk after negative mutation results

PLA — definition

PLA (Pigmented Lesion Assay) — definitionNoninvasive adhesive patch (tape-stripping) assay detecting gene expression markers (e.g., LINC00518, PRAME, TERT) intended to triage pigmented skin lesions for melanoma

LimitationsStudies report variable analytic failure rates and discordance with histopathology; clinical utility in routine practice is unproven

SpecimenSuperficial adhesive patch collection rather than excisional biopsy

31-GEP (DecisionDx-Melanoma) — definition

31-GEP (DecisionDx-Melanoma) — definitionA 31-gene expression profile test used to stratify cutaneous melanoma patients' risk of sentinel node positivity, recurrence, and metastasis (Class 1/2 results)

Reported outputsClass 1A/1B (lower risk) and Class 2A/2B (higher risk) with associated differences in metastasis-free survival and OS in observational cohorts

Guideline contextEvidence of prognostic value exists but clinical utility to change outcomes remains under evaluation; AAD/NCCN recommend adjunctive use only

GEP — general definition

GEP (gene expression profile) — general definitionMolecular assays measuring expression of multiple genes to classify tumor biology, prognosis, or predict therapy response (examples include 31-gene, 15-gene, 40-gene panels)

ApplicationsUsed for prognostication, triage (e.g., SLNB decision), or adjunctive diagnosis in ambiguous lesions

LimitationsClinical utility varies by tumor type and assay; prospective outcome data often limited

CGH — definition

CGH — definitionComparative genomic hybridization: array-based technique to detect copy-number variations used as an adjunct to distinguish melanomas from nevi

Use-caseHelpful in diagnostically equivocal melanocytic lesions as adjunct to expert dermatopathology

Performance noteStudies report high discrimination (e.g., ~95% in small series) between naevi and melanoma

40-GEP — definition

40-GEP — definitionA 40-gene expression profile developed to stratify localized high-risk cutaneous squamous cell carcinoma into Class 1, Class 2A, and Class 2B for metastatic risk prediction

Reported performanceThree-year metastasis-free survival by class reported as ~91.4% (Class1), 80.6% (Class2A), and 44.0% (Class2B) in validation cohorts

Clinical noteMay inform adjuvant radiation therapy decisions in multidisciplinary context; prospective outcome impact remains under study

CUP — definition

CUP — definitionCancer of unknown primary: metastatic malignant disease where the primary tumor site cannot be determined after standard diagnostic evaluation

Molecular roleGEP and CGP may aid diagnosis or identify actionable alterations for trial matching, but GEP-guided site-specific therapy has not proven survival benefit

Testing recommendationUse molecular testing case-by-case with clinicopathologic correlation and documentation of intended clinical use

cfDNA blood-based test — definition (example)

cfDNA blood-based test (Shield/Guardant reference)Plasma cfDNA assays that detect tumor-derived DNA for cancer screening/detection (example: Guardant Shield evaluated in ECLIPSE) — high sensitivity for CRC but low sensitivity for advanced precancerous lesions

Performance exampleECLIPSE study: sensitivity ~83.1% for CRC overall; specificity ~89.6%; low sensitivity for advanced precancerous lesions (~13.2%)

InterpretationInvestigational for population screening pending prospective outcome data; not a replacement for colonoscopy

mSEPT9 — definition

mSEPT9 — definitionMethylated SEPT9 circulating DNA biomarker measured in plasma assays (e.g., Epi proColon) for colorectal cancer detection; meta-analyses report sensitivity ~0.69 and specificity ~0.92

Screening roleNot considered optimal screening by ACG/USPSTF; may be used in select individuals who refuse standard screening but has lower sensitivity for early lesions

Performance caveatSensitivity higher in advanced-stage CRC; performance varies by assay methodology and population

MMR/MSI — definition

MMR/MSI — definitionMismatch repair deficiency / microsatellite instability testing to identify Lynch syndrome and guide immunotherapy decisions in colorectal cancer

RecommendationNCCN recommends universal MMR/MSI testing for individuals with colon or rectal cancer

MethodologyCan be performed by IHC, PCR, or NGS-based methods per guideline and lab capabilities

TTNB — definition for pancreatic cyst sampling

TTNB — definitionThrough‑the‑needle biopsy obtained via endoscopic ultrasound for sampling pancreatic cystic lesions to provide tissue for histology and targeted NGS

UtilityNGS on TTNB samples reports high sensitivity (~83.7%) and specificity (~81.8%) for diagnosing mucinous cysts in cohort studies

RiskTTNB has ~9.9% adverse event risk and specimen adequacy requirements; combine molecular findings with cytology and clinical context

MCD — definition

MCD — definitionMulti-cancer detection tests analyzing cfDNA methylation or other signals to detect cancer presence and predict tissue of origin (e.g., Galleri)

Performance characteristicsHigh specificity in validation sets (e.g., 99.3%) but sensitivity varies by cancer type and stage; PPV among positives can be low in screening populations

Policy stanceConsidered investigational for population screening pending prospective outcome data; positive signals require diagnostic workup

TTMV-HPV DNA (NavDx) — definition

TTMV‑HPV DNA / NavDx — definitionTumor tissue‑modified viral HPV DNA assay performed on plasma to detect HPV-derived cfDNA for diagnosis, monitoring, or recurrence detection in HPV-associated cancers (NavDx)

Reported performanceStudies report high pretreatment sensitivity (~91.5%) and high specificity (≈100%) for diagnostic cohorts and high specificity for surveillance with sensitivity ~88.4%

Evidence statusPromising diagnostic/surveillance performance but overall clinical utility and standardized protocols remain under evaluation

Tumor‑informed MRD assay — definition

Tumor‑informed MRD assay (e.g., Signatera) — definitionPersonalized ctDNA assay created from whole-exome sequencing of tumor tissue to design patient‑specific targets for serial plasma MRD monitoring

Intended useAssess molecular residual disease after definitive therapy to prognosticate recurrence risk and potentially guide treatment, though clinical utility is not yet established

Policy noteRoutine use for surveillance or therapy monitoring considered not established/ investigational pending prospective outcome data

WGTA / WES / WGS / RNA‑NGS — definition

WGTA / WES / WGS / RNA‑NGS — definitionWhole genome/transcriptome or whole exome sequencing combining DNA and RNA analyses to identify comprehensive actionable targets and transcriptomic information

Potential yieldWGTA may identify a high proportion of potentially actionable findings (e.g., 83% in some cohorts) though proportion receiving WGTA‑informed therapy is lower (e.g., ~37%)

Coverage stanceRoutine use to inform clinical decision‑making is not supported by sufficient evidence and is considered investigational in many contexts

TTMV HPV DNA (NavDx) — additional definition

TTMV HPV DNA (NavDx) — additional noteAssay detects tumor tissue‑derived HPV DNA fragments in plasma for diagnosis and surveillance of HPV-related oropharyngeal cancer; positive results are highly specific but negative results do not exclude disease

Surveillance dataSurveillance cohorts report sensitivity ~88.4% and specificity 100% with high PPV for confirmed recurrences; median lead time to pathologic confirmation reported in cohorts

Evidence limitationsMost studies are retrospective or industry-supported; further prospective validation and protocol standardization recommended

Breast GEP coverage applies to newly diagnosed ER+/HER2‑ invasive breast cancer meeting specified nodal and clinical criteria, and for selected individuals on adjuvant hormonal therapy for decisions regarding extended endocrine therapy; the policy also states that use of more than one predictive GEP for the same tumor is not medically necessary (with a specified exception for BCI).

Coding and technical eligibility require using the applicable CPT, HCPCS, or proprietary U‑codes listed in the policy; codes are provided for reference and may be subject to prior authorization per payer rules.

Prosigna usage is limited to its intended population and is not intended for N2 disease; ordering Prosigna for N2 patients would be outside the assay’s intended use.

For indeterminate thyroid nodules (Bethesda III/IV), molecular testing (for example Afirma GSC, ThyroSeq v3) may be considered to help avoid diagnostic surgery when high sensitivity/NPV assays are used and results will influence the decision about surgery; tests with limited validation are not supported for routine use.

NSCLC eligibility for broad NGS or panel testing should follow histology and clinical features consistent with guideline recommendations (adenocarcinoma or nonsquamous histology, or features suggesting driver mutations), and cfDNA may be used when tissue is insufficient or the patient is unfit for biopsy.

Prostate molecular testing prior to definitive therapy should be reserved for settings where biopsy or clinical risk factors indicate the result will influence management; documentation of PSA, Gleason score, clinical stage, percent positive cores, and intended management impact is expected.

In the post‑prostatectomy setting, Decipher and similar genomic classifiers may be considered when the result would inform decisions about adjuvant versus salvage therapy, but routine use without documentation of expected management impact and consideration of available trial evidence is discouraged.

Thyroid testing eligibility emphasizes selecting assays with adequate analytic and clinical validation (e.g., Afirma GSC, ThyroSeq v3) and using test results together with cytology, sonographic features, and patient preference to guide management.

Genomic profiling alone is insufficient to establish a diagnosis of anaplastic thyroid cancer; molecular results may aid differential diagnosis but cannot replace histopathology.

For melanoma, ancillary molecular techniques (CGH, FISH, GEP) may be used as adjuncts in diagnostically equivocal lesions; prognostic GEP for routine management is discouraged except in contexts where multidisciplinary documentation supports its intended impact on care.

Cutaneous lesion adhesive patch tests and 31‑GEP platforms have mixed and generally low‑quality evidence; their use should be limited to adjunctive diagnostic contexts or research settings until higher‑quality outcome data are available.

When submitting test claims, include supporting evidence citations and trial data where available (e.g., Hayes assessments, MINDACT, DETERMIND) to substantiate medical necessity if requested.

Attach relevant study citations or assessment summaries to PA requests when appropriate.

Documentation Required

Document specimen adequacy (type, quality, handling) for molecular tests

Document specimen adequacy (type and adequacy) for molecular testing; include notes on sample handling and whether tissue quantity/quality met assay requirements since success rates vary by specimen and processing.

Record DNA/RNA quantity metrics and any sample QC failures if available.

Documentation Required

Document prior non-NGS testing and clinical context before broad NGS

When ordering broad hybrid-capture NGS after prior non-NGS testing was negative, document prior testing history and clinical features (e.g., light/absent tobacco exposure in lung cancer) that increase the probability of actionable alterations.

Include dates and results of prior non-NGS tests in the clinical record.

Documentation Required

Provide PSA, Gleason, stage, and percent positive cores with prostate GEC orders

For prostate genomic classifiers, include clinical data with orders (PSA, Gleason score, clinical T stage, percent positive cores) and document how test results are expected to influence management decisions (e.g., active surveillance vs definitive therapy).

Attach relevant clinical risk group information to the test order.

Documentation Required

Document how test results will influence patient management

Document the expected management-impact rationale when ordering molecular biomarker tests — show that results are likely to influence decisions such as surveillance versus definitive treatment or adjuvant therapy selection.

State the specific management decision that the test result will inform.

Documentation Required

Document patient counseling and clinical context for thyroid nodule testing

For indeterminate thyroid nodules, counsel patients on benefits and limitations of testing and document the clinical context (radiographic, cytologic features, and patient preference) when ordering molecular diagnostics.

Record the informed discussion and that results would affect surgical decisions.

Documentation Required

Document indication and tumor metrics for uveal melanoma GEP orders

When ordering uveal melanoma GEP testing, document indication for biopsy, tumor size/thickness, clinical staging, and how results will inform follow-up or management given limited evidence of impact.

Include biopsy rationale and intended surveillance/management changes tied to GEP result.

Documentation Required

Include clinicopathologic correlation and intended clinical use for CUP profiling

For CUP profiling orders, include clinicopathologic correlation, prior immunohistochemistry results, and a clear statement of intended clinical use (e.g., site-specific therapy or trial enrollment) to support the request.

Attach IHC panel results and a plan describing how genomic findings will change management.

Documentation Required

Follow specialty society lab requirements and use validated labs

Follow specialty society laboratory recommendations (ASCP/CAP/AMP/ASCO) and laboratory QA expectations when ordering molecular tests; ensure testing is performed in validated laboratories and document relevant lab QA if requested.

Documentation Required

Provide lesion size, sampling method, and cytology for pancreatic cyst testing

When submitting claims for pancreatic cyst molecular analysis, include lesion size, sampling method (EUS‑TTNB vs cyst fluid aspiration), cytology results, and intended impact on management because sensitivity/specificity vary by sample type.

Indicate whether TTNB or cyst-fluid aspiration was performed and include cyst dimensions.

Documentation Required

Document intended use and follow-up plan when ordering MCD tests

For multi-cancer detection (MCD) tests, document intended use (screening vs symptomatic evaluation) and a diagnostic follow-up plan because positive signals often require extensive downstream evaluation.

Describe the planned diagnostic pathway if the MCD test is positive.

Documentation Required

Include indication, prior treatments, imaging, and tumor sequencing for ctDNA/MRD tests

For ctDNA/MRD testing, include the indication, prior treatments, imaging correlation, and tumor tissue sequencing (for tumor‑informed assays) in documentation, as evidence of clinical utility is limited.

Provide prior tumor sequencing reports for tumor‑informed MRD assays.

Denial Risk

Insufficient evidence tests risk noncoverage — provide supporting data if ordering

Tests flagged by independent assessments as having insufficient evidence (e.g., Select mdx, Confirm mdx, PancraGEN, NavDx) risk noncoverage; include high‑quality supporting data if ordering these assays.

Attach peer-reviewed validation studies or assessments when available.

Documentation Required

Integrate assay results with routine clinical data and document intended influence on management

Ensure test results are interpreted in the context of routine clinical data (imaging, histology, clinicopathologic factors) and document that results will be used alongside standard data to influence management.

State explicitly how assay results complement clinicopathologic variables in decision-making.

Denial Risk

Do not rely on molecular profiling alone for ATC diagnosis; document adjunctive role

Molecular profiling alone is not sufficient for diagnosing anaplastic thyroid cancer (ATC); document that genomic results are adjunctive and that histopathology remains the diagnostic standard.