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Currentsierra health and lifePolicy 2026T0588OO

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

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Defines medical necessity and coverage criteria for molecular and gene expression testing for solid tumor cancers (tissue and liquid biopsy) for UnitedHealthcare Commercial and Individual Exchange plans. Affects ordering clinicians, laboratories, and members under those plans.

Policy Summary

Payersierra health and life

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

Policy CodePolicy 2026T0588OO

Change TypeAnnual review — no material changes

Effective DateMay 1, 2026

Next Review DateN/A

Key ActionOrder molecular or gene expression testing only when results are likely to change management and document clinical rationale and intended management impact.

SourceLink

POLICY UPDATE CHANGES

No material clinical or coverage changes in this revision.

Commercial & ExchangePlan applicability

MultipleBreast GEP tests supported

≤50NGS panel threshold (NSCLC)

>20Unproven examples listed

~200+Codes enumerated

Coverage Criteria — Molecular & Gene Expression Testing

Breast Cancer Gene Expression Profiling (GEP)

Proven and medically necessary when used to inform treatment decisions in individuals with invasive breast cancer in the following situations:

Timing

Newly diagnosed criteria: Lymph node negative (including micrometastases ≤2 mm) or 1–3 positive ipsilateral axillary lymph nodes; No distant metastases; Hormone receptor–positive; HER2 receptor negative; Adjuvant chemotherapy is not precluded due to other factors (e.g., advanced age, significant comorbidities)
All conditions must be met for newly diagnosed individuals
On adjuvant hormonal therapy criteria: Hormone receptor–positive; HER2 receptor negative; Individual and treating physician have discussed potential test results and will use results to guide decision regarding extended adjuvant endocrine therapy
All conditions must be met for testing during adjuvant hormonal therapy

Policy Summary

Payersierra health and life

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

Policy CodePolicy 2026T0588OO

Change TypeAnnual review — no material changes

Effective DateMay 1, 2026

Next Review DateN/A

Key ActionOrder molecular or gene expression testing only when results are likely to change management and document clinical rationale and intended management impact.

SourceLink

On This Page

Test repetition limitation: Use of more than one predictive GEP for the same tumor in an individual with breast cancer is unproven and not medically necessary; exception: BCI may be used once to evaluate the role of extended endocrine therapy even if a prior GEP was used for adjuvant chemotherapy decision-making

Limits multiple predictive GEPs; BCI exception noted

Population and assay alignment with guidelines: Assays considered include Oncotype DX (21-gene), MammaPrint (70-gene), Prosigna/PAM50 (50-gene), EndoPredict (12-gene/EPclin), and Breast Cancer Index (BCI); use should align with professional guideline contexts (e.g., ASCO/NCCN/NICE) regarding node status and menopausal status

ASCO: postmenopausal or >50 y with N0 or 1–3 nodes—Oncotype DX, MammaPrint, BCI, EndoPredict; Oncotype DX may be used in premenopausal node-negative individuals; no assays recommended for HER2+ or triple-negative disease

Non-Small Cell Lung Cancer (NSCLC) molecular profiling

Proven and medically necessary when performed as multigene molecular profiling under specified constraints.

NSCLC profiling criteria: Multiplexed multigene molecular profiling is indicated for non–small cell lung cancer (particularly adenocarcinoma or nonsquamous histology) to identify actionable genomic alterations and guide targeted therapy selection; testing may be performed on tumor tissue or plasma cfDNA/ctDNA when tissue is unavailable or patient is unfit for biopsy

Broad panel-based NGS is preferred where available; cfDNA should not routinely replace tissue testing and tissue-based analysis should follow if cfDNA is negative for a driver

Panel size constraint: Panel-based genomic profiling with ≤50 genes is considered proven for NSCLC; panels >50 genes may be considered only when consistent with FDA-cleared/approved companion diagnostic testing or per guideline-preferred validated panels≤50 genes unless FDA companion diagnostic

Reflects gene-count threshold and FDA-exception

cfDNA use conditions: Plasma cfDNA/ctDNA (liquid biopsy) testing may be used when tumor tissue is insufficient or biopsy is not feasible; if cfDNA testing fails to identify an actionable driver, follow-up tissue-based molecular testing is recommended

Aligns with ASCO/NCCN guidance

Prostate Cancer GEP and classifiers

Proven and medically necessary for biopsy-proven, untreated, localized adenocarcinoma of the prostate when ordered by appropriate specialists and used to inform treatment decisions.

Ordering and specialist requirement: Test must be ordered by a physician specializing in treatment of organ‑confined prostate cancer (urology/surgical oncology, radiation oncology, or medical oncology)

Specialist ordering required

Candidate and life expectancy: Individual is treatment-naïve and a candidate for either active surveillance or definitive therapy; life expectancy is greater than 10 yearslife expectancy >10 years

All listed conditions must be met

Allowed risk groups by assay: GPS (Oncotype DX Prostate), Prolaris, Decipher biopsy GC may be used for individuals in very low, low, or favorable intermediate risk groups to assist decision-making regarding active surveillance vs definitive therapy; Prolaris/Decipher may also be applied to unfavorable intermediate and high-risk groups as applicable

Assay-specific risk group applicability per guidelines

Post-prostatectomy Decipher RP: Decipher Prostate RP genomic classifier is proven and medically necessary to inform adjuvant treatment after radical prostatectomy when adverse pathologic features are present (eg, Gleason ≥8, extracapsular extension, positive margins, seminal vesicle invasion) OR when PSA is detectable (>0) after prostatectomy

Either adverse features OR PSA > 0 qualifies

Selective use and documentation: Testing is covered only when results are expected to affect management decisions (e.g., selection for active surveillance, adjuvant therapy decisions post‑RP); documentation of pre-test clinical risk factors (PSA, clinical T stage, Grade Group, number/percent positive cores) and intended management impact must accompany the order

Routine/unindicated testing is not recommended

Thyroid nodules with indeterminate cytology

Proven and medically necessary when all of the following are met:

Indeterminate thyroid nodule criteria: Fine-needle aspiration cytology demonstrates follicular-pattern indeterminate cytology (Bethesda category III [AUS/FLUS] or IV [follicular neoplasm/suspicious for follicular neoplasm]); AND the molecular test result will be used to guide a decision between diagnostic surgery versus active surveillance/observation

Test choice should be consistent with published evidence demonstrating high sensitivity and NPV (examples: Afirma GSC, ThyroSeq v3)

Nondiagnostic cytology and exceptions: In select nondiagnostic cytology cases where repeat FNA is not feasible or results are indeterminate and molecular testing is expected to change management, molecular testing may be considered; if thyroidectomy is already clearly indicated based on clinical factors, molecular testing is unnecessary

Guidelines recommend repeat FNA or core biopsy where feasible prior to molecular testing

CGP for ATC: Comprehensive genomic profiling (CGP) is proven and medically necessary for confirmed anaplastic thyroid cancer (ATC) to identify actionable alterations for systemic therapy

CGP for ATC is distinct from indeterminate nodule testing

Limit on multiple tests: Use of more than one molecular profile test on the same indeterminate thyroid nodule is unproven and not medically necessary

Multiple concurrent molecular classifiers are discouraged

Uveal Melanoma GEP

Proven and medically necessary when used to assist with predicting disease severity and making treatment decisions:

Uveal melanoma criteria: Primary, localized uveal melanoma; no clinical or radiographic evidence of metastatic disease; and the individual has not previously had DecisionDx-UM testing for the current diagnosis

Testing intended to stratify metastatic risk and inform surveillance intensity/treatment decisions when biopsy is performed

Specimen and biopsy consideration: Biopsy is not required for initial diagnosis or first-line treatment selection but when biopsy is performed for prognostic purposes, molecular/chromosomal testing (GEP or chromosome analysis) is preferred over cytology alone

Discuss risks/benefits of biopsy and interpret results with clinical factors such as tumor size and chromosome status

Evidence and limitations: Evidence supports prognostic discrimination by GEP (eg, class 1 vs class 2) but quality varies; use results in conjunction with tumor size and other prognostic factors when making management decisions

Routine use without consideration of tumor size and clinical context is not supported

Evidence-based clinical contexts

Evidence summary and clinical contexts where gene expression assays inform care (breast cancer focus)

Assay general evidence: Multiple commercial gene expression assays (Oncotype DX, MammaPrint, Prosigna/PAM50, EndoPredict, BCI) have varying levels of evidence supporting prognostic utility in early-stage ER+/HER2- breast cancer and may assist in adjuvant chemotherapy and extended endocrine therapy decisions.

Oncotype DX and MammaPrint have been evaluated in large prospective trials; Oncotype DX has highest-level evidence for predicting chemotherapy benefit in select populations

Oncotype DX specific evidence: Oncotype DX (21-gene) provides a Recurrence Score prognostic for distant recurrence; randomized data (eg, RxPONDER/TAILORx) demonstrate variable chemotherapy benefit by menopausal status and node status (notable benefit in premenopausal subgroups in some analyses)

Evidence supports prognostic and selective predictive use per guidelines

MammaPrint specific evidence: MammaPrint (70-gene) classifies low- versus high-risk patients; prospective randomized MINDACT demonstrated that clinically high/genomically low-risk women may safely forgo chemotherapy with small absolute differences in outcomes and influenced treatment recommendations in multiple observational studies

MammaPrint informs chemotherapy decisions in ER+/HER2- early breast cancer within trial-defined contexts

Assay evidence and clinical implications

Evidence summaries and clinical implications for genomic assays in early breast cancer:

Oncotype DX: Retrospective and prospective-retrospective evidence shows the 21-gene Recurrence Score correlates with pathological stage and predicts distant recurrence; randomized trials provide data on chemotherapy benefit stratified by RS and menopausal status21-gene panel

Oncotype DX favored by NCCN for prediction of chemo benefit

Prosigna/PAM50: Prosigna provides a 10-year risk-of-recurrence (ROR) score for postmenopausal women with HR+, stage I–II disease (N0 or N1); not intended for N2 disease50-gene assay; not for N2

Prognostic value established; predictive utility for radiotherapy benefit not established

MammaPrint / BluePrint: MammaPrint (70-gene) and complementary BluePrint (80-gene) subtype profiling have prospective and randomized evidence (eg, MINDACT) supporting prognostic classification and influence on chemotherapy and neoadjuvant therapy decisions; CNB-to-surgical concordance for MammaPrint/BluePrint is high in multiple studies70-gene and 80-gene

Evidence supports clinical utility in selected ER+/HER2- early breast cancer cohorts

EndoPredict / BCI: EndoPredict (EPclin) and BCI provide prognostic information and have some prospective data indicating changes in treatment recommendations; BCI may predict benefit of extended endocrine therapy in selected analyses though some assessments find evidence limited12-gene EPclin; BCI markers

Use for EET decision-making supported by guideline caveats and further studies recommended

Assay evidence summaries and guideline-indicated use

Evidence summaries and inferred coverage stance from reported clinical utility and guideline recommendations:

MammaPrint / BluePrint implications: MammaPrint influences adjuvant chemotherapy recommendations (MINDACT, WSG-PRIMe, IMPACt) and may identify patients who can avoid chemotherapy; BluePrint can refine molecular subtype and influence neoadjuvant therapy choice but does not replace pathology

Clinicians changed systemic therapy recommendations in substantial proportions post-test

EndoPredict implications: EndoPredict (EPclin) provides prognostic risk and in prospective trials changed adjuvant chemotherapy recommendations in a significant fraction of patients; prospective data remain limited

Supports selective use in clinicopathologic contexts

BCI and extended endocrine therapy: BCI predicts late recurrence and has evidence suggesting prediction of benefit from extended endocrine therapy in meta-analyses; guideline statements allow BCI use to aid EET decisions after 5 years in 0–3 node patients, though some assessments find evidence limited

BCI may be used once to inform EET even if prior GEP used for chemo decisions

Guideline-linked limitations: Professional guidelines (ASCO, NCCN, ESMO, NICE) specify node status and menopausal constraints (eg, ASCO: postmenopausal or >50 with N0 or 1–3 nodes for several assays; no assays for HER2+ or triple-negative disease), and NICE places additional constraints for use in premenopausal node-positive women

Assay use should align with guideline-recommended contexts

Guideline-derived clinical use statements

Guideline summaries and applicability for gene expression assays and molecular testing:

Breast cancer GEP guidance (ASCO/NCCN/ESMO/NICE): ASCO: Oncotype DX, MammaPrint, BCI, and EndoPredict may guide adjuvant endocrine and chemotherapy in postmenopausal or >50 individuals with ER+, HER2- early breast cancer with N0 or 1–3 nodes; Oncotype DX may be used in premenopausal node-negative patients; BCI may aid EET decisions after 5 years. NCCN prefers Oncotype DX (21-gene) for prognosis and chemotherapy benefit prediction; NICE provides conditional and age/menopausal constraints (eg, disallows MammaPrint to guide chemo in premenopausal 1–3 node patients).

Use must be integrated with clinical factors and shared decision-making

NSCLC testing guidance: ASCO/NCCN/Cap-AMP/IASLC: molecular testing recommended in tumors with adenocarcinoma component or nonsquamous histology; multiplexed NGS panels preferred; cfDNA may be used when tissue is limited but not as routine replacement for tissue; TMB should not be used alone to select immunotherapy

Broad panels preferred; include BRAF, EGFR, ALK, ROS1, RET, etc.

Prostate GCs guidance: ASCO/AUA/ASTRO/NCCN: tissue-based genomic biomarkers may be offered selectively when assay results are likely to affect management (eg, active surveillance selection, post‑RP adjuvant decisions); routine ordering is not recommended; Decipher may be considered post‑RP to inform adjuvant therapy

Ordering specialists should document clinical justification

Coverage statements and evidence-supported criteria

Coverage and clinical utility statements summarized from guideline and evidence syntheses in this segment:

NSCLC biomarker testing summary: Molecular biomarker testing is appropriate in tumors with an adenocarcinoma component or nonsquamous histology and when clinical features suggest a higher probability of an oncogenic driver; broad panel-based NGS is preferred where available; single‑gene routine stand‑alone assays (eg, RET, KRAS, MET) are not recommended outside trials

If cfDNA used and no driver found, follow-up tissue testing recommended

cfDNA use statement: cfDNA/plasma testing should not routinely replace tissue testing; cfDNA may be used when tissue is insufficient or patient is unfit for biopsy and should trigger tissue testing if no actionable driver is found

Aligns with ASCO/NCCN guidance

Prostate genomic classifier evidence summary: Genomic classifiers (GPS, Decipher, Prolaris) are associated with biochemical recurrence, metastasis, and prostate cancer–specific mortality; Decipher has trial-derived ancillary analyses and large cohort data supporting prognostic validity, but evidence of improved long-term clinical outcomes when acted upon is limited

Selective use recommended with documentation

Limitations and evidence gaps: Evidence quality varies by context; routine use of many multigene prognostic assays for routine adjuvant decision-making is not established and may require prior authorization or documentation of intended management impact

Ongoing trials may address evidence gaps

Selective coverage criteria

Covered when ALL of the following are met

Selective clinical impact: The assay is ordered only when the result, considered with routine clinical factors, is likely to affect management (for example, change decision between active surveillance vs definitive therapy or influence adjuvant chemotherapy or extended endocrine therapy choices)

ASCO/AUA/ASTRO endorse selective ordering; routine ordering is not recommended

Appropriate patient population: Patient has disease characteristics and risk group where the genomic classifier has been validated or guideline-endorsed to inform management (examples: early-stage ER+/HER2- breast cancer with N0 or 1–3 nodes in specified age/menopausal groups; localized prostate cancer with specific risk groups and life expectancy ≥10 years)

Aligns testing with guideline-specified populations

Documented pre-test justification: Pre-test clinical documentation must include tumor type, receptor status (when applicable), nodal status, clinical risk factors, and the intended management change expected from test results; ordering clinician should be managing the relevant cancer type

Supports prior authorization and medical necessity review

Covered when testing is expected to change management / diagnostic utility

Coverage considered when testing meets guideline-endorsed, management‑changing indications or when evidence supports diagnostic utility in indeterminate thyroid nodules.

Prostate cancer — selective use: Cover tissue-based genomic assays (Decipher, Oncotype DX Prostate/GPS, Prolaris) when ALL of the following are met: (1) testing is requested for individuals with clinically localized prostate cancer where the assay result, when combined with routine clinical factors, is likely to change management (eg, active surveillance vs definitive therapy; post‑radical prostatectomy adjuvant treatment decisions), AND (2) documentation demonstrates assessment of standard clinical/pathologic risk factors and that genomic results are expected to alter management

Derived from ASCO, AUA/ASTRO, and NCCN guidance

Thyroid — indeterminate nodules: Cover validated molecular classifiers (eg, Afirma GSC, ThyroSeq v3, ThyGeNEXT/ThyraMIR combinations) for Bethesda III/IV nodules when results will influence the decision to proceed to diagnostic surgery versus observation; require documentation of Bethesda category and that testing selection is consistent with evidence demonstrating high sensitivity/NPV

Meta-analyses and prospective studies support high sensitivity/NPV for select assays

Thyroid limitations and counseling: Recognize variable specificity/PPV of tests; negative/benign results do not obviate clinical surveillance when indicated and patients must be counseled about test limitations

Guidelines recommend consideration of repeat FNA or core biopsy prior to molecular testing when feasible

Molecular testing considerations and evidence summaries

Guidance and evidence summaries for use of molecular/genomic tests in thyroid nodules and cutaneous melanoma:

Thyroid indeterminate nodules — role: Molecular testing may be considered to supplement malignancy risk assessment for Bethesda III (AUS/FLUS) or Bethesda IV (follicular neoplasm) nodules when clinical, radiographic, and cytologic features do not definitively indicate surgery and when test results would influence management

Institutional malignancy rates and test characteristics should guide test selection

ThyraMIR / miRNA classifiers: miRNA classifiers (eg, ThyraMIR), alone or combined with mutation panels, have shown improved sensitivity and NPV in some studies but require further validation and prospective clinical utility data

Evidence includes smaller cohorts; performance varies

Cutaneous melanoma — 31-GEP: 31-GEP testing may inform decisions about sentinel lymph node biopsy and surveillance intensity in T1–T2 melanomas when results would change management; results should be integrated with clinicopathologic features and interpreted with caution given variable evidence quality

Prospective and registry data show reduced SLNB rates and prognostic stratification but guideline bodies urge prospective validation

Pigmented Lesion Assay (PLA) and tape-stripping: PLA may reduce unnecessary biopsies in selected settings but studies show variable sensitivity/specificity and higher-quality prospective data are needed before broad adoption

Pooled sensitivity ~86.9% for selected marker combos; study quality and real-world discordance observed

Coverage conclusions and criteria

Coverage and clinical utility conclusions described in this section

Diagnostic adjuncts for melanocytic lesions: Ancillary molecular techniques (CGH, FISH, GEP) may be used as adjuncts for diagnostically equivocal melanocytic neoplasms and should be interpreted with expert dermatopathologic correlation

Not a replacement for clinical/pathologic assessment

Prognostic GEP for melanoma and uveal melanoma: Prognostic GEP tests (eg, 31-GEP for cutaneous melanoma; 15-GEP for uveal melanoma) provide prognostic discrimination but current evidence does not uniformly demonstrate added clinically actionable value beyond clinicopathologic factors; uveal melanoma GEP is preferred over cytology when biopsy is performed

Routine prognostic testing discouraged until better use criteria are defined

cSCC 40-GEP: 40-GEP may stratify metastatic risk in high-risk cSCC and has retrospective and prospective validation cohorts suggesting utility to inform adjuvant radiation therapy decisions in selected high-risk patients, but prospective confirmation and independent guideline endorsement remain limited

Consider use when result would change management and in multidisciplinary discussion

CUP site-of-origin testing stance: Molecular site-of-origin tests for CUP have variable diagnostic confidence and randomized trials have not demonstrated consistent survival benefit for GEP-guided site-specific therapy; molecular profiling (NGS/GEP) may be adjunctive but is not standard for directing site-specific therapy

NGS may identify actionable alterations for targeted therapy/trial enrollment; tissue testing preferred over cfDNA when feasible

Molecular testing in Cancer of Unknown Primary (CUP) — stance and conditions

Coverage and use considerations for molecular testing in CUP and solid tumors:

CUP testing general: Molecular profiling (GEP, NGS) may be considered as adjunctive testing in CUP but is not established as standard management for determining site-specific therapy; randomized trials have not shown clear survival benefit for GEP-directed site-specific therapy

NCCN/ESMO do not recommend routine GEP-based site-directed therapy; testing should be individualized

When profiling may add value: Comprehensive genomic profiling can identify actionable alterations or biomarkers (eg, ERBB2, PIK3CA, BRAF, MSI) that enable targeted therapy or trial enrollment and may provide diagnostic clues when GEP confidence is low

DNA sequencing sometimes provides greater diagnostic value than GEP in unresolved CUPs

Specimen preference: Tumor tissue testing is preferred for CUP workup; cfDNA/plasma testing may be considered if tissue is unobtainable but should be followed by tissue testing when feasible

Pathology and oncology collaboration recommended for test selection

Colorectal cancer — prognostic and screening molecular tests

Colorectal cancer molecular testing considerations:

Tumor biomarker testing for therapy selection: Tumor testing for KRAS/NRAS/BRAF/HER2 and MSI/MMR is recommended in advanced/metastatic CRC to guide targeted therapy selection; NGS is the preferred methodology where available

ASCP/CAP/AMP/ASCO guidelines support these recommendations

cfDNA screening and prognostic assays: Emerging cfDNA blood-based screening tests demonstrate promising sensitivity in some prospective studies (eg, Shield/Guardant) but evidence of impact on outcomes is incomplete; prognostic gene-expression signatures (eg, Oncotype DX Colon, 15-gene) have variable validation and require prospective studies before routine use for adjuvant decisions

ACG recommends against mSEPT9 as sole screening modality

Universal MMR/MSI testing is recommended for any individual with colon or rectal cancer to identify Lynch syndrome and to inform immunotherapy decisions in metastatic disease

NCCN recommendation

Coverage considerations for CRC molecular testing

Summary of guidance and evidence-driven coverage considerations

CRC guideline-based testing: Universal MMR/MSI testing is recommended for all patients with colorectal cancer; molecular testing for KRAS/NRAS/BRAF/HER2 is indicated to guide targeted therapies per NCCN; NGS is preferred methodology

Follow guideline-specified gene panel testing for metastatic disease

Multigene prognostic tests—limited use: Tumor-based multigene prognostic tools (eg, recurrence score panels, Immunoscore, post-surgical ctDNA) currently lack sufficient evidence for routine use to guide adjuvant therapy and should be considered investigational or limited to research/clinical trials

ASCO and NCCN note uncertainty and encourage trial enrollment

Septin 9 (mSEPT9) screening stance: Blood-based mSEPT9 testing is not recommended as an optimal sole screening modality for average-risk populations due to limited sensitivity and is discouraged by ACG

Not optimal for population screening

Coverage considerations for pancreatic molecular testing

Pancreatic cancer and cyst molecular testing

Pancreatic cyst molecular testing: Targeted NGS of pancreatic cyst fluid or TTNB samples may aid classification of mucinous cysts/IPMN and detection of mutations associated with advanced neoplasia (eg, KRAS, GNAS, TP53, PIK3CA, PTEN) and can inform decisions about surgery versus surveillance when results will change management

Evidence shows high sensitivity/specificity in selected cohorts (eg, PancreaSeq, targeted 51-gene panels), but studies are limited and test choice should be integrated with imaging and cytology

Pancreatic tumor molecular profiling: Tumor somatic profiling is indicated in metastatic or locally advanced pancreatic cancer when targeted therapy is being considered; germline testing is recommended per NCCN for confirmed pancreatic cancer

Follow guideline-based indications for germline and somatic testing

PancraGEN and evidence limits: Some commercial cyst-risk assays (eg, PancraGEN) lack sufficient peer-reviewed evidence and may be considered investigational or not covered pending further validation

ACG guidance: molecular markers may be considered when diagnosis is unclear and would change management

Coverage considerations and criteria

Coverage and clinical-use considerations drawn from evidence and guideline statements in these sections

Pancreatic cyst / IPMN testing conditions: Molecular testing of TTNB or pancreatic cyst fluid may aid diagnosis of mucinous cysts and detection of advanced neoplasia; consider testing when results will change management and correlate with imaging and cytology

High sensitivity/specificity reported in selected cohorts but further validation needed

Multi-cancer detection (MCD) tests: MCD tests (cfDNA methylation or targeted panels) demonstrate high specificity but variable sensitivity that increases with stage; current evidence does not establish clinical utility for population screening and routine use is not supported

Investigational for asymptomatic population screening pending outcomes trials

NavDx (TTMV-HPV DNA): NavDx shows high specificity and moderate-to-high sensitivity in selected diagnostic and surveillance cohorts for HPV-associated OPSCC but overall evidence is limited and clinical utility (impact on outcomes) is unproven; consider adjunctive use with clinical/radiographic correlation or within research protocols

Hayes assessment found limited evidence; specificity high, sensitivity ~88–92% in cohorts

All other molecular testing for solid tumor cancer that is not specifically listed as a covered, proven, or medically necessary indication is considered unproven and not medically necessary. This includes, but is not limited to: NGS panels >50 genes or comprehensive genomic profiling (CGP) unless explicitly specified elsewhere in this policy, measurable residual disease (MRD) assays in solid tumors (tumor‑informed or tumor‑naïve), multi‑cancer early detection tests, whole exome/genome/transcriptome assays, and named commercial assays enumerated in the policy’s unproven list (examples: CancerTYPE ID®, PancraGEN®, Galleri®, NavDx®, DecisionDx®‑Melanoma/DecisionDx®‑SCC, DermTech PLA™, SelectMDx™, ConfirmMDx™, ExoDX™, Signatera™, Guardant Reveal™).

Use of gene expression profiling (GEP) assays for breast cancer indications outside the specific invasive‑breast criteria in this policy (for example, for ductal carcinoma in situ [DCIS] or other non‑specified treatment decisions) is unproven and not medically necessary. The policy specifically limits proven GEP use to invasive, hormone receptor–positive, HER2‑negative disease in the defined clinical contexts and states that testing for other indications lacks sufficient evidence of efficacy.

Consistent with the general exclusions, several individual assays and contexts related to breast GEP or DCIS are listed as unproven and not medically necessary (see the policy’s enumerated exclusions). Ordering multiple predictive GEPs for the same tumor is likewise not medically necessary, except that a single BCI test may be used to evaluate the role of extended endocrine therapy even if a prior GEP was used to inform adjuvant chemotherapy decisions.

Covered Indications by Tumor Type

Applicable Procedure Codes and Coding Notes

Applicable molecular test codesmixed

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, and 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, and 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 (luminal, luminal infiltrated, basal, basal claudin-low, neuroendocrine-like).
0020M	Oncology (central nervous system), analysis of 30000 DNA methylation loci by methylation array, utilizing DNA extracted from tumor tissue, diagnostic algorithm reported as probability of matching a reference tumor subclass.
0005U	Oncology (prostate) gene expression profile by real-time RT-PCR of 3 genes (ERG, PCA3, and SPDEF), urine, algorithm reported as risk score.
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.
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.

Applicable molecular oncology U/M codes (partial list)mixed

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, and 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, and 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 (luminal, luminal infiltrated, basal, basal claudin-low, neuroendocrine-like).
0020M	Oncology (central nervous system), analysis of 30000 DNA methylation loci by methylation array, utilizing DNA extracted from tumor tissue, diagnostic algorithm reported as probability of matching a reference tumor subclass.
0005U	Oncology (prostate) gene expression profile by real-time RT-PCR of 3 genes (ERG, PCA3, and SPDEF), urine, algorithm reported as risk score.
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.

Applicable molecular oncology U codes (continued)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.
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.

Applicable CPT codes and high-level panel CPT codesCPTCovered

81445	Solid organ neoplasm, genomic sequence analysis panel, 5-50 genes, interrogation for sequence variants and copy number variants or rearrangements, if performed; DNA analysis or combined DNA and RNA analysis.
81449	Solid organ neoplasm, genomic sequence analysis panel, 5-50 genes, interrogation for sequence variants and copy number variants or rearrangements, if performed; RNA analysis.
81455	Solid organ or hematolymphoid neoplasm or disorder, 51 or greater genes, genomic sequence analysis panel, interrogation for sequence variants and copy number variants or rearrangements, or isoform expression or mRNA expression levels, if performed; DNA analysis or combined DNA and RNA analysis.
81456	Solid organ or hematolymphoid neoplasm or disorder, 51 or greater genes, genomic sequence analysis panel, interrogation for sequence variants and copy number variants or rearrangements, or isoform expression or mRNA expression levels, if performed; RNA analysis.
81457	Solid organ neoplasm, genomic sequence analysis panel, interrogation for sequence variants; DNA analysis, microsatellite instability.
81458	Solid organ neoplasm, genomic sequence analysis panel, interrogation for sequence variants; DNA analysis, copy number variants and microsatellite instability.
81459	Solid organ neoplasm, genomic sequence analysis panel, interrogation for sequence variants; DNA analysis or combined DNA and RNA analysis, copy number variants, microsatellite instability, tumor.
81462	Solid organ neoplasm, genomic sequence analysis panel, cell-free nucleic acid (e.g., plasma), interrogation for sequence variants; DNA analysis or combined DNA and RNA analysis, copy number variants and rearrangements.
81463	Solid organ neoplasm, genomic sequence analysis panel, cell-free nucleic acid (e.g., plasma), interrogation for sequence variants; DNA analysis, copy number variants, and microsatellite instability.
81464	Solid organ neoplasm, genomic sequence analysis panel, cell-free nucleic acid (e.g., plasma), interrogation for sequence variants; DNA analysis or combined DNA and RNA analysis, copy number variants, microsatellite instability, tumor mutation burden, and rearrangements.

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Applicable CPT/HCPCS Codesmixed

81462	Solid organ neoplasm, genomic sequence analysis panel, cell-free nucleic acid (e.g., plasma), interrogation for sequence variants; DNA analysis or combined DNA and RNA analysis, copy number variants and rearrangements.
81463	Solid organ neoplasm, genomic sequence analysis panel, cell-free nucleic acid (e.g., plasma), interrogation for sequence variants; DNA analysis, copy number variants, and microsatellite instability.
81464	Solid organ neoplasm, genomic sequence analysis panel, cell-free nucleic acid (e.g., plasma), interrogation for sequence variants; DNA analysis or combined DNA and RNA analysis, copy number variants, microsatellite instability, tumor mutation burden, and rearrangements.
81479	Unlisted molecular pathology procedure.
81504	Oncology (tissue of origin), microarray gene expression profiling of > 2000 genes, utilizing formalin-fixed paraffin-embedded tissue, algorithm reported as tissue similarity scores.
81518	Oncology (breast), mRNA, gene expression profiling by real-time RT-PCR of 11 genes (7 content and 4 housekeeping), utilizing formalin-fixed paraffin-embedded tissue, algorithms reported as percentage risk for metastatic recurrence and likelihood of benefit from extended endocrine therapy.
81519	Oncology (breast), mRNA, gene expression profiling by real-time RT-PCR of 21 genes, utilizing formalin-fixed paraffin embedded tissue, algorithm reported as recurrence score.
81520	Oncology (breast), mRNA gene expression profiling by hybrid capture of 58 genes (50 content and 8 housekeeping), utilizing formalin-fixed paraffin-embedded tissue, algorithm reported as a.
81521	Oncology (breast), mRNA, microarray gene expression profiling of 70 content genes and 465 housekeeping genes, utilizing fresh frozen or formalin-fixed paraffin-embedded tissue, algorithm reported as index related to risk of distant metastasis.
81522	Oncology (breast), mRNA, gene expression profiling by RT-PCR of 12 genes (8 content and 4 housekeeping), utilizing formalin-fixed paraffin-embedded tissue, algorithm reported as recurrence risk score.

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This section lists applicable procedure and temporary/PLA codes and their brief descriptions for reference. It does not itself establish coverage or exclusion for those codes; explicit coverage, exclusion, and medical‑necessity statements are provided in other sections of the policy.

NGS panel gene count threshold (NSCLC)

NGS panel gene-count threshold (NSCLC)Multigene molecular profiling for NSCLC is considered proven and medically necessary when panels contain no more than 50 genes; panels >50 genes are acceptable only when used consistent with an FDA‑cleared/approved companion diagnostic.

Specimen typesApplies to tissue or liquid biopsy (cfDNA/ctDNA) for NSCLC molecular profiling.

ExceptionPanels >50 genes allowed only when consistent with FDA companion diagnostic testing as specified in related policy references.

Panel gene count thresholds — examples

Small-to-moderate panels (5–50 genes)CPT codes 81445/81449 describe genomic sequence analysis panels interrogating 5–50 genes.

Large panels (51+ genes)CPT codes 81455/81456 (and many U‑codes) describe panels of 51 or greater genes for comprehensive interrogation (DNA and/or RNA).

Very large / expanded panels (100s–600+ genes)Multiple U‑codes (e.g., 0538U) and listed proprietary codes describe targeted sequencing panels spanning hundreds (e.g., 152–600 genes) or >20,000 methylation regions for broad CGP applications.

DNA methylation sites threshold for CNS methylation profiling (CPT 81524)

CPT code81524 (CNS methylation profiling)

Site count thresholdDNA methylation analysis of at least 10,000 methylation sites is specified for CPT 81524.

SpecimenDNA extracted from formalin-fixed tumor tissue; algorithms report tumor subclass probability and MGMT promoter methylation status if performed.

Oncotype DX panel size

Oncotype DX (breast) gene countOncotype DX Breast analyzes expression of a 21‑gene panel to calculate a Recurrence Score (RS).

Intended useUsed to estimate 10‑year recurrence risk and to inform chemotherapy decisions in early-stage ER+, HER2- breast cancer (node‑negative and select node‑positive contexts).

Assay platformRT‑PCR–based assay performed on tumor tissue (FFPE).

Decipher GC score range and GPS analytic unit notes

Decipher GC score rangeDecipher genomic classifier (GC) reports scores on a 0–1 scale to estimate prostate cancer progression/metastasis risk.

GPS (Oncotype DX Prostate) analytic unitsGenomic Prostate Score (GPS) is analyzed in association studies per 20‑unit and per 10‑point increases (reported in pooled analyses).

Clinical contextBoth Decipher GC and GPS are used to prognosticate outcomes and inform management decisions in localized prostate cancer when results will affect care.

Provider Actions, Prior Authorization, and Documentation

Note

Reference codes are for reference only — verify coverage

The policy includes a reference list of CPT/HCPCS/PLA/temporary codes for molecular and genomic tests; listing of a code does not imply coverage or payment — verify the member’s benefit plan and prior authorization requirements before ordering.

Listing of codes is for reference only and does not guarantee coverage or reimbursement.
Benefit coverage is determined by the member-specific benefit plan document and applicable laws.

Prior Authorization

Codes may be subject to prior authorization — confirm with payer

The document enumerates procedure codes that may be subject to prior authorization, but the excerpts do not define an explicit payer PA policy — providers should assume some codes may require prior authorization and confirm with the member’s plan.

Prior authorization requirements are not specified in this excerpt; confirm PA processes with the payer prior to testing.
Inclusion of a code in the policy does not imply it is covered or exempt from PA.

Prior Authorization

PA may be required for listed molecular oncology CPT/HCPCS codes

Prior authorization may apply to molecular oncology services billed under the listed CPT/HCPCS codes (examples include 81462, 81463, 81464, 81479, 81504, 81518–81523, 81524, 81551–81552, 81599, and G0327); providers should check PA requirements for these codes with the plan.

Examples of listed CPT/HCPCS codes that may be reviewed for authorization include 81462–81464, 81479, 81504, 81518–81523, 81524, 81551, 81552, 81599, and G0327.
Use of unlisted procedure codes (e.g., 81479, 81599) may trigger additional review or claim adjudication.

Documentation Required

Document that genomic assay will inform adjuvant therapy decisions

When genomic assays are ordered to inform therapy decisions (for example MammaPrint or Oncotype DX), the assays are intended to stratify recurrence risk and influence adjuvant chemotherapy or endocrine therapy recommendations; documentation that results will affect treatment decisions is expected.

Genomic assays classify recurrence risk (e.g., MammaPrint low/high) to aid adjuvant systemic therapy decisions.
Document clinical risk and intended treatment decision when ordering.

Note

Order breast GEP only within ASCO‑recommended indications

Align testing indications with ASCO guidance: for guiding adjuvant endocrine or chemotherapy in early-stage ER+, HER2- breast cancer, use tests consistent with ASCO recommendations (Oncotype DX, MammaPrint, BCI, EndoPredict, Prosigna per their specified menopausal/node contexts).

Oncotype DX, MammaPrint, BCI, and EndoPredict may be used in postmenopausal or >50 individuals with node‑negative or 1–3 node ER+/HER2- disease.
No genomic assays are recommended by ASCO for HER2‑positive or triple‑negative breast cancer.

Prior Authorization

No explicit payer PA rules in excerpt — verify plan processes

The excerpts do not provide an explicit payer prior authorization rule set; providers must follow the plan’s PA processes and cannot rely on this policy text alone to determine PA requirements.

No payer-specific prior authorization rules are specified in these excerpts.
Confirm prior authorization criteria and submission requirements with the member’s plan.

Prior Authorization

Prefer broad NGS for NSCLC; cfDNA only when tissue unavailable

For NSCLC, broad multigene NGS panels are preferred; cfDNA (liquid biopsy) is limited to specific circumstances (insufficient tissue or patient unfit for biopsy) and should be followed by tissue testing if no driver is found — document tissue unavailability when using cfDNA.

Prefer broad, panel‑based NGS for NSCLC where feasible; many marketed NGS assays exceed 50 genes.
Use cfDNA only when tissue is insufficient or the patient is unfit for invasive sampling; if cfDNA is negative for a driver, perform tissue‑based analysis when feasible.

Note

Order tests selectively — routine ordering discouraged

Order molecular and genomic tests selectively: only request assays when results are likely to affect clinical management; routine or reflex ordering is discouraged and may prompt PA or denial.

Tests should be requested when the result, together with clinical factors, is expected to change management (e.g., active surveillance vs definitive therapy).
Routine/unindicated testing is not recommended by guideline bodies and may lead to non‑coverage.

Prior Authorization

PA should demonstrate testing will change management

When a test is being requested to affect management decisions, prior authorization should require documentation that the testing is expected to change management (for example, active surveillance vs definitive therapy in prostate cancer or adjuvant chemo decision in breast cancer).

PA requests should demonstrate that standard clinical/pathologic risk factors were assessed and that genomic results would alter treatment.
Provide objective clinical rationale linking test use to a planned management change.

Prior Authorization

PA for thyroid nodule testing requires indeterminate cytology and management rationale

For indeterminate thyroid nodules, prior authorization should require documentation of indeterminate cytology (Bethesda III or IV) and that molecular testing results would influence the decision between diagnostic surgery and observation (or repeat FNA/imaging where feasible).

Document Bethesda category (III/IV) cytology and how test results will affect surgical decision‑making.
Consider repeat FNA or imaging prior to molecular testing when feasible per guidelines.

Prior Authorization

PA may be required for prognostic GEP — show actionable benefit

Prior authorization may be required for prognostic GEP tests when requested for management decisions that lack established clinical utility; PA should show that the assay will provide actionable information beyond clinicopathologic factors.

Provide evidence that the prognostic GEP result will change clinical decisions beyond existing clinicopathologic variables.
Tests that do not demonstrate added clinical actionability may be subject to denial.

Prior Authorization

PA for CUP profiling requires justification of panel and clinical impact

For cancers of unknown primary (CUP), prior authorization may be required for comprehensive genomic profiling or GEP; panels should be justified relative to diagnostic yield and clinical impact, and tissue testing is preferred when feasible.

Document why CGP/GEP is expected to inform therapy selection or trial eligibility in the specific CUP case.
State whether tissue testing was performed or is not feasible; prefer tumor tissue testing over cfDNA when possible.

Prior Authorization

PA recommended for investigational or uncertain multigene tests

Multigene assays lacking established evidence (for example Immunoscore, many investigational multigene panels, and post‑surgical ctDNA assays) may require prior authorization and documentation of investigational use or clinical trial enrollment.

Provide clinical justification and references when ordering assays considered investigational.
Consider PA or research/trial documentation for investigational assays.

Prior Authorization

PA recommended for MCED/cfDNA assays; document rationale and follow‑up plan

Prior authorization may be required for multi‑cancer detection (MCD) tests and broad cfDNA assays because current evidence does not support routine screening use; document the clinical rationale and planned downstream management if a test is positive.

MCD tests lack evidence for population screening and may not be covered for asymptomatic screening.
If ordering an MCD/cfDNA test, document intended follow-up diagnostic steps and how a positive result would change care.

Prior Authorization

PA/justification expected for tumor‑informed MRD assays (Signatera)

Tumor‑informed MRD assays (e.g., Signatera) currently lack sufficient evidence for routine use; prior authorization or documentation (e.g., trial enrollment or explicit clinical rationale) may be required when such assays are requested for surveillance or treatment monitoring.

Hayes and NICE assessments identify insufficient prospective evidence to support routine MRD use for changing management.
Consider limiting use to clinical trials or require documented rationale and intended management actions based on results.

Documentation Required

Consider patient age when using genomic risk to guide therapy

Age affects treatment sequencing: evidence shows younger women (<50) may derive chemotherapy benefit even with low genomic risk; document age and discuss how assay results will interact with age and clinical risk to guide therapy.

MINDACT and subgroup analyses indicate age‑dependent chemotherapy benefit.
Include patient age in the clinical justification and shared decision‑making documentation.

Step Therapy

Consider repeat FNA or imaging before molecular testing for AUS/FLUS

Before ordering molecular testing for AUS/FLUS (Bethesda III) thyroid nodules, consider repeat FNA or additional imaging when feasible; document prior steps in the medical record.

ATA and AAES guidance recommend repeat FNA or core biopsy prior to molecular testing when clinically appropriate.
Document prior diagnostic steps (repeat FNA, imaging) in the PA or medical records.

Step Therapy

Stepwise approach: histology/IHC first, then molecular tests if needed

Use a stepwise diagnostic approach: perform histopathology and immunohistochemistry first for diagnostically unresolved tumors, then consider targeted molecular tests (NGS, GEP) if they are expected to add diagnostic or therapeutic value.

NCCN and ESMO recommend integrating histology/IHC before proceeding to molecular profiling in CUP and other diagnostic dilemmas.
Document prior diagnostic workup results before ordering molecular profiling.

Step Therapy

Sequence germline and somatic testing per NCCN for pancreatic cancer

Follow guideline‑aligned sequencing for pancreatic cancer: offer germline testing per NCCN for confirmed pancreatic cancer and reserve tumor somatic profiling for metastatic/locally advanced disease when targeted therapy is being considered.

NCCN recommends germline testing for all individuals with confirmed pancreatic cancer.
Perform tumor somatic profiling in metastatic/locally advanced cases when results may inform targeted therapy.

Step Therapy

Require documented rationale or trial enrollment when ordering MRD assays

When requesting Signatera or similar MRD assays, consider requiring documentation that use is investigational or for a documented indication (e.g., clinical trial) and that providers have a plan for how MRD results would change management.

Hayes and NICE note lack of prospective evidence for clinical outcome benefit when acting on MRD results.
Document trial enrollment or explicit management actions tied to MRD positivity/negativity.

Documentation Required

Medical records may be required to support coverage determination

Payers may request medical records to verify that a member meets clinical criteria for coverage; include relevant clinicopathologic data and management intent when submitting prior authorization requests.

Medical records documentation may be required to assess eligibility and clinical justification for testing.
Benefit coverage is determined by the member’s benefit plan and applicable laws; records do not guarantee coverage.

Documentation Required

Include tumor type, indication, and specific assay in documentation

Required clinical documentation should include tumor tissue type, test indication (diagnosis, prognosis, or treatment decision), and the specific multi‑gene or molecular assay requested; supporting clinicopathologic data must be provided with PA requests.

Specify tumor type, stage, receptor status (when applicable), nodal status, and the exact assay name/code.
State the clinical question (e.g., adjuvant chemo decision, rule‑out malignancy in indeterminate thyroid nodule).

Documentation Required

Document specimen type and concordance for MammaPrint/BluePrint

When using core needle biopsy specimens for MammaPrint/BluePrint testing, document specimen type and report concordance considerations (studies report ~90.9% total agreement CNB vs SR); include CNB vs surgical resection specimen details when available.

FLEX study showed 90.9% total agreement between CNB and surgical resection for MammaPrint with high NPV and PPV.
Document whether the assay was run on CNB or surgical resection specimen and include concordance data if relevant.

Documentation Required

Document how test results will be used in clinical decision‑making and counseling

When genomic assay results are used to make clinical decisions, document how results were integrated with clinical risk factors and that shared decision‑making occurred; the treating oncologist should explain results and treatment implications to the patient.

Test results should be interpreted alongside clinicopathologic factors and discussed with the patient.
Oncologist involvement in interpreting and explaining tumor profiling results is recommended by NICE and NCCN.

Documentation Required

If using cfDNA due to tissue unavailability, document and plan tissue follow‑up

If ordering cfDNA/plasma testing because tissue is unavailable or biopsy is contraindicated, document tissue unavailability or patient contraindication and plan for follow‑up tissue testing if no oncogenic driver is identified.

NCCN states cfDNA may be used when tissue is insufficient or patient unfit for biopsy, but tissue testing should follow if cfDNA fails to identify a driver.
Document the reason tissue testing is not feasible.

Documentation Required

Document clinical rationale and patient counseling for thyroid nodule testing

Document the clinical rationale, imaging, cytology, and that the patient was counseled regarding benefits and limitations before ordering molecular testing for indeterminate thyroid nodules.

ATA and AAES recommend counseling patients on benefits/limitations and documenting how results will influence the decision to operate or observe.
Include imaging and cytology details in the record submitted for PA.

Documentation Required

Document histology and standard diagnostic workup before molecular profiling

Before tumor molecular profiling, document histology and results of standard diagnostic workup (including immunohistochemistry) and state whether tissue testing was preferred; if cfDNA is used, provide justification.

NCCN and ESMO recommend tumor tissue testing when feasible and require histology/IHC results prior to or alongside molecular profiling.
If cfDNA is used, document why tissue was not feasible.

Denial Risk

Ordering tests listed as unproven risks denial

Tests listed as unproven or not medically necessary in the policy (e.g., NGS panels >50 genes unless specified, MRD assays in solid tumors, multi‑cancer early detection tests, NavDx, PancraGEN, Signatera, WGTA/WES/WGS/WTS) may be denied as not medically necessary.

Policy explicitly lists NGS panels >50 genes (unless otherwise specified) and MRD assays in solid tumors among unproven tests.
Whole exome/genome/transcriptome assays and MCED tests are listed as unproven and may be denied.

Denial Risk

Do not use GEPs to guide therapy in HER2+ or triple‑negative BC — risk of non‑coverage

ASCO and other guidelines do not recommend genomic assays for HER2‑positive or triple‑negative breast cancer; ordering GEPs in these populations to guide adjuvant chemotherapy may risk non‑coverage.

ASCO explicitly states no assays are recommended for HER2‑positive or triple‑negative breast cancer.
Use of assays in these populations to guide adjuvant therapy may be denied.

Denial Risk

Using cfDNA instead of available tissue may risk non‑coverage

Use cfDNA (liquid biopsy) instead of tissue only in selected circumstances (insufficient tissue or patient unfit for biopsy); using cfDNA in lieu of available tissue may be considered inappropriate and risk non‑coverage.

NCCN and ASCO state cfDNA should not replace tissue diagnosis when tissue is available.
Document tissue unavailability or contraindication when relying on cfDNA.

Denial Risk

Insufficient evidence for some prostate assays may lead to denial

Many prostate genomic assays have limited high‑quality evidence for some indications; lack of demonstrated clinical utility or routine/unindicated use may trigger denial or request for additional documentation.

Hayes and guideline assessments report low to intermediate evidence quality for several prostate assays.
Routine ordering without showing likely management impact is discouraged and may be denied.

Denial Risk

Routine/unindicated testing risks denial — document management impact

Routine or unindicated ordering of molecular biomarkers is discouraged by ASCO and AUA/ASTRO; ordering tests unlikely to change management increases the risk of denial — include explicit management impact in the request.

Guidelines recommend selective use when the assay result is likely to affect decisions.
Document intended management change to support medical necessity.

Documentation Required

Interpret molecular results with clinical and pathologic context

Interpret molecular results in the clinical context: molecular testing must be integrated with clinical, radiographic, and cytologic findings; using tests outside these contexts or to replace standard diagnostic procedures may not meet intended use and risk non‑coverage.

NCCN and ATA/AAES emphasize contextual interpretation alongside expert pathology.
Tests used to replace definitive diagnostic standards (e.g., histopathology for ATC) may not be appropriate.

Denial Risk

Prognostic GEP without actionable benefit may be denied

Guideline bodies caution against routine prognostic GEP testing when it does not provide actionable information beyond clinicopathologic factors; ordering such tests without showing added actionability may lead to denial.

NCCN indicates current GEP platforms for cutaneous melanoma do not reliably add actionable prognostic information beyond clinicopathologic factors.
Provide evidence that the test result will change management when requesting coverage.

Denial Risk

PancraGEN use may be denied due to insufficient evidence

PancraGEN lacks sufficient evidence for pancreatic cyst risk assessment per Hayes and may be denied; document stronger peer‑reviewed evidence or limit use to research contexts.

Hayes found insufficient evidence to support PancraGEN for pancreatic cyst risk assessment.
Consider alternative validated tests or clinical trial enrollment.

Denial Risk

MCD screening tests are not supported for routine screening — coverage unlikely

Multi‑cancer detection (MCD) tests are not supported for routine asymptomatic population screening and may not be covered; if ordered, document a compelling clinical rationale and intended downstream diagnostic actions.

Current evidence does not establish clinical utility of MCD tests for screening asymptomatic individuals.
Plans may require PA or deny claims for MCD testing used for routine screening.

Denial Risk

NavDx has limited evidence — expect additional review or possible non‑coverage

NavDx (TTMV‑HPV DNA) has limited evidence; use for diagnosis or surveillance may prompt additional review or non‑coverage unless clear clinical justification and concordant imaging/pathology correlation are documented.

Hayes assessment found limited evidence and no demonstrated clinical utility affecting outcomes for NavDx.
Document correlation with imaging/clinical findings and intended management changes when ordering.

Denial Risk

WGTA/WES/WGS/WTS routinely lack evidence — risk of non‑coverage

Whole‑exome, whole‑genome, and whole‑transcriptome analyses (WGTA/WES/WGS/WTS) lack sufficient evidence to support routine clinical use to inform treatment decisions and may be denied; provide strong justification or limit to research settings.

Policy states insufficient peer‑reviewed evidence to support routine use of these comprehensive assays.
Ordering such broad assays without clear clinical benefit may result in denial.

Not Covered / Unproven Tests and Indications

Examples of tests and test categories that are not supported by sufficient evidence and are therefore listed as not covered or unproven include: NGS panels >50 genes (unless specifically allowed), tumor-informed and tumor‑naïve MRD assays in solid tumors (e.g., Signatera, Guardant Reveal, RaDaR), multi‑cancer detection (MCD) screening assays (e.g., Galleri), and comprehensive whole‑exome/whole‑genome/whole‑transcriptome profiling intended for routine clinical decision‑making. The policy cites lack of demonstrated clinical utility as the rationale for noncoverage of these categories.

Evidence is insufficient to support using Oncotype DX (or related recurrence score assays) to predict chemotherapy benefit in individuals with N2 nodal status (four to nine positive lymph nodes). The policy notes Hayes assessments and trial evidence do not substantiate predictive utility of Oncotype DX in this higher nodal burden population.

Several other breast cancer profiling and DCIS assays lack adequate evidence of clinical utility and are considered unproven. Examples include Theros H/I, the 41‑gene and 76‑gene (Rotterdam) signatures, DCISionRT, and the Oncotype DX DCIS score. Available assessments (e.g., Hayes) report low or limited quality evidence and recommend additional prospective validation before routine clinical use.

The policy does not support routine, solitary use of tumor mutation burden (TMB) alone to select immune checkpoint inhibitor therapy in advanced NSCLC. It also discourages routine stand‑alone single‑gene testing (e.g., RET, KRAS, MET) outside of inclusion within larger panels, consistent with guideline recommendations favoring multiplexed NGS panels for driver detection.

Tests and assays for which evidence of analytic or clinical validity or clinical utility is insufficient are considered unproven or low‑value. Examples highlighted include certain diagnostic/prognostic melanoma assays and non‑validated commercial implementations (e.g., some PLA, myPath, or other proprietary assessments). The policy underscores that such tests should not be used routinely until higher‑quality evidence supports clinical benefit.

Molecular site‑of‑origin or tissue‑of‑origin GEP tests for cancers of unknown primary (e.g., CancerTYPE ID and similar assays) are not supported as standard management to direct site‑specific therapy. The policy references reviews and guideline statements indicating insufficient peer‑reviewed evidence that such testing improves outcomes when used alone to assign targeted, site‑directed treatments.

Tests intended for pancreatic cyst risk stratification or asymptomatic population screening that lack validated clinical utility are not supported. Specifically, the policy cites PancraGEN and routine use of multi‑cancer detection (MCD) tests for asymptomatic screening as not supported by sufficient evidence and therefore not medically necessary for those indications.

Routine use of comprehensive sequencing assays — whole exome, whole genome, or whole‑transcriptome sequencing — to inform clinical decision‑making in solid tumor cancers is not supported due to insufficient evidence of clinical utility in peer‑reviewed literature and is therefore considered unproven for routine care.

Routine use of individualized tumor‑informed MRD assays for monitoring treatment response or for surveillance after treatment (example: Signatera) is not supported. The policy notes available assessments identify clinical‑validity signals but find insufficient evidence that acting on MRD results improves patient outcomes; thus routine use is considered not medically necessary outside of research or protocolized contexts.

Definitions and Test Descriptions

Comprehensive Genomic Profiling (CGP) — definition and scope

DefinitionComprehensive Genomic Profiling (CGP) is a next‑generation sequencing–based test able to detect multiple classes of genomic alterations (eg, SNVs, indels, copy‑number changes, fusions, MSI, TMB) from a single sample.

ScopeCGP can include DNA and RNA analyses and may report actionable variants, MSI, and tumor mutation burden to support targeted therapy selection or clinical trial eligibility.

Specimen typesPerformed on tumor tissue (FFPE/fresh) or, in some cases, cell‑free nucleic acid (plasma) when appropriate.

Liquid Biopsy — definition and intended use

DefinitionLiquid biopsy: testing of bodily fluids (most commonly blood/plasma) to detect tumor‑derived DNA, RNA, or cells (eg, cfDNA/ctDNA) for detection, treatment selection, or monitoring.

Intended useMay be used as an alternative when tissue is insufficient or patient unfit for biopsy; not recommended routinely as a tissue substitute.

LimitationsNegative liquid biopsy should prompt tissue testing when feasible; analytic and clinical validity vary by assay and indication.

Measurable Residual Disease (MRD) — definition and clinical context

DefinitionMeasurable residual disease (MRD) describes detection of very small amounts of cancer cells or tumor genetic material after treatment, often via sensitive assays detecting circulating tumor DNA (ctDNA).

MethodologyTumor‑informed MRD assays use prior tumor sequencing (eg, WES) to design patient‑specific ctDNA assays; tumor‑naive assays use fixed panels.

Clinical contextMRD assays show prognostic associations but routine clinical utility for altering management or improving outcomes is not established per policy assessments.

Genomic sequence analysis panel (CPT codes 81445–81464) — definition

Definition (panel CPT range)Genomic sequence analysis panels (CPT codes 81445–81464) encompass targeted panels of varying gene counts and analysis types (DNA and/or RNA) used to detect sequence variants, copy number changes, and rearrangements.

ExamplesCPT descriptors differentiate 5–50 gene panels (81445/81449) from 51+ gene panels (81455/81456) and plasma cfDNA panels (81462–81464).

Use caseThese CPT ranges are used across tumor types to categorize panel complexity for coverage and coding purposes.

Multi-gene analysis — definition

DefinitionMulti‑gene analysis generally refers to gene panels containing five or more genes, although exceptions may apply for specific tests or clinical contexts.

ApplicationUsed to identify actionable variants, inform prognosis, or generate expression signatures depending on platform and panel composition.

Coding noteSpecific CPT/HCPCS codes map to panel size categories (eg, 81445/81449 for 5–50 genes; 81455/81456 for 51+ genes).

Expression signature — definition and usage

DefinitionAn expression signature combines expression levels of a defined set of genes into an algorithm‑derived score or classifier used for diagnosis, prognosis, or predicting treatment response.

UsageReported as numeric scores, risk categories, or classes (eg, recurrence score, ROR, Class 1/2) to support clinical decision‑making alongside clinicopathologic factors.

ExamplesOncotype DX RS, Prosigna ROR, BCI, MammaPrint risk categories are all expression‑signature outputs used in breast cancer contexts.

Prosigna (PAM50) — assay and nodal limitation

AssayProsigna (PAM50) measures expression of 50 genes on FFPE breast tumor tissue to generate a Risk‑of‑Recurrence (ROR) score and category.

Intended population/limitationIntended for postmenopausal women with HR+, Stage I–II (N0 or N1) breast cancer; not intended for individuals with N2 nodal status.

OutputProvides numerical ROR score and categorical risk to inform prognosis and adjuvant therapy discussions (not predictive of radiotherapy benefit).

MammaPrint — 70‑gene signature and sample types

DefinitionMammaPrint is a 70‑gene expression signature (70‑GS) that classifies tumors as low‑ or high‑risk of distant recurrence and can be performed on fresh, frozen, or FFPE tumor tissue.

Clinical impactEvidence (eg, MINDACT, WSG‑PRIMe) shows MammaPrint influences adjuvant chemotherapy recommendations and can identify patients who may avoid chemo.

Companion assayBluePrint (80‑gene) is complementary for molecular subtyping but evidence for additional clinical utility is limited.

EPclin — EndoPredict score definition and components

Assay and componentsEPclin (EndoPredict) combines a 12‑gene expression signature with tumor size and nodal status to produce an EPclin numeric risk score (approximately 1.1–6.2).

UseProvides 10‑year distant recurrence risk estimates in ER+, HER2‑ early breast cancer; evidence base limited but supportive for prognostic use.

InterpretationEPclin integrates molecular and clinicopathologic variables to stratify patients for adjuvant therapy discussions.

MammaPrint (70‑GS) — alternate entry

Alternate MammaPrint entryMammaPrint (70‑GS) described as the Amsterdam Signature — a 70‑gene classifier for distant recurrence risk in early breast cancer.

Related assaysUsed alongside subtyping assays (eg, BluePrint) or other GEPs (Oncotype, Prosigna) to inform adjuvant decisions.

Clinical evidenceProspective and randomized trials (eg, MINDACT) and observational studies support clinical impact in selected populations.

BCI — Breast Cancer Index definition

DefinitionBreast Cancer Index (BCI) combines the HOXB13:IL17BR (H/I) ratio with a Molecular Grade Index (MGI) to estimate risk of late (5–10 year) and overall (0–10 year) distant recurrence.

Clinical useEvidence suggests BCI may predict benefit from extended endocrine therapy; ASCO allows consideration in select post‑treatment contexts (eg, after 5 years of ET).

SpecimenPerformed on FFPE breast tumor tissue with an algorithmic score output used in clinical decision‑making for EET.

DCISionRT DS — decision score definition

DefinitionDCISionRT Decision Score (DS) is a 0–10 score combining 7 gene molecular markers and clinicopathologic factors to stratify 10‑year DCIS recurrence risk and potential radiotherapy benefit.

Score interpretationScores 0–3 considered low risk; 3–10 considered elevated risk for recurrence.

Evidence limitationsSystematic reviews and Hayes assessments find limited evidence for routine use to guide RT decisions; clinical outcome impact remains uncertain.

Oncotype DX DCIS score — definition and score range

DefinitionOncotype DX DCIS is an RT‑PCR–based assay assessing expression of 12 genes from excised DCIS tissue to calculate a 0–100 score estimating 10‑year local recurrence risk.

Score rangeReported Decision Score (DS) ranges 0–100; used to estimate 10‑year risk of recurrence and potentially guide radiotherapy decisions.

Evidence considerationsHayes found overall low‑quality evidence and clinical outcome benefit of DCIS score–guided decisions is unproven.

Liquid biopsy (ctDNA/cfDNA) — definition and use cases

DefinitionLiquid biopsy (ctDNA/cfDNA): analysis of circulating tumor DNA/cell‑free DNA in blood to detect genomic alterations and monitor treatment response when tissue profiling is infeasible.

Use casesUsed for detection of actionable somatic mutations, monitoring treatment response, and in select settings for early detection; not a routine replacement for tissue testing.

LimitationsSensitivity varies by tumor type, stage, and assay; negative results should prompt tissue testing when feasible.

cfDNA — circulating tumor DNA definition

DefinitioncfDNA (circulating tumor cell‑free DNA) refers to tumor‑derived DNA fragments in plasma used for noninvasive genomic profiling (liquid biopsy).

Clinical roleUsed to detect somatic mutations, monitor MRD, and assist molecular profiling when tissue not available; analytic platforms include NGS and ddPCR.

CaveatsAssay performance and clinical validity vary; cfDNA should not routinely replace tissue‑based diagnosis when tissue is obtainable.

Decipher GC — 22‑gene classifier definition and score range

DefinitionDecipher GC is a 22‑gene expression classifier that provides a continuous risk score between 0 and 1 to predict prostate cancer progression, metastasis, and prostate‑cancer specific mortality.

UseApplied to biopsy or post‑prostatectomy specimens to inform prognostic stratification and adjuvant treatment considerations in selected contexts.

EvidenceValidated in randomized‑trial‑derived analyses and large real‑world cohorts showing prognostic discrimination across outcomes.

GPS (Oncotype DX Prostate) — definition

DefinitionGenomic Prostate Score (GPS; Oncotype DX Prostate) is a 17‑gene expression assay intended to prognosticate outcomes (biochemical recurrence, metastasis, PCa‑specific mortality) in localized prostate cancer.

Analytic interpretationGPS associations are commonly reported per 20‑unit increments (and sometimes per 10‑point increases) in analyses of prognostic outcomes.

Ordering contextUsed to aid decisions about active surveillance versus definitive therapy when ordered by prostate cancer specialists and results will affect management.

CCR (Clinical Cell‑cycle Risk) score — definition

DefinitionClinical Cell‑cycle Risk (CCR) score integrates a cell‑cycle progression (CCP/Prolaris) gene expression result with clinical CAPRA data to stratify recurrence risk and guide active surveillance versus curative therapy decisions.

ComponentsCombines molecular CCP score with clinical variables (eg, PSA, grade, stage) to produce a composite CCR metric used in risk stratification.

Clinical roleMay inform biopsy and treatment decisions; evidence varies by cohort and context.

EPI (ExoDx Prostate IntelliScore) — definition and threshold usage

DefinitionExoDx Prostate IntelliScore (EPI) is a urine exosome‑derived gene expression assay to assess risk of high‑grade prostate cancer and aid biopsy decision‑making.

SpecimenUrine‑based exosomal RNA assay used alongside PSA and clinical factors to triage biopsy decisions.

Threshold useValidated cut points have been proposed to maximize sensitivity for grade group ≥2 disease in some studies.

NCCN prostate risk groups — definitions

DefinitionNCCN prostate risk groups classify patients into very low, low, intermediate (favorable/unfavorable), high, and very high risk categories based on clinical/pathologic features (cT stage, Grade Group, PSA, biopsy core involvement).

UseRisk group assignment informs consideration of genomic testing (eg, selective use of Decipher/GPS/Prolaris) when results will change management.

Clinical implicationGenomic assays are recommended selectively within these risk strata per guideline statements; routine testing not endorsed for all patients.

Indeterminate thyroid cytology — Bethesda III/IV definition

DefinitionIndeterminate thyroid cytology refers to Bethesda category III (AUS/FLUS) or IV (follicular neoplasm/suspicious for follicular neoplasm) fine‑needle aspiration results where diagnosis is uncertain.

Clinical contextMolecular testing (eg, Afirma GSC, ThyroSeq v3, ThyraMIR) may help rule‑in or rule‑out malignancy and influence decisions about diagnostic surgery versus surveillance.

DocumentationCoverage considerations require documentation of Bethesda III/IV cytology and that testing will alter management.

ThyraMIR — miRNA‑based thyroid classifier

DefinitionThyraMIR is a miRNA‑based thyroid classifier that, when combined with mutation panels, has shown improved sensitivity and negative predictive value for indeterminate thyroid nodules in some studies.

MethodmiRNA expression profiling typically performed on FNA material and may be combined with targeted mutation panels (eg, ThyGeNEXT) to improve diagnostic performance.

EvidenceStudies report increased sensitivity and NPV when miRNA classifiers are added to mutation testing, but further prospective utility data are needed.

31‑GEP / DecisionDx‑Melanoma — definition and intended use

Definition31‑GEP (DecisionDx‑Melanoma) is a 31‑gene expression profile intended to predict risk of sentinel lymph node positivity and recurrence/metastasis in cutaneous melanoma.

Intended useUsed to inform decisions about sentinel lymph node biopsy (SLNB) and surveillance intensity in T1‑T2 melanomas when results would change management.

Evidence and limitationsProspective studies report reductions in SLNB rates and prognostic stratification, but guideline bodies note variable evidence quality and recommend cautious use.

PLA (Pigmented Lesion Assay) — noninvasive assay definition

DefinitionPigmented Lesion Assay (PLA) is a noninvasive adhesive tape‑stripping assay that measures expression of markers (eg, LINC00518, PRAME, TERT) to help rule out melanoma and reduce unnecessary biopsies.

SpecimenAdhesive patch (tape‑strip) collection from suspicious pigmented lesions; molecular assay of RNA markers.

Evidence limitationsStudies show variable sensitivity/specificity and significant study limitations; clinical utility and long‑term outcome impact remain uncertain.

GEP (gene expression profile) — general definition

DefinitionGene expression profile (GEP) is a molecular assay measuring expression of a set of genes to classify tumors into risk categories or predict outcomes (eg, Class 1 vs Class 2).

ApplicationsUsed for diagnostic adjuncts, prognostic classification, and prediction of therapy response across tumor types (breast, prostate, melanoma, uveal melanoma, cSCC).

InterpretationResults should be interpreted alongside clinicopathologic and expert pathology assessment; evidence quality and guideline recommendations vary by indication.

CGH — CNV detection method definition

DefinitionComparative Genomic Hybridization (CGH) is a method to detect copy number variations across the genome and can aid in distinguishing melanomas (characterized by CNVs) from benign naevi.

Use caseCGH may be used as an adjunctive diagnostic tool in histologically equivocal melanocytic lesions.

SpecimenTypically performed on FFPE tissue specimens with array platforms.

GEP — tissue‑of‑origin definition

DefinitionTissue‑of‑origin GEP: gene expression profiling assays that classify tumor tissue by transcriptional patterns to predict the likely tissue of origin in cancers of unknown primary (CUP).

LimitationsGEP for CUP provides variable confidence; DNA sequencing may add diagnostic value and current guideline guidance does not endorse GEP‑guided site‑specific therapy as standard of care.

Example codesCPT 81540 describes a 92‑gene tissue‑of‑origin microarray GEP test for tumor classification.

CGP / NGS — definition and capabilities

DefinitionCGP/NGS: comprehensive genomic profiling or next‑generation sequencing capable of detecting DNA alterations, TMB, MSI, and other biomarkers to identify actionable targets.

CapabilitiesMay include DNA and RNA analyses, fusion detection, copy number, MSI, and TMB reporting depending on platform and panel design.

Clinical roleUsed to identify targeted therapy options, trial eligibility, and diagnostic clues in CUP and advanced cancers when applied per guideline contexts.

cfDNA — reiterated definition

Definition (reiterated)cfDNA: cell‑free DNA in plasma used for cancer detection or profiling when tissue testing is infeasible; part of liquid biopsy modalities.

Clinical cautioncfDNA sensitivity is assay‑ and tumor‑dependent; negative cfDNA does not exclude actionable tumor mutations and should prompt tissue testing when feasible.

ExamplesCPT/HCPCS descriptors include plasma cfDNA panels (81462–81464) for cell‑free nucleic acid panel testing.

MSI/MMR — definition and clinical relevance

DefinitionMSI/MMR: microsatellite instability and mismatch repair status used to identify Lynch syndrome and to inform immunotherapy decisions in metastatic colorectal cancer.

Clinical implicationsUniversal tumor testing for MMR/MSI is recommended in CRC to identify hereditary risk and guide therapy; NGS is a preferred methodology for comprehensive evaluation.

Testing roleMSI/MMR results inform adjuvant decisions in stage II CRC and immunotherapy eligibility in advanced disease.

mSEPT9 (Septin 9) — plasma cfDNA marker definition

DefinitionmSEPT9 (Septin 9) is a plasma cfDNA methylation marker evaluated for colorectal cancer screening (commercially as Epi proColon/ColoHealth).

PerformanceMeta‑analyses report pooled sensitivity ~0.69 and specificity ~0.92; performance improves in later‑stage disease and when combined with FIT/FOBT.

Screening contextNot considered an optimal sole screening modality for average‑risk populations per guideline assessments; use is limited to specific scenarios.

Multi‑cancer detection (MCD) tests — definition and limitations

DefinitionMulti‑cancer detection (MCD) tests measure biomarkers (eg, cfDNA methylation) in body fluids to detect multiple cancer types and sometimes predict tissue of origin.

LimitationsHigh specificity reported but variable sensitivity by cancer type and stage; current evidence does not support routine asymptomatic population screening and professional societies do not endorse MCD testing for population screening.

Research statusBeing studied in randomized trials to assess impact on late‑stage incidence and mortality; coverage limited pending outcome data.

TTMV‑HPV DNA (NavDx) — liquid biopsy assay definition

DefinitionTTMV‑HPV DNA (NavDx) is a plasma ddPCR‑based liquid biopsy assay that detects tumor tissue‑modified viral HPV DNA for diagnosis, monitoring, and surveillance of HPV‑related cancers (eg, OPSCC).

PerformancePublished cohorts report high specificity (near 100%) and sensitivity in the high‑80s to low‑90s for diagnosis and surveillance, with some false negatives (~1 in 10).

Clinical useMay be considered adjunctively in diagnosis and surveillance when correlated with clinical and radiographic findings; persistent positive results without corroboration have no established actionable implication outside trials.

Tumor‑informed MRD assay — definition and methodology

DefinitionTumor‑informed MRD assays (eg, Signatera) are individualized ctDNA tests that use prior tumor sequencing (eg, whole exome sequencing) to design personalized panels targeting patient‑specific somatic mutations for sensitive MRD detection.

MethodologyBaseline tumor tissue sequencing identifies somatic variants used to create a personalized multiplex PCR/NGS assay for longitudinal plasma monitoring.

Evidence/limitationsClinical validity for prognostication exists in multiple cohorts, but evidence of clinical utility (improving outcomes by acting on MRD) is insufficient for routine use per assessments.

TTMV‑HPV DNA (NavDx) — reiterated assay definition

Definition (reiterated)TTMV‑HPV DNA (NavDx) is a ddPCR plasma assay detecting tumor‑derived HPV DNA fragments for diagnosis and surveillance of HPV‑related oropharyngeal cancers.

Clinical cautionHigh specificity reported, but sensitivity imperfect; use only as adjunct to clinical/radiographic correlation and not as sole determinant of management.

Evidence statusFurther prospective validation needed to define routine surveillance or management roles; coverage may be limited or require prior authorization.

Eligibility Requirements and Patient Selection

General eligibility statements describe that molecular and gene‑expression assays are intended for use in defined, tumor‑specific clinical contexts where evidence supports prognostic, diagnostic, or predictive utility. These high‑level requirements (such as tumor type, receptor status, nodal status, and intent to use results to change management) are detailed in the tumor‑specific coverage criteria sections rather than repeated here.

For colorectal cancer and related tumor types, eligibility for molecular testing aligns with guideline‑driven indications: universal tumor MMR/MSI testing for any diagnosed colon or rectal cancer, and tumor profiling for KRAS/NRAS/BRAF/HER2 when needed to inform targeted therapy decisions. Prognostic or multigene assays and post‑surgical ctDNA remain investigational for routine adjuvant decision‑making and are supported only in research or when results would clearly alter management.

Pancreatic tumor and cyst testing eligibility is limited to situations where molecular results will influence management. Targeted NGS of cyst fluid or TTNB samples may be considered to help classify mucinous cysts/IPMNs or identify mutations associated with advanced disease if findings would change surveillance or surgical decisions; germline testing for confirmed pancreatic cancer follows NCCN guidance.

For uveal melanoma, prognostic GEP (e.g., DecisionDx‑UM or comparable 15‑gene profiles) is considered when biopsy is performed on primary, localized uveal melanoma without evidence of metastatic disease and when results will be used to inform surveillance and treatment planning; prior DecisionDx‑UM testing for the current diagnosis excludes repeat testing for the same diagnosis.

Eligibility requirements are assay‑ and tumor‑specific and appear in each tumor section; providers should reference the applicable coverage criteria block for the specific assay and clinical scenario to confirm whether testing meets documented eligibility criteria.

NGS panel contexts: multigene molecular profiling is appropriate where guideline recommendations support its use (for example in NSCLC). The policy specifies a practical panel size constraint for proven NSCLC testing — panels of ≤50 genes are considered within the defined proven approach unless a larger panel is required as part of an FDA‑cleared or approved companion diagnostic; liquid biopsy (cfDNA) use is limited to specific clinical circumstances when tissue is unavailable or the patient is unfit for biopsy.

Breast assay contexts: GEP assays (e.g., Oncotype DX, MammaPrint, Prosigna, EndoPredict, BCI) are covered when used in evidence‑based scenarios (invasive ER+/HER2‑ disease, specified nodal and menopausal contexts) and when results are expected to influence adjuvant chemotherapy or extended endocrine therapy decisions. Use outside these contexts is unproven.

Breast GEP use per ASCO: for postmenopausal or individuals >50 with early‑stage ER+/HER2‑ disease who are node‑negative or have 1–3 positive nodes, Oncotype DX, MammaPrint, BCI, and EndoPredict may be used to guide adjuvant therapy decisions; Oncotype DX may be used in premenopausal node‑negative ER+/HER2‑ patients. Testing should be ordered when results will be used by the treating clinician to change management.

ASCO guidance–aligned breast GEA contexts: providers should ensure testing indications and patient characteristics align with guideline recommendations (receptor status, nodal status, and menopausal/age context) and that results will be integrated with clinicopathologic factors to guide treatment decisions.

NSCLC/NGS contexts: multiplexed NGS panels are preferred to identify actionable driver mutations in NSCLC (particularly adenocarcinoma or nonsquamous histology). When tissue is limited, cfDNA (liquid biopsy) may be used, but should not routinely replace tissue testing; negative cfDNA results should prompt tissue‑based testing when feasible.

Prostate registry/usage contexts: genomic classifiers (GPS, Prolaris, Decipher) are intended for use when ordered by clinicians managing prostate cancer and when results will influence management decisions such as selection for active surveillance versus definitive therapy; Decipher may be used post‑prostatectomy to inform adjuvant therapy when adverse pathological features or detectable PSA are present.

Thyroid indeterminate cytology contexts: molecular testing (e.g., Afirma GSC, ThyroSeq v3, ThyGeNEXT/ThyraMIR) is appropriate for Bethesda III/IV nodules when results will influence the decision to proceed to diagnostic surgery versus observation; tests should be selected based on evidence supporting high sensitivity and negative predictive value.

For cases with nondiagnostic cytology or where surgery is clearly indicated, molecular testing is unnecessary. When molecular testing is considered for nondiagnostic or indeterminate nodules, documentation should demonstrate the result will affect management and that the clinician has counseled the patient on test limitations.

Melanoma prognostic GEP contexts: 31‑GEP and other prognostic classifiers may be considered as adjuncts in T1‑T2 cutaneous melanoma when test results would influence sentinel lymph node biopsy decisions or surveillance intensity, but results must be interpreted together with clinicopathologic staging; routine prognostic molecular testing is discouraged until prospective utility is established.

CUP contexts: comprehensive genomic profiling (NGS) or GEP may be considered as adjunctive testing in cancers of unknown primary to identify actionable alterations or help generate diagnostic hypotheses, but using GEP alone to assign site‑specific therapy is not supported as standard of care; tissue testing is preferred and molecular profiling should be justified relative to expected impact on management.

CRC testing specifics: universal tumor MMR/MSI testing for colorectal cancers is recommended to identify Lynch syndrome and inform immunotherapy decisions; targeted testing for KRAS/NRAS/BRAF/HER2 is recommended to guide treatment selection, preferably using NGS panels per guideline recommendations.

Pancreatic cyst molecular testing contexts: targeted NGS of cyst fluid or TTNB specimens may be used to classify mucinous cysts/IPMNs and detect mutations (e.g., KRAS, GNAS, TP53, PIK3CA, PTEN) associated with advanced disease when results will alter management (surgery vs surveillance); PancraGEN specifically lacks sufficient evidence and is not supported.

MRD/Signatera contexts: tumor‑informed MRD assays have demonstrated prognostic associations with relapse in multiple studies, but because evidence that acting on MRD results improves outcomes is lacking, routine postoperative or surveillance use (e.g., Signatera) is considered unsupported outside of research or protocolized use with documented rationale.

Background and Rationale

Molecular and gene expression profiling play roles across solid tumors in refining diagnosis, estimating prognosis, and informing treatment selection. The policy distinguishes proven, evidence‑based applications (specific assays and indications) from numerous unproven or investigational uses; key definitions (e.g., CGP, NGS, liquid biopsy, MRD) and the expectation that tests be used to change management underpin coverage determinations.