UnitedHealthcare molecular oncology coverage update

Breast Cancer GEP — Proven/Medically Necessary

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

Breast GEP indications

Newly diagnosed (within 6 months)
- Lymph node negative (including micrometastases ≤ 2 mm) or 1–3 positive ipsilateral axillary lymph nodes
- No distant metastases
- Hormone receptor–positive (ER and/or PR)
- HER2 receptor negative
- Adjuvant chemotherapy is not precluded due to other factors (e.g., advanced age, significant comorbidities)
Currently receiving adjuvant hormonal therapy
- Hormone receptor–positive
- HER2 receptor negative
- Discussion between patient and treating physician prior to testing and decision to use results to guide extended adjuvant hormonal therapy

Assay selection should follow guideline-preferred use (e.g., Oncotype DX preferred for many pN0/pN1 settings) and test results must be interpreted with clinicopathologic factors and shared decision-making

Prolaris use in prostate cancer — Proven/Medically Necessary

Proven and medically necessary for biopsy-proven, untreated, localized adenocarcinoma of the prostate when all criteria are met:

Prolaris criteria

Ordered by a physician specializing in organ-confined prostate cancer (urology, radiation oncology, surgical oncology, or medical oncology)
Biopsy-proven, untreated, localized adenocarcinoma of the prostate with no clinical evidence of metastasis or lymph node involvement
Results will be used to assist treatment decision-making when the individual has not yet received treatment and is a candidate for active surveillance or definitive therapy
Life expectancy greater than 10 years
Risk group: Very Low, Low, Favorable Intermediate, Unfavorable Intermediate, or High-Risk prostate cancer

Uveal Melanoma GEP — Proven/Medically Necessary

GEP (e.g., DecisionDx-UM) is proven and medically necessary when used to assist with predicting disease severity and making treatment or monitoring decisions in uveal melanoma when:

ALL of the following

Individual has primary, localized uveal melanoma
No evidence of metastatic disease
Individual has not previously had DecisionDx-UM testing for the current diagnosis

Thyroid nodule molecular testing — Proven/Medically Necessary

Molecular testing for indeterminate thyroid nodules is proven and medically necessary when ALL of the following are met:

ALL of the following

Fine needle aspiration cytology is indeterminate (Bethesda category III or IV)
A validated commercial molecular test (e.g., Afirma GSC, ThyroSeq v3) is selected appropriate to the clinical question
Results of the test will be used to inform a decision between surveillance and diagnostic surgery (i.e., results will alter management)

Other solid tumor molecular testing

Refer to InterQual CP for detailed medical necessity clinical coverage criteria for comprehensive genomic profiling, liquid biopsy, and other organ‑specific indications; selections below summarize typical covered contexts.

ANY of the following

Use InterQual CP: Comprehensive Genomic Profiling for Solid Tumor and Liquid Biopsy criteria for organ-specific indications (e.g., lung, colon, pancreas)

CGP or liquid biopsy may be covered when results will inform therapeutic selection, clinical trial eligibility, or when tumor tissue is unavailable and the test will change management

Assay-specific clinical utility summaries

Assays discussed below include typical intended clinical uses and evidence-based utility summaries:

Oncotype DX Breast (21-gene): Used to generate a 21-gene Recurrence Score to estimate 10-year distant recurrence risk and to inform adjuvant chemotherapy decisions in early-stage ER+/HER2- breast cancer (node-negative and select 1–3 node-positive patients); predictive utility for chemotherapy benefit supported by high-level evidence in specific subgroups

Prosigna (PAM50): Provides a Risk of Recurrence (ROR) score for 10-year distant recurrence in postmenopausal women with HR+ N0 or N+ (1–3 nodes); not intended for N2 disease

MammaPrint / BluePrint / EndoPredict / BCI: MammaPrint (70-gene) may inform chemotherapy omission in selected clinically high/genomically low patients (MINDACT); BluePrint subtyping complements MammaPrint but is insufficient alone; EndoPredict and BCI provide prognostic information and may influence adjuvant and extended endocrine therapy decisions with variable evidence strength

Assay-specific coverage criteria

Covered when ALL of the following are met (per assay intended populations and evidence):

Prosigna intended population: Postmenopausal women with HR+ invasive breast cancer, N0 (Stage I/II) or N+ (1–3 ipsilateral axillary nodes) using FFPE tumor tissue; not intended for N2 disease

MammaPrint intended population: Early-stage breast cancer (ER+, HER2- contexts described in trials) using tumor tissue (fresh, frozen, or FFPE) to assign low or high distant recurrence risk and inform adjuvant chemotherapy decisions

BluePrint intended use: Complementary use with MammaPrint to assign molecular subtype; BluePrint alone lacks sufficient evidence to direct therapy

ASCO-aligned coverage indications (summarized)

Per summarized evidence and ASCO/NCCN guidance, genomic assays may be used to guide adjuvant therapy decisions in specified populations when combined with clinical features:

Adjuvant decision-making (postmenopausal/age>50): Oncotype DX, MammaPrint, BCI, and EndoPredict may be used to guide adjuvant endocrine and chemotherapy in early-stage ER+, HER2- breast cancer that is node-negative or with 1–3 positive nodes

Premenopausal considerations: For premenopausal individuals, Oncotype DX may be used in node-negative ER+, HER2- disease; benefit in premenopausal N1 (1–3 nodes) may be age-dependent

Extended endocrine therapy: BCI may be offered to individuals with 0–3 positive nodes after five years of endocrine therapy to aid decisions about extended endocrine therapy

Not recommended populations: Genomic assays are not recommended to guide adjuvant therapy in HER2-positive or triple-negative breast cancer or in individuals with ≥4 positive nodes

Assay-specific evidence affecting coverage

Evidence summaries affecting clinical utility and likely coverage considerations:

MammaPrint evidence: MINDACT randomized trial (n=6,693) demonstrated that among clinically high/genomically low women omitting chemotherapy resulted in small absolute differences in DMFS; registry and observational studies show substantial changes in chemotherapy recommendations after MammaPrint

EndoPredict evidence: Prospective and retrospective studies (including Penault-Llorca) show EndoPredict (EPclin) can change adjuvant recommendations (~36% change) though randomized outcome data are limited

BCI evidence: BCI predicts late distant recurrence and may predict benefit from extended endocrine therapy but evidence is limited and further prospective validation is recommended

DCIS assays evidence: DCISionRT and Oncotype DX DCIS stratify recurrence risk and impact radiotherapy recommendations in registries, but clinical outcome benefit is not established

Covered with criteria (guideline- and evidence-driven indications)

Summarized guidance from major clinical guidelines and assessments:

Breast cancer - guideline synthesis: NCCN and ASCO recognize gene expression assays as adjuncts to clinicopathologic factors; Oncotype DX is preferred for many pN0/pN1 settings and has highest-level evidence for predicting chemotherapy benefit in select subgroups

Prostate cancer - genomic classifiers: Genomic classifiers (Decipher, GPS/Oncotype DX Prostate, Prolaris) provide prognostic information that may inform active surveillance or adjuvant decisions, but prospective trial evidence of outcome benefit is limited; Decipher has the strongest evidence base

Evidence-supported genomic classifier (Decipher) use

Covered when supported by evidence of clinical validity and utility as cited:

Decipher genomic classifier has multiple studies and systematic reviews demonstrating independent prognostic value for biochemical failure, metastasis, adverse pathology, and cancer-specific outcomes; coverage may be considered when results will inform management decisions (e.g., active surveillance selection, adjuvant therapy planning)

GPS and Prolaris use to guide management

Covered when used to inform decision-making and accompanied by appropriate clinical context:

GPS (Oncotype DX Prostate): GPS may predict adverse pathology and assist preoperative counseling and surgical planning; consider coverage when results will change management

Prolaris (CCP/CCR): Prolaris CCP/CCR scores provide prognostic stratification and may support selection of active surveillance in low-risk patients; coverage considered when results will influence management

Not medically necessary / investigational assays

Not routinely covered due to insufficient evidence of clinical utility:

Other prostate and diagnostic assays: Tests such as ExoDx Prostate, Select mdx, Confirm mdx, and similar assays have low or insufficient evidence per assessments and are considered investigational or not medically necessary for routine use unless compelling documentation demonstrates expected management impact

Selective use of prostate genomic assays

Covered when ALL of the following are met (per guideline-aligned, selective use):

Selective prostate genomic testing

Assay is a validated commercial test with peer-reviewed evidence (e.g., Decipher, Oncotype DX Prostate/GPS, Prolaris)
Individual has localized prostate cancer or post-prostatectomy findings where the result is likely to affect management (e.g., initial risk stratification with life expectancy ≥10 years or informing adjuvant therapy post-RP)
Documentation of clinical risk group (NCCN category), life expectancy, and intended management change is provided

Ordering physician should be a specialist in organ-confined prostate cancer and records should document how the test result will change management

Coverage for molecular testing in indeterminate thyroid nodules

Covered when ALL of the following are met for indeterminate thyroid nodules:

ALL of the following

Fine needle aspiration cytology is Bethesda category III or IV (indeterminate)
A validated commercial molecular test (e.g., Afirma GSC or ThyroSeq v3) is ordered to inform decision between surveillance and diagnostic surgery
Results will alter clinical management (for example, avoid diagnostic surgery or proceed to surgery) and documentation shows how management would change

If clinical, sonographic, or other features already mandate surgery, molecular testing is unnecessary and not indicated

Indeterminate thyroid nodule testing

Coverage may be considered when molecular testing will inform management of indeterminate thyroid nodules and is applied consistent with professional guidance and institutional performance data:

Thyroid molecular testing general criteria

Nodule cytology is indeterminate (Bethesda III or IV)
Molecular testing is used as an adjunct when clinical/sonographic features do not already mandate surgery
Institutional malignancy rates and test performance characteristics are considered when selecting a specific assay

Patients should be counseled on benefits, limitations, and uncertainties of molecular testing prior to ordering

When testing is not needed

When testing is not needed: If clinical factors already support proceeding to thyroidectomy (i.e., surgery is clearly indicated), molecular testing is unnecessary and not medically necessary as a preoperative measure

Melanoma GEP testing

Melanoma multigene expression profiles may be used to stratify SLNB risk or prognosis when results would alter management decisions, recognizing evidence limitations and guideline cautions:

31-GEP use in cutaneous melanoma: Consider 31-gene GEP testing for T1–T2 cutaneous melanoma when sentinel lymph node biopsy (SLNB) decision is uncertain and the test result would change management; evidence shows potential reductions in SLNB but long-term outcome data are still accruing and routine prognostic use is discouraged by guidelines

Ancillary diagnostic techniques: Ancillary molecular techniques (CGH, FISH, targeted GEP, NGS) may be used as adjuncts for equivocal melanocytic neoplasms when interpreted in context of expert dermatopathology and clinical findings

Guideline-aligned coverage considerations

Coverage stance and criteria summary based on guideline-aligned evidence in this section:

Cutaneous melanoma - diagnostic adjunct: Ancillary molecular techniques may be used for equivocal melanocytic neoplasms as an adjunct to clinical and expert dermatopathologic examination; interpret in context of CP factors

Cutaneous melanoma - prognostic caution: Routine prognostic GEP testing for cutaneous melanoma is discouraged until prospectively validated and shown to change management or improve outcomes

Uveal melanoma - biopsy and prognostic testing: Biopsy is not routinely required for initial diagnosis or first-line treatment; if biopsy is performed for prognostic purposes molecular/chromosomal testing (including GEP) is preferred over cytology and may guide intensity of monitoring and referrals after discussion of risks/benefits

Cutaneous melanoma

NCCN positions summarized:

Cutaneous melanoma - NCCN position: Current GEP platforms do not provide clinically actionable prognostic information beyond established clinicopathologic factors; prospective validation is required before routine clinical use

Non-invasive patch testing may help guide biopsy decisions for suspicious melanocytic lesions but evidence quality is limited; document how results will influence management

Uveal melanoma

NCCN position on uveal melanoma:

Uveal melanoma - NCCN position: Biopsy is not usually necessary for initial diagnosis or first-line treatment; when biopsy is performed, molecular/chromosomal testing for prognostic purposes is preferred over cytology and GEP can be used to stratify risk to guide follow-up and referrals after discussion of biopsy risks/benefits

Cutaneous squamous cell carcinoma (cSCC)

Evidence summary and stance on 40-GEP for cSCC:

cSCC 40-GEP prognostic use: 40-GEP provides prognostic risk stratification (Class 1, 2A, 2B) that may improve identification of individuals at higher metastatic risk and inform adjuvant radiation therapy decisions; use should be integrated in multidisciplinary decision-making given study limitations and potential conflicts of interest

Cancers of Unknown Primary (CUP)

Cancers of Unknown Primary (CUP) — diagnostic and therapeutic molecular testing considerations:

CUP diagnostic utility: Molecular tests (GEP and NGS/CGP) can provide diagnostic evidence and identify actionable alterations in a subset of CUP cases, but randomized trials have not consistently demonstrated survival benefit from GEP-directed site-specific therapy; DNA/NGS may provide added diagnostic value in many unresolved cases

When to consider CGP/NGS in CUP: Consider pan-cancer NGS/CGP after initial histologic/immunohistochemical evaluation to identify actionable alterations or clinical trial eligibility; tumor tissue preferred, cfDNA acceptable if tissue not feasible

Guideline and evidence summaries relevant to coverage

Coverage-relevant guideline summaries from professional organizations:

CRC biomarker testing: Universal MMR/MSI testing is recommended for any individual with colon or rectal cancer to identify Lynch syndrome, inform immunotherapy decisions for metastatic disease, and aid stage II adjuvant considerations; testing for KRAS/NRAS, BRAF, HER2 is recommended for advanced/metastatic CRC with NGS preferred

CUP molecular profiling guidance: ESMO and NCCN note GEP/NGS may provide diagnostic information in CUP but randomized trials have not proven benefit of GEP-directed site-specific therapy; molecular profiling may be considered after histology determination

Blood-based CRC screening tests: cfDNA screening tests show variable sensitivity and are not replacements for established screening modalities per guideline cautions

Covered with criteria and informational recommendations

Coverage expectations and clinical recommendations summarized from guidelines and evidence presented in this section:

Colorectal cancer molecular testing: Perform universal MMR/MSI testing for any individual with colon or rectal cancer; determine KRAS/NRAS, BRAF, HER2 status for advanced disease; NGS is an acceptable/preferred method

Pancreatic cyst/tumor molecular testing: Targeted NGS of pancreatic cyst fluid or EUS-obtained biopsy may be considered when results will change management (e.g., characterize mucinous cysts or detect advanced neoplasia), consistent with ACG conditional recommendations

MCD tests: Current evidence does not support routine use of multi-cancer detection tests for population screening; prospective outcome studies are required before routine coverage

Coverage stance by test category

Summary coverage stance and rationale by test category based on available evidence:

Multi-cancer detection (MCD/MCED): High specificity but variable sensitivity by cancer type and stage; routine population screening coverage not supported until outcome studies demonstrate clinical benefit

ctHPV / TTMV-HPV DNA (NavDx): Promising sensitivity/specificity for HPV-associated OPSCC and recurrence monitoring but lacks standardized protocols and demonstrated impact on outcomes; evidence currently insufficient for routine coverage in many indications

Tumor-informed/tumor-naive MRD assays (e.g., Signatera): Provide prognostic information and earlier detection of recurrence in selected cancers, but current evidence is insufficient to support routine use to guide adjuvant therapy decisions outside clinical trials

Comprehensive tumor profiling (WGTA/WES/WGS/RNA-NGS): Can identify high rates of actionable findings and inform therapy when combined with multidisciplinary review, but routine use is limited by evidence gaps and access to matched therapies; consider case-by-case or research/clinical-trial contexts

Evidence-guided coverage stance summaries

Guidance and limitations summarized from cited studies and guideline statements:

RNA-NGS with DNA-NGS in advanced NSCLC: Concurrent RNA- and DNA-NGS increases detection of actionable structural variants versus DNA-NGS alone and may be considered in advanced NSCLC when tissue suffices; evidence limited by retrospective single-platform studies

WGTA/WES/WTS in advanced cancers: WGTA and combined DNA/RNA approaches can identify many actionable findings and inform treatment recommendations in multidisciplinary programs, but impact on survival is uncertain and access to matched therapies limits clinical effect

ctDNA/CTC for MRD or routine monitoring: Professional societies (ASCO, ASCO/CAP, ESMO, NCCN) indicate insufficient evidence to recommend routine use of ctDNA/CTC for MRD detection or to guide adjuvant therapy outside clinical trials; routine coverage for these indications is not supported

All molecular testing for solid tumor cancers that is not explicitly described as covered in this policy is considered unproven and not medically necessary. Examples include, but are not limited to, NGS panels > 50 genes or comprehensive genomic profiling (CGP) unless otherwise specified, whole exome/genome/transcriptome sequencing, multi‑cancer detection platforms, and named tests listed by the policy as unproven. Such tests may be denied when submitted for coverage because current evidence does not demonstrate sufficient clinical validity or utility to inform management decisions.

The policy includes an enumerated list of applicable procedure codes for reference and claim processing; this section provides code descriptors only and does not, by itself, establish coverage or clinical criteria. Use the specific CPT/PLA code that corresponds to the assay performed when submitting claims and supporting documentation.

The Prosigna (PAM50) assay is specifically described as not intended for individuals with N2 disease (four to nine positive lymph nodes). Requests to use Prosigna in the N2 population are unsupported by the test’s intended use statements and may be denied.

Prosigna’s intended population is postmenopausal individuals with hormone receptor–positive invasive breast cancer who are node‑negative or have limited nodal involvement (N0 or select N1). The assay is not intended for use in individuals with N2 disease, and evidence is insufficient to support using Prosigna to guide adjuvant therapy decisions when four to nine lymph nodes are positive.

Gene expression profiling assays and other commercial genomic tests that lack sufficient peer‑reviewed evidence of clinical validity and utility are unsupported. Examples include (but are not limited to) the Breast Cancer Gene Expression Ratio (Theros H/I), 41‑gene and 76‑gene signatures, and other named assays listed in the policy; these tests are considered investigational or not medically necessary unless future evidence demonstrates benefit.

Genomic assays are not recommended to guide systemic therapy decisions in individuals with HER2‑positive or triple‑negative breast cancer. Major guideline reviews (ASCO, NCCN, NICE) do not support using GEPs to direct adjuvant chemotherapy or endocrine decisions in these biologic subtypes.

Many additional commercially available genomic panels and proprietary signatures lack adequate evidence of clinical validity or utility; as such, these additional panels are not supported for routine coverage. Use of such tests should be limited to research settings or considered only with clear documentation that results will change management.

Routine ordering of molecular biomarkers when the test result is unlikely to affect clinical management is discouraged. Tests should be requested only when the clinician documents that the assay result will inform a specific management decision (for example, omission or receipt of adjuvant therapy, selection for active surveillance, or a change in surgical approach). Orders made for informational purposes alone may be denied.

Independent assessments (e.g., Hayes) identified limited or low‑quality evidence for some thyroid molecular tests. Where external assessments indicate inadequate evidence (for example, certain evaluations of ThyGeNEXT/ThyraMIR or limited data for ThyroSeq v3), coverage may be restricted and prior authorization or additional documentation may be required to justify use.

Professional societies (AAD, NCCN) discourage routine molecular prognostic testing—including gene expression profiling—for cutaneous melanoma outside of clinical studies. Routine prognostic use is not recommended until prospective validation demonstrates that results change management and improve outcomes.

Current commercially available gene expression profiling platforms for cutaneous melanoma have not demonstrated consistent, clinically actionable improvement beyond established clinicopathologic factors. As a result, routine prognostic GEP for cutaneous melanoma is not supported unless results would clearly alter management and justification is documented.

Major guideline reviews and expert panels advise caution: professional societies note that tumor‑based prognostic profiling tools are not ready for routine use and that ctDNA/MRD and other prognostic tumor‑profiling tools lack sufficient evidence of clinical utility for many indications. Tests should be used judiciously and primarily in contexts where they will change management or within research settings.

Multi‑cancer detection (MCD/MCED) assays and other population screening ctDNA tests are not supported for population screening in routine clinical practice. Current evidence does not establish sufficient clinical utility or guideline endorsement for asymptomatic population screening, and pre‑symptomatic ctDNA testing should be limited to prospective clinical trials.

PancraGEN and similar pancreatic cyst risk classifiers have been judged by independent assessments (Hayes) to have insufficient evidence to support routine clinical use for pancreatic cyst risk stratification. These assays are currently not supported for routine coverage based on available data.

Whole exome sequencing (WES), whole genome sequencing (WGS), whole‑transcriptome analysis, and combined WGTA approaches currently lack sufficient peer‑reviewed evidence to support routine clinical use to inform treatment decisions across solid tumors. Coverage for these broad sequencing approaches is unlikely outside defined research programs or exceptional, well‑documented circumstances.

Pre‑symptomatic ctDNA cancer detection assays (tests intended for asymptomatic early detection outside established screening programs) should only be offered within prospective clinical trials at this time. Guideline groups note that sensitivity, false‑positive rates, and clinical impact are not yet sufficiently defined for routine screening.

Ordering more than one predictive gene expression profile for the same tumor is considered not medically necessary because evidence does not support incremental clinical benefit from performing multiple predictive GEPs on the same malignancy. An exception is noted for a single use of the Breast Cancer Index to inform extended endocrine therapy after prior GEP used for chemotherapy decisions.

Applicable Procedure Codes and Coding Guidance

Applicable procedure codes (partial list)mixed

0005U	Oncology (prostate) gene expression profile by real-time RT-PCR of 3 genes (ERG, PCA3, and SPDEF), urine, algorithm reported as risk score.
0011M	Oncology, prostate cancer, mRNA expression assay of 12 genes (10 content and 2 housekeeping), RT-PCR test utilizing blood plasma and urine, algorithms to predict high-grade prostate cancer risk.
0012M	Oncology (urothelial), mRNA, gene expression profiling by real-time quantitative PCR of five genes (MDK, HOXA13, CDC2 (CDK1), IGFBP5, 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 209 genes, utilizing formalin-fixed paraffin-embedded tissue, algorithm reported as molecular subtype.
0018U	Oncology (thyroid), microRNA profiling by RT-PCR of 10 microRNA sequences, utilizing fine needle aspirate, algorithm reported as a positive or negative result for moderate to high risk of malignancy.
0019U	Oncology, RNA, gene expression by whole transcriptome sequencing, formalin-fixed paraffin embedded tissue or fresh frozen tissue, predictive algorithm reported as potential targets for therapeutic agents.
0020M	Oncology (central nervous system), analysis of 30000 DNA methylation loci by methylation array, utilizing DNA extracted from tumor tissue, diagnostic algorithm reported as probability of matching a reference tumor subclass.

Applicable CPT/PLA/Category III codes and descriptionsmixed

0022U	Targeted genomic sequence analysis panel, non-small cell lung neoplasia, DNA and RNA analysis, 23 genes.
0026U	Oncology (thyroid), DNA and mRNA of 112 genes, NGS, fine needle aspirate, algorithmic categorical result.
0036U	Exome (somatic mutations), paired FFPE tumor and normal specimen, sequence analyses.
0037U	Targeted genomic sequence analysis, solid organ neoplasm, DNA analysis of 324 genes, with MSI and TMB.
0045U	Oncology (breast DCIS), mRNA, gene expression profiling of 12 genes by RT-PCR, algorithm reported as recurrence score.
0047U	Oncology (prostate), mRNA, gene expression profiling of 17 genes by RT-PCR, risk score.
0048U	Oncology (solid organ neoplasia), DNA, targeted sequencing of 468 cancer-associated genes, with matched normal specimen.
0069U	Oncology (colorectal), microRNA, RT-PCR profiling of miR-31-3p, algorithm expression score.
0089U	Oncology (melanoma) gene expression profiling by RT-qPCR PRAME and LINC00518 superficial collection using adhesive patch(es).
0090U	Oncology (cutaneous melanoma), mRNA profiling of 23 genes by RT-PCR, algorithmic result.

1–10 of 111

1/12

Breast oncology expression assay codesCPT

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.
81523	Oncology (breast), mRNA, next-generation sequencing gene expression profiling of 70 content genes and 31 housekeeping genes, utilizing formalin-fixed paraffin-embedded tissue, algorithm reported as index related to risk to distant metastasis.
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.
81521	Oncology (breast), mRNA, microarray gene expression profiling of 70 content genes and 465 housekeeping genes, utilizing fresh frozen or FFPE tissue, algorithm reported as index related to risk of distant metastasis.

Other oncology assay CPT/HCPCS codesmixed

81525	Oncology (colon), mRNA, gene expression profiling by real-time RT-PCR of 12 genes (7 content and 5 housekeeping), utilizing FFPE tissue, algorithm reported as a recurrence score.
81529	Oncology (cutaneous melanoma), mRNA, gene expression profiling by RT-PCR of 31 genes (28 content and 3 housekeeping), utilizing FFPE tissue, algorithm reported as recurrence risk, including likelihood of sentinel lymph node metastasis.
81540	Oncology (tumor of unknown origin), mRNA, gene expression profiling by RT-PCR of 92 genes (87 content and 5 housekeeping) to classify tumor into main cancer type and subtype, utilizing FFPE tissue, algorithm reported as a probability of a predicted main cancer type and subtype.
81541	Oncology (prostate), mRNA gene expression profiling by RT-PCR of 46 genes (31 content and 15 housekeeping), utilizing FFPE tissue, algorithm reported as a disease-specific mortality risk score.
81542	Oncology (prostate), mRNA, microarray gene expression profiling of 22 content genes, utilizing FFPE tissue, algorithm reported as metastasis risk score.
81546	Oncology (thyroid), mRNA, gene expression analysis of 10,196 genes, utilizing fine needle aspirate, algorithm reported as a categorical result (e.g., benign or suspicious).
81551	Oncology (prostate), promoter methylation profiling by real-time PCR of 3 genes (GSTP1, APC, RASSF1), utilizing FFPE tissue, algorithm reported as a likelihood of prostate cancer detection on repeat biopsy.
81552	Oncology (uveal melanoma), mRNA, gene expression profiling by RT-PCR of 15 genes (12 content and 3 housekeeping), utilizing fine needle aspirate or FFPE tissue, algorithm reported as risk of metastasis.
81599	Unlisted multianalyte assay with algorithmic analysis.
G0327	Colorectal cancer screening; blood-based biomarker.

Assay product names discussed (examples)mixed

Oncotype DX (Oncology 21-gene / breast)	Oncotype DX Breast 21-gene recurrence score (referenced via codes 81519/81522/81523 descriptions and evidence summaries).
MammaPrint / BluePrint (70-gene / 80-gene)	MammaPrint 70-gene signature and BluePrint 80-gene molecular subtype assay (referenced in evidence summaries and CPT/PLA code descriptions such as 81521/81523).
Prosigna (PAM50)	Prosigna PAM50 Risk of Recurrence (50-gene) assay (referenced in Prosigna description and ROR discussion).
EndoPredict (EPclin)	EndoPredict 12-gene assay (EPclin) described in evidence summaries and definitions.
Breast Cancer Index (BCI)	BCI assay combining HOXB13:IL17BR ratio and Molecular Grade Index for late recurrence risk estimation (discussed in evidence summaries).
DCISionRT / Oncotype DX DCIS	DCISionRT and Oncotype DX DCIS assays described for DCIS recurrence risk stratification and radiotherapy decision support.

Breast cancer newly diagnosed window

WindowWithin the last 6 months

Applies toIndividuals with newly diagnosed invasive breast cancer

Required tumor featuresHR-positive and HER2-negative

Nodal allowanceNode-negative (including micrometastases ≤2 mm) or 1–3 ipsilateral axillary positive nodes

Metastatic statusNo distant metastases

Lymph node positive allowance

Allowed positive nodes0–3 ipsilateral axillary lymph nodes

MicrometastasesMicrometastases ≤ 2 mm are permitted

Not intended forN2 disease (4–9 positive nodes) for some assays (e.g., Prosigna not intended for N2)

ContextApplies when results will inform adjuvant therapy decisions

Oncotype DX RS categories

Common RS categoriesTAILORx/commonly referenced cutoffs: RS <11, RS 11–25, RS >25 (or historical groupings: <11, 11–25, 26–30/31–50, >30)

UsageRS used to estimate 10-year distant recurrence risk and to help inform adjuvant chemotherapy decisions

Distribution examplesReported cohorts: ~16% had RS >30; TAILORx proportions: ~16.2% <11, 65.8% 11–25, 18.0% >25 in cited analyses

MyProstateScore threshold

Rule-out threshold10

Performance at thresholdSensitivity 97% and NPV 98% for grade group ≥2 cancer

Intended use populationMen referred for prostate biopsy (validation cohort described)

ExoDx (EPI) cut-points discussed

Primary cut-point (validated)15.6 — avoids ~26% unnecessary biopsies; NPV ~89%

Alternate cut-point20 — avoids ~40% unnecessary biopsies; NPV ~89%

PopulationMen age ≥50 with PSA 2–10 ng/mL considered for initial biopsy in validation studies

Provider Actions, Prior Authorization, and Documentation Requirements

Prior Authorization

Prior Authorization and Code Listing

Prior authorization may be required for many molecular oncology assays. Submit prior authorization requests when indicated by the member's benefit plan before testing to avoid claim denials or delays. Include the specific CPT or PLA (proprietary laboratory analysis) code(s) for the assay on the request; listing of a code in this policy does not guarantee coverage. Clinical justification that links the test result to an anticipated change in management (e.g., decision to give or withhold adjuvant therapy, avoid or proceed with surgery, select targeted therapy, or enroll in a trial) is recommended and may be required for authorization.

Provide CPT and PLA codes on the prior authorization and claims submission.
Clinical rationale should state how results will affect immediate treatment decisions or diagnostic workup.
If testing is for screening or unproven indications, prior authorization is commonly required and may be denied.

Billing Rule

Codes Required for Authorization / Claim Processing

Use the CPT and PLA codes listed in the Applicable Codes section when requesting authorization or submitting claims. Where multiple codes apply (e.g., panel plus add-on), list all relevant codes and specimen source. Inclusion of a CPT/PLA code in the policy is for reference only and does not guarantee payment — coverage is determined by benefit terms and medical necessity review.

Report specimen type (tumor tissue, FNA, plasma) with the code when applicable.
Include modifier information and any supporting pathology/cytology report when submitting.
Examples of commonly referenced codes: 81522, 81523, 81540, 81445–81462, 0022U, 0026U, 0597U (see Applicable Codes).

Billing Rule

Assay Coding and Prior Authorization

Assay-specific coding must reflect the technology and intended purpose (e.g., prognostic GEP, tumor origin classifier, cfDNA/MRD). For proprietary tests that have PLA (Gxxxx) codes, supply the PLA code(s) on the prior authorization and claim. Incorrect or incomplete coding increases the risk of claim denial or misprocessing.

List both the assay PLA code(s) and corresponding CPT molecular panel codes if applicable.
If a test has no specific PLA code and is billed under a generic NGS panel CPT, provide method, genes covered, and rationale.
When multiple assays are proposed for the same clinical question, document why each is necessary; multiple predictive GEPs for a single tumor are considered unproven.

Documentation Required

Prior Authorization: Clinical Justification Recommended

Prior authorization requests should include clinical documentation that supports medical necessity. Provide relevant prior tumor testing status, stage, receptor status, cytology/pathology reports, imaging results, PSA/PSA-density (prostate), or prior treatments as applicable to the indication.

Clearly state the intended clinical management change expected from test results (e.g., to omit chemotherapy, to recommend active surveillance, to avoid diagnostic surgery).
Attach pathology/cytology reports (including Bethesda category for thyroid FNAs) and recent staging information.
For ctDNA or MRD testing, describe how a positive or negative result will alter surveillance or adjuvant therapy plans.

Prior Authorization

Prior Authorization for Multigene Assays

Multigene assays (GEP, CGP, NGS panels) frequently require prior authorization. Authorization review will consider evidence of clinical utility for the specific indication and whether testing is within guideline-supported populations. Tests with limited or conflicting evidence may require more detailed justification.

Specify which multigene assay is being requested and the clinical scenario (e.g., early-stage ER+/HER2- breast cancer, indeterminate thyroid nodule).
If requesting a multigene NGS panel for advanced disease, indicate prior single-gene testing performed and why broader profiling is needed.
When multiple multigene tests are available for an indication, document preferred sequencing if applicable (e.g., guideline-preferred assays first).

Note

Laboratory Quality and Access

Authorize tests performed by CLIA-certified laboratories with appropriate quality programs (e.g., CAP accreditation, participation in external QA). Where available, local laboratory performance characteristics and access to timely results should be considered when selecting a testing laboratory.

Confirm the performing lab is CLIA-certified; include lab name and CLIA number on requests when possible.
For FDA-cleared/approved or analytically validated tests, include documentation of test version and intended use.
Labs participating in external quality assurance or registries (when recommended by NICE or professional societies) are preferred.

Prior Authorization

Prior Authorization Likely for Assays with Limited Evidence

Prior authorization is likely required for assays with limited or insufficient evidence of clinical utility (e.g., large unvalidated NGS panels, multi-cancer detection for screening, WGTA/WES/WGS, many proprietary tests listed as unproven). Such tests carry higher denial risk and generally require strong clinical rationale and plan for downstream management.

Tests identified as unproven in policy (see list) are subject to prior authorization and may be non-covered.
Provide evidence or peer-reviewed justification if requesting an unproven test for a specific patient scenario.
Document why standard, guideline-recommended testing is insufficient or not feasible.

Prior Authorization

Prior Authorization for Prostate Genomic Tests

Prostate genomic tests (e.g., Decipher, Oncotype DX Prostate/GPS, Prolaris) often require prior authorization. Provide clinical parameters (PSA, Gleason score/grade group, clinical T-stage, percent positive cores, life expectancy) and the specific management decision the assay will inform (e.g., active surveillance vs definitive therapy, adjuvant treatment planning).

Attach biopsy pathology report, PSA and imaging as applicable.
If requesting biopsy-based genomic testing to support active surveillance, show how result will change surveillance or treatment thresholds.
For tests proposed outside guideline-supported populations, include a clear justification.

Prior Authorization

Prior Authorization for Thyroid Molecular Testing

Molecular testing for indeterminate thyroid nodules (e.g., Afirma GSC, ThyGeNEXT/ThyraMIR) may require prior authorization. Include Bethesda category, ultrasound characteristics, surgical candidacy, and how results will change surgical decision-making. Tests with limited evidence (e.g., Afirma XA, other CGP thyroid panels) may be considered unproven.

Provide FNA cytology report (Bethesda III/IV) and discuss whether molecular testing could avoid or prompt diagnostic surgery.
Document patient counseling regarding benefits and limitations of molecular testing.
If molecular testing is requested despite clear surgical indication, note AAES guidance that testing is unnecessary when thyroidectomy is preferred.

Prior Authorization

Prior Authorization for Prognostic / Molecular Tests

Prior authorization is recommended before ordering prognostic or molecular tests intended solely for risk stratification (e.g., many prognostic GEPs) because routine use without clear management implications may be denied. Authorization reviewers will assess whether clinicopathologic (CP) models have been considered and whether results would change management.

Document prior use of CP variables and why molecular testing adds incremental actionable information.
For melanoma and uveal melanoma prognostic testing, document intended surveillance or therapeutic changes tied to classifier results.
Avoid ordering prognostic tests when surgery or definitive therapy is already indicated and would not be altered by results.

Prior Authorization

Prior Authorization for CUP Molecular Profiling

For cancers of unknown primary (CUP), prior authorization for molecular profiling may be required. Provide prior histology/immunohistochemistry results, why standard workup was insufficient, and how site-specific therapy guided by profiling would alter management or trial eligibility.

Document that tumor tissue testing is preferred; if using cell-free DNA, explain why tissue was not feasible.
If seeking profiling to support trial enrollment (e.g., CUPISCO), include trial matching intention.
Note that GEP for tissue-of-origin has not shown consistent survival benefit; justify use in the individual case.

Prior Authorization

MCD Testing and Downstream Workup

When ordering multi-cancer detection (MCD) tests or other screening-type molecular assays, document intended downstream diagnostic workup plans and the anticipated impact of positive and negative results. MCD testing for population screening is not currently guideline-recommended and may be denied or require prior authorization.

Describe planned diagnostic pathway for a positive MCD result to limit unnecessary procedures.
If MCD testing is requested in symptomatic patients, document symptoms and how the result will change diagnostic urgency.
Be aware that MCD positives often lead to imaging and additional tests; include a plan to minimize low-yield invasive procedures.

Prior Authorization

Prior Authorization for Tests without Established Clinical Utility

Tests without established clinical utility (unproven assays, large unsupported panels, WGTA/WES/WGS) may require prior authorization and are at higher risk for non-coverage. Regulatory and laboratory compliance information (CLIA, CAP, FDA status) should be provided when available.

If requesting WGTA/WES/WGS, include reason why targeted testing is insufficient and how results will change therapy or trial eligibility.
Provide CLIA/CAP accreditation details and any FDA clearance/approval information for the assay.
For investigational uses, document enrollment intent in clinical trial when applicable.

Denial Risk

Denial Risk for Unproven or Non-Guideline Use

Denials are more likely for unsupported assays, use outside guideline-indicated populations, or when clinical justification is insufficient. Review policy lists of unproven tests prior to submission and provide detailed rationale when requesting exceptions.

Examples of high-denial risk: multi-cancer screening in asymptomatic populations, unvalidated large NGS panels, WGTA/WGS/WES for routine care.
When seeking exception, include peer-reviewed literature or trial eligibility that justifies testing.
If test is requested for research or non-covered indication, note this clearly to avoid claim confusion.

Documentation Required

Required Clinical Documentation

Required clinical documentation varies by indication. At minimum, include relevant history, pathology/cytology reports, staging, prior molecular testing results, and a clear statement of how the test result will affect immediate management. For thyroid FNA molecular testing, include Bethesda category and ultrasound findings; for prostate assays include PSA, cores involved, and Gleason/Grade Group.

Attach operative/pathology reports, imaging summaries, and prior molecular or IHC results.
State the specific clinical decision that the test will inform (e.g., omit chemotherapy, proceed with surgery, change systemic therapy).
For WGTA/WES/WTS requests, provide prior testing done and rationale for broader sequencing.

Documentation Required

Shared Decision-Making Documentation

Document shared decision-making when genomic assay results may influence major treatment choices (e.g., chemotherapy omission, extended endocrine therapy, active surveillance). Record that risks, benefits, and uncertainties of testing were discussed and how the patient’s values influenced the plan.

Include a note that the patient and clinician discussed possible outcomes and management implications prior to testing.
For assays used to decide on extended endocrine therapy or to avoid procedures, document patient preference and counseling.
When test results may prompt trial enrollment, document patient interest and eligibility review.

Documentation Required

Documentation for DCIS and Limited-Evidence Assays

For DCIS assays and other tests where evidence is limited, include documentation that explains how the result will change radiation or surgical recommendations and acknowledge the limited long-term outcome data.

Attach pre- and post-test treatment recommendations when available.
Explain alternative management strategies considered without testing.
Note limitations of evidence and plan for follow-up given uncertain long-term outcomes.

Documentation Required

Document Intended Management Impact and Tumor Metrics

Document intended management impact and key tumor metrics (e.g., tumor size, nodal status, receptor status, percent tumor in biopsy) when requesting prognostic or predictive assays. For uveal melanoma or other tests where biopsy has risks, include documentation of biopsy counseling covering risks and benefits.

State the specific management decision that will be altered by the test result.
Include tumor-specific metrics relevant to interpretation (e.g., thickness/ulceration for melanoma, nodal status for breast).
For prognostic biopsies that carry procedural risk, provide documentation of informed counseling and consent considerations.

Documentation Required

MMR / MSI Testing Documentation

For MMR/MSI testing, include prior tumor testing status and stage; indicate whether testing is for Lynch syndrome screening, immunotherapy decision-making, or prognostic assessment. Attach relevant pathology and prior molecular results.

State the clinical purpose (e.g., universal screening for Lynch, stage II adjuvant decision, metastatic therapy selection).
Include prior IHC or PCR results if available.
Document how MSI/MMR result will alter treatment or genetic counseling referral.

Documentation Required

Document Clinical Actions Tied to ctDNA Results

If ordering ctDNA (cfDNA) tests, document planned clinical actions tied to positive or negative results (e.g., additional imaging, initiation/escalation of adjuvant therapy, clinical trial consideration). Note that ctDNA results without concordant clinical or radiographic findings may be of uncertain actionability.

Specify surveillance or treatment steps that will follow a positive ctDNA result.
For postoperative MRD testing, state timing relative to surgery and how a positive result would change management.
Be cautious interpreting plasma HPV ctDNA without clinical/radiographic correlates; document planned confirmatory evaluation.

Documentation Required

WGTA / WES / WTS Documentation Requirements

When requesting whole-genome, whole-exome, or whole-transcriptome testing (WGTA/WES/WTS), include detailed documentation: prior targeted testing performed, the intended clinical question, anticipated actionable findings, and plan for accessing resulting targeted therapies or trials. These tests have limited evidence for routine use and are frequently subject to prior authorization review.

Provide prior testing history (single-gene or panel results) and why broader sequencing is necessary.
State how identified alterations would be acted upon (e.g., available on-label options, off-label use with evidence, clinical trial enrollment).
Include lab accreditation and bioinformatics/reporting plan if available.

Step Therapy

Step Therapy and Preferred Assay Sequencing

Step therapy or preferred assay sequencing may apply in some clinical scenarios; when guideline-preferred assays exist (e.g., Oncotype DX or MammaPrint per NCCN/ASCO guidance for specific breast cancer subgroups), justify use of non-preferred assays and document prior use of preferred tests if applicable.

If a non-preferred assay is requested, include rationale and prior preferred assay results if available.
Document that alternative, guideline-recommended tests were considered or are unavailable.
For premenopausal node-positive breast cancer, note ASCO guidance regarding expected chemotherapy benefit regardless of assay result when applicable.

Note

Clinical Risk Assessment and Pre-Test Considerations

Some biomarkers are recommended prior to invasive procedures (e.g., certain prostate or thyroid biomarkers to avoid biopsy) and clinical risk assessment should be documented before genomic testing. Avoid ordering tests that will not change management when surgery or definitive therapy is already indicated.

Document clinical risk assessment and alternatives (repeat FNA, imaging) considered before molecular testing.
For prostate and thyroid, clarify whether results are intended to avoid or prompt biopsy/surgery.
Do not order molecular testing when the planned management would be unchanged by the result.

Tests and Uses Not Covered

Testing using broad NGS panels that interrogate more than 50 genes (or CGP) is considered not covered unless an exception in the policy explicitly permits the test. Other widely listed unsupported tests (for example, MRD assays, whole exome/genome/transcriptome analyses, multi‑cancer detection tests and several named commercial tests) are similarly not covered due to insufficient evidence of clinical utility. Use of unlisted multianalyte assays without appropriate coding (for example, CPT 81599) or inadequate documentation may trigger administrative review or denial.

This section provides an enumerated list of CPT/PLA and Category III codes associated with molecular oncology assays for billing and prior authorization workflows. The code list is informational only; prior authorization requirements and clinical coverage criteria remain governed by the policy’s medical necessity sections and applicable UnitedHealthcare rules. Use the specific procedure code that corresponds to the assay and document the clinical indication when requesting authorization or submitting claims.

Oncotype DX is not supported for predicting chemotherapy benefit in individuals with N2 disease (four to nine positive lymph nodes); evidence is insufficient to recommend its use in this population. Similarly, Prosigna is not intended for N2 and evidence does not support use of recurrence scores to guide chemotherapy decisions when four or more nodes are positive. Requests for these indications are therefore not covered.

BluePrint molecular subtyping alone has insufficient evidence to supplant pathological subtyping or to be used as a standalone determinant of treatment selection. BluePrint may be informative when used in conjunction with validated assays (for example, MammaPrint) but standalone use to dictate therapy is not supported.

Gene expression profiling assays and other genomic tests that lack sufficient peer‑reviewed evidence of clinical validity and utility—such as the 41‑gene panel, 76‑gene Rotterdam signature, and other named or proprietary assays listed in the policy—are not covered for routine clinical decision‑making. Coverage may be reconsidered if high‑quality prospective evidence supporting clinical benefit is published.

Genomic assays are not covered to guide systemic therapy decisions in individuals with HER2‑positive or triple‑negative breast cancer. Major guideline reviews do not recommend GEP use in these biologic subtypes and evidence does not support predictive utility for chemotherapy selection in these populations.

Several prostate cancer–related commercial assays lack adequate evidence to support routine use. Tests such as ExoDx Prostate, Select mdx, Confirm mdx, and similar assays have limited or low‑quality evidence for clinical utility and are therefore not routinely covered for guiding biopsy or treatment decisions unless robust supporting documentation is provided. Established genomic classifiers with stronger evidence (Decipher, Oncotype DX Prostate, Prolaris) may be considered when criteria are met.

Many molecular biomarkers and proprietary tests do not provide sufficient actionable data to change management in a way that improves outcomes. Assays lacking demonstrated clinical validity, comparative effectiveness, or impact on patient management are listed as not covered; exceptions require high‑quality evidence and explicit policy support.

Independent assessments (Hayes) identified limited or inadequate evidence for several thyroid molecular tests. Tests with insufficient or very low‑quality evidence may be not covered or may require additional justification; Afirma GSC and ThyroSeq v3 have more supportive data but some other platforms (e.g., ThyGeNEXT/ThyraMIR) were judged to have inadequate evidence to reclassify indeterminate nodules reliably.

Prognostic gene expression profiling for routine use in cutaneous melanoma is not covered because current platforms have not demonstrated clinically actionable utility beyond clinicopathologic variables. CancerTYPE ID and similar tumor‑of‑origin classifiers also lack consistent evidence of improved outcomes when used to direct standard empiric therapy for CUP, and routine use for these indications is not covered.

Routine use of CancerTYPE ID (tumor‑of‑origin GEP) and similar site‑of‑origin assays for cancers of unknown primary is not covered as standard management because randomized and comparative data do not demonstrate consistent clinical benefit from GEP‑directed site‑specific therapy versus empiric therapy. Molecular profiling may be considered selectively after histologic workup and when results could identify actionable targets or trial eligibility.

Prognostic multigene panels for colon cancer (for example, ColonSentry and Oncotype DX Colon Recurrence Score) lack sufficient evidence per independent assessments and guideline reviews, including Hayes and ASCO, and are therefore not covered for routine clinical use to guide adjuvant therapy decisions or recurrence risk estimation.

PancraGEN and similar pancreatic cyst risk classifiers were assessed as having insufficient evidence to support routine clinical use for pancreatic cyst risk stratification; multi‑cancer detection tests (MCD/MCED) are not supported for population screening. These uses are therefore not covered outside research or exceptional documented circumstances.

Routine use of whole genome/transcriptome analysis (WGTA), whole exome sequencing (WES), whole genome sequencing (WGS), and whole‑transcriptome sequencing (WTS) to inform clinical decision‑making is not covered due to insufficient peer‑reviewed evidence demonstrating consistent improvement in patient outcomes. Case‑by‑case consideration in research settings or when standard testing options are exhausted may be appropriate with prior authorization and supporting documentation.

Pre‑symptomatic ctDNA or other blood‑based cancer detection tests intended for asymptomatic early detection are not covered outside of prospective clinical trials. Guideline panels (NCCN, ASCO) and evidence reviews advise that such testing should be confined to research given current limitations in sensitivity, positive predictive value, and understood clinical impact.

Definitions and Test Descriptions

Comprehensive Genomic Profiling (CGP)

DefinitionNext-generation sequencing test able to detect multiple classes of genomic alterations (SNVs, indels, CNVs, rearrangements), MSI and TMB in a single sample

Typical specimenTumor tissue (FFPE) or matched tumor/normal specimens; may be performed on plasma cfDNA for specific panels

Panel sizeRanges from targeted panels (5-50 genes) to large CGP panels (51+ genes) and whole-exome/genome approaches

Liquid Biopsy

DefinitionTesting of bodily fluid (commonly plasma) to identify circulating tumor-derived DNA, RNA, cells, or other molecules for detection, treatment selection, or monitoring

Common applicationscfDNA for targeted mutation detection, MRD surveillance, and multi-cancer detection assays

Specimen considerationsPlasma cfDNA is typical; test performance varies by tumor type and stage

Measurable Residual Disease (MRD)

DefinitionVery small number of cancer cells or tumor-derived genetic material detectable during or after treatment; often assessed via highly sensitive NGS or tumor-informed assays

Assay typesTumor-informed (patient-specific) and tumor-naïve approaches; personalized assays require baseline tumor sequencing

Current evidence stancePrognostic information shown in select cancers but clinical utility for guiding therapy remains unproven for routine use

MRD (alternate)

Tumor-informed MRDAssays that use tumor tissue sequencing to design patient-specific ctDNA targets (example: Signatera)

PurposeDetects MRD post-treatment and may identify recurrence earlier than imaging

EvidenceEvidence predominantly retrospective or limited; clinical utility for guiding adjuvant therapy not established

Genomic sequence panel

DefinitionMulti-gene panels designed to interrogate sequence variants, copy number alterations, and rearrangements; categorized by gene count (eg, 5-50 genes; 51+ genes)

CodingCorresponds to CPT codes for 5-50 gene panels (81445/81449) and 51+ gene panels (81455/81456) as listed in the policy

SpecimensPerformed on tumor tissue (FFPE) or cfDNA depending on code/test; sample quality affects analytic success

Multi-gene analysis

DefinitionTesting that evaluates five or more genes collectively to inform diagnosis, prognosis, or therapy selection

IncludesExpression assays, targeted DNA/RNA panels, methylation assays, and larger CGP platforms

Policy noteSome multi-gene analyses lack sufficient evidence for routine coverage; refer to specific test evidence

Expression signature/recurrence score

DefinitionA defined combination of gene expression levels reported as a classifier, score, or index related to risk of recurrence or other outcomes

ExamplesOncotype DX RS, Prosigna ROR, MammaPrint risk categories, BCI score, EndoPredict EPclin

Clinical roleUsed to inform prognosis and, for some assays, to predict benefit from adjuvant therapy when applied to indicated populations

ROR (Prosigna)

TermROR (Risk of Recurrence) score from Prosigna (PAM50)

Genes measured50-gene PAM50 panel measured from FFPE tumor tissue

Intended populationPostmenopausal women with HR+ N0 or N+ (1-3) disease; not intended for N2

MammaPrint (70-GS)

TermMammaPrint (70-gene signature)

OutputBinary low- or high-risk classification for distant recurrence

SpecimenFresh, frozen, or FFPE tumor tissue; used in MINDACT trial evidence

BluePrint (80-GS)

TermBluePrint (80-gene) molecular subtype assay

PurposeClassifies tumors as Luminal A/B, HER2, or Basal to assign molecular subtype

Evidence noteEvidence insufficient to support BluePrint as sole determinant of therapy outside combined use with MammaPrint

EndoPredict / EPclin

TermEndoPredict / EPclin (12-gene)

Components8 disease-relevant genes + 3 normalization genes + 1 DNA reference; combines nodal status and tumor size to generate EPclin

Score rangeEPclin risk score ~1.1–6.2

Breast Cancer Index (BCI)

TermBreast Cancer Index (BCI)

CompositionCombines HOXB13:IL17BR ratio (H/I) with Molecular Grade Index (MGI) to predict late (5–10 year) and overall recurrence risk

Intended useMay inform extended endocrine therapy decisions in select patients (0–3 nodes)

DCISionRT

TermDCISionRT

OutputDecision score (0–10) combining molecular and clinicopathologic factors to stratify 10-year DCIS recurrence risk

Intended useInform radiotherapy decisions after breast-conserving surgery for DCIS; evidence limited

GEP / Genomic Expression Assay

DefinitionGenomic Expression Assays (GEP) — multi-gene tests that provide prognostic and sometimes predictive information to aid adjuvant therapy decisions

ExamplesOncotype DX, MammaPrint, Prosigna, BCI, EndoPredict

Clinical noteAppropriate use depends on tumor subtype, nodal status, menopausal status, and evidence for each assay

Genomic Classifier (GC) / GPS

DefinitionGenomic Classifier (GC) / Genomic Prostate Score (GPS) — transcriptomic or gene-panel assays to estimate risk of adverse pathology, biochemical recurrence, metastasis, and prostate-cancer specific mortality

ExamplesDecipher GC, Oncotype DX GPS, Prolaris (CCP/CCR)

Typical specimenProstate biopsy tissue or post-prostatectomy tissue (FFPE)

Decipher genomic classifier (GC)

TermDecipher genomic classifier (GC)

UtilityIndependently prognostic for biochemical failure, metastasis, adverse pathology, and prostate cancer-specific mortality in multiple studies and large cohorts

Evidence scaleMultiple systematic reviews and large real-world studies support prognostic validity, but impact on long-term outcomes remains uncertain

Oncotype DX Genomic Prostate Score (GPS)

TermOncotype DX Genomic Prostate Score (GPS)

Genes17-gene expression assay performed on prostate biopsy tissue

Clinical rolePredicts adverse pathology and aids preoperative counseling and management decisions

Prolaris (CCP/CCR)

TermProlaris (CCP/CCR)

DescriptionCell cycle progression (CCP) gene expression test and combined clinical-cell cycle risk (CCR) score providing prognostic information about tumor aggressiveness

Use caseMay inform selection of active surveillance versus definitive treatment in localized prostate cancer

ExoDx Prostate (EPI)

TermExoDx Prostate (EPI)

Assay typeUrine exosome three-gene expression assay intended to discriminate high-grade (≥GG2) prostate cancer

Cut-pointsValidated cut-points discussed: 15.6 and 20 with performance metrics as cited

Afirma GSC / ThyroSeq v3

ExamplesAfirma GSC, Afirma XA, ThyroSeq v3

PurposeCommercial molecular classifiers to assess malignancy risk in indeterminate thyroid nodules (Bethesda III/IV)

Performance summaryMeta-analyses show high sensitivity and NPV (TSv3 and GSC strong); specificity varies by platform

Afirma XA / GSC

TermAfirma XA / GSC

ScopeAfirma XA: expanded RNA panel (~593 genes/variants/fusions); Afirma GSC: whole-transcriptome RNA classifier for benign vs suspicious categorization

Intended useRule-out utility in Bethesda III/IV nodules with high sensitivity and NPV in pooled analyses

ThyroSeq v3 Genomic Classifier

TermThyroSeq v3 Genomic Classifier

PerformanceMeta-analyses and cohort studies report high sensitivity and NPV; TSv3 noted as best overall performer in cited meta-analysis

Intended populationBethesda III/IV indeterminate thyroid nodules

31-GEP / i31-GEP

Term31-GEP / i31-GEP

Genes31-gene expression profile for cutaneous melanoma

Intended usePredicts SLNB positivity risk and stratifies recurrence/mortality risk in T1–T2 melanoma when results would change management

GEP (general)

DefinitionGene expression profiling (GEP) — molecular tests that classify tumors into risk categories based on expression of selected genes

Clinical roleProvide prognostic or predictive information to guide treatment decisions in indicated settings

LimitationsClinical utility varies by assay and tumor type; some GEP uses remain investigational

PLA (Pigmented Lesion Assay)

TermPLA (Pigmented Lesion Assay)

MethodNon-invasive adhesive patch (tape-stripping) analyzing RNA markers (e.g., LINC00518, PRAME, TERT)

UseAdjunct to clinical/dermoscopic assessment to help rule out melanoma and potentially reduce unnecessary biopsies; evidence quality limited

GEP (definition duplicate)

NoteDuplicate of GEP definition — multi-gene expression tests used for prognostic/diagnostic classification

ContextSee GEP entries for assay-specific details and evidence-based indications

Policy implicationMany GEPs are covered in specific, evidence-aligned indications; others remain unproven

CGP (definition duplicate)

Duplication noticeCGP definition aligns with Comprehensive Genomic Profiling entry — NGS to detect classes of genomic alterations

OverlapCGP and large genomic panels mapped to CPT/PLA codes for 51+ gene panels and broad profiling

Coverage stanceCGP may be covered in select indications (e.g., CUP, advanced tumors) per criteria; broad panels >50 genes are generally not covered unless specified

MMR/MSI testing

TestMMR/MSI testing

PurposeIdentify Lynch syndrome, inform immunotherapy decisions in metastatic disease, and inform stage II adjuvant decisions

RecommendationUniversal MMR/MSI testing recommended for any person with colon or rectal cancer (NCCN)

cfDNA blood-based testing

DefinitionCell-free DNA (cfDNA) — circulating tumor-derived DNA fragments in plasma assessed for tumor mutations, methylation, or other markers

ApplicationsCRC screening (e.g., Shield), MRD, mutation detection when tissue unavailable; performance varies by indication and stage

Evidence cautioncfDNA screening shows promising sensitivity for CRC but lower sensitivity for advanced precancerous lesions; routine replacement of established screening not recommended

MMR/MSI (duplicate)

DuplicateMMR/MSI testing definition repeat — see MMR/MSI entry

UseTesting to inform Lynch syndrome workup and immunotherapy eligibility

Coding noteOften included in tumor profiling panels or single-gene assays; document results when ordering CGP

MCD test definition

DefinitionMulti-Cancer Detection (MCD/MCED) tests — blood-based assays (often methylation or cfDNA-based) designed to detect cancer signals across many organ types

Intended usePopulation screening of asymptomatic individuals — investigational pending outcome trials

Current stanceNot supported for population screening by guideline bodies; further prospective outcome studies needed

tumor-informed MRD assay definition

DefinitionTumor-informed MRD assay — personalized ctDNA assay using tumor tissue sequencing to design patient-specific blood targets

ExampleSignatera (tumor-informed personalized ctDNA assay)

Evidence noteShows prognostic detection of recurrence earlier than imaging in select studies, but routine clinical utility to guide therapy remains unproven

Signatera example

ExampleSignatera — individualized ctDNA assay using tumor exome sequencing to monitor MRD

Use-casePostoperative MRD surveillance in CRC and other cancers in studies; potential early recurrence detection

Policy noteRoutine use for guiding adjuvant therapy is not established; primarily used in research or select programs

MCD/MCED definition

DefinitionMulti-cancer detection (MCD/MCED) — blood tests analyzing cfDNA methylation or other signals to detect cancer across multiple types

PerformanceHigh specificity reported (often ≥95%) with variable sensitivity by cancer type and stage

Clinical recommendationNot recommended for routine population screening pending outcome data; consider in trials

Whole Genome/Transcriptome Analysis (WGTA)

DefinitionWhole Genome/Transcriptome Analysis (WGTA) — combined whole-genome (DNA) and whole-transcriptome (RNA) sequencing to detect somatic variants and expression changes

Potential valueHigh rates of actionable findings reported; RNA data often contributes substantially to therapy recommendations

LimitationsAccess to matched therapies, prospective outcome data, and feasibility limit routine coverage

ctDNA definition

DefinitionCirculating tumor DNA (ctDNA) — tumor-derived fragments of cell-free DNA in plasma assessed for tumor-specific mutations, copy number changes, or viral DNA

ApplicationsScreening, MRD detection, treatment monitoring, and mutation detection when tissue unavailable

Evidence cautionClinical utility varies by indication; routine use for MRD or screening is not yet supported outside trials

Molecular and genomic testing (including gene expression profiling, comprehensive genomic profiling, next‑generation sequencing, and liquid biopsy) can provide diagnostic, prognostic, and treatment‑selection information for solid tumors. This policy distinguishes assays with sufficient evidence and guideline support for specific indications from many other molecular tests that remain unproven, and it aligns coverage with published evidence, major professional society guidance, and independent test assessments. Use of covered assays generally requires that results will inform a specific management decision and that appropriate clinical documentation is provided.

Eligibility Requirements and Ordering Context

Policy‑level eligibility is determined by clinical indication, test‑specific intended use, and whether the test result is expected to change patient management. Requests for testing must document the clinical diagnosis, pertinent biomarker and staging information, and how the assay result will influence treatment or surveillance decisions. Benefit coverage remains subject to state, federal, and contractual terms applicable to the member.

Clinical eligibility for assays governed by this policy requires the ordering clinician to document that the individual meets the test‑specific criteria described in the policy (for example, hormone receptor and HER2 status and nodal status for breast GEP; Bethesda category for thyroid molecular testing; localized disease and life‑expectancy considerations for prostate genomic tests). Absent documentation that results will inform management, testing is unlikely to be approved.

For prostate genomic assays, testing is typically considered in the context of newly diagnosed localized prostate cancer or post‑prostatectomy when results would influence decisions such as selection for active surveillance versus definitive therapy, or adjuvant/salvage planning. The ordering clinician should document clinical risk group (NCCN risk category), life expectancy, and specific management decisions that testing will inform.

For indeterminate thyroid nodules (Bethesda III/IV), molecular testing is eligible when a validated commercial classifier (for example, Afirma GSC or ThyroSeq v3) is ordered to help decide between surveillance and diagnostic surgery and when test results would change management. Documentation should include cytology category, sonographic features, and discussion with the patient of benefits and limitations.

Breast gene expression profiling tests are eligible when used within the assay‑intended populations described in this policy (for example, early‑stage, hormone receptor–positive, HER2‑negative disease; node‑negative or select 1–3 node‑positive patients within applicable time windows) and when results will be used to inform adjuvant chemotherapy or extended endocrine therapy decisions. Document hormone receptor/HER2 status, nodal status, timing relative to diagnosis or surgery, and how results will alter management.

Melanoma GEP testing may be considered in T1–T2 cutaneous melanoma when the result would change the decision to perform a sentinel lymph node biopsy or alter surveillance intensity; given guideline cautions, testing should be limited to cases where clinical and clinicopathologic factors leave management uncertain and where documentation shows the result will influence care. Routine prognostic use without demonstrated impact on management is not eligible.

Comprehensive tumor profiling and WGTA/WES/WTS approaches are considered for advanced or metastatic disease when standard testing has been exhausted and identification of actionable variants may change systemic therapy choices or suggest clinical trial eligibility. These broad profiling approaches generally require prior authorization, multidisciplinary review, and documentation that results are likely to influence treatment. Routine use for initial staging or when results will not change management is not eligible.

Pre‑symptomatic ctDNA testing, routine MRD testing to guide adjuvant therapy decisions, and multi‑cancer detection (MCD) screening in asymptomatic individuals are not eligible for routine coverage and should only be performed in the setting of prospective clinical trials. Requests for such testing for screening or surveillance outside trials will be considered not medically necessary.

When testing is requested, required documentation should include relevant clinical data (e.g., pathology report, receptor status, staging, Bethesda cytology), the specific assay and CPT/PLA code, rationale for testing, and clear explanation of how the test result will impact management. Absence of such documentation may result in denial.

Coverage decisions are subject to the member’s benefit plan, state regulatory requirements, and UnitedHealthcare policies. Even when a test meets medical‑necessity criteria in this policy, prior authorization may be required per payer rules, and claims should include the specific assay code and supporting clinical documentation.

Ordering clinicians should generally be specialists involved in the individual’s cancer care (for example, oncologists, urologists, radiation oncologists, endocrine surgeons) who can interpret results and integrate them into management. Some assays (e.g., Prolaris) specify ordering by physicians who specialize in organ‑confined prostate cancer.

For thyroid molecular testing, clinicians should confirm that cytology is indeterminate (Bethesda III or IV), review sonographic and clinical features, and counsel patients regarding the test’s limitations and how results will influence the choice between surveillance and surgery. If clinical indications already mandate surgery, molecular testing is unnecessary.

When prognostic testing is performed (for example, uveal melanoma GEP), document discussion of biopsy risks and benefits, how prognostic information will alter surveillance or referral patterns, and multidisciplinary decision‑making. These records support appropriate use and prior authorization when required.

For tumor profiling in colorectal and pancreatic cancers, document prior tumor testing status (e.g., KRAS/NRAS/BRAF, MMR/MSI, HER2) and clinical stage; NGS panels are acceptable and preferred for determining targeted therapy–relevant alterations in advanced disease per guideline recommendations.

Additional Provider Guidance

Documentation Required

Offer genetic counseling and germline testing for males with breast cancer

Males with breast cancer should be offered genetic counseling and germline testing; include documentation of counseling and germline testing orders when applicable.

Document that genetic counseling was offered and whether germline testing was performed.
Oncologist should discuss results, risks, and implications with the patient.

Documentation Required

Document pre‑test counseling on benefits, limitations, and uncertainties

Document that patients were counseled on benefits, limitations, and uncertainties of molecular testing prior to ordering; counseling should be reflected in the medical record for authorization and clinical context.

For thyroid nodules and other molecular tests, include documented counseling per ATA/AAES guidance.
Record shared decision‑making conversation content when testing will influence major management.

Documentation Required

Document germline testing and counseling for pancreatic cancer per NCCN

NCCN recommends germline genetic testing for patients with confirmed pancreatic cancer; document that genetic counseling was provided and germline testing ordered per NCCN guidance when applicable.

Include documentation of germline testing orders and counseling in authorization submission for pancreatic cancer patients.
Follow NCCN germline testing pathways for justification.

Note

Prolaris requires specialist ordering—document ordering clinician specialty

Prolaris must be ordered by a physician specializing in organ‑confined prostate cancer (urology, radiation oncology, or medical oncology); include ordering clinician specialty in authorization requests.

List the ordering physician specialty on the request (required for Prolaris coverage).
Ensure the clinician documents intended use to guide active surveillance or definitive therapy decisions.

Note

Specialist ordering and result counseling expected (oncology/urology)

Ordering clinicians are typically oncology or urology specialists who can interpret results and counsel patients; documentation should show that an appropriate specialist is managing the test and follow‑up decisions.

Oncologists/urologists commonly order tests that guide adjuvant or surveillance decisions.
Document which specialist will act on results and provide patient counseling.

Documentation Required

Ordering clinician should counsel patient on results and management implications

When genomic assay results are returned, the oncologist (or ordering specialist) should counsel the patient about the meaning, risks, benefits, and how the result will influence management; document that counseling in the medical record.

Shared decision‑making documentation should accompany test results used to alter therapy.
Include a summary of the counseling discussion in the chart.

Note

Order complex assays from appropriate specialties and document rationale

Tests for CUP, uveal melanoma, and other complex indications are typically ordered in oncology or urology contexts; ensure the ordering specialty and clinical rationale are documented in the authorization request.

For CUP, document prior histology workup and intended use of profiling (diagnosis vs actionable alterations).
For uveal melanoma, document biopsy decision and planned management changes based on prognostic testing.

Prior Authorization

Order tests only when results will influence management and document intent

Only order genomic or molecular tests when results will influence management decisions; include explicit documentation that results will be used to change surveillance, therapy selection, or surgical approach.

For breast GEP, document that adjuvant chemotherapy will be considered/omitted based on assay result.
For thyroid nodules, document that molecular results will determine surgery vs observation.

Documentation Required

Require multidisciplinary discussion and documentation for uveal melanoma prognostic testing

For uveal melanoma prognostic testing, ensure multidisciplinary discussion (ophthalmology, oncology, pathology) regarding biopsy risks and expected management impact and document the discussion prior to ordering prognostic GEP.

Document the multidisciplinary review and patient counseling about biopsy risk and how prognostic class will change surveillance/referrals.
Record tumor metrics and planned follow‑up intensity tied to prognostic class.

Documentation Required

Document pathologist‑oncologist collaboration for CUP molecular testing

For CUP workup, ensure collaboration between pathologists and oncologists to justify use of immunohistochemistry, GEP, and NGS on a case‑by‑case basis and document the collaboration in the record or prior authorization request.

Document that standard histologic and IHC workup was completed prior to molecular testing.
State whether tumor tissue was available and, if not, why cfDNA was chosen.

Documentation Required

Document multidisciplinary oversight when ordering high‑complexity profiling

Where multidisciplinary care is appropriate for complex molecular testing decisions (e.g., WGTA/WES/WTS, MRD testing, high‑complexity CGP), document the team review and rationale for testing to support authorization.

Include multidisciplinary tumor board notes or summary when available.
Describe how the team intends to act on probable findings.

Note

Document oncology/gastroenterology ordering for pancreatic/colorectal tests

For pancreatic and colorectal molecular testing, ordering typically originates from oncology or gastroenterology specialists managing the patient; include specialty and rationale in the authorization request.

For pancreatic cancer, document that the patient is a candidate for systemic therapy and that profiling could identify actionable alterations (e.g., NTRK).
For CRC, document need for KRAS/NRAS/BRAF and MSI/MMR testing if not already done.

Note

Specialist oversight required when ordering investigational assays

When tests are investigational or lack strong evidence, specialist oversight is implied; ensure a specialist documents why the investigational assay is needed and how results will change management.

Specialist justification should include therapeutic options enabled by the result or trial access rationale.
Requests for investigational tests should include evidence of multidisciplinary review.

OpenPayer

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

Coverage Criteria and Evidence-Based Indications

Covered Indications (by Tumor Type and Test)

Applicable Procedure Codes and Coding Guidance

Provider Actions, Prior Authorization, and Documentation Requirements

Tests and Uses Not Covered

Definitions and Test Descriptions

Eligibility Requirements and Ordering Context

Background and Evidence Context

Additional Provider Guidance

Revision History and Administrative Notes