Molecular Oncology Testing for Solid Tumor Cancer Diagnosis, Prognosis, and Treatment Decisions (for Nebraska Only)
This part of the policy describes molecular and gene-expression assays used for solid tumor oncology (particularly breast cancer), summarizes evidence for several commercially available genomic assays, and lists applicable procedural codes for those tests. It is intended for clinicians and billing staff ordering, performing, or coding molecular oncology testing.
Policy Summary
PayerUnitedHealthcare
PolicyMolecular Oncology Testing for Solid Tumor Cancer Diagnosis, Prognosis, and Treatment Decisions (for Nebraska Only)
Policy CodePolicy N/A
Change TypeCode list update
Effective Date03/01/2026
Next Review DateN/A
Key ActionProviders should interpret genomic and gene-expression assay results alongside clinicopathologic factors and document how test results will influence management to support coverage and prior authorization requests.
Updated list of applicable CPT/PLA codes; added 0611U, 0612U, 0613U, and 81524 (03/01/2026).
21number of specific CPT/HCPCS codes listed in this excerpt
5major breast genomic assays discussed
>=5 genesdefinition used in policy for 'multi-gene' panels
90.9%
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total agreement between CNB and SR for MammaPrint (FLEX)
29.1%treatment recommendation change after MammaPrint/BluePrint (WSG-PRIMe)
03/01/2026Most recent policy revision date
Evidence-based Coverage Criteria and Clinical Conclusions
General evidence-based conclusions (narrative criteria)
Summarized findings and utility statements from the evidence and guideline bodies:
ALL of the following
MammaPrint (70-gene) combined with BluePrint (80-gene) provides prognostic classification and can predict chemotherapy sensitivity and endocrine sensitivity; useful for neoadjuvant and adjuvant decision-making in early ER+/HER2- breast cancer in select populations (e.g., clinical high-risk but genomic low-risk).
MINDACT trial: among clinically high-risk but genomic low-risk women, withholding chemotherapy resulted in a 1.5 percentage point lower 5-year distant metastasis-free survival vs chemotherapy; about 46% of clinically high-risk women might avoid chemotherapy based on 70-gene signature.
MammaPrint/BluePrint on core needle biopsy shows high concordance with surgical specimens (FLEX, NBREaST II), supporting use on CNB to guide neoadjuvant therapy decisions.
EndoPredict (EPclin) yields a risk score incorporating gene expression plus nodal status and tumor size; evidence supports prognostic value for 10-year distant recurrence risk in ER+, HER2- early-stage breast cancer but prospective outcome data and applicability in premenopausal women remain limited.
EndoPredict demonstrated predictive signal for response to neoadjuvant endocrine therapy (ABCSG-34 trial) and influenced adjuvant chemotherapy recommendations (Penault-Llorca study).
Breast Cancer Index (BCI) shows predictive value for benefit from extended endocrine therapy (EET) in several studies and meta-analysis; Hayes assessment found insufficient evidence to fully support BCI for predicting EET benefit or estimating late recurrence risk in all relevant populations—additional prospective data needed.
DCISionRT and Oncotype DX DCIS are assays intended to predict DCIS recurrence risk and potential radiotherapy benefit; current evidence is limited and Hayes assessments rate the evidence as low/insufficient, though registry and validation studies suggest potential prognostic and predictive utility that requires further validation.
Other gene expression assays (e.g., 41-gene, 76-gene 'Rotterdam', Breast Cancer Gene Expression Ratio/Theros H/I) lack sufficient evidence of clinical utility at this time.
Guideline guidance (ASCO, ESMO, NCCN): gene expression assays (Oncotype DX, MammaPrint, BCI, EndoPredict, ProSigna) may be used to guide adjuvant therapy in selected early-stage ER+/HER2- patients, with caveats by menopausal status and nodal involvement. No assays recommended for HER2+ or triple-negative disease for adjuvant chemo decision-making.
Clinical context and utility summary (narrative criteria)
Key assertions from evidence and guidelines regarding when molecular tests may be considered:
ANY of the following
Tissue-based genomic biomarkers (Oncotype DX Prostate/GPS, Decipher, Prolaris, ProMark) may be offered selectively when the assay result, considered with routine clinical factors, is likely to affect management (e.g., decision for active surveillance vs definitive therapy).
Routine ordering of molecular biomarkers is not recommended.
Decipher may be considered post-prostatectomy to inform adjuvant therapy decisions when adverse features are present (NCCN: category 2B).
Urine or serum adjunctive markers (e.g., ExoDx/EPI, MyProstateScore, Select mdx, PHI, 4Kscore) may be used to further risk stratify patients when the result would influence the decision to proceed with biopsy.
Test-specific evidence statements (evidence-based conclusions present in this part)
Summaries of clinical validity and utility findings by assay:
ANY of the following
Decipher genomic classifier: Multiple studies and systematic reviews (including a 42-study synthesis covering 30,407 individuals) show Decipher is independently prognostic for endpoints (biochemical failure, metastasis, adverse pathology, PCa-specific and overall survival); evidence strongest for intermediate-risk and post-prostatectomy decision-making. Prospective randomized trial evidence pending (NCT04396808).
Oncotype DX GPS: Multiple observational and prospective studies show GPS is independently predictive of adverse pathology (EPE, SVI, PSM) and may improve preoperative counseling and surgical planning; GPS associated with decisional conflict reduction and correlates with adverse pathology in RP specimens.
Prolaris/CCP/CCR: Evidence supports prognostic ability for mortality and progression in several cohorts; CCR score may increase selection and durability of active surveillance in low-risk patients, but limitations exist and Hayes assessments have found insufficient evidence for some Prolaris biopsy/post-prostatectomy uses regarding clinical utility.
Limitations and study-quality considerations
Common limitations reported across studies and assessments:
ALL of the following
Many studies are retrospective or observational, with potential selection bias.
Several studies had sample quality issues or substantial proportions of trial samples failing quality control (e.g., older archived tissues).
Multiple study authors have financial or employment ties to test manufacturers, introducing potential conflict of interest.
Prospective randomized clinical outcome trials demonstrating improved long-term patient outcomes from using these tests are limited or lacking.
Clinical utility and performance conclusions (narrative evidence synthesis)
Summarized findings and limitations from studies and assessments for molecular tests in thyroid nodules and melanoma.
ALL of the following
ThyroSeq v3 and Afirma GSC show high sensitivity and NPV in multiple studies and meta-analyses for Bethesda III/IV indeterminate thyroid nodules, potentially allowing rule-out of malignancy and avoidance of diagnostic surgery in many cases.
Study limitations include retrospective designs, lack of universal surgical confirmation for negative tests, limited long-term follow-up, and variable specificity/PPV between tests.
ThyroSeq v3 (prospective study) reported sensitivity ≈94-95%, specificity ≈82%, NPV ≈97% at a cancer/NIFTP incidence of 28%; false-negative rate ~3%.
Participants were from specialized centers; generalizability limited.
Afirma GSC and Afirma XA demonstrated high sensitivity/NPV in several large datasets, but standalone XA sensitivity was lower (49% in one series); XA may add genomic detail when used after GSC suspicious results.
Analytical validation shows reasonable reproducibility; clinical utility still requires more outcome data.
Guideline and evidence synthesis conclusions (narrative criteria)
Key summary conclusions and conditional guidance from guideline bodies and evidence assessments in this document segment:
ALL of the following
Ancillary molecular techniques (CGH, FISH, GEP) may be used as adjuncts for equivocal melanocytic neoplasms (AAD; NCCN).
Adjunct to clinical and expert dermatopathologic examination; interpret in context.
Routine prognostic molecular testing (including GEP) for cutaneous melanoma is discouraged until better use criteria are defined; application for clinical management is not recommended outside clinical studies (AAD).
Not recommended to guide sentinel lymph node eligibility, follow-up, or therapy outside studies.
Testing primary cutaneous melanoma for oncogenic mutations (e.g., BRAF, NRAS) is not recommended in the absence of metastatic disease (AAD).
Testing primary cutaneous melanoma for oncogenic mutations (e.g., BRAF, NRAS) is not recommended in the absence of metastatic disease (AAD).
Summary of evidence-based positions and recommended further action
This section describes evidence strength, guideline recommendations, and research needs for specific molecular tests:
ANY of the following
Cell-free DNA (cfDNA) blood tests for colorectal cancer screening (e.g., methylated SEPT9/Epi proColon, other cfDNA tests): Evidence shows modest sensitivity and high specificity in some studies; overall body of evidence judged low quality and not a replacement for standard screening. Professional societies (ACG, USPSTF) recommend against or do not include serum tests for CRC screening.
ColonSentry (7-gene RNA blood test): Hayes 2024 found insufficient evidence to support use for predicting CRC risk.
Oncotype DX Colon Recurrence Score (12-gene): Hayes 2024 found very low-quality evidence; limited support for routine use. Some studies show prognostic information when integrated with clinical-pathologic factors, but predictive value for treatment benefit is not established.
Novel gene expression signatures (e.g., 61-gene -> 15-gene signatures) for stage II CRC: Early validation studies report promising prognostic performance but require further prospective validation and assessment of impact on treatment decisions.
Evidence-based conclusions and practical recommendations in this section
Summarized conclusions from the studies and guideline bodies presented:
ALL of the following
Multi-cancer detection (MCD/MCED) tests show high specificity but variable sensitivity that increases with cancer stage; clinical utility for population screening and impact on mortality remain unproven and require further prospective study.
Examples: PATHFINDER, SYMPLIFY, CCGA validation; specificity often >99%, sensitivity stage-dependent.
When MCD detects a cancer signal, positive predictive value and accuracy for site-of-origin prediction can be high in some cohorts, but false positives and delays to diagnostic resolution occur.
PATHFINDER: 38% of signal-detected participants subsequently diagnosed with cancer; diagnostic median resolution 79 days.
NavDx / TTMV-HPV assays demonstrate promising sensitivity and high specificity in some studies for diagnosis and surveillance of HPV-related OPSCC, but evidence is limited in quality, lacks standardized protocols, and has insufficient demonstration of clinical utility to inform treatment decisions.
Hayes and ECRI assessments cited; 2023–2024 reviews find evidence insufficient for routine use.
Guideline statements referenced in this part
Selected guideline notes and conclusions referenced (informational only):
ANY of the following
NCCN Rectal cancer guideline indicates ctDNA has no proven role in the nonoperative management of rectal cancer.
NCCN Cutaneous Melanoma guideline (v3.2024) states that ctDNA and emerging molecular techniques should be prospectively compared for clinical utility; no recommendations regarding ctDNA are made.
FDA approvals and CLIA regulation information noted for laboratories — FDA approval alone is not a basis for coverage (informational).
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.
81450
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 mutation burden, and rearrangements.
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.
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 recurrence risk score.
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.
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.
81524
Oncology (central nervous system tumor), DNA methylation analysis of at least 10,000 methylation sites, utilizing DNA extracted from formalin-fixed tumor tissue, algorithm(s) reported as probability of matching a reference tumor family and class, and MGMT promoter methylation status, if performed.
81525
Oncology (colon), 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 a recurrence score.
81529
Oncology (cutaneous melanoma), mRNA, gene expression profiling by real-time RT-PCR of 31 genes (28 content and 3 housekeeping), utilizing formalin-fixed paraffin-embedded tissue, algorithm reported as recurrence risk, including likelihood of sentinel lymph node metastasis.
81540
Oncology (tumor of unknown origin), mRNA, gene expression profiling by real-time RT-PCR of 92 genes (87 content and 5 housekeeping) to classify tumor into main cancer type and subtype, utilizing formalin-fixed paraffin-embedded tissue, algorithm reported as a probability of a predicted main cancer type and subtype.
1–10 of 16
1/2
HCPCS / screening biomarker codeHCPCS
G0327
Colorectal cancer screening; blood-based biomarker
Procedure/assay codes mentioned or impliedmixed
G0452
Molecular pathology procedures — placeholder (document text does not list explicit CPT/HCPCS).
Actionable Billing, Authorization, and Documentation Guidance
Documentation Required
Use of assay-specific interpretation and clinicopathologic integration
Interpret breast gene-expression assay results in the context of clinicopathologic factors and integrate assay-specific interpretation (e.g., Recurrence Score models that combine RS with tumor grade, size, and age). Codes: 81520, 81521, 81519.
81520
81521
81519
Prior Authorization
Potential coding for unlisted tests
When a test does not map to a listed CPT, providers should submit unlisted molecular pathology codes and expect payer review prior to reimbursement; use 81479 or 81599 for novel multianalyte/algorithmic assays.
81479
81599
Key Definitions and Acronyms
Definitions
Multi-gene analysisFor this policy excerpt, generally refers to a gene panel containing five or more genes.
FFPEFormalin-fixed paraffin-embedded tissue
FNAFine needle aspirate
CNBCore needle biopsy
SRSurgical resection specimen
DMFSDistant metastasis-free survival
DRDistant recurrence
ET
Clinical and Technical Background
Technologies for molecular profiling of solid tumors span a wide range from targeted single‑gene assays to broad genome‑scale approaches. These include DNA sequencing (targeted panels, whole‑exome/genome), RNA expression assays and gene‑expression classifiers, microarrays, methylation profiling, and circulating tumor (cell‑free) DNA (cfDNA/ctDNA) 'liquid biopsy' techniques. For the purposes of this policy, a multi‑gene panel generally denotes assays evaluating five or more genes, and different platforms provide distinct types of information — DNA sequence variants, copy number changes, fusion events, methylation patterns, or composite expression scores derived from predefined gene sets (see assay descriptions and CPT/PLA code listings for assay‑specific details).
In breast cancer, several commercially available gene expression assays (GEAs) — notably Oncotype DX (21‑gene), MammaPrint (70‑gene), Prosigna/PAM50 (50‑gene), EndoPredict (12‑gene/EPclin) and the Breast Cancer Index (BCI) — produce prognostic recurrence risk estimates and, for some assays and subgroups, predictive information about the likely benefit of adjuvant chemotherapy or extended endocrine therapy. High‑quality prospective and prospective‑retrospective studies exist for the major assays, but the degree of predictive evidence varies by assay and clinical subset: Oncotype DX has the strongest prospective trial evidence supporting chemotherapy benefit prediction in specific populations, while MammaPrint demonstrated in MINDACT that a proportion of clinically high‑risk but genomically low‑risk women may safely avoid chemotherapy with only a small absolute difference in 5‑year distant metastasis‑free survival. Other assays (e.g., BCI, EndoPredict) supply prognostic data and may inform extended endocrine therapy decisions or neoadjuvant therapy selection, but prospective outcome evidence and applicability in premenopausal or node‑positive subgroups are more limited.
Evidence strength is assay‑ and population‑dependent. Systematic reviews and guideline assessments report that the five widely commercialized breast GEAs have high‑level evidence supporting prognostic capability in selected patient groups but differ in predictive performance across menopausal status, nodal involvement (node‑negative versus 1–3 positive nodes), and age. Several studies and registries show that GEAs change physician recommendations (for example, treatment recommendation change rates of ~29% for MammaPrint/BluePrint and ~36% after EndoPredict in prospective cohorts), and core needle biopsy results can be concordant with surgical specimens (MammaPrint/BluePrint concordance ~90.9%), supporting use of some GEAs on preoperative tissue to guide neoadjuvant decisions.
Policy Thresholds and Key Quantitative Cutoffs
Key thresholds and cutpoints
Multi-gene panel definition thresholdPanel containing five or more genes (policy definition).
MyProstateScore thresholdThreshold 10 for ruling out Grade Group ≥2 (reported sensitivity 97%, NPV 98%).
Policy Revision History
03/01/2026revisedLatest
Updated list of applicable CPT codes to reflect annual edits; added 0611U, 0612U, 0613U, and 81524 (policy history notes these code additions and archives previous policy version CS152NE.I).
Policy Summary
PayerUnitedHealthcare
PolicyMolecular Oncology Testing for Solid Tumor Cancer Diagnosis, Prognosis, and Treatment Decisions (for Nebraska Only)
Policy CodePolicy N/A
Change TypeCode list update
Effective Date03/01/2026
Next Review DateN/A
Key ActionProviders should interpret genomic and gene-expression assay results alongside clinicopathologic factors and document how test results will influence management to support coverage and prior authorization requests.
Other molecular biomarkers lacking sufficient evidence should not be offered.
ExoDx Prostate (EPI): Randomized controlled utility study shows EPI influenced biopsy decisions and reduced missed high-grade cancers in one trial; assay failure rates reported (~5.7%-7.1%). Diagnostic accuracy studies demonstrate improved discrimination vs standard of care; cutpoints trade sensitivity vs biopsy avoidance.
MyProstateScore: Large validation (n=1,525) suggests at threshold 10 the test has high sensitivity (97%) and NPV (98%) for ruling out GG≥2; further validation and long-term outcome data needed.
Select mdx and Confirm mdx: Hayes assessments (2024) found overall very low-quality evidence for Select mdx and insufficient evidence for Confirm mdx to inform clinical outcomes or repeat biopsy decisions; further study required.
Other genomic panels: Many commercially available tests lack sufficient evidence for clinical validity and utility at this time.
Hayes and other HTA assessments find limited-to-moderate quality evidence for some tests (Afirma GSC, ThyroSeq v3) for analytic/clinical validity, but insufficient evidence of improved health outcomes for several molecular panels.
Assessments highlight lack of reference-standard surgical follow-up for many negative results.
Clinical practice guidelines (ATA, AAES, AACE/ACE/AME, NCCN) generally endorse considering molecular testing as an adjunct for indeterminate thyroid cytology (Bethesda III/IV) but do not designate a single optimal test; testing should be selected based on the clinical question and institutional context.
Guidelines recommend counseling patients on benefits/limitations and considering local malignancy rates.
For cutaneous melanoma, 31-GEP tests (DecisionDx-Melanoma and others) and pigmented lesion assays (PLA) have variable evidence for prognostic stratification or triage of biopsy; evidence quality is low-to-moderate and clinical utility (impact on outcomes) remains uncertain.
Some studies report reductions in sentinel lymph node biopsy (SLNB) rates when 31-GEP is used to guide decisions, and registry analyses suggest survival associations, but causality and mechanism are unclear.
PLA (tape-stripping / DermTech) shows variable sensitivity and specificity across studies; concerns exist about study quality, sample failure rates, discordance with histopathology, and lack of outcome data.
Economic and real-world impact uncertain per HTA reports.
NCCN: Current GEP platforms for cutaneous melanoma do not provide clinically actionable prognostic information beyond clinicopathologic factors; clinical utility not established.
Prospective validation and comparison with CP models required.
NCCN (Uveal Melanoma): Biopsy not usually required for initial diagnosis but may be used when diagnostic uncertainty exists; molecular/chromosomal testing preferred over cytology if biopsy performed and helpful for prognostic stratification.
Risks/benefits of biopsy for prognostic purposes should be carefully considered.
Hayes assessments (various tests: PLA, myPath, DecisionDx-UM, CancerTYPE ID): overall evidence quality often low; many assessments conclude insufficient evidence to support routine clinical use for prognostication or to change management outside studies.
Specific tests have variable evidence; see individual study summaries.
For cSCC, multiple recent studies and consensus reports suggest 40-GEP can stratify metastatic risk and may inform adjuvant radiation therapy decisions, but many studies were retrospective and/or industry-supported; clinical guideline endorsement is limited.
Expert consensus exists but no broad guideline mandate.
For CUP, GEP and CGP/NGS can assist diagnosis in a subset of cases; DNA-based sequencing may offer greater diagnostic/therapeutic value than GEP in some studies, but randomized data showing outcome benefit of site-specific therapy guided by GEP/NGS are limited or mixed.
ESMO and NCCN do not recommend routine GEP-guided site-specific therapy; consider on case-by-case basis.
For CRC screening/recurrence prediction, evidence for blood-based cfDNA tests and transcript-based risk tests (e.g., ColonSentry) is evolving; current evidence insufficient to support routine use for risk prediction or screening replacement.
ECLIPSE study reported sensitivity/specificity for a cfDNA Shield test but further studies on outcomes and longitudinal testing needed.
CDX2 expression as prognostic biomarker: Retrospective studies suggest CDX2-negative tumors have worse outcomes and may derive benefit from adjuvant chemotherapy, but results are exploratory and need randomized validation.
Pancreatic cancer molecular testing (NGS of tumor or cyst fluid, PancreaSeq, PancraGEN, PancreaSeq Genomic Classifier): Some targeted NGS panels (e.g., PancreaSeq) show promise in identifying mucinous cysts and advanced neoplasia with high sensitivity/specificity in cohort studies; other tests (PancraGEN) currently lack sufficient published evidence per Hayes.
Note: Sample adequacy and analytic thresholds are limiting factors.
EUS-guided sampling approaches (TTNB, LBC, EUS-FNB) can provide material suitable for NGS in many cases; reported success rates vary and some samples fail nucleic acid thresholds.
Multi-cancer detection (MCD) blood tests (e.g., GRAIL Galleri): Early studies show high specificity and variable sensitivity that increases with stage; PATHFINDER feasibility study showed many positives are false positives and diagnostic workup burden exists. No professional society currently endorses MCD for population screening; evidence insufficient for demonstrated clinical utility in asymptomatic screening populations.
Tumor-informed ctDNA MRD assays (e.g., Signatera) show clinical validity signals in multiple retrospective/prospective observational studies for prognostication and early detection of recurrence, but robust prospective evidence demonstrating improved patient outcomes or standardized indications for routine use is lacking.
Hayes and NICE assessments note insufficient evidence for routine use; multiple ongoing trials.
Comprehensive tumor profiling (WES/WGS/whole transcriptome) can identify clinically actionable alterations and inform treatment in a subset of patients, but evidence is insufficient to broadly recommend these approaches as routine for informing clinical decision-making across all solid tumors.
Some programs (POG, pediatric WES/WTS) report actionable findings and therapeutic changes in a subset of patients.
Major oncology guideline organizations (ASCO, ESMO, NCCN) generally state insufficient evidence to recommend routine use of ctDNA/ctHPV/MCED/MRD assays for screening, surveillance, or to direct adjuvant therapy outside of clinical trials, with some conditional acknowledgment of prognostic validity in select settings.
NCCN: pre-symptomatic MCED only in clinical trials; NCCN panels caution routine MRD/ctDNA use outside trials.
Documentation Required
Use genomic assay results in shared decision-making
Incorporate multigene assay results (examples: MammaPrint, EndoPredict, BCI) into shared decision-making about adjuvant chemotherapy, endocrine therapy (including extended endocrine therapy), and radiotherapy when guideline criteria apply.
MammaPrint
EndoPredict
BCI
Prior Authorization
Potential prior authorization for genomic assays
Prior authorization processes commonly require documentation that the clinical indication and patient characteristics are consistent with guideline-supported uses (for example, ER+/HER2- early-stage disease with specified nodal status); follow payer-specific PA procedures.
Denial Risk
Denial risk if used outside guideline-supported populations
There is increased denial risk when genomic assays are used outside guideline-supported populations (e.g., HER2-positive or triple-negative disease, or patients with ≥4 positive nodes) because evidence does not support those uses.
Avoid use for HER2+ or triple-negative BC to guide adjuvant chemo decisions
No data supporting use in patients with four or more positive nodes
Documentation Required
Use tests alongside clinical judgement and other risk factors
Use gene-expression and molecular test results alongside clinical judgment, tumor staging, and other risk tools; explain how results will be interpreted in the context of clinical factors during shared decision-making.
Prior Authorization
No specific PA extracted in this excerpt
This policy excerpt does not specify an explicit prior authorization rule for genomic assays; it summarizes evidence and guideline-based indications only.
Documentation Required
Consider testing only when result will change management
Order molecular/genomic tests only when the result is expected to change management (e.g., active surveillance versus definitive therapy in prostate cancer; adjuvant vs no adjuvant therapy decisions).
Active surveillance vs definitive therapy decisions
Post-prostatectomy adjuvant therapy decisions when adverse features present
Documentation Required
Interpret results within clinical context
Interpret genomic test results in clinical context by combining assay findings with PSA, Gleason/Grade Group, clinical T stage, percent positive cores, and life expectancy; do not use genomic tests in isolation.
PSA
Gleason/Grade Group
Clinical T stage
Percent positive cores
Life expectancy
Prior Authorization
Expect selective use per guidelines
Document clinical rationale for selective use per guidelines (show how test results will influence decisions such as active surveillance eligibility or changes in surgical/radiation planning) to support coverage or prior authorization requests.
Denial Risk
Tests lacking evidence may be denied
Tests with insufficient evidence (examples: Select mdx, Confirm mdx) may be denied; provide clinical justification and evidence if ordering such assays.
Select mdx
Confirm mdx
Documentation Required
Counsel patients on molecular testing limitations
Counsel patients with indeterminate thyroid nodules about benefits, limitations, uncertainties, and possible need for ongoing surveillance or surgery despite negative molecular results.
Discuss variable specificity/PPV
Explain potential need for surveillance or surgery despite negative test
Documentation Required
Consider institutional malignancy rates when interpreting test performance
Assess and document local/institutional malignancy prevalence and test performance before applying published sensitivity/NPV estimates to patient care decisions.
Prior Authorization
Potential requirement for test justification
For molecular testing of indeterminate thyroid nodules, be prepared to document the cytology (Bethesda category) and clinical indication that justify testing (e.g., Bethesda III/IV where results will affect surgical decisions).
Document Bethesda category (III/IV)
Document that results will be used to make decisions about further surgery
Documentation Required
Use molecular tests as adjuncts and document clinicopathologic correlation
Use molecular assays (CGH, FISH, GEP, NGS) as adjuncts for melanocytic lesions or CUP and document clinicopathologic correlation; do not rely on GEP alone to make definitive management changes.
Document that molecular results were interpreted with clinical and dermatopathologic findings
Avoid sole reliance on GEP for definitive management
Prior Authorization
Consideration before prognostic/molecular testing for melanoma
Obtain prior authorization or robust medical necessity documentation when ordering prognostic/molecular GEP testing for melanoma to support coverage if used to guide management outside of clinical studies.
Documentation Required
Biopsy decision and prognostic testing in uveal melanoma
When performing biopsy for prognostic testing in uveal melanoma, document a discussion of biopsy risks and benefits and the rationale for prognostic molecular testing versus relying on clinicopathologic staging.
Documentation Required
CUP molecular testing rationale
For CUP molecular testing, document how the GEP/NGS results are expected to influence diagnosis or treatment selection and consider multidisciplinary review; outcome benefit from site-specific therapy guided by GEP is not established.
Document expected diagnostic or therapeutic impact
Consider multidisciplinary tumor board review
Documentation Required
Confirm sample adequacy and method for pancreatic/pancreatic cyst testing
Confirm and document specimen type and nucleic acid yield when ordering pancreatic or pancreatic cyst testing; studies report variable sample adequacy and failures to reach recommended DNA/RNA thresholds (many samples failed to reach >150 ng).
Record DNA/RNA yield (ng) and sample type (FFPE, LBC, frozen, cyst fluid)
Be aware of reported thresholds and failure rates
Prior Authorization
Consider confirmatory diagnostic pathway for positive MCD results
After a positive multi-cancer detection (MCD) blood test, providers should be prepared to pursue diagnostic workup (imaging, labs, procedures); PATHFINDER reported median diagnostic resolution times and substantial downstream testing burden.
Expect imaging and laboratory evaluation
Median diagnostic resolution reported (PATHFINDER)
Denial Risk
Limited evidence — potential for non-coverage or case-by-case review
Because evidence is limited for many emerging tests (examples: ColonSentry, PancraGEN, some PancreaSeq uses, multi-cancer detection), expect potential non-coverage, case-by-case review, or requirements for evidence submission.
ColonSentry
PancraGEN
PancreaSeq
MCD tests (e.g., Galleri)
Documentation Required
Use in clinical trials or with documented justification
Guideline bodies recommend offering MCD/ctDNA assays in the context of prospective clinical trials or with clear documentation that results will influence management; document trial participation or justification when ordering these tests.
Document clinical trial enrollment or rationale for testing
Follow guideline recommendations (NCCN/ASCO/ESMO)
Documentation Required
Interpretation caution and need for confirmatory diagnostics
Interpret positive MCD or ctDNA signals with caution and pursue appropriate confirmatory diagnostics (imaging, pathology); be aware of false positives and variable time to diagnostic resolution reported in feasibility studies.
Pursue site-directed imaging/pathology
Inform patients about potential false positives and delays
Denial Risk
Potential non-coverage / limited coverage risk
Many molecular/ctDNA assays lack sufficient evidence of clinical utility; payers may deem them experimental/investigational and not cover routine use outside guideline-recommended contexts or clinical trials.
Experimental/investigational coverage risk for numerous assays
Documentation Required
Use guidelines and evidence when ordering molecular/ctDNA tests
Order molecular and ctDNA tests in accordance with specialty guidelines (NCCN, ASCO, ESMO, ATA) and evidence; note that FDA approval alone does not guarantee coverage and laboratories are regulated under CLIA.
Follow specialty guideline indications
FDA approval alone is not a basis for coverage
Ensure testing lab CLIA compliance
Documentation Required
Check state/contractual requirements
Check federal, state, and contractual benefit plan requirements when determining coverage and prior authorization because those requirements may differ from this policy; in event of conflict, the state/contract governs.
Documentation Required
Note code updates
Update coding and billing lists to reflect newly added codes (0611U, 0612U, 0613U, and 81524) as noted in the 03/01/2026 policy revision.
0611U
0612U
0613U
81524
Endocrine therapy
NETNeoadjuvant endocrine therapy
NCTNeoadjuvant chemotherapy
GEAGene expression assay — a test evaluating expression of multiple genes to provide prognostic or predictive information.
ctDNA / cfDNACirculating tumor DNA / cell-free DNA — fragments of tumor-derived DNA detectable in blood, used for 'liquid biopsy' molecular testing.
GC / GECGenomic classifier / genomic expression classifier — multi-gene tests (e.g., Decipher, GPS) designed to predict prognosis or guide treatment decisions.
GPS (Genomic Prostate Score)Oncotype DX prostate genomic score — a 17-gene expression assay intended to predict adverse pathology and assist in risk stratification.
Decipher GCA genomic classifier (22-gene) that provides prognostic information including risk of metastasis and adverse outcomes; has evidence for use in post-prostatectomy settings.
Prolaris / CCP / CCRCell cycle progression (CCP) score (Prolaris) and combined clinical-cell-cycle risk (CCR) used for prognostication and active surveillance decision-making.
EPI / ExoDxUrine exosome gene expression assay (ExoDx Prostate IntelliScore) designed to risk-stratify for high-grade prostate cancer to inform biopsy decisions.
GGGrade Group (Gleason grade grouping) used to classify prostate cancer aggressiveness.
Bethesda categories III/IVCytology classifications denoting indeterminate thyroid nodule cytology: AUS/FLUS (III) and Follicular neoplasm / Suspicious for follicular neoplasm (IV).
NPVNegative predictive value — probability that a negative test result truly indicates absence of disease.
PPVPositive predictive value — probability that a positive test result truly indicates presence of disease.
GEC / GSCGenomic Expression Classifier (older) / Genomic Sequencing Classifier (Afirma versions) used to classify thyroid nodules as benign or suspicious.
31-GEP31-gene expression profile test (DecisionDx-Melanoma) intended to provide prognostic risk stratification for cutaneous melanoma.
PLAPigmented Lesion Assay — a noninvasive adhesive patch/tape-stripping test (eg, DermTech) that assays gene expression markers (e.g., LINC00518, PRAME, TERT) to assist triage of pigmented skin lesions.
GEPGene expression profiling — molecular assay classifying tumors by RNA expression patterns to provide diagnostic or prognostic information.
CGHComparative genomic hybridization — technique to detect copy number variations across the genome.
CUPCancer of unknown primary — metastatic malignancy for which the primary site cannot be identified after standard workup.
MFSMetastasis-free survival — time without development of distant metastasis.
cfDNACell-free DNA circulating in blood used for detection of tumor-derived alterations or methylation signatures.
MCDMulti-cancer detection blood tests that assay circulating biomarkers (often cfDNA methylation) to signal possible presence of cancer across multiple tissues.
NGSNext-generation sequencing used to detect mutations and other genomic alterations in tissue, cyst fluid, or blood.
MCD / MCEDMulti-cancer detection or multi-cancer early detection blood tests that analyze cell-free DNA methylation or other signals to detect presence and potential site of origin of multiple cancer types.
ctDNACirculating tumor DNA — tumor-derived fragmented DNA present in the bloodstream used for detection of tumor-specific alterations or residual disease.
TTMV-HPV DNA / NavDxTumor tissue-modified viral HPV DNA assays (NavDx) designed to detect circulating HPV DNA associated with HPV-related cancers (e.g., oropharyngeal squamous cell carcinoma) for diagnosis or surveillance.
Tumor-informed MRD assayPersonalized ctDNA test (e.g., Signatera) that first sequences tumor tissue to design individualized assays to monitor molecular residual disease post-treatment.
WGTA / WES / WGS / WTSWhole genome/transcriptome/exome or whole-transcriptome sequencing approaches for comprehensive tumor profiling to identify somatic and germline alterations.
CLIAClinical Laboratory Improvement Amendments — federal standards for laboratory testing; laboratories performing genetic tests are regulated under CLIA.
InterQualA third-party clinical criteria tool UnitedHealthcare may use to assist in administering health benefits.
At the same time, important limitations exist across studies: many analyses are retrospective or prospective‑retrospective, some cohorts were enriched or selected and may not generalize to all clinical populations, archived sample quality and assay failure rates have been reported, and conflicts of interest are common among study authors. Prospective randomized trials demonstrating long‑term patient benefit from assay‑directed management remain limited for many tests, and guideline bodies emphasize integrating genomic results with clinicopathologic factors and shared decision‑making rather than using assays in isolation.
In practice, assay results should be interpreted in the context of tumor stage, nodal status, menopausal status (where relevant), comorbidities, and patient preferences. For breast cancer this means using GEAs selectively in early‑stage, hormone receptor‑positive, HER2‑negative disease — typically node‑negative or with 1–3 positive nodes — and tailoring expectations to the specific assay's evidence base (for example, Oncotype DX for chemotherapy prediction in selected patients; MammaPrint to identify clinically high‑risk but genomically low‑risk patients per MINDACT; BCI for considerations about extended endocrine therapy). Documentation of clinical indication and discussion with the patient about the assay’s prognostic versus predictive role and evidence limitations is recommended prior to testing.
Uveal melanoma tumor thickness risk thresholdsClass 2 tumors: thickness ≥ 7.0 mm associated with increased metastasis risk vs <7.0 mm; Class 1 tumors: thickness ≥ 9.0 mm associated with increased risk vs <9.0 mm.
cfDNA test invalid result rate (ECLIPSE)Invalid cfDNA test results reported at 3.7% in ECLIPSE study.
MCD positive rate (PATHFINDER)1.4% of tested adults ≥50 years had a detected cancer signal in PATHFINDER.
True-positive proportion among MCD positives (PATHFINDER)38% of MCD-positive participants were subsequently diagnosed with cancer (PATHFINDER true-positive proportion).
cfDNA test sensitivity/specificity examplesECLIPSE Shield: sensitivity 83.1% for CRC, specificity ~89.6% for advanced neoplasia (study results reported).
SYMPLIFY / MCED performance notesSYMPLIFY (symptomatic) reported PPV 75.5%, sensitivity 66.3%, specificity 98.4%; MCED specificity often >99% with sensitivity increasing by stage (literature summary).
Policy numeric definition summaryPolicy statistics note 'multi-gene' definition as >=5 genes and list related thresholds and rates in studies (see policy thresholds table).
6,693MINDACT trial participants
90.9%CNB vs SR concordance for MammaPrint (FLEX)
29.1%Treatment recommendation change rate after MammaPrint/BluePrint (WSG-PRIMe)
36%Treatment decision change rate after EndoPredict (Penault-Llorca prospective study)