ModifiedCentenePolicy N/A

Molecular Analysis of Solid Tumors and Hematologic Malignancies

Policy governing molecular (somatic) genomic testing of solid tumors and hematologic malignancies to identify driver mutations, tumor characteristics (e.g., TMB, MSI, fusions), and guide targeted therapy selection; affects providers ordering tumor or hematologic malignancy molecular profiling. This window covers overview and coding examples.

Policy Summary

PayerCentene

PolicyMolecular Analysis of Solid Tumors and Hematologic Malignancies

Policy CodePolicy N/A

Change TypeMultiple additions and revisions (MRD, TMB, code updates, scope expansions)

Effective DateN/A

Next Review DateNov 1, 2025

Key ActionDocument required clinical documentation to support diagnosis, stage, and that testing will change management and obtain prior authorization when specified codes/criteria apply.

SourceLink

POLICY UPDATE CHANGES

Solid Tumor Minimal Residual Disease (MRD) Testing criteria and related default frequency guidance were added.

HPV-related MRD testing indications and CMS LCD criteria were incorporated.

Multiple updates to lists of CPT/HCPCS and U-codes and to panel/test definitions (e.g., replacing certain codes and adding Broad RNA Fusion Panel Tests).

Tumor Mutational Burden (TMB) guidance aligned with multiple NCCN tumor-specific recommendations and FDA KEYTRUDA label for TMB-H (>=10 mut/Mb).

Added Solid Tumor Minimal Residual Disease (MRD) Testing criteria and CPT code 0422U to the policy reference table; added CPT codes 81457–81459 for tumor-type agnostic panels.

Replaced CPT code 0329U with 0297U under Cancer Exome and Genome Sequencing and removed CPT 0079U from Genetic Testing to Confirm the Identity of Laboratory Specimens.

Broad RNA Fusion Panels are now covered for acute lymphoblastic leukemia; multiple tumor-type expansions and alignment edits made across tumor-specific criteria to match updated NCCN guidance.

Tumor Mutational Burden (TMB) criteria restructured to any recurrent, refractory, metastatic, or advanced stage III/IV cancer (excluding CNS tumors) with progression and no satisfactory treatment options.

HLA typing for transplantation criteria set was created and investigational designation removed for appropriate transplant indications.

Coverage expanded for tumor-specific CEBPA and ESR1 variant analyses per updated NCCN guidance.

Trek Health ingests and normalizes Transparency in Coverage data and payer policy updates to give provider organizations a clear view of how commercial reimbursement behaves across markets, payers, and services. Our platform transforms raw payer disclosures into structured intelligence that supports contract evaluation, payer negotiations, and service line strategy. By combining market benchmarks with ongoing policy visibility, Trek helps teams identify variability, risk, and opportunity in commercial reimbursement. The result is faster insight, stronger negotiating positions, and more informed financial decisions.

11/2024Last revision

0422UNew MRD CPT

81457-59Added agnostic panel codes

once/diagnosisDefault MRD frequency

>=10 mut/MbTMB-H threshold

MRD tissue, HLA non-transplantInvestigational areas

Coverage Criteria

Myeloproliferative Neoplasms (MPNs) Panels

I. Myeloproliferative neoplasm (MPN) molecular profiling panels (81206, 81207, 81208, 81219, 81270, 81279, 81338, 81339) are considered medically necessary when ALL of the following are met:

ALL of the following

The member/enrollee is suspected to have a myeloproliferative neoplasm (MPN) (examples: polycythemia vera, essential thrombocythemia, primary myelofibrosis, chronic myeloid leukemia).
The panel includes, at a minimum, testing of the following genes: JAK2, CALR, and MPL.
The testing is part of the member's initial genetic evaluation for suspected MPN, OR prior single-gene testing for JAK2, CALR, and MPL was negative and broader panel testing is now needed to evaluate for additional somatic alterations.

Tumor Specific BCR/ABL1 Kinase Domain Analysis

I. Tumor-specific BCR::ABL1 kinase domain analysis (81170) is considered medically necessary when ALL of the following are met:

ALL of the following

The member/enrollee has a diagnosis of chronic myeloid leukemia (CML) OR Philadelphia chromosome–positive acute lymphoblastic leukemia (Ph-positive ALL).
There is clinical concern for resistance or treatment failure such as inadequate initial response to tyrosine kinase inhibitor (TKI) therapy, loss of response to TKI therapy, disease progression to accelerated or blast phase, or relapsed/refractory disease.

Tumor Specific BCR/ABL1 FISH, Qualitative, or Quantitative Tests

I. Tumor-specific BCR::ABL1 FISH, qualitative, or quantitative tests (0016U, 0040U, 81206, 81207, 81208, 81479, 88271, 88274, 88275, 88291) are considered medically necessary when ANY of the following indications are present:

ANY of the following

The member/enrollee is suspected to have a myeloproliferative neoplasm (e.g., polycythemia vera, essential thrombocythemia, primary myelofibrosis, chronic myeloid leukemia).
The member/enrollee is undergoing diagnostic workup for acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), chronic myeloid leukemia (CML), or B‑cell lymphoma.
Quantitative BCR::ABL1 testing is being used to monitor disease progression or minimal residual disease (MRD) when monitoring will inform management for ALL, AML, CML, or B‑cell lymphoma.

NSCLC Molecular Profiling

I. Lung cancer focused molecular profiling panels (0022U, 81457) are considered medically necessary when ALL of the following are met:

ALL of the following

The member/enrollee has a diagnosis of advanced (stage IIIb or higher) or metastatic lung adenocarcinoma, large cell lung carcinoma, squamous cell lung carcinoma, or non-small cell lung cancer (NSCLC) not otherwise specified (NOS).
The member/enrollee is seeking further cancer treatment (e.g., systemic therapy).

ALL of the following

Repeat testing: Repeat lung cancer–focused molecular profiling panels are considered medically necessary when there is documented progression on targeted therapy for non-small cell lung cancer.

Cutaneous Melanoma Molecular Profiling

I. Cutaneous melanoma focused molecular profiling panels (81445, 81457) are considered medically necessary when ALL of the following are met:

ALL of the following

The member/enrollee has stage III melanoma or higher, OR recurrent melanoma.
The member/enrollee is seeking further cancer treatment (e.g., systemic therapy).
Either the member has not had previous somatic testing via a multigene cancer panel for the same primary melanoma diagnosis, OR the member previously had panel testing for a prior primary melanoma and now has a new primary melanoma for which testing is ordered.

Acute Myeloid Leukemia / Myelodysplastic Syndromes

I. Acute myeloid leukemia (AML)–focused molecular profiling panels (0050U, 81450) are considered medically necessary when ANY of the following are present:

ANY of the following

The member/enrollee has a suspected or confirmed diagnosis of acute myeloid leukemia (AML).

ALL of the following

Repeat testing for hematologic panels: Repeat broad molecular profiling panels (81450, 81455) are considered medically necessary when the member has relapsed or refractory AML, or has relapsed after allogeneic hematopoietic cell transplant, or when disease progression on treatment necessitates repeat genomic evaluation to guide management.

Myeloproliferative Neoplasms (MPN) — Additional Guidance

I. Myeloproliferative Neoplasms (MPN) — single-gene and panel testing considerations

ANY of the following

Tumor-specific JAK2 variant analysis (0017U, 0027U, 81270) is medically necessary when the member is suspected to have an MPN, has ALL, or is suspected to have MDS.
Tumor-specific CALR (81219) and MPL (81338, 81339) variant analyses are considered medically necessary when the member is suspected to have an MPN or suspected to have MDS.
When initial targeted testing (e.g., JAK2) is negative but clinical suspicion remains, multigene MPN panels that include JAK2, CALR and MPL are appropriate and considered medically necessary as described in the MPN Panels criteria.

BCR::ABL1 Testing

I. Tumor-specific BCR::ABL1 testing summary — diagnostic and monitoring contexts

ANY of the following

Cytogenetic or FISH-based detection of BCR::ABL1 is medically necessary for diagnostic evaluation when CML or Ph‑positive ALL is suspected.
Quantitative BCR::ABL1 PCR testing is medically necessary for monitoring response to therapy and for MRD assessment when the results will guide change in management (dose change, therapy switch, or transplant consideration).

Guideline-supported covered indications

Guideline-supported covered indications: the policy aligns with NCCN/ASCO/CMS recommendations. Examples below summarize covered, guideline-supported scenarios (not exhaustive):

ANY of the following

NSCLC: molecular testing (broad NGS panel or equivalent) for advanced/metastatic disease and for earlier-stage disease when perioperative systemic therapy is being considered (NCCN).
Colorectal cancer: testing for KRAS, NRAS, and BRAF for all patients with metastatic colorectal cancer (NCCN).
Ovarian, fallopian tube, primary peritoneal cancer: somatic BRCA1/2 testing to inform maintenance therapy (NCCN/ASCO).
MPN: initial testing for JAK2, and if negative, testing for CALR and MPL, or use of a multigene panel including these genes (NCCN).

Solid Tumor MRD Testing - Medically Necessary

I. Evidence-based solid tumor minimal residual disease (MRD) testing (cell-free DNA tests: 0340U, 0422U, 81479) is considered medically necessary when ALL of the following are met:

ALL of the following

The identification of recurrent, refractory, or progressive disease would require a change in management.
The member is not undergoing concurrent molecular laboratory testing for surveillance or monitoring for recurrent, refractory, or progressive disease (to avoid duplicative testing).
One of the following clinical contexts applies:
ANY of the following
- The member is currently being treated for cancer and (a) the test has not previously been done for this cancer diagnosis, OR (b) there is clinical suspicion that the tumor molecular profile has changed.

Coding and Procedure Codes

Tumor-Type Agnostic / Common Panel CPT Codes (examples)CPT

0037U	Tumor-type agnostic solid tumor molecular profiling panel (FoundationOne CDx example)
0048U	Tumor-type agnostic solid tumor molecular profiling panel (MSK-IMPACT example)
0250U	Tumor-type agnostic solid tumor molecular profiling panel (PGDx elio tissue complete example)
0329U	Tumor-type agnostic solid tumor molecular profiling panel (Oncomap ExTra example)
0334U	Tumor-type agnostic solid tumor molecular profiling panel (Guardant360 TissueNext example)
0379U	Tumor-type agnostic solid tumor molecular profiling panel (Quest Expanded Panel example)
0391U	Tumor-type agnostic solid tumor molecular profiling panel (Strata Select example)
0473U	Tumor-type agnostic solid tumor molecular profiling panel (example)
0481U	Tumor-type agnostic solid tumor molecular profiling panel (example PLA/unique test identifier)
81445	Targeted multi-gene tumor panel (CPT)

1–10 of 14

1/2

RNA Fusion Panel CodesCPT

81449	Targeted RNA fusion panel (5-50 genes)
0444U	Aventa FusionPlus (broad RNA fusion PLA)
81456	Broad RNA fusion panel (CPT)

Hematologic / Myeloid Panel CodesCPT

81450	Broad molecular profiling panel for hematologic malignancies
81455	Comprehensive hematologic/myeloid panel (CPT)
81450	(duplicate entry intentionally consolidated)

Tumor-specific and single-gene testing codesCPT

81170	BCR/ABL1 kinase domain analysis
81210	BRAF variant analysis
81162	BRCA1/2 tumor NGS
81219	CALR variant analysis
81218	CEBPA variant analysis
81235	EGFR variant analysis
81479	ESR1 variant analysis or TMB/Misc mapping as used
0023U	FLT3 variant assay (example PLA)
0046U	FLT3 MRD assay (example PLA)
81120	IDH1 variant analysis

1–10 of 17

1/2

Example ICD groups referencedICD-10

C00-D49	Neoplasms, benign and malignant range (example group)
Z85	Personal history of malignant neoplasm
C91	Lymphoid leukemias
C34	Malignant neoplasm of bronchus and lung
C71	Malignant neoplasm of brain
C96	Other and unspecified malignant neoplasms of lymphoid, hematopoietic and related tissue
D46.9	Myelodysplastic syndrome, unspecified
C92	Myeloid leukemias

Tumor-Type Agnostic Panels (Covered with criteria)CPTCovered

0037U	Covered tumor-type agnostic panel (example)
0048U	Covered tumor-type agnostic panel (example)
0250U	Covered tumor-type agnostic panel (example)
0329U	Covered tumor-type agnostic panel (example)
0334U	Covered tumor-type agnostic panel (example)
0379U	Covered tumor-type agnostic panel (example)
0391U	Covered tumor-type agnostic panel (example)
0473U	Covered tumor-type agnostic panel (example)
0481U	Covered tumor-type agnostic panel (example PLA/unique test identifier)
81445	Covered targeted multigene panel

1–10 of 14

1/2

Targeted RNA Fusion Panels (covered)CPTCovered

81449

Targeted RNA fusion panels (5-50 genes) — covered when criteria met

Broad RNA Fusion Panels (covered)CPTCovered

0444U	Aventa FusionPlus PLA — covered for ALL per criteria
81456	Broad RNA fusion panel CPT — covered for ALL per criteria

Hematologic malignancy panels (covered)CPTCovered

81450

Broad molecular profiling for hematologic malignancies — covered when criteria met

MPN panels / related codesCPT

81206	MPN panel component JAK2 testing
81207	MPN panel component
81208	MPN panel component
81219	CALR variant analysis
81270	JAK2 variant analysis (CPT)
81279	MPN-related test code
81338	MPL variant analysis
81339	MPL variant analysis

Single-gene and other tumor-specific testsCPT

81170	BCR/ABL1 kinase domain analysis
81162	BRCA1/2 tumor NGS
81210	BRAF variant analysis
81235	EGFR variant analysis
81275	KRAS variant analysis
81276	KRAS variant analysis
81287	MGMT promoter methylation analysis
81288	MLH1 promoter methylation analysis
81301	MSI analysis
81311	NRAS variant analysis

1–10 of 21

1/3

Tumor Specific IDH1/IDH2CPT

81120	IDH1 variant analysis
81121	IDH2 variant analysis

Tumor Specific IGHVCPT

81261	IGHV somatic hypermutation analysis
81262	IGHV somatic hypermutation analysis
81263	IGHV somatic hypermutation analysis

Tumor Specific JAK2CPT

0017U	JAK2 variant PLA
0027U	JAK2 variant PLA
81270	JAK2 CPT

Tumor Specific KITCPT

81272	KIT variant analysis
81273	KIT variant analysis

Tumor Specific KRASCPT

81275	KRAS mutation analysis
81276	KRAS mutation analysis

Tumor Specific MGMT methylationCPT

81287

MGMT promoter methylation analysis

Tumor Specific MLH1 methylationCPT

81288

MLH1 promoter methylation analysis

Tumor Specific MPLCPT

81338	MPL variant analysis
81339	MPL variant analysis

Tumor Specific MSICPT

81301

Microsatellite instability analysis

Tumor Specific NRASCPT

81311

NRAS variant analysis

Tumor Specific NPM1CPT

0049U	NPM1 PLA
81310	NPM1 CPT

Tumor Specific PIK3CACPT

0155U	PIK3CA PLA
81309	PIK3CA CPT

Tumor Specific TP53CPT

81352

TP53 variant analysis

HLA Typing for TransplantationCPT

81370	HLA typing
81371	HLA typing
81372	HLA typing
81373	HLA typing
81376	HLA typing
81378	HLA typing
81379	HLA typing
81380	HLA typing
81382	HLA typing

Hematologic MRD testingCPTCovered

0171U	MRD NGS-based assay (hematologic)
0364U	MRD assay (hematologic)

Evidence-Based cfDNA MRD (covered with criteria)CPTCovered

0340U	Signatera (example cfDNA MRD)
0422U	Guardant360 Response/Reveal (cfDNA MRD)
81479	TMB/related mapping used in MRD context

Emerging MRD (investigational)CPTExperimental

0229U	Emerging MRD PLA (investigational)
0306U	Emerging MRD PLA (investigational)
0307U	Emerging MRD PLA (investigational)

HPV-related cfDNA MRD (covered with criteria)CPTCovered

0356U

NavDx HPV-related cfDNA MRD assay

Provider Actions and Authorization

Billing Rule

Confirm coding and authorization before submission

Coding references in this policy are provided for informational purposes only; inclusion or exclusion of any CPT/PLA/HCPCS codes in the document does not guarantee coverage. Providers must confirm the correct billing codes and any prior-authorization requirements with the payer and current coding guidance before claim submission.

Prior Authorization

Prior authorization expected for tumor‑agnostic panels and 81449

Certain tumor-type agnostic panel codes and targeted RNA fusion panel 81449 are covered only when the member meets the policy's medical necessity criteria; documentation of diagnosis, stage, and prior testing is expected for authorization.

Examples of tumor-type agnostic panel codes: 0037U, 0048U, 0250U, 0329U, 0334U, 0379U, 0391U, 0473U, 81445, 81455, 81457-81459

Not Covered / Investigational

The examples of tests, laboratories, CPT codes, and ICD codes included in this policy are provided for informational purposes only and are not comprehensive. Inclusion or exclusion of any code does not guarantee coverage; providers should confirm current coding and authorization requirements prior to claim submission.

Targeted RNA fusion panels (CPT 81449) and tumor-type agnostic multigene panels are covered only for the specific indications enumerated in the policy (for 81449: ALL, glioma, histiocytosis, sarcoma, KIT/PDGFRA‑negative GIST, NSCLC after negative DNA‑based NGS, and metastatic/advanced solid tumors when a fusion‑targeted therapy is approved or DNA testing was negative). Use of these panel types for indications not listed in the policy is considered investigational and not medically necessary.

Any use of the listed tumor‑type agnostic panels (e.g., PLA/CPT codes such as 0037U, 0048U, 81445, 81457–81459) outside the explicitly enumerated covered diagnoses or clinical situations is considered investigational and not medically necessary. Repeat use is only allowed in the limited progression scenarios specified in the criteria.

Minimal residual disease (MRD) analyses that currently lack sufficient evidence of clinical validity (for example, tissue‑based MRD listed under codes 0229U, 0306U, 0307U) are considered investigational. HLA typing is medically necessary only for donor/recipient evaluation for bone marrow or solid organ transplantation and is investigational for non‑transplant indications.

The policy identifies certain solid tumor MRD assays with insufficient evidence, cancer exome/genome sequencing (examples: 0036U, 0297U, 81415, 81416, 81425, 81426), and separately billed specimen identity/genetic confirmation testing (e.g., 81265, 81266, 81479) as investigational when billed outside established criteria; these tests therefore are not covered per the policy.

Definitions

inv-160: Somatic genomic profiling definition

DefinitionSomatic genomic profiling: testing of tumor tissue (or hematologic samples) to identify somatic oncogenic mutations for diagnosis, prognosis, and treatment selection.

Specimen sourcesIncludes direct tumor tissue testing and, for hematologic malignancies, blood or bone marrow sampling; cfDNA is covered elsewhere.

PurposeAims to identify driver mutations to inform targeted therapy, prognosis, diagnosis, and potential MRD monitoring.

inv-161: Tumor characteristics (TMB, MSI, gene fusions)

Tumor characteristics includedTumor characteristics include tumor mutational burden (TMB), microsatellite instability (MSI)/MMR status, and gene fusions.

Clinical relevanceThese characteristics can predict response to therapies (e.g., immunotherapy) and guide testing across tumor types.

Covered Indications (by tumor/test)

Eligibility Requirements

Eligibility requirements for specific tests are detailed within each criteria group above; refer to the per‑test criteria sections for the required diagnosis, prior testing, and timing conditions that must be met for medical necessity.

Document‑level eligibility notes: clinical documentation must support the diagnosis, disease stage, prior testing results (for example prior DNA‑based NGS when required), and that identification of recurrence or progression would change management. For certain assays (e.g., evidence‑based cfDNA MRD and TMB), test‑specific timing and prior‑test conditions apply and are listed in the respective criteria.

Per‑code eligibility: tumor‑type agnostic panel and targeted RNA fusion panel codes require that the member meet the specific clinical indications listed for those CPT/PLA codes; submission should include documentation of diagnosis, stage, and prior testing where applicable.

Targeted RNA fusion panel (CPT 81449) eligibility requires one of the listed diagnoses or scenarios (e.g., ALL, glioma, KIT/PDGFRA‑negative GIST, NSCLC after negative DNA NGS). Broad RNA fusion panels (0444U, 81456) are medically necessary only for acute lymphoblastic leukemia.

Tumor‑type agnostic panels (codes such as 0037U, 0048U, 81457–81459) have defined covered tumor types and scenarios (e.g., advanced/metastatic disease, NSCLC regardless of stage, resectable pancreatic adenocarcinoma); panels used outside those enumerated indications are investigational.

Broad molecular panels for hematologic malignancies (e.g., 81450, 81455) are medically necessary for initial evaluation or diagnosis in AML, newly diagnosed ALL, MDS, suspected MPN (including after negative JAK2/CALR/MPL testing), and CML with progression as specified in the criteria.

Background

Molecular analysis of tumors identifies somatic oncogenic or 'driver' mutations that inform targeted therapy selection, diagnostic clarification, prognostic assessment, tumor characteristics (such as TMB, MSI, and gene fusions), and in validated settings, minimal residual disease (MRD) monitoring. Testing approaches include tumor‑only and tumor‑normal paired analyses; providers should counsel patients about the potential for incidental germline findings prior to somatic profiling.

Revision History

2024-11-20additionLatest

Solid Tumor Minimal Residual Disease (MRD) Testing criteria added aligning with CMS MolDX LCD, including requirements for intended-use population and demonstration of analytic/clinical validity.

2024-11-20clarification

Default MRD testing frequency guidance added: once per cancer diagnosis for patients with cancer and once every 12 months for patients without cancer when guideline regimen is absent.

This revision includes multiple updates to CPT/HCPCS/U‑code mappings and additions; see the coding section for the detailed list of added, replaced, and removed codes (examples include replacement of some U‑codes and addition of new CPT codes for tumor‑type agnostic panels and MRD testing).

Policy Summary

PayerCentene

PolicyMolecular Analysis of Solid Tumors and Hematologic Malignancies

Policy CodePolicy N/A

Change TypeMultiple additions and revisions (MRD, TMB, code updates, scope expansions)

Effective DateN/A

Next Review DateNov 1, 2025

Key ActionDocument required clinical documentation to support diagnosis, stage, and that testing will change management and obtain prior authorization when specified codes/criteria apply.

SourceLink

On This Page

AML/ALL/MDS: targeted and broad hematologic panels for diagnosis, prognostic stratification, and treatment selection as per NCCN guidance (including FLT3, NPM1, CEBPA, IDH1/2 where indicated).

MRD: hematologic MRD testing (0171U, 0364U) for ALL, multiple myeloma, and CLL when used to guide therapy decisions (NCCN).

The member is not currently being treated for cancer and (a) the test has not been done in the past 12 months, OR (b) there is clinical suspicion for tumor recurrence.

The test and intended use align with available evidence or the CMS MolDX LCD: examples include Guardant360 Response or Guardant Reveal for specified colorectal cancer indications, and Signatera for specified metastatic and immune checkpoint inhibitor monitoring indications (see policy reference).

ANY of the following

Test-specific examples: Covered MRD uses per evidence/LCD include: diagnosis of disease progression/recurrence for advanced colorectal, bladder and breast cancers (per test-specific evidence); monitoring response to immune checkpoint inhibitor therapy for colorectal cancer (Guardant) or any solid tumor (Natera/Signatera) as supported by evidence for the specific assay and indication.
Frequency note: Absent specific guideline recommendations, default frequency is once per cancer diagnosis for patients with cancer, or once every 12 months for patients without cancer; repeat testing may be medically necessary sooner if there is clinical evidence of change in tumor genetics or disease status.

Targeted RNA fusion panel: 81449

Prior Authorization

Code-specific indication documentation required

Specific multigene tumor‑type agnostic panel codes and lung cancer–focused panel codes (e.g., 0022U, 81457) are constrained to defined clinical indications in the criteria and require supporting documentation when submitted.

Tumor‑type agnostic panels limited to listed diagnoses (e.g., advanced/metastatic disease, NSCLC regardless of stage, resectable pancreatic adenocarcinoma, CNS tumors)
Lung panels (0022U, 81457) require advanced/metastatic disease and that the member is seeking further cancer treatment

Prior Authorization

Prior auth for evidence‑based cfDNA MRD surveillance

Prior authorization is required when ordering evidence‑based cfDNA MRD tests (codes 0340U, 0422U, 81479) used for surveillance/monitoring; documentation must show that identifying recurrence/progression will change management and that concurrent molecular surveillance is not occurring.

Covered MRD cfDNA codes include 0340U, 0422U, and use of 81479 per criteria
Clinical-state and test‑specific indications (e.g., Guardant360 Response/Reveal, Signatera) must be met

Prior Authorization

Prior authorization may be required for select MRD, TMB, and investigational codes

Prior authorization may be required for listed tests such as HPV‑related MRD (0356U) and TMB (81479), and for tests designated investigational or covered-with-criteria; submitters should follow payer prior‑authorization processes when medical‑necessity criteria are used to approve coverage.

HPV‑related cfDNA MRD — code 0356U
TMB testing — code 81479
Emerging MRD and exome/genome sequencing examples listed may require prior review

Prior Authorization

Prior authorization may be required for broad molecular panels

When ordering broad molecular (NGS) panels for advanced or metastatic disease, prior authorization may be required per plan rules; ensure documentation supports the tumor type and clinical scenario listed in policy criteria.

Broad panel ordering should align with guideline‑recommended indications (e.g., NGS for advanced/metastatic NSCLC)
Payer plan-level prior authorization rules may apply

Prior Authorization

Prior authorization summary for MRD testing: intended use and management impact

MRD testing requires that the patient have a personal history of cancer within the test's intended use and that the test result would lead to a definitive change in management per NCCN or other established guidelines; prior authorization should reflect these requirements.

CMS MolDX LCD conditions apply: intended‑use population, guideline‑supported change in management, and demonstrated analytic/clinical validity
Documentation must show anticipated management impact

Billing Rule

MRD testing frequency — default rules

Default MRD testing frequency guidance: for patients with cancer, MRD testing is generally limited to once per cancer diagnosis; for patients without known cancer, absent guideline regimen, the default is once every 12 months unless specific guideline recommendations indicate otherwise.

NGS‑based MRD services may be performed once per patient per cancer diagnosis unless there is clinical evidence of change
Concert default: once per diagnosis (with cancer) or once every 12 months (without cancer) when guidelines are absent

Prior Authorization

Prior authorization for newly added CPT codes may be required

Newly added or updated CPT codes in the policy (e.g., 0422U for MRD and 81457–81459 for tumor‑type agnostic panels, and 0297U replacements) may require prior authorization per payer processes; confirm payer coverage and authorization requirements for these codes before ordering.

CPT 0422U added for Solid Tumor MRD testing
CPT 81457, 81458, 81459 added to tumor‑type agnostic panel criteria

Prior Authorization

Confirm prior‑auth and benefit rules; follow plan/NCD/LCD requirements

Coverage determinations require adherence to this clinical policy and plan‑level administrative policies; prior authorization may be required per the Health Plan's procedures and member benefit documents — verify benefit and any Medicare NCD/LCD applicability before submission.

Follow applicable NCDs/LCDs for Medicare members
State Medicaid provisions supersede policy where applicable

Step Therapy

Sequence ESR1 testing after progression on specified endocrine therapies

ESR1 (81479) testing is indicated only after disease progression following one or two prior lines of endocrine therapy, including a regimen containing a CDK4/6 inhibitor; documentation should show prior endocrine therapy lines.

Member must have ER‑positive, HER2‑negative breast cancer and progression after 1–2 endocrine therapy lines including a CDK4/6 inhibitor

Denial Risk

Avoid repeat single‑gene testing after targeted therapy progression

Repeat single‑gene testing (for example BRAF or KIT) after progression on targeted therapy is not considered clinically useful and may not be necessary; ordering such repeat tests risks non‑coverage.

Avoid repeat testing using the same approach following progression on BRAF‑ or KIT‑directed therapy unless specifically indicated

Step Therapy

Stepwise testing (e.g., JAK2 then MPL/CALR) is acceptable

Stepwise or sequential testing approaches (e.g., JAK2 first, then MPL/CALR if negative) are acceptable per NCCN guidance; using a stepwise approach instead of an upfront multigene panel for MPN workup is allowed.

Initial JAK2 testing recommended; if negative, test MPL and CALR or use a multigene panel including these genes

Documentation Required

Pre‑test disclosure of potential incidental germline findings

Providers should communicate the potential for incidental germline findings to patients prior to somatic mutation profiling and document that pre‑test discussion or counseling occurred.

Discuss possibility of clinically relevant germline variants arising from tumor testing
Document pre‑test discussion in the medical record

Documentation Required

Document diagnosis, stage, treatment intent, and prior testing

Clinical documentation must support the diagnosis, stage, treatment intent, and prior testing results (for example, negative DNA‑based NGS when required) to substantiate medical necessity when requesting authorization or submitting claims.

Include diagnosis, tumor stage, reason for testing (e.g., seeking further treatment), and prior molecular test results as applicable
For RNA fusion panels (81449) show prior DNA‑based NGS result if required by criteria

Documentation Required

Document minimum gene content for colorectal panels (KRAS/NRAS/BRAF)

For colorectal cancer–focused panels, documentation must show the panel includes at minimum KRAS, NRAS, and BRAF to meet criteria for medical necessity.

Ensure panel gene content includes KRAS, NRAS, and BRAF and document this in the order or lab requisition

Documentation Required

Require prior MLH1 loss on IHC before ordering MLH1 methylation testing

MLH1 promoter methylation testing (81288) requires prior tumor testing showing loss of MLH1 by immunohistochemistry; include the IHC result in the clinical documentation.

Attach prior tumor IHC demonstrating MLH1 loss when requesting MLH1 methylation testing

Documentation Required

Document clinical utility for cfDNA MRD (management‑impact requirement)

For evidence‑based cfDNA MRD testing, documentation must show that identification of recurrent/refractory/progressive disease would change management and that the member is not undergoing concurrent molecular surveillance.

State how a positive MRD result would alter treatment decisions
Confirm absence of concurrent molecular surveillance testing

Documentation Required

HPV‑related MRD documentation: history and management‑impact

HPV‑related cfDNA MRD testing (0356U) requires documentation of a personal history of HPV‑driven oropharyngeal cancer and that identifying recurrence would change management; also confirm absence of concurrent surveillance by other methods.

Document prior diagnosis of HPV‑driven oropharyngeal cancer
Describe how detecting recurrence would change treatment or surveillance

Documentation Required

TMB documentation: advanced disease and prior progression required

For TMB testing (81479), documentation must demonstrate recurrent/relapsed/refractory/metastatic or advanced stage III/IV disease, progression after prior treatment, exhaustion of satisfactory treatment options, and absence of a CNS primary.

Include staging and prior treatment history
State that no satisfactory treatment options remain

Documentation Required

RBC genotyping documentation for multiple myeloma and anti‑CD38 therapy

Red blood cell genotyping in multiple myeloma (codes 0001U, 0180U, 0221U) requires documentation supporting a multiple myeloma diagnosis and that the patient is being treated with or will receive daratumumab or isatuximab; also indicate prior testing interval per criteria.

Document multiple myeloma diagnosis and planned/ongoing anti‑CD38 therapy
Confirm test has not been done for the current episode or within past 12 months as applicable

Documentation Required

Document BCR::ABL1 transcript type and quantitative RT‑PCR use

When ordering BCR::ABL1 testing for MRD monitoring, document the transcript type (e.g., p190 vs p210) and use of quantitative RT‑PCR, and include these testing details in the request or supporting records.

Specify transcript type and whether RT‑qPCR will be used for serial monitoring

Documentation Required

HLA documentation for transplant: full loci and donor/donor family testing

For transplantation HLA testing, documentation must include full HLA typing results (class I: A, B, C; class II: DRB1, DQB1) and, when applicable, donor/family typing and final crossmatch results provided to the transplant program.

Report required loci (A, B, C, DRB1, DQB1) in the lab report
Provide donor/family typing and final crossmatch documentation before transplant when applicable

Documentation Required

MRD documentation: establish intended‑use history and management change

MRD test documentation must establish the patient has a personal history of cancer within the intended use population and that identification of recurrence/progression would lead to a definitive change in management per NCCN or other established guidelines.

Link the requested MRD assay to the test's intended use population
Cite guideline(s) indicating the result would alter management

Documentation Required

Cite guidelines (NCCN versions) when documenting clinical justification

Clinical rationale submitted for testing should reference guideline‑based indications (including applicable NCCN guideline versions) to support medical necessity and authorization requests.

Cite the specific NCCN guideline and version that supports the indication
Include tumor type, stage, and how testing aligns with guideline recommendations

Documentation Required

Align documentation to benefits, guidelines, and NCD/LCD requirements

Support medical necessity with documentation aligned to member benefits and guideline criteria; follow applicable NCDs/LCDs and plan administrative procedures when submitting prior‑authorization requests or claims.

Verify member benefit terms, exclusions, and state Medicaid constraints before ordering
Reference applicable NCDs/LCDs for Medicare members

Billing Rule

Coding inclusion is not a guarantee of coverage

Inclusion of a code in the policy reference list does not guarantee coverage. Providers should verify current coding guidance and payer coverage prior to claim submission to avoid denial.

Codes in the document are illustrative examples and not determinative of coverage
Confirm up‑to‑date coding and payer rules before billing

Denial Risk

Denial risk: tumor‑type agnostic panels used outside listed indications

Tumor‑type agnostic panels are investigational for indications other than those explicitly listed and may be denied if used outside the policy's covered indications.

Panels 0037U, 0048U, 0250U, 0329U, 0334U, 0379U, 0391U, 0473U, 81445, 81455, 81457‑81459 are investigational for non‑listed indications

Denial Risk

Denial risk: 81449 investigational outside listed indications

Targeted RNA fusion panels (81449) are investigational for indications other than those listed in policy and may be denied if ordered outside the specified diagnoses/criteria.

81449 is covered only for listed diagnoses (e.g., ALL, glioma, histiocytosis, sarcoma, GIST negative for KIT/PDGFRA, NSCLC after negative DNA NGS, metastatic tumors with fusion‑targeted therapy)

Denial Risk

Investigational use denial risk for tumor‑type agnostic panels

Tumor‑type agnostic solid tumor molecular profiling panels are considered investigational for all indications not specifically listed and may be denied when used for other indications.

Denial Risk

Denial risk: HLA typing for non‑transplant indications

HLA typing will be considered investigational and not medically necessary for all indications other than donor/recipient evaluation for bone marrow or solid organ transplantation; ordering HLA testing for non‑transplant indications risks denial.

HLA testing (81370–81382) is covered only for transplant donor/recipient evaluation

Denial Risk

Denial risk: emerging MRD assays with insufficient clinical validity

MRD assays listed as having insufficient evidence of clinical validity (e.g., 0229U, 0306U, 0307U) are considered investigational and may be denied.

Solid tumor tissue–based MRD assays with these codes are investigational

Denial Risk

Solid tumor MRD tissue assays considered investigational (denial risk)

MRD analysis using solid tumor tissue (codes 0229U, 0306U, 0307U) is investigational and therefore at risk for denial when billed for indications lacking demonstrated clinical validity.

Denial Risk

Denial risk: cancer exome/genome sequencing considered investigational

Cancer exome and genome sequencing (e.g., 0036U, 0297U, 81415, 81416, 81425, 81426) is considered investigational and may be denied when performed for indications lacking established clinical utility.

Denial Risk

Denial risk: separately billed specimen identity testing

Genetic testing to confirm specimen identity (e.g., 81265, 81266, 81479) when billed separately is considered investigational and may be denied.

Denial Risk

Risk of coverage issues for not following guideline‑recommended testing

Failure to perform guideline‑recommended molecular testing (for example, broad panel‑based NGS for advanced/metastatic NSCLC when feasible) may risk coverage issues if testing is clinically indicated per guidelines.

Follow NCCN recommendations for tumor‑type testing to avoid potential coverage problems

Denial Risk

MRD intended‑use and evidence risk for denial

MRD tests must be used within their intended‑use populations and demonstrate clinical validity; lack of intended‑use evidence or insufficient evidence that results change management may trigger denial.

CMS MolDX LCD criteria require intended‑use population, guideline‑supported management change, and demonstration of detection before clinical/radiographic evidence

Denial Risk

Denial risk for tests without established clinical validity/utility

Tests that lack established clinical utility or validity, per the Concert general approach and technology assessments, do not meet the threshold for coverage and are at risk for denial.

Denial Risk

Denial risk from use of removed or unsupported codes/tests

Use of tests or codes that were removed from the policy reference table (or otherwise not supported by the updated CPT/code list) may risk non‑coverage; verify current supported tests/codes prior to ordering or billing.

Examples noted in revisions include replacement of codes (e.g., 0329U replaced by 0297U) and removal of others

Denial Risk

Denial risk from benefit/exclusion mismatches

Coverage decisions are subject to the member's benefit document terms, exclusions, and state Medicaid provisions; mismatches between ordered tests and member benefits may lead to denial.

For Medicaid members, state Medicaid rules take precedence over this policy where conflicts exist

Documentation Required

Document guideline‑based rationale and pre/post‑test genetic counseling

Pre‑ and post‑test genetic counseling expectations should be documented when testing is performed per guideline‑based indications; document that guideline‑aligned counseling occurred or that rationale for testing was discussed with the patient.

Policy references NCCN indications and expects clinicians to document guideline‑based rationale and pertinent counseling
For scenarios with guideline‑recommended germline testing (e.g., ovarian cancer BRCA1/2), counseling is implied and should be documented

Repeat testing using the same testing approach (for example repeat single‑gene BRAF or KIT testing) after progression on targeted therapy has not demonstrated clinical utility in the evidence cited and is described as not clinically useful.

MRD testing is covered only when used within the test's intended use population and when a positive result would lead to a definitive change in patient management per CMS LCD and guideline criteria. MRD assays used outside these intended populations or without demonstrated impact on management are not supported.

Tests that lack established clinical validity or clinical utility as defined in the policy (including many cancer exome/genome sequencing approaches and standalone specimen‑identity genetic testing) do not meet thresholds for coverage and are considered investigational.

The policy reference table has been updated and specific tests removed when they do not meet the policy's minimum content or criteria (for example, the Praxis Extended RAS Panel [Illumina] code 0111U was removed from the reference table and is no longer supported as meeting criteria).

Emerging‑evidence solid tumor MRD assays for which clinical validity has not been established are treated as investigational under a separate criteria set. Such tests (e.g., the tissue‑based MRD codes noted above) may be denied until independent evidence or guideline endorsement demonstrates adequate validity and clinical utility.

Measurement examplesTMB assessed in mut/Mb; MSI by PCR/NGS; fusions by RNA or DNA fusion panels depending on panel design.

inv-162: Minimal Residual Disease (MRD) — assays and codes

MRD assay typesMRD assays include cfDNA platforms (e.g., Guardant360 Response/Reveal, Signatera) and other proprietary PLA/UC tests referenced in policy.

Representative codesEvidence‑based cfDNA MRD: 0340U, 0422U, 81479; Hematologic MRD: 0171U, 0364U; Emerging MRD: 0229U, 0306U, 0307U.

Coverage conditionCoverage depends on intended use, clinical validity, and CMS LCD/NCCN‑aligned criteria.

inv-163: Tumor-Type Agnostic Panel definition

DefinitionTumor‑type agnostic panel: broad NGS panels that evaluate multiple genes across tumor types to identify actionable alterations; covered for specified indications when criteria met.

Example codesPolicy examples include PLA/CPT codes such as 0037U, 0048U, 81445, 81457-81459 among others.

Typical useUsed for advanced/metastatic disease or specific tumor types per NCCN guidance where broad profiling informs therapy.

inv-164: Broad molecular profiling panels for hematologic malignancies definition

DefinitionBroad molecular profiling panels for hematologic malignancies: multigene NGS panels performed on bone marrow or blood for evaluation of AML, ALL, MDS, suspected MPN, or CML with progression; examples include CPT 81450, 81455.

IndicationsCovered for initial evaluation/diagnosis of AML, newly diagnosed ALL, newly diagnosed MDS, suspected MPN (initial evaluation or after negative JAK2/CALR/MPL), and CML with progression.

Repeat testingRepeat panels allowed in defined relapse/progression scenarios as described in policy.

inv-165: Targeted vs Broad RNA fusion panel definitions

Targeted vs Broad RNA fusion panelsTargeted RNA fusion panels: 5–50 genes (CPT 81449). Broad RNA fusion panels: 51+ genes using RNA-only analysis (0444U, 81456).

Coverage differencesTargeted panels covered for multiple diagnoses; broad panels are medically necessary only for ALL per policy.

Investigational stanceBoth panel types are investigational for indications not listed in the policy.

inv-166: Evidence-based cfDNA MRD definition

Evidence‑based cfDNA MRD definitioncfDNA MRD assays with sufficient evidence of clinical utility and validity (e.g., Guardant360 Response/Reveal, Signatera) when used per policy criteria are considered evidence‑based and may be covered.

Clinical conditionsCovered when identification of recurrence would change management and testing is not concurrent with other molecular surveillance.

Representative codes0340U, 0422U, and 81479 cited as evidence‑based cfDNA MRD examples.

inv-167: Emerging MRD testing definition

Emerging MRD testing definitionMRD assays with insufficient evidence of clinical validity (examples: COLVERA 0229U; Invitae 0306U/0307U; Northstar 0486U) are considered emerging and investigational.

Specimen limitationPolicy specifically flags tissue‑based MRD assays with insufficient validity as investigational.

Coverage implicationEmerging MRD tests are not covered until clinical validity/utility is established per policy and LCD guidance.

inv-168: Tumor mutational burden (TMB) definition

TMB definitionTumor mutational burden (TMB) is a measurement of mutations carried by tumor cells and is a predictive biomarker studied for association with immunotherapy response.

Unit of measureExpressed as mutations per megabase (mut/Mb).

Clinical useUsed to inform potential benefit from immune checkpoint inhibitors in select indications per guidelines and FDA labeling.

inv-169: Advanced cancer definition

Advanced cancer definitionAdvanced cancer: disease unlikely to be cured or controlled with treatment; may be locally advanced or metastatic and treated to shrink tumor, slow growth, or relieve symptoms.

Clinical implicationMany molecular testing recommendations apply specifically to advanced or metastatic disease where treatment choices expand beyond curative intent.

inv-170: Broad panel-based NGS definition

Broad panel‑based NGS definitionNext‑generation sequencing assays that analyze multiple genes simultaneously and are typically recommended for advanced/metastatic disease and many hematologic evaluations.

Use caseMay be performed as single assay or tiered approaches; rapid testing followed by broad NGS acceptable in some scenarios (e.g., NSCLC).

inv-171: MSI/MMR definition

MSI/MMR definitionMicrosatellite instability (MSI) or mismatch repair (MMR) deficiency testing evaluates tumor MMR status and is recommended universally or in specified scenarios for multiple tumor types per NCCN.

Testing methodsCan be performed by PCR or NGS as appropriate to the tumor type and guideline recommendation.

inv-172: MRD testing definition

MRD testing general definitionMinimally invasive molecular DNA/RNA assays that detect minimal/measurable residual disease post‑treatment intended to identify recurrence/progression earlier than clinical/radiographic evidence when validated for the intended use population.

Specimen typesIncludes cfDNA (plasma) assays and bone marrow/peripheral blood assays for hematologic MRD; tissue‑based MRD tests may be investigational depending on evidence.

inv-173: TMB-H definition (>=10 mut/Mb)

TMB‑High definitionTMB‑High (TMB‑H) is defined as ≥10 mutations per megabase (mut/Mb) per the FDA pembrolizumab (KEYTRUDA) label.

Regulatory contextApplied when considering FDA‑labeled pembrolizumab use for unresectable or metastatic TMB‑H solid tumors after prior treatment.

inv-174: MRD general definition

MRD general roleMRD testing aims to detect residual tumor cells post‑treatment to identify recurrence or progression that may change management when clinical validity is established.

Coverage dependencyCoverage requires intended‑use clinical history, impact on management per NCCN/LCD, and demonstrated analytic/clinical validity.

inv-175: Solid Tumor MRD term

Solid tumor MRD termSolid Tumor MRD: cfDNA or other minimally invasive assays to monitor residual disease in solid tumors; evidence‑based vs emerging evidence categories defined.

Evidence categoriesEvidence‑based cfDNA MRD (e.g., Signatera, Guardant) versus Emerging MRD assays with insufficient clinical validity (0229U, 0306U, 0307U).

inv-176: TMB coverage scope

TMB coverage scope summaryTMB testing coverage applies to any recurrent, relapsed, refractory, metastatic, or advanced stage III/IV cancer (excluding CNS tumors) after progression on prior treatment when no satisfactory treatment options remain.

Documentation requirementClinical documentation must demonstrate progression and exhaustion of satisfactory options and align with guideline justification.

inv-177: MRD Testing criteria sets summary

MRD criteria sets summaryPolicy separates MRD into Evidence‑Based cfDNA MRD (covered with criteria), HPV‑related cfDNA MRD (covered with criteria), and Emerging Evidence MRD (investigational) based on CMS LCD and clinical validation evidence.

Key evidence requirementIdentification of molecular recurrence/progression must precede clinical/radiographic evidence and would change management per guidelines.

Frequency guidanceWhen guidelines lack specific regimens, default frequency: once per cancer diagnosis (patients with cancer) or once every 12 months (patients without cancer).

inv-178: HLA Typing for Transplantation definition

HLA typing for transplant definitionHLA typing determines human leukocyte antigen compatibility for hematopoietic transplantation (class I A,B,C and class II DRB1, DQB1) and aligns with transplant guidance and OPTN requirements.

Coverage limitationHLA typing is medically necessary only for transplant donor/recipient evaluation; investigational for other indications.

Reporting expectationFinal crossmatch results and required loci must be reported to the transplant program per OPTN and transplant guidelines.

MLH1 promoter methylation testing (81288) requires prior tumor testing demonstrating loss of MLH1 by immunohistochemistry before methylation analysis is considered medically necessary.

Evidence‑based cfDNA MRD assays (e.g., Signatera, Guardant360 Response/Reveal; codes 0340U, 0422U, 81479) are medically necessary only when the test result would change management, the patient is not undergoing concurrent molecular surveillance, and the timing/prior‑test conditions in the criteria (such as not done in past 12 months when not currently treated) are met.

Red blood cell genotyping (examples 0001U, 0180U, 0221U) in multiple myeloma is covered when prior testing criteria are satisfied (for example, test not previously performed for current episode or not performed in past 12 months) and the patient will receive or is receiving anti‑CD38 therapy (daratumumab or isatuximab).

Example tumor‑specific code notes: colorectal panels (81445, 81457) are medically necessary for suspected or proven metastatic colorectal cancer only when the panel includes at minimum KRAS, NRAS, and BRAF.

IGHV and related Ig rearrangement testing should be performed on adequate excisional or incisional biopsy material and is indicated for diagnostic workup and prognostication in CLL/SLL and other B‑cell lymphomas per NCCN recommendations.

Policy reference CPT changes and code mappings were updated in this revision. Providers should use the updated code list in the policy coding section and be aware that replaced or removed codes (per the policy changelog) may no longer map to covered criteria.

Tumor‑specific coverage was expanded in places to align with updated NCCN guidance; some indications were broadened and CPT codes (81457–81459) added to tumor‑type agnostic panel criteria — follow the per‑test criteria for the exact tumor types and staging requirements.

MRD and TMB updates: TMB coverage was restructured to disease‑state criteria applicable to recurrent/refractory/metastatic or advanced stage III/IV cancers (excluding CNS primaries) with progression and no satisfactory treatment options, and the FDA TMB‑H threshold of >=10 mutations/megabase is referenced where applicable.

The prior MRD criteria were retired and replaced by two new LCD‑based criteria sets: an evidence‑based cfDNA MRD criteria set and an HPV‑related MRD criteria set. CPT code 0422U was added to the policy reference table for Solid Tumor MRD testing.

Coverage criteria across multiple molecular testing categories were updated and expanded to align with current NCCN guidance and CMS LCDs. Updates include broader disease‑state TMB criteria, added/clarified RNA fusion panel and tumor‑type agnostic panel indications, expanded tumor‑specific gene analyses, and newly created MRD and HLA typing criteria sets.