CurrentBlue Cross Blue Shield - TennesseePolicy N/A

In Vitro Chemoresistance and Chemosensitivity Assays

This policy governs coverage decisions for laboratory in vitro assays that test tumor sensitivity or resistance to chemotherapeutic agents, affecting clinicians ordering these tests and laboratories performing them under Blue Cross Blue Shield - Tennessee benefits. It outlines which assays do and do not meet coverage criteria and provides background, evidence, and applicable coding references.

Policy Summary

PayerBlue Cross Blue Shield - Tennessee

PolicyIn Vitro Chemoresistance and Chemosensitivity Assays

Policy CodePolicy N/A

Change TypeNo material change

Effective DateN/A

Next Review DateN/A

Key ActionSubmit claims using the listed CPT/HCPCS codes with supporting laboratory reports and clinical rationale; expect denial for assays that do not meet coverage criteria.

SourceLink

POLICY UPDATE CHANGES

No material clinical or coverage changes in this revision.

2Not covered assay groups

multipleProprietary assays mentioned

~15Procedure codes listed

numerousEvidence references

Coverage Determinations

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inv-01: Not Medically Necessary — In vitro chemosensitivity/chemoresistance assays

Not covered when the following assays are used:

Primary noncoverage statement: In vitro chemosensitivity assays (e.g., histoculture drug response assay, fluorescent cytoprint assay) DO NOT MEET COVERAGE CRITERIA.

Document explicitly lists chemosensitivity assays as not meeting coverage

Primary noncoverage statement: In vitro chemoresistance assays (e.g., extreme drug resistance [EDR] assays) DO NOT MEET COVERAGE CRITERIA.

Document explicitly lists chemoresistance assays as not meeting coverage

The policy excludes coverage for in vitro chemosensitivity assays and in vitro chemoresistance assays because there is an insufficient body of published scientific literature demonstrating that these tests are required and beneficial for diagnosing or guiding treatment for an individual’s illness. The document explicitly states that assays such as histoculture drug response assays and fluorescent cytoprint assays (chemosensitivity) and extreme drug resistance (EDR) assays (chemoresistance) DO NOT MEET COVERAGE CRITERIA due to this lack of evidence.

Many laboratories offer laboratory-developed tests (LDTs) for chemosensitivity/chemoresistance. Per the policy, these LDTs are not FDA-approved or -cleared and are regulated under the Centers for Medicare & Medicaid Services as CLIA '88 high-complexity tests. FDA clearance or approval is not currently required for clinical use, but LDTs must be validated and performed in-house under CLIA requirements.

Accordingly, in vitro chemosensitivity assays and in vitro chemoresistance assays are considered not medically necessary for routine clinical use and do not meet this policy’s coverage criteria.

inv-21: Clinical research / investigational settings where assay-directed therapy is being evaluated

Assay-directed therapy may be evaluated in research or investigational settings; published studies report correlations but are insufficient to support routine clinical coverage.

Research/Investigational Context: Use of in vitro chemosensitivity or chemoresistance assays is limited to clinical research or investigational settings evaluating assay-directed therapy; existing studies report correlations between assay results and outcomes but do not establish benefit for routine clinical use.

Policy summarizes multiple studies but does not support routine clinical utilization

Study evidence examples: Selected studies include: Tatar et al. (2016) — three assays in ovarian carcinoma; Krivak et al. (2014) and Rutherford et al. (2013) — ChemoFx studies in ovarian cancer; Hoffman (2018) — HDRA in gastric/colon cancer; Howard et al. (2017) — ChemoID in glioblastoma; Chen et al. (2018) — ATP-TCA in lung cancer; Shuford et al. (2021) — 3D cell-based assay in high-grade glioma.

Cited examples illustrate the evidence base summarized in policy

Evidence limitation: Authors of cited studies commonly conclude that larger prospective trials comparing standard versus assay-directed therapy with clinical endpoints (eg, overall survival) are required before routine clinical implementation.

inv-22: Oncology use cases to predict tumor response using ex vivo/cell-based assays

Examples of oncology applications and proprietary ex vivo or cell-based assays referenced in the policy (listed with associated proprietary codes/manufacturers where provided).

Gynecologic oncology (example): ChemoFX® — live tumor cell culture and chemotherapeutic response assay; proprietary CPT codes 81535 (first drug/combination) and 81536 (each additional drug/combination) (Lab/manufacturer: Helomics, Corp.).

Proprietary test and codes listed in policy

Motility contrast tomography assay: Onco4D™ — response to chemotherapy drugs using motility contrast tomography, reported as likelihood of sensitivity or resistance; proprietary code 0083U (Animated Dynamics, Inc.).

Proprietary test and code listed in policy

Brain tumor 3D assay: 3D Predict Glioma — spheroid cell culture in a 3D microenvironment, 12-drug panel with tumor-response prediction (proprietary code 0248U; KIYATEC®, Inc.).

Proprietary test and code listed in policy

Procedure and Pathology Codes

Procedure and pathology codes referencedmixed

81535	Oncology (gynecologic), live tumor cell culture and chemotherapeutic response by DAPI stain and morphology, predictive algorithm reported as a drug response score; first single drug or drug combination (Proprietary test: ChemoFX®)
81536	Oncology (gynecologic), live tumor cell culture and chemotherapeutic response by DAPI stain and morphology, predictive algorithm reported as a drug response score; each additional single drug or drug combination (Proprietary test: ChemoFX®)
86849	Unlisted immunology procedure.
88104	Cytopathology, fluids, washings or brushings, except cervical or vaginal; smears with interpretation.
88199	Unlisted cytopathology procedure.
88305	Level IV - Surgical pathology, gross and microscopic examination.
88313	Special stain including interpretation and report; Group II, all other.
88358	Morphometric analysis; tumor (eg, DNA ploidy).
89050	Cell count, miscellaneous body fluids (eg, cerebrospinal fluid, joint fluid), except blood.
89240	Unlisted miscellaneous pathology test.

1–10 of 11

1/2

Procedure and pathology codes referencedmixed

81535	Oncology (gynecologic), live tumor cell culture and chemotherapeutic response by DAPI stain and morphology, predictive algorithm reported as a drug response score; first single drug or drug combination (Proprietary test: ChemoFX®)
81536	Oncology (gynecologic), live tumor cell culture and chemotherapeutic response by DAPI stain and morphology, predictive algorithm reported as a drug response score; each additional single drug or drug combination
86849	Unlisted immunology procedure
88104	Cytopathology, fluids, washings or brushings, except cervical or vaginal; smears with interpretation
88199	Unlisted cytopathology procedure
88305	Level IV - Surgical pathology, gross and microscopic examination
88313	Special stain including interpretation and report; Group II, all other
88358	Morphometric analysis; tumor (eg, DNA ploidy)
89050	Cell count, miscellaneous body fluids (eg, cerebrospinal fluid, joint fluid), except blood
89240	Unlisted miscellaneous pathology test

1–10 of 11

1/2

Proprietary assay CPT/HCPCS codesmixed

0248U	Oncology (brain), spheroid cell culture in a 3D microenvironment, 12 drug panel, tumor-response prediction for each drug (Proprietary test: 3D Predict Glioma)
0249U	Oncology (breast), semiquantitative analysis of 32 phosphoproteins and protein analytes, includes laser capture microdissection, with algorithmic analysis and interpretative report (Proprietary test: Theralink® RPPA)
0285U	Oncology, response to radiation, cell-free DNA, quantitative branched chain DNA amplification, plasma, reported as a radiation toxicity score (Proprietary test: RadTox™ cfDNA)
0564T	Oncology, chemotherapeutic drug cytotoxicity assay of cancer stem cells (CSCs), from cultured CSCs and primary tumor cells, categorical drug response reported based on percent of cytotoxicity observed, a minimum of 14 drugs or drug combinations (Reported for ChemoID®)

Billing, Documentation, and Provider Guidance

Denial Risk

Noncovered assay categories

Claims for in vitro chemosensitivity and chemoresistance assays do not meet coverage criteria and may be denied. These tests lack sufficient published evidence demonstrating clinical benefit for selecting chemotherapy; submitters should not expect coverage for assays billed under proprietary or unlisted assay codes unless coverage criteria are specifically met by separate policy language.

Examples of noncovered assay categories include in vitro chemosensitivity assays (e.g., histoculture drug response assay, fluorescent cytoprint assay) and extreme drug resistance (EDR) assays.

Documentation Required

Laboratory validation and certification

Laboratory-developed tests (LDTs) must be validated and performed under CLIA high-complexity requirements. LDTs are not FDA-approved or -cleared but remain regulated under CMS/CLIA; providers should ensure documentation of laboratory validation, CLIA certification, and relevant analytic performance is available on request.

Document CLIA certification and validation records for laboratory-developed proprietary assays.
Provide analytic validation data and evidence of laboratory quality controls when submitting claims.

Documentation Required

Submit listed procedure codes with clinical documentation

Submit the specific CPT/HCPCS/proprietary codes used with complete clinical documentation, including pathology/lab reports and the clinical rationale linking test results to patient management. Claims for proprietary or unlisted assays billed with listed codes may be denied if adequate documentation is not provided.

Include the test report, interpretation, and how the result changes therapy selection when submitting codes such as 81535, 81536, 0083U, 0248U, 0249U, 0285U, 0564T, 86849, 88199, 89240.
When billing unlisted codes (e.g., 86849, 88199, 89240), attach a detailed report and rationale for medical necessity.

Note

Guideline-driven therapy preference

When selecting chemotherapy, follow established, evidence-based guideline-directed therapy rather than relying on proprietary assay results to choose agents. Major oncology organizations do not endorse routine use of chemosensitivity/resistance assays to direct individual patient chemotherapy outside clinical trials.

Oncologists should base chemotherapy recommendations on published clinical trial evidence and individual patient factors.
Participation in clinical trials evaluating these assays is encouraged; assay-directed selection is not recommended as standard care.

Denial Risk

Potential denial for improper coding/documentation

Tests billed with proprietary or unlisted assay codes may be denied if billed improperly or if documentation is insufficient. Providers should proactively supply the assay methodology, validation, CLIA status, and an explicit statement of how the test result will alter patient management to reduce risk of denial.

Claims for proprietary assays billed to listed codes without supporting documentation are at risk for denial.
When in doubt, include lab validation reports, CLIA certificate, full test interpretation, and treatment rationale.

Billing Rule

Coding and report documentation

Provider action: For assays that use proprietary test codes or unlisted procedure codes, ensure coding is accurate and that detailed reports accompany the claim. If using an assay not explicitly covered by policy, obtain prior authorization when available and document attempts to justify medical necessity.

List the specific CPT/HCPCS/proprietary codes on the claim and attach the full report.
Obtain prior authorization when the payer requires it; otherwise, submit documentation justifying medical necessity and laboratory validation.

Ordering and Submission Requirements

Note

Ordering requirements and government policy precedence

No specific provider-type ordering restriction is stated in this policy; if a conflict exists between this policy and applicable government (Medicare/Medicaid) policy, the government policy supersedes.

Government policy (e.g., LCD/NCD) takes precedence over this policy when conflict exists
Policy does not limit which provider types may order these tests in the provided excerpt

Documentation Required

Order must specify assay name, code, and include rationale/report

The order for testing and the claim should specify the proprietary assay name and the corresponding procedure code, and should include the clinical rationale and the laboratory report when submitting the claim.

Specify proprietary assay (e.g., ChemoFX®, Onco4D™) and associated CPT/HCPCS code on the order
Include clinical justification and the laboratory report with the claim

Terminology and Assay Definitions

EDR definition — Extreme Drug Resistance assay explanation

TermEDR (Extreme Drug Resistance) assay

DescriptionAn assay that exposes cultured tumor cells to high concentrations of chemotherapeutic agents to identify drugs showing extreme resistance (i.e., agents of least likely clinical benefit).

ContextListed among non-covered in vitro chemoresistance assays in the policy; used to detect drug resistance rather than guide standard-of-care selection.

MTT definition — describes colorimetric MTT assay and interpretation

TermMTT assay (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide)

DescriptionA colorimetric cell viability assay in which viable tumor cells reduce MTT to a colored formazan dye; dye intensity is used to estimate cell viability and infer drug resistance or sensitivity.

ContextCited as a non-proprietary example of in vitro chemosensitivity assays examined in the evidence base for the policy.

ATP-TCA definition — describes ATP-tumor chemosensitivity assay

TermATP-TCA (Adenosine Triphosphate–Tumor Chemosensitivity Assay)

DescriptionAn assay that measures cell viability by quantifying intracellular ATP after drug exposure; ATP levels are used to estimate chemosensitivity of tumor cells to tested agents.

ContextIncluded among non-proprietary assays (alongside MTT and DISC) discussed in the policy's clinical background and evidence summary.

LDT definition — laboratory-developed test definition and context

TermLDT (Laboratory-Developed Test)

DescriptionA test developed and validated by an individual laboratory and performed in-house; regulated by CMS under CLIA as high-complexity tests and not FDA-approved or -cleared for clinical use.

ImplicationLDTs referenced in the policy must be validated and performed under CLIA requirements; FDA clearance/approval is not currently required for clinical use per the document.

OpenPayer

In Vitro Chemoresistance and Chemosensitivity Assays

Coverage Determinations

Noncovered Tests and Categories

Procedure and Pathology Codes

Billing, Documentation, and Provider Guidance

Ordering and Submission Requirements

Terminology and Assay Definitions

Clinical and Technical Background

Frequency and Repetition Rules