CurrentAetnaPolicy 0758

Tumor Chemoresistance Assays

Defines Aetna's coverage stance on tumor chemoresistance and chemosensitivity assays used to guide chemotherapy selection; applies to providers submitting claims for these laboratory assays.

Policy Summary

PayerAetna

PolicyTumor Chemoresistance Assays

Policy CodePolicy 0758

Change TypeNo material changes

Effective DateJun 20, 2008

Next Review DateAug 22, 2024

Key ActionDo not use in‑vitro chemoresistance assays to select chemotherapy regimens; these assays are considered experimental and investigational and may be denied.

SourceLink

POLICY UPDATE CHANGES

No material clinical or coverage changes in this revision.

2008-06-20policy effective date

2023-10-11last review

2024-08-22next review

5 RCTsRCTs in ASCO review

~82bibliographic refs

Coverage Determination and Criteria

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Coverage determination

Covered when ALL of the following are met:

Experimental and Investigational Determination: Tumor chemoresistance assays are considered experimental and investigational by Aetna because there is insufficient evidence that these assays influence management decisions such that clinical outcomes are improved.

Policy-level coverage determination

Aetna considers tumor chemoresistance assays experimental and investigational because there is insufficient evidence that these assays influence clinical management decisions in a way that improves patient outcomes. Claims for services that are billed as tumor chemoresistance or related assay testing may be denied on this basis.

The American Society of Clinical Oncology (ASCO) clinical practice guideline (Partridge et al., 2014) states that in‑vitro chemoresistance assays should not be used to select treatment. The guideline reflects the absence of adequate evidence showing that tailoring chemotherapy based on these assays improves outcomes.

This Clinical Policy Bulletin is intended to assist in administering plan benefits and does not constitute a contract or medical advice. It provides a partial, general description of plan or program benefits; treating providers remain responsible for medical advice and treatment decisions for members.

ASCO does not support the use of in‑vitro chemoresistance assays to direct selection of chemotherapy regimens. In addition, the U.S. Food and Drug Administration has cited examples of insufficiently validated laboratory‑developed tests (LDTs) used to predict chemotherapy response that may have caused patient harm when used to guide treatment decisions.

Billing Codes

CPT codes related to the policyCPT

87230	Toxin or antitoxin assay, tissue culture (e.g., Clostridium difficile toxin)
88104	Cytopathology, fluids, washings or brushing, except cervical or vaginal; smears with interpretation
88305	Level IV surgical pathology, gross and microscopic examination
88313	Special stain including intrepretation and report; Group II, all other (e.g., iron, trichrome), except stain for microorganisms, stains for enzyme constituents, or immunocytochemistry and immunohistochemistry
88358	Morphometric analysis; tumor (e.g., DNA ploidy)
89050	Cell count, miscellaneous body fluids (e.g., cerebrospinal fluid, joint fluid), except blood

Other CPT codes related to the policyCPT

88230	Tissue culture for non-neoplastic disorders; lymphocyte
88233	skin or other solid tissue biopsy
88235	amniotic fluid or chorionic villus cells
88237	Tissue culture for neoplastic disorders; bone marrow, blood cells
88239	solid tumor

HCPCS range referencedHCPCS

J9000-J9999

Chemotherapy drugs

ICD-10 codes referencedICD-10

C00.0-D49.9	Neoplasms
Z51.11-Z51.12	Encounter for antineoplastic chemotherapy and immunotherapy

Provider Actions, Prior Authorization, and Denial Risk

Prior Authorization

Prior Authorization / Denial Risk

Prior authorization: No specific prior authorization process is specified in the extracted policy text. However, providers should be aware that tumor chemoresistance assays are considered experimental and investigational by Aetna and that claims for these assays may be denied; appropriate justification and documentation should be submitted if providers choose to request coverage determination. Codes associated with these assays (see coding list) may be subject to review and denial when billed for neoplasm-related indications.

No specific prior authorization requirement stated in extracted material; submit clinical justification if requesting coverage.
Anticipate denial risk for tests billed with neoplasm (C00.0-D49.9) or chemotherapy encounter (Z51.11-Z51.12) diagnoses.
Affected codes (examples): CPT 87230, 88104, 88305, +88313, 88358, 89050; related CPTs 88230, 88233, 88235, 88237, 88239; HCPCS range J9000-J9999 for chemotherapy drugs.

Documentation Required

ASCO Guideline and LDT Safety Note

ASCO guidance: The American Society of Clinical Oncology (ASCO) states that in‑vitro chemoresistance assays should not be used to select treatment. This guideline position supports the determination that such assays are not medically necessary for directing chemotherapy regimens.

Provider action: Do not use in‑vitro chemoresistance assay results as the sole basis for selecting chemotherapy regimens; document rationale for any deviation.
LDT concern: FDA cited the Duke Chemotherapy Assessment Test as an insufficiently validated LDT that may have caused harm; insufficient validation is a rationale for denying coverage.

Denial Risk

Provider Actions

Provider actions: Because Aetna designates tumor chemoresistance assays as experimental/investigational due to insufficient evidence of improved clinical outcomes, providers should expect coverage denial unless compelling, documented justification is provided through the plan's coverage review process. Clinical Policy Bulletins are administrative guidance and do not guarantee coverage.

When ordering or billing for these assays, include detailed clinical rationale and supporting evidence if requesting an exception or preauthorization review.
Be prepared for medical record review and potential claim denial for neoplasm-related indications.
Use the related policy (CPB 0245) and submitted evidence to support any coverage requests.

Background and Scope

Chemoresistance and chemosensitivity assays are in‑vitro laboratory tests performed on tumor tissue or cells to evaluate whether specific chemotherapeutic agents are likely to be ineffective (chemoresistance) or effective (chemosensitivity) for an individual patient. Typical methods isolate tumor cells, expose them to single agents or drug panels, and assess cell survival, growth, or metabolic activity to infer drug response. Variants include assays claiming very high negative predictive value (for example, extreme drug resistance (EDR) assays with reported NPV >99%) and other laboratory‑developed approaches; however, available evidence does not demonstrate that use of these assays to select therapy leads to improved clinical outcomes.

Key Definitions

inv-23: Definition — Chemoresistance assay

DefinitionAn in-vitro laboratory test intended to identify chemotherapeutic agents that are ineffective (resistant) against a patient's tumor.

Typical processIsolation of tumor cells, incubation with anti-cancer drugs, assessment of cell growth/survival, interpretation of results.

Common examplesExtreme Drug Resistance (EDR) assay; Duke University Chemotherapy Assessment Test; used alone or with molecular profiling (e.g., BioSpeciFx, Target Now).

inv-24: Definition — Chemosensitivity assay

DefinitionAn in-vitro laboratory test performed to evaluate tumor growth response to a known chemotherapeutic drug or panel of drugs to identify potentially effective agents.

PurposeTo assess whether tumor growth is inhibited by specific drugs or panels to help guide selection of potentially effective chemotherapy.

Relationship to chemoresistance assaysShares principles with chemoresistance assays but focuses on identifying potentially effective (sensitive) agents rather than deselecting ineffective ones.

inv-25: Definition — Extreme Drug Resistance (EDR) assay

DefinitionAn assay designed to provide very high negative predictive value (>99%) to deselect ineffective chemotherapies by measuring thymidine uptake after drug exposure.

MethodTumor cells from fresh biopsy are labeled with tritiated thymidine; uptake after exposure to clinically relevant drug concentrations is measured to identify extreme resistance.

Interpretation thresholdExtreme resistance identified when thymidine incorporation is inhibited by less than 1 standard deviation of the median cell inhibition measured for several hundred reference tumor samples.

inv-26: Definition — Non-coding RNAs (ncRNAs) including miRNAs, snoRNAs, lncRNAs

DefinitionTranscripts without protein-coding potential including microRNAs (miRNAs), small nucleolar RNAs (snoRNAs), long non-coding RNAs (lncRNAs) and circular RNAs (circRNAs).

Role in chemoresistanceDeregulated ncRNAs (miRNAs, lncRNAs, snoRNAs) are implicated as regulators of drug resistance and potential prognostic biomarkers or therapeutic targets.

Clinical implicationInvestigators suggest tumor-specific ncRNAs may help predict response and guide individualized chemotherapy, but further translational research is needed.

inv-27: Definition — Laboratory Developed Test (LDT)

DefinitionA diagnostic test developed and used within a single laboratory (laboratory developed test, LDT).

Regulatory noteFDA has cited insufficiently validated LDTs (example: Duke University Chemotherapy Assessment Test) as having potentially caused patient harm when used to guide chemotherapy.

Coverage implicationUse of insufficiently validated LDTs to select chemotherapy may lead to denial of clinical utility or adverse regulatory attention.

inv-28: Policy History / Definitions link indicator

Policy history accessPolicy History (link indicated) — Last Review: 10/11/2023; Next Review: 08/22/2024; Effective: 06/20/2008.

Definitions linkDefinitions (link indicated) — opens policy definitions page for related terms.

Review notesReview history and detailed change log available via linked Review History in the policy bulletin.

Biomarkers and Molecular Findings

inv-29: Biomarkers listed — MGMT, GSTP1, mutant p53, TFAP2E, DKK4, miR-125b

MGMTO(6)-methylguanine-DNA methyltransferase (MGMT) — overexpression associated with in-vitro resistance in malignant gliomas (reported 67% overexpression).

GSTP1Glutathione S-transferase pi (GSTP1) — overexpression associated with in-vitro resistance in malignant gliomas (reported 49% overexpression).

mutant p53Mutant p53 — detected in a substantial percentage of brain tumors and associated with drug resistance (reported 41% overexpression).

TFAP2ETFAP2E — listed among biomarkers of interest in chemoresistance research within the policy background.

DKK4DKK4 — listed among biomarkers of interest in chemoresistance research within the policy background.

miR-125bmiR-125b — included in the list of specific biomarkers discussed in the policy background and literature summaries.

inv-30: Biomarkers listed — miRNAs, lncRNAs, ncRNAs

miRNAsMicroRNAs (miRNAs) — implicated in drug resistance across multiple cancers and discussed as potential predictive biomarkers and therapeutic targets.

lncRNAsLong non-coding RNAs (lncRNAs) — deregulated lncRNAs play roles in chemoresistance and may serve as prognostic biomarkers or targets.

ncRNAs (general)Non-coding RNAs (ncRNAs) — includes miRNAs, snoRNAs, lncRNAs and circRNAs; implicated in mechanisms of chemoresistance in hepatocellular and colorectal cancers.

inv-31: Biomarker — CD44s / CD44v6

CD44sCD44 standard (CD44s) — high expression associated with chemoresistance in ovarian cancer (OR 5.94) and shorter disease-free survival in a meta-analysis (24 studies, 2,267 patients).

CD44v6CD44 variant 6 (CD44v6) — expression was not correlated with FIGO stage, tumor differentiation, nodal metastasis, or overall survival in analyzed studies.

Clinical interpretationHigh CD44s expression potentially indicates poor prognosis and is associated with chemotherapy resistance, but further confirmation is needed before clinical application.

Therapeutic Strategies and Preclinical Evidence

Preclinical finding	Model / context	Implication for overcoming chemoresistance	Coverage status
Axl inhibition increases sensitivity to doxorubicin	Preclinical breast cancer models: gene expression and phospho-RTK comparison between MCF-7 (sensitive) and MCF-7/ADR (doxorubicin-resistant); Axl analyzed across 57 breast cancer cell lines; in vitro Axl inhibitor R428 combined with doxorubicin	Axl silencing or pharmacologic inhibition (R428) enhanced cell death with doxorubicin and reduced invasive/metastatic potential, suggesting the Gas6/Axl axis as a therapeutic target to overcome multi-drug resistance	Experimental
STAT5b targeting sensitizes pancreatic cancer cells to gemcitabine	Preclinical pancreatic ductal adenocarcinoma cell line studies (multiple PDAC lines including PANC-1, AsPC-1, BxPC3); STAT5b expression manipulated by shRNA or overexpression	STAT5b knockdown reduced chemoresistance to gemcitabine and increased apoptosis (PARP and cleaved caspase-3 activation); overexpression increased resistance, indicating STAT5b as a potential target to sensitize PDAC to gemcitabine	Experimental

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