Tumor Chemoresistance Assays
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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.
No material clinical or coverage changes in this revision.
Coverage Determination and Criteria
Coverage determination
Covered when ALL of the following are met:
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
| 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 |
| J9000-J9999 | Chemotherapy drugs |
| C00.0-D49.9 | Neoplasms |
| Z51.11-Z51.12 | Encounter for antineoplastic chemotherapy and immunotherapy |
Provider Actions, Prior Authorization, and Denial Risk
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.
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.
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
Biomarkers and Molecular Findings
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 |
Policy Dates and Revision History
Policy last reviewed on 2023-10-11.
Policy effective since 2008-06-20.
Next scheduled review on 2024-08-22.
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