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In Vitro Chemoresistance and Chemosensitivity Assays

Policy Number: MP-097

Latest Review Date: July 2021

Category:  Laboratory

Policy Grade:  Active Policy but no longer scheduled for regular literature reviews and updates


In vitro chemoresistance assays, including, but not limited to, Extreme Drug Resistance assay, are considered investigational.

In vitro chemosensitivity assays, including, but not limited to, the Histoculture Drug Response Assay (HDRA), a fluorescent cytoprint assay, or the ChemoFX assay, are considered investigational.


In vitro chemoresistance and chemosensitivity assays have been developed to provide information about the characteristics of an individual patient’s malignancy to predict potential responsiveness of their cancer to specific drugs. Oncologists may sometimes use these assays to select treatment regimens for a patient. Several assays have been developed that differ concerning the processing of biological samples and detection methods. However, all involve similar principles and share protocol components including: 1) isolation of cells and establishment in an in vitro medium (sometimes in soft agar); 2) incubation of the cells with various drugs; 3) assessment of cell survival; and 4) interpretation of the result.

A variety of chemosensitivity and chemoresistance assays have been clinically evaluated in human trials. All assays use characteristics of cell physiology to distinguish between viable and nonviable cells to quantify cell kill following exposure to a drug of interest. With few exceptions, drug doses used in the assays are highly variable depending on tumor type and drug class, but all assays require drug exposures ranging from several-fold below physiologic relevance to several-fold above physiologic relevance. Although a variety of assays exist to examine chemosensitivity or chemoresistance, only a few are commercially available. Examples of available assays are outlined below.

Methods Using Differential Staining/Dye Exclusion

Differential Staining Cytotoxicity Assay

The Differential Staining Cytotoxicity Assay relies on dye exclusion of live cells after mechanical disaggregation of cells from surgical or biopsy specimens by centrifugation. Cells are then established in culture and treated with the drugs of interest at three dose levels; the middle relevant dose, which could be achieved in therapy; ten-fold lower dose than the physiologically relevant dose; and, ten-fold higher dose. Exposure time ranges from four to six days; then, cells are re-stained with fast green dye and counterstained with hematoxylin and eosin. The fast green dye is taken up by dead cells, and hematoxylin and eosin differentiate tumor cells from normal cells. The intact cell membrane of a live cell precludes staining with the green dye. Drug sensitivity is measured by the ratio of the number of live cells in the treated samples to the number of live cells in the untreated controls.

Ex-Vivo Analysis of Programmed Cell Death Functional Profiling Assay

The Ex-Vivo Analysis of Programmed Cell Death (EVA/PCD®) assay (Rational Therapeutics) measures differential staining of cells after apoptotic and nonapoptotic cell death markers in tumor samples are exposed to chemotherapeutic agents. Tumor specimens obtained through biopsy or surgical resection are disaggregated using DNase and collagenase IV to yield tumor clusters of the desired size (50-100 cell spheroids). Because these cells are not proliferated, these microaggregates are believed to approximate the human tumor microenvironment more closely. These cellular aggregates are treated with the dilutions of the chemotherapeutic drugs of interest and incubated for three days. After drug exposure is completed, a mixture of nigrosin B and fast green dye with glutaraldehyde-fixed avian erythrocytes is added to the cellular suspensions. The samples are then agitated, cytospin-centrifuged, air-dried, and counterstained with hematoxylin and eosin. The endpoint of interest for this assay is cell death, as assessed by the number of cells differentially stained due to changes in cellular membrane integrity.

Fluorometric Microculture Cytotoxicity Assay

The fluorometric microculture cytotoxicity assay is another cell viability assay that relies on the measurement of fluorescence generated from cellular hydrolysis of fluorescein diacetate to fluorescein in viable cells. Cells from tumor specimens are incubated with cytotoxic drugs; drug resistance is associated with higher levels of fluorescence.

Methods Using Radioactive Precursors by Macromolecules in Viable Cells

Tritiated Thymine

Tritiated thymine incorporation measures uptake of tritiated thymidine by DNA of viable cells. Using proteases and DNAse to disaggregate the tissue, samples are seeded into single-cell suspension cultures on soft agar. They are then treated with the drug(s) of interest for four days. After three days, tritiated thymidine is added. After 24 hours of additional incubation, cells are lysed, and radioactivity is quantified and compared with a blank control consisting of cells that were treated with sodium azide. Only cells that are viable and proliferating will take up the radioactive thymidine. Therefore, there is an inverse relationship between update of radioactivity and sensitivity of the cells to the agent(s) of interest.

Extreme Drug Resistance Assay

The Oncotech Extreme Drug Resistance assay (EDR®) (Exiqon Diagnostics, Tustin, CA; no longer commercially available) is methodologically similar to the thymidine incorporation assay, using metabolic incorporation of tritiated thymidine to measure cell viability; however, single cell suspensions are not required, so the assay is simpler to perform. Tritiated thymidine is added to the cultures of tumor cells, and uptake is quantified after various incubation times. Only live (resistant) cells will incorporate the compound. Therefore, the level of tritiated thymidine incorporation is directly related to chemoresistance. The interpretation of the results is unique in that resistance to the drugs is evaluated as opposed to the evaluation of responsiveness. Tumors are considered to be highly resistant when thymidine incorporation is at least one standard deviation above reference samples.

Methods Quantifying Cell Viability Using Colorimetric Assay

Histoculture Drug Resistance Assay

The Histoculture Drug Resistance Assay HDRA® (AntiCancer Inc., San Diego, CA) evaluates cell growth after chemotherapy treatment based on a colorimetric assay that relies on mitochondrial dehydrogenases in living cells. Drug sensitivity is evaluated by quantification of cell growth in the three-dimensional collagen matrix. There is an inverse relationship between the drug sensitivity of the tumor and cell growth. Concentrations of drug and incubation times are not standardized and vary depending on drug combination and tumor type.

Methods Using Chemoluminescent Precursors by Macromolecules in Viable Cells

Adenosine Triphosphate Bioluminescence Assay

The Adenosine Triphosphate (ATP) Bioluminescence Assay relies on measurement of ATP to quantify the number of viable cells in a culture. Single cells or small aggregates are cultured, then exposed to drugs. Following incubation with drug, the cells are lysed and the cytoplasmic components are solubilized under conditions that will not allow enzymatic metabolism of ATP. Luciferin and firefly luciferase are added to the cell lysis product. This catalyzes the conversion of ATP to adenosine di- and monophosphate and light is emitted proportionally to metabolic activity. This is quantified with a luminometer. From the measurement of light, the number of cells can be calculated. A decrease in ATP indicates drug sensitivity, whereas no loss of ATP suggests that the tumor is resistant to the agent of interest.

ChemoFX Assay

The ChemoFX® (Helomics Corporation, previously called Precision Therapeutics, Pittsburgh, PA) assay also relies on quantifying ATP-based on chemoluminescence. Cells must be grown in a monolayer rather than in a three-dimensional matrix.


The most recent literature review was updated through June 2, 2021.

Summary of Evidence

For individuals who have cancer who are initiating chemotherapy who receive chemoresistance assays, the evidence includes correlational observational studies. The relevant outcomes are overall survival, disease-specific survival, test accuracy and validity, and quality of life. Some retrospective and prospective correlational studies have suggested that chemoresistance assays may be associated with chemotherapy response. However, prospective studies have not consistently demonstrated that chemoresistance assay results are associated with survival. Furthermore, no studies were identified that compared outcomes for patients managed using assay-directed therapy with those managed using physician-directed therapy. Large, randomized, prospective clinical studies comparing clinical outcomes are needed. The evidence is insufficient to determine the effects of the technology on health outcomes.

For individuals who have cancer who are initiating chemotherapy who receive chemosensitivity assays, the evidence includes a randomized controlled trial (RCT), nonrandomized studies, and correlational observational studies. The relevant outcomes are overall survival, disease-specific survival, test accuracy and validity, and quality of life. The most direct evidence on the effectiveness of chemosensitivity assays in the management of patients with cancer comes from several studies comparing outcomes for patients managed using a chemosensitivity assay with those managed using standard care, including a randomized controlled trial. Although some improvements in tumor response were noted in the randomized controlled trial, there were no differences in survival outcomes. One small nonrandomized study reported improved overall survival in patients receiving chemosensitivity-guided therapy compared with patients receiving standard chemotherapy. A number of retrospective and prospective studies of several different chemosensitivity assays have suggested that patients whose tumors have higher chemosensitivity have better outcomes. Currently, additional studies to determine whether the clinical use of in vitro chemosensitivity testing leads to better outcomes are needed. The evidence is insufficient to determine the effects of the technology on health outcomes.

Practice Guidelines and Position Statements

The purpose of the following information is to provide reference material. Inclusion does not imply endorsement or alignment with the evidence review conclusions.

National Comprehensive Cancer Network (NCCN)

Epithelial Ovarian Cancer/ Fallopian Tube Cancer/ Primary Peritoneal Cancer

Current NCCN (v.1.2021) guidelines for the treatment of epithelial ovarian cancer, fallopian tube cancer, and primary peritoneal cancer state that "Chemosensitivity/resistance and/or other biomarker assays are being used in some NCCN Member Institutions for decisions related to future chemotherapy in situations where there are multiple equivalent chemotherapy options available. The current level of evidence is not sufficient to supplant standard-of-care chemotherapy (category 3)."

Gastric Cancer

The NCCN (v.2.2021) guidelines for the treatment of gastric cancer do not discuss the use of chemoresistance or chemosensitivity assays as part of cancer management.

Breast Cancer

The NCCN (v.4.2021) guidelines for the treatment of breast cancer do not discuss the use of chemoresistance or chemosensitivity assays as part of cancer management.


The NCCN (v.2.2021) guidelines for the treatment of cutaneous melanoma do not discuss the use of chemoresistance or chemosensitivity assays as part of cancer management.

Non-Small Cell Lung Cancer

The NCCN (v.4.2021) guidelines for the treatment of non-small cell lung cancer do not discuss the use of chemoresistance or chemosensitivity assays as part of cancer management.

Uterine Neoplasms

The NCCN (v.2.2021) guidelines for the treatment of uterine neoplasms do not discuss the use of chemoresistance or chemosensitivity assays as part of cancer management.

American Society of Clinical Oncology (ASCO)

The updated American Society of Clinical Oncology (2011) clinical guidelines on the use of chemotherapy sensitivity and resistance assays did not recommend use of chemotherapy sensitivity and resistance assays unless in a clinical trial setting.

U.S. Preventive Services Task Force Recommendations

Not Applicable.


Chemoresistance assays, chemosensitivity assays, drug sensitive, drug resistant, chemotherapy, drug sensitivity testing (DST), Thymidine Incorporation Assay, MTT, ATP-Cell Viability Assay, Differential Staining Cytotoxicity (DiSC) Assay, ChemoFx® Assay, Extreme Drug Resistance Assay (EDR), and Histoculture Drug Response Assay (HDRA), Oncotech, CorrectChemo® assay, ChemoID, 3D Predict Glioma


Clinical laboratories may develop and validate tests in-house and market them as a laboratory service; laboratory-developed tests must meet the general regulatory standards of the Clinical Laboratory Improvement Amendments. Chemoresistance and chemosensitivity assays discussed in this review are available under the auspices of the Clinical Laboratory Improvement Amendments. Laboratories that offer laboratory-developed tests must be licensed by the Clinical Laboratory Improvement Amendments for high-complexity testing. To date, the U.S. Food and Drug Administration has chosen not to require any regulatory review of this test.


Coverage is subject to member’s specific benefits.  Group specific policy will supersede this policy when applicable.

ITS: Home Policy provisions apply

FEP contracts: Special benefit consideration may apply. Refer to member’s benefit plan. FEP does not consider investigational if FDA approved and will be reviewed for medical necessity.


 CPT codes:


Oncology (brain), spheroid cell culture in a 3D microenvironment, 12 drug panel, tumor-response prediction for each drug (used for 3D Predict Glioma) (Effective 7/1/2021)


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 (Effective 1/1/2020)


Oncology (gynecologic), liver tumor cell culture and chemotherapeutic response by DAPI stand and morphology, predictive algorithm reported as a drug response score; first single drug or drug combination (used for ChemoFX®)


each additional single drug or drug combination (List separately in addition to code for primary procedure)

The extreme drug resistance assay is a multistep laboratory procedure that might be identified by the following CPT codes:


Toxin or antitoxin assay, tissue culture


Cytopathology, fluids, washings or brushings; except cervical or vaginal; smears with interpretation


Level IV surgical pathology, gross and microscopic examination


Special stains including interpretation and report; Group II all other (e.g., iron, trichrome), except stain for microorganisms, stains for enzyme constituents, or immunocytochemistry and immunohistochemistry


Morphometric analysis; tumor


Cell count, miscellaneous body fluids


CPT codes:


Unlisted immunology procedure


Unlisted miscellaneous pathology test


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Medical Policy Group, April 2003 (1)

Medical Policy Administration Committee, May 2003

Available for comment June 3-July 18, 2003

Medical Policy Group, September 2004 (3)

Medical Policy Administration Committee, October 2004

Available for comment October 15-November 29, 2004

Medical Policy Group, October 2006 (1)

Medical Policy Group, October 2008 (1)

Medical Policy Panel, April 2010

Medical Policy Group, May 2010 (2)

Medical Policy Administration Committee, May 2010

Available for comment May 26-July 9, 2010

Medical Policy Group, October 2010 (1): Caris Target Now added, Description and Key Points updated

Medical Policy Administration Committee, November 2010

Available for comment November 4 – December 20, 2010

Medical Policy Group, January 2011 (2): References Updated

Medical Policy Group, February 2011 (2): References Updated

Medical Policy Group, May 2011 (1): References Updated

Medical Policy Group, December 2011 (1): 2012 Code Updates – verbiage change to code 88313

Medical Policy Group, January 2012 (1) Addition of code 89240 to policy; no change in policy statement

Medical Policy Administration Committee, January 2012

Available for comment January 30 – March 14, 2012

Medical Policy Group, March 2012 (1): Update to Key Points related to MPP update; no new references added; no change in policy statement

Medical Policy Panel, April 2013

Medical Policy Group, October 2013 (1): Update to Description, Key Points and References; no change to policy statement

Medical Policy Panel, April 2014

Medical Policy Group, April 2014 (1): Update to Description, Key Points, Governing Bodies and References; no change to policy statement.

Medical Policy Panel, April 2015

Medical Policy Group, May 2015 (3): 2015 Updates to Description, Key Points, Key Words, Current Coding – CPT codes effective 01/01/16 specific to ChemoFX® added – 81535 and 81536; Policy statement changed to include CorrectChemo® assay, no change to intent.

Medical Policy Group, November 2015: 2016 Annual Coding Update. Created previous coding section and moved cpt codes 86849 and 89240 under this section.

Medical Policy Panel, July 2016

Medical Policy Group, July 2016 (3): 2016 Updates to Description, Key Points, & References; no change to policy statement.

Medical Policy Panel, September 2017

Medical Policy Group, October 2017 (3): 2017 Updates to Description, Key Points & References; no change to policy statement.

Medical Policy Panel, July 2018

Medical Policy Group, July 2018 (9): 2018 Updates to Description and Key Points; no change to policy statement.

Medical Policy Panel, July 2019

Medical Policy Group, July 2019 (9): 2019 Updates to Description and Key Points; no change to policy statement.

Medical Policy Group, November 2019: 2020 Annual Coding Update. Added CPT code 0564T to Current coding section. Added key word: ChemoID. Updated Key Points.

Medical Policy Panel, July 2020

Medical Policy Group, July 2020 (9): 2020 Updates to Description and Key Points, no references added. No change to policy statement.

Medical Policy Group, May 2021 (9): Quarterly Coding Update. CPT code 0248U added to current coding section. Key word added: 3D Predict Glioma

Medical Policy Panel, July 2021

Medical Policy Group, July 2021 (9): 2021 Updates to Key Points, Description, References. Policy statement updated to remove “not medically necessary”; separated one policy statement into two policy statements (one for in vitro chemoresistance assays and one for in vitro chemosensitivity assays) for easier readability. No change to policy statement intent.

Medical Policy Group: Active Policy but no longer scheduled for regular literature reviews and updates (July 13, 2021).

This medical policy is not an authorization, certification, explanation of benefits, or a contract. Eligibility and benefits are determined on a case-by-case basis according to the terms of the member’s plan in effect as of the date services are rendered. All medical policies are based on (i) research of current medical literature and (ii) review of common medical practices in the treatment and diagnosis of disease as of the date hereof. Physicians and other providers are solely responsible for all aspects of medical care and treatment, including the type, quality, and levels of care and treatment.

This policy is intended to be used for adjudication of claims (including pre-admission certification, pre-determinations, and pre-procedure review) in Blue Cross and Blue Shield’s administration of plan contracts.

The plan does not approve or deny procedures, services, testing, or equipment for our members. Our decisions concern coverage only. The decision of whether or not to have a certain test, treatment or procedure is one made between the physician and his/her patient. The plan administers benefits based on the member’s contract and corporate medical policies. Physicians should always exercise their best medical judgment in providing the care they feel is most appropriate for their patients. Needed care should not be delayed or refused because of a coverage determination.

As a general rule, benefits are payable under health plans only in cases of medical necessity and only if services or supplies are not investigational, provided the customer group contracts have such coverage.

The following Association Technology Evaluation Criteria must be met for a service/supply to be considered for coverage:

1. The technology must have final approval from the appropriate government regulatory bodies;

2. The scientific evidence must permit conclusions concerning the effect of the technology on health outcomes;

3. The technology must improve the net health outcome;

4. The technology must be as beneficial as any established alternatives;

5. The improvement must be attainable outside the investigational setting.

Medical Necessity means that health care services (e.g., procedures, treatments, supplies, devices, equipment, facilities or drugs) that a physician, exercising prudent clinical judgment, would provide to a patient for the purpose of preventing, evaluating, diagnosing or treating an illness, injury or disease or its symptoms, and that are:

1. In accordance with generally accepted standards of medical practice; and

2. Clinically appropriate in terms of type, frequency, extent, site and duration and considered effective for the patient’s illness, injury or disease; and

3. Not primarily for the convenience of the patient, physician or other health care provider; and

4. Not more costly than an alternative service or sequence of services at least as likely to produce equivalent therapeutic or diagnostic results as to the diagnosis or treatment of that patient’s illness, injury or disease.