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Circulating Tumor DNA and Circulating Tumor Cells for Cancer Management (Liquid Biopsy)

Policy Number: MP-256

Latest Review Date: October 2019

Category: Laboratory

Policy Grade: C

POLICY:

Effective for dates of service on or after September 6, 2019:

Detection of circulating tumor cells and cell free DNA in cancer management may be considered medically necessary for:

  • Patients with Stage IIIB/IV non-small cell lung cancer (NSCLC), liquid biopsy (plasma genotyping) for EGFR mutations to predict treatment response to an EGFR tyrosine kinase inhibitor (TKI) when:
    • an invasive biopsy is medically contraindicated or quantity of tissue available for mutation testing is insufficient;
    • If no genetic alteration is detected by plasma genotyping, or if circulating tumor DNA (ctDNA) is insufficient/not detected, tissue-based genotyping should be considered

Liquid biopsy for all other mutations in NSCLC (e.g. ALK and ROS rearrangements) is considered not medically necessary and investigational.

Liquid biopsy for screening, detection, and monitoring any other malignancy or tumor is considered not medically necessary and investigational.


Effective for dates of service on or prior to September 5, 2019:

The use of circulating tumor DNA and/or circulating tumor cells is considered not medically necessary and investigational for all indications reviewed herein.


DESCRIPTION OF PROCEDURE OR SERVICE:

Circulating tumor DNA (ctDNA) and circulating tumor cells (CTCs) in peripheral blood, referred to as “liquid biopsy,” have several potential uses for guiding therapeutic decisions in patients with cancer or being screened for cancer. For patients with non-small cell lung cancer (NSCLC) detection of “driver mutations” or resistance variants is important for selecting patients for targeted therapy. This evidence review evaluates uses for liquid biopsies that are not addressed in a separate review. If a separate evidence review exists, then conclusions reached there supersede conclusions here.

Liquid biopsy refers to the analysis of circulating tumor DNA (ctDNA) or circulating tumor cells (CTCs) as methods of noninvasively characterizing tumors and tumor genome from the peripheral blood.

Circulating Tumor DNA

Normal and tumor cells release small fragments of DNA into the blood, which is referred to as cell-free DNA (cfDNA). Cell-free DNA from nonmalignant cells is released by apoptosis. Most cell-free tumor DNA is derived from apoptotic and/or necrotic tumor cells, either from the primary tumor, metastases, or CTCs. Unlike apoptosis, necrosis is considered a pathologic process, and generates larger DNA fragments due to an incomplete and random digestion of genomic DNA. The length or integrity of the circulating DNA can potentially distinguish between apoptotic and necrotic origin. Circulating tumor DNA can be used for genomic characterization of the tumor.

Circulating Tumor Cells

Intact CTCs are released from a primary tumor and/or a metastatic site into the bloodstream. The half-life of a CTC in the bloodstream is short (one-two hours), and CTCs are cleared through extravasation into secondary organs. Most assays detect CTCs through the use of surface epithelial markers such as EpCAM and cytokeratins. The primary use in detecting CTCs is for prognostic purposes through quantification of circulating levels.

Detecting ctDNA and CTCs

Detection of ctDNA is challenging because ctDNA is diluted by nonmalignant circulating DNA and usually represents a small fraction (<1%) of total cfDNA. Therefore, more sensitive methods than the standard sequencing approaches (e.g., Sanger sequencing) are needed.

Highly sensitive and specific methods have been developed to detect ctDNA, for both single-nucleotide variants (e.g., BEAMing [which combines emulsion polymerase chain reaction [PCR] with magnetic beads and flow cytometry] and digital PCR) and copy-number variants. Digital genomic technologies allow for enumeration of rare variants in complex mixtures of DNA.

Approaches to detecting ctDNA can be considered targeted, which includes the analysis of known genetic mutations from the primary tumor in a small set of frequently occurring driver mutations, which can impact therapy decisions or untargeted without knowledge of specific variants present in the primary tumor, and include array comparative genomic hybridization, next-generation sequencing, and whole exome and genome sequencing.

CTC assays usually start with an enrichment step that increases the concentration of CTCs, either on the basis of biologic properties (expression of protein markers) or physical properties (size, density, electric charge). CTCs can then be detected using immunologic, molecular, or functional assays.

Predictive Biomarkers in Non-Small Cell Lung Cancer

Several predictive genetic biomarkers have been identified for non-small-cell lung cancer (NSCLC). Somatic genome alterations known as “driver mutations” are usually transformative variants arising in cancer cells in genes encoding for proteins important in cell growth and survival. Randomized controlled trials have demonstrated improved efficacy, often in conjunction with decreased toxicity, of matching targeted therapies to patients with specific driver mutations. Several such targeted therapies are approved by the Food and Drug Administration (FDA) for NSCLC. Guidelines generally suggest the analysis of either the primary NSCLC tumor or of a metastasis for the presence of a set of driver mutations to select an appropriate treatment.

EGFR Variants

Specific EGFR variants confer sensitivity to treatment with tyrosine kinase inhibitors (TKIs), such as erlotinib, gefitinib, afatinib, and osimertinib; the most common variants are deletions in exons 19 and an exon 21 substitution variant (L858R). These variants are referred to as TKI-sensitizing variants and are found in approximately 10% of white patients and up to 50% of Asian patients. The prevalence of EGFR variants is not well characterized in other ethnic or racial groups but is estimated to be 10% to 15% in studies including general U.S. populations. TKIs are indicated as first-line treatment for patients with sensitizing variants; progression-free survival is improved with the use of TKIs. Patients receiving TKIs have fewer treatment-related adverse events than patients receiving cytotoxic chemotherapy.

Tyrosine Kinase Inhibitor-Resistance Variants

EGFR Variants

The EGFR variant T790M has been associated with acquired resistance to TKI therapy. When the T790M variant is detected in tissue biopsies from patients with suspected resistance to TKI therapy, osimertinib is recommended as second-line therapy. However, the use of osimertinib as first-line therapy for patients who have EGFR-sensitizing variants is emerging and may prevent the development of T790M resistance.

*Note that targeted therapy in metastatic colorectal cancer, use of liquid biopsy for detection or risk assessment of prostate cancer, and use of AR-V7 CTC liquid biopsy for metastatic prostate cancer are addressed in separate reviews.

KEY POINTS:

The most recent literature review was conducted through August 1, 2019.

Summary of Evidence

Circulating tumor DNA (ctDNA) and circulating tumor cells (CTCs) in peripheral blood, referred to as “liquid biopsy,” have several potential uses for guiding therapeutic decisions in patients with cancer or being screened for cancer. This evidence review evaluates uses for liquid biopsies not addressed in a separate review. If a separate evidence review exists, then conclusions reached there supersede conclusions here.

For individuals who have advanced cancer who receive testing of ctDNA to select targeted treatment, the evidence includes observational studies. Relevant outcomes are overall survival, disease-specific survival, test accuracy and validity, morbid events, and medication use. Given the breadth of methodologies available to assess ctDNA, the clinical validity of each commercially available test must be established independently, and these data are lacking, outside of lung and colorectal cancer, which are covered in a separate review. The clinical validity of FoundationOne Liquid compared to tissue biopsy with FoundationOne comprehensive genetic testing was evaluated in four industry sponsored observational studies. Published studies reporting clinical outcomes and/or clinical utility are lacking. The uncertainties concerning clinical validity and clinical utility preclude conclusions about whether variant analysis of ctDNA can replace variant analysis of tissue. The evidence is insufficient to determine the effects of the technology on health outcomes.

For individuals who have advanced cancer who receive testing of CTCs to select targeted treatment, the evidence includes observational studies. Relevant outcomes are overall survival, disease-specific survival, test accuracy and validity, morbid events, and medication use. Given the breadth of methodologies available to assess CTCs, the clinical validity of each commercially available test must be established independently, and these data are lacking. Published studies reporting clinical outcomes and/or clinical utility are lacking. The uncertainties concerning clinical validity and clinical utility preclude conclusions about whether the use of CTCs can replace variant analysis of tissue. The evidence is insufficient to determine the effects of the technology on health outcomes.

For individuals who have cancer who receive testing of ctDNA to monitor treatment response, the evidence includes observational studies. Relevant outcomes are overall survival, disease-specific survival, test accuracy and validity, morbid events, and medication use. Given the breadth of methodologies available to assess ctDNA, the clinical validity of each commercially available test must be established independently, and these data are lacking. Published studies reporting clinical outcomes and/or clinical utility are lacking. The uncertainties concerning clinical validity and clinical utility preclude conclusions about whether the use of ctDNA should be used to monitor treatment response. The evidence is insufficient to determine the effects of the technology on health outcomes.

For individuals who have cancer who receive testing of CTCs to monitor treatment response, the evidence includes a randomized controlled trial, observational studies, and systematic reviews of observational studies. Relevant outcomes are overall survival, disease-specific survival, test accuracy and validity, morbid events, and medication use. Given the breadth of methodologies available to assess CTCs, the clinical validity of each commercially available test must be established independently, and these data are lacking. The available randomized controlled trial found no effect on overall survival when patients with persistently increased CTC levels after first-line chemotherapy were switched to an alternative cytotoxic therapy. Other studies reporting clinical outcomes and/or clinical utility are lacking. The uncertainties concerning clinical validity and clinical utility preclude conclusions about whether the use of CTCs should be used to monitor treatment response. The evidence is insufficient to determine the effects of the technology on health outcomes.

For individuals who have received curative treatment for cancer who receive testing of ctDNA to predict risk of relapse, the evidence includes observational studies. Relevant outcomes are overall survival, disease-specific survival, test accuracy and validity, morbid events, and medication use. Given the breadth of methodologies available to assess ctDNA, the clinical validity of each commercially available test must be established independently, and these data are lacking. Published studies reporting clinical outcomes and/or clinical utility are lacking. The uncertainties concerning clinical validity and clinical utility preclude conclusions about whether the use of ctDNA should be used to predict relapse response. The evidence is insufficient to determine the effects of the technology on health outcomes.

For individuals who have received curative treatment for cancer who receive testing of CTCs to predict risk of relapse, the evidence includes observational studies. Relevant outcomes are overall survival, disease-specific survival, test accuracy and validity, morbid events, and medication use. Given the breadth of methodologies available to assess CTCs, the clinical validity of each commercially available test must be established independently, and these data are lacking. Published studies reporting clinical outcomes and/or clinical utility are lacking. The uncertainties concerning clinical validity and clinical utility preclude conclusions about whether the use of CTCs should be used to predict relapse response. The evidence is insufficient to determine the effects of the technology on health outcomes.

For individuals who are asymptomatic and at high risk for cancer who receive testing of ctDNA to screen for cancer, no evidence was identified. Relevant outcomes are overall survival, disease-specific survival, test accuracy, and test validity. Published data on clinical validity and clinical utility are lacking. The evidence is insufficient to determine the effects of the technology on health outcomes.

For individuals who are asymptomatic and at high risk for cancer who receive testing of CTCs to screen for cancer, the evidence includes observational studies. Relevant outcomes are overall survival, disease-specific survival, test accuracy, and test validity. Given the breadth of methodologies available to assess CTCs, the clinical validity of each commercially available test must be established independently, and these data are lacking. Published studies reporting clinical outcomes and/or clinical utility are lacking. The evidence is insufficient to determine the effects of the technology on health outcomes.

For individuals with advanced NSCLC who receive testing for biomarkers of EGFR TKIs sensitivity using ctDNA with the cobas EGFR Mutation Test v2 (liquid biopsy), the evidence includes numerous studies assessing the diagnostic characteristics of liquid biopsy compared with tissue. The relevant outcomes are overall survival (OS), disease-specific survival (DSS), and test validity. Current evidence does not permit determining whether cobas or tissue biopsy is more strongly associated with patient outcomes or treatment response. No RCTs providing evidence of the clinical utility of cobas were identified. The cobas EGFR Mutation Test has adequate evidence of clinical validity for the EGFR TKI-sensitizing variants. The Food and Drug Administration has suggested that a strategy of liquid biopsy followed by referral (reflex) tissue biopsy of negative liquid biopsies for the cobas test would result in an overall diagnostic performance equivalent to tissue biopsy. Several additional studies of the clinical validity of cobas have shown it to be moderately sensitive and highly specific compared with a reference standard of tissue biopsy. A chain of evidence demonstrates that the reflex testing strategy with the cobas test should produce outcomes similar to tissue testing while avoiding tissue testing in approximately two-thirds of patients with EGFR TKI-sensitizing variants. Patients who cannot undergo tissue biopsy would likely otherwise receive chemotherapy. The cobas test can identify patients for whom there is a net benefit of targeted therapy vs chemotherapy with high specificity. The evidence is sufficient to determine that the technology results in a meaningful improvement in the net health outcome.

For individuals with advanced NSCLC who receive testing for biomarkers of EGFR TKI sensitivity using ctDNA (liquid biopsy) with the Guardant360, OncoBEAM, or InVision tests, the evidence includes several studies assessing the diagnostic characteristics of liquid biopsy compared with tissue. The relevant outcomes are overall survival (OS), disease-specific survival (DSS), and test validity. Current evidence does not permit determining whether liquid or tissue biopsy is more strongly associated with patient outcomes or treatment response. No RCTs providing evidence of the clinical utility of these tests were identified. The Guardant360, OncoBEAM, and InVision tests have adequate evidence of clinical validity for the EGFR TKI-sensitizing variants. A strategy of liquid biopsy followed by referral (reflex) tissue biopsy of negative liquid biopsies for the tests would result in an overall diagnostic performance similar to tissue biopsy. A chain of evidence demonstrates that the reflex testing strategy with the Guardant360, OncoBEAM, or InVision tests should produce outcomes similar to tissue testing while avoiding tissue testing in approximately two-thirds of patients with EGFR TKI-sensitizing variants. Patients who cannot undergo tissue biopsy would likely otherwise receive chemotherapy. These tests can identify patients for whom there is a net benefit of targeted therapy vs chemotherapy with high specificity. The evidence is sufficient to determine that the technology results in a meaningful improvement in the net health outcome.

For individuals with advanced NSCLC who receive testing for biomarkers of EGFR TKI sensitivity using ctDNA with tests other than the cobas EGFR Mutation Test v2, Guardant360, OncoBEAM, or InVision tests the evidence includes studies assessing the diagnostic characteristics of liquid biopsy compared with tissue reference standard. The relevant outcomes are overall survival, disease-specific survival, and test validity. Given the breadth of molecular diagnostic methodologies available to assess ctDNA, the clinical validity of each commercially available test must be established independently. None of the commercially available tests other than the cobas, Guardant360, OncoBEAM, and InVision tests have multiple studies of adequate quality to estimate the performance characteristics with sufficient precision. Current evidence does not permit determining whether a liquid biopsy or tissue biopsy is more strongly associated with patient outcomes or treatment response. No RCTs providing evidence of the clinical utility of those methods of liquid biopsy were identified. The evidence is insufficient to determine the effects of the technology on health outcomes.

For individuals with advanced NSCLC who receive testing for biomarkers other than EGFR using a liquid biopsy to select a targeted therapy, the evidence includes studies assessing the diagnostic characteristics of liquid biopsy compared with the tissue biopsy reference standard. The relevant outcomes are overall survival (OS), disease-specific survival (DSS), and test validity. Given the breadth of molecular diagnostic methodologies available to assess ctDNA, the clinical validity of each commercially available test must be established independently. None of the commercially available tests have multiple studies of adequate quality to estimate the performance characteristics with sufficient precision for variants other than EGFR. No RCTs providing evidence of the clinical utility of those of methods of liquid biopsy were found. The evidence is insufficient to determine the effects of the technology on health outcomes.

For individuals with advanced NSCLC who progressed on EGFR TKIs who receive testing for biomarkers of EGFR TKI resistance using liquid biopsy, the evidence includes studies assessing the diagnostic characteristics of liquid biopsy. The relevant outcomes are overall survival (OS), disease-specific survival (DSS), and test validity. For variants that indicate EGFR TKI resistance and suitability for alternative treatments with osimertinib, liquid biopsy is moderately sensitive and moderately specific compared with a reference standard of tissue biopsy. Given the moderate clinical sensitivity and specificity of liquid biopsy, using liquid biopsy alone or in combination with tissue biopsy might result in the selection of different patients testing positive for EGFR TKI resistance. It cannot be determined whether patient outcomes are improved. However, although there is higher discordance in the liquid versus tissue results for the resistance variant, retrospective analyses have suggested that patients positive for T790M in liquid biopsy have outcomes with osimertinib that appear to be similar overall to patients positive by a tissue-based assay. The evidence is insufficient to determine the effects of the technology on health outcomes. Although the evidence is limited, the College of American Pathologists (CAP), the International Association for the Study of Lung Cancer (IASLC), and the Association for Molecular Pathology (AMP) published joint guidelines endorsed by American Society of Clinical Oncology (ASCO) with an expert consensus opinion that physicians may use liquid biopsy (cell-free DNA) to identify EGFR T790M variants in patients with progression or resistance to EGFR targeted TKIs and that testing of the tumor sample is recommended if the liquid biopsy result is negative. Similarly, the National Comprehensive Cancer Network guidelines also state that at progression on erlotinib, afatinib, gefitinib or dacomitinib when testing for the T790M resistance variant, liquid biopsy should be considered and when a liquid biopsy is negative tissue-based testing is strongly recommended.

Practice Guidelines and Position Statements

National Comprehensive Cancer Network (NCCN)

Network National Comprehensive Cancer Network guidelines (v.3.2019) discuss the role of liquid biopsy in the management of non-small-cell lung cancer. The guidelines state that cell-free/circulating tumor DNA testing should not be used in lieu of tissue diagnosis. They also state that cfDNA testing can be used if the patient is not medically fit for tissue sample or there is insufficient tissue for molecular analysis and follow-up with tissue-based analysis will be done if plamsa-based analysis is negative. The guidelines also state that at progression onerlotinib, afatinib, gefitinib or dacomitinib when testing for T790M, plasma-based testing should be considered and when plasma-based testing is negative tissue-based testing is strongly recommended.

National Comprehensive Cancer Network (NCCN) guidelines for breast cancer (v.1.2019) state that the use of circulating tumor cells in metastatic breast cancer is not yet included in algorithms for disease assessment and monitoring. The guidelines for melanoma (v.2.2019) reference papers on circulating tumor DNA in the discussion of molecular characteristics of metastatic disease with the statement, ‘A number of tests have been developed for detecting BRAF and KIT mutations common in metastatic melanoma. The sensitivity and accuracy of these tests vary, and improved assays are in development.’

National Comprehensive Cancer Network guidelines (v.6.2018) on the management of non-small-cell lung cancer state that “if repeat biopsy is not feasible, plasma biopsy should be considered,” but it is not stated to which biomarkers this statement applies. In the text discussion of osimertinib, the guidelines state that “Data suggest that plasma genotyping (also known as liquid biopsy or plasmas biopsy) may be considered instead of tissue biopsy to detect whether patients have T790M; however, if the plasma biopsy is negative, then tissue biopsy is recommended if feasible.”

International Association for the Study of Lung Cancer

The International Association for the Study of Lung Cancer (2018) published a statement paper on liquid biopsy for advanced non-small-cell lung cancer. The work preparing the statement was supported by unrestricted grants from Guardant Health, Astra Zeneca, Biocept, and Roche. The statement made the following recommendations:

  • “The criteria used to select treatment-naive patients for molecular testing of ctDNA [circulating tumor DNA] is the same used for molecular testing using DNA isolated from tissue.”
  • “Liquid biopsy can be considered at the time of initial diagnosis in all patients who need tumor molecular profiling, but it is particularly recommended when tumor tissue is scarce, unavailable, or a significant delay potentially greater than two weeks is expected in obtaining tumor tissue.”

The following tests are acceptable to detect epidermal growth factor receptor (EGFR)-sensitizing variants and results are sufficient to start a first-line treatment with an EGFR tyrosine kinase inhibitor:

  • Cobas EGFR Mutation Test v2.
  • Droplet digital polymerase chain reaction next-generation sequencing panels.
  • Multiplex panels using next-generation sequencing platforms could be considered to detect EGFR, ALK, ROS1, or BRAF variants and a positive result would be adequate to initiate first-line therapy.

A next-generation sequencing multiplex panel was preferred to detect T790M and other common resistance alterations. A positive result for EGFR T790M should be considered adequate to initiate osimertinib in the second-line setting.

College of American Pathologists, the International Association for the Study of Lung Cancer, and the Association for Molecular Pathology

The College of American Pathologists (CAP), the International Association for the Study of Lung Cancer (IASLC), and the Association for Molecular Pathology (AMP) (2018) published a guideline on molecular testing for the selection of lung cancer patients for treatment with targeted tyrosine kinase inhibitors. The American Society of Clinical Oncology (ASCO) also endorsed the joint College of American Pathologists/International Association for the Study of Lung Cancer/Association for Molecular Pathology guidelines with minor modifications.

The guidelines noted the following recommendation regarding liquid biopsy for activating EGFR mutations and a consensus opinion regarding liquid biopsy for the T790M resistance mutation.

  • Recommendation: "In some clinical settings in which tissue is limited and/or insufficient for molecular testing, physicians may use a cfDNA assay to identify [activating] EGFR mutations."
  • Expert Consensus Opinion: "Physicians may use plasma cfDNA methods to identify EGFR T790M mutations in lung adenocarcinoma patients with progression or secondary clinical resistance to EGFR targeted TKIs; testing of the tumor sample is recommended if the plasma result is negative."
  • No recommendation: "There is currently insufficient evidence to support the use of circulating tumor cell molecular analysis for the diagnosis of primary lung adenocarcinoma, the identification of EGFR or other mutations, or the identification of EGFR T790M mutations at the time of EGFR TKI resistance."

National Institute for Health and Care Excellence

The National Institute for Health and Care Excellence (NICE) (2018) issued an innovation briefing on plasma EGFR mutation tests for adults with locally advanced or metastatic NSCLC in2018. The briefing reviewed seven ctDNA tests available in Europe and concluded:

  • "The intended place in therapy would be as an alternative to tissue EGFR testing or before tumor testing to inform decisions about prescribing EGFR-TKIs. Plasma testing may be particularly useful for people whose disease has developed resistance to an EGFR-TKI and who could be offered second-line EGFR-TKIs, if appropriate, without having further tissue testing."
  • "The main points from the evidence summarized in this briefing are from seven non-UK-based prospective studies with 2,106 adults. They show that the diagnostic accuracy of plasma EGFR mutation testing has a similar specificity, but lower sensitivity, compared with tissue EGFR mutation testing in adults with locally advanced or metastatic NSCLC."
  • "Key uncertainties around the evidence or technology are that tests for identifying EGFR-TK mutations are rapidly evolving and there is no established gold-standard test against which to evaluate them."

U.S. Preventive Services Task Force Recommendations

Not applicable.

KEY WORDS:

CellSearch System, CellSearch Epithelial Cell Kit, circulating tumor cells, CTCs, metastatic disease, MAINTRAC, GeneSearch™ BLN test kit, Janssen, Veridex, Liquid Biopsy, circulating tumor DNA, ctDNA, Oncotype SEQ™, next-generation sequencing (NGS), CancerIntercept™, FoundationACT™, Safe Sequencing System (Safe-SeqS), CAncer Personalized Profiling by deep Sequencing (CAPP-Seq), Circulogene, Theranostics, Biocept, CellTracks® Autoprep, CellSpotter Analyzer®, Trovagene, Trovera, Guardant360 Panel, FirstSight, FoundationOne, plasma genotyping, EGFR, TKI, tyrosine kinase inhibitor, Cobas, Cobas EGFR Mutation Test v2, Guardant 360 test, Oncobeam Test, NSCLC, non-small cell lung cancer, Guardant Health, Roche Molecular Systems, Sysmex, PCR test, InVisionFirst-Lung test, InVisionFirst, osimertinib, EGFR T7900 resistant variant, EGFR T7900, resistant variant

APPROVED BY GOVERNING BODIES:

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. Several companies market tests that detect tumor markers from peripheral blood, including TKI sensitizing variants for NSCLC. 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 (FDA) has chosen not to require any regulatory review of this test. Clinical laboratories accredited through the College of American Pathologists enroll in proficiency testing programs to measure the accuracy of the test results. There are currently no College of American Pathologists proficiency testing programs available for ctDNA testing to ensure the accuracy of ctDNA laboratory-developed tests.

The CellSearch® System (Janssen Diagnostics, formerly Veridex) is the only FDA-approved device for monitoring patients with metastatic disease and CTCs. In 2004, the CellSearch® System was cleared by FDA for marketing through the 510(k) process for monitoring metastatic breast cancer, in 2007 for monitoring metastatic colorectal cancer, and in 2008 for monitoring metastatic prostate cancer. The system uses automated instruments manufactured by Immunicon for sample preparation (CellTracks® AutoPrep) and analysis (CellSpotter Analyzer®), together with supplies, reagents, and epithelial cell control kits manufactured by Veridex. FDA product code: NQI.

In June 2016, cobas EGFR Mutation Test v2 (Roche Molecular Systems), a real-time PCR test, was approved by the FDA through the premarket approval process (P150047). This plasma test is a real-time PCR test approved as a companion diagnostic aid for selecting NSCLC patients who have EGFR exon 19 deletions, and L858R substitution variants, for treatment with erlotinib. A premarket approval supplement expanded the indication to include the test as a companion diagnostic for treatment with gefitinib in 2018 (P120019). Patients who test negative for the variants detected should be referred for (or "reflexed" to) routine biopsy with tissue testing for EGFR variants. A previously approved version two of this test, which used tissue biopsy specimens, was also approved for detection of T790M variants in tissue, which are used to select patients to receive osimertinib. Approval of version two of the plasma test did not include detection of T790M variants.

No other ctDNA tests have FDA approval. Guardant Health (Guardant 360) and Foundation Medicine (FoundationACT™) were granted Expedited Access for Premarket Approval and De Novo Medical Devices Intended for Unmet Medical Need for Life Threatening or Irreversibly Debilitating Diseases or Conditions in 2018. FoundationACT™ is currently marketed as FoundationOne Liquid.

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. Several companies market tests that detect tumor markers from peripheral blood, including TKI-sensitizing variants for NSCLC. Laboratories that offer laboratory-developed tests must be licensed by the Clinical Laboratory Improvement Amendments for high-complexity testing. To date, the FDA has chosen not to require any regulatory review of this test. Clinical laboratories accredited through the College of American Pathologists enroll in proficiency testing programs to measure the accuracy of the test results. There are currently no College of American Pathologists proficiency testing programs available for ctDNA testing to ensure the accuracy of ctDNA laboratory-developed tests.

BENEFIT APPLICATION:

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

ITS: Home Policy provisions apply

FEP contracts: FEP does not consider investigational if FDA approved and will be reviewed for medical necessity.

CURRENT CODING:

CPT Codes:

There are no specific CPT codes for this type of testing. It would likely be reported using any existing CPT molecular pathology code(s) that is applicable (i.e., 81161-81355, 81400-81409), along with the unlisted molecular pathology procedure code.

86152

Cell enumeration using immunologic selection and identification in fluid specimen (e.g., circulating tumor cells in blood);

86153

Cell enumeration using immunologic selection and identification in fluid specimen (e.g., circulating tumor cells in blood); physician interpretation and report, when required

81479

Unlisted molecular pathology procedure

Previous Coding:

CPT Codes:

For FirstSight (colorectal):

0091U

Oncology (colorectal) screening, cell enumeration of circulating tumor cells, utilizing whole blood, algorithm, for the presence of adenoma or cancer, reported as a positive or negative result (Effective 07/01/19)

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  153. Taniguchi K, Uchida J, Nishino K, et al. Quantitative detection of EGFR mutations in circulating tumor DNA derived from lung adenocarcinomas. Clin Cancer Res. Dec 15 2011; 17(24):7808-7815.
  154. Terstappen LW, Rao C, Gross S, and Weiss AJ. Peripheral blood tumor cell load reflects the clinical activity of the disease in patients with carcinoma of the breast. Int J Oncol 2000; 17(3):573-578.
  155. Thalgott M, Rack B, Horn T, et al. Detection of circulating tumor cells in locally advanced high-risk prostate cancer during neoadjuvant chemotherapy and radical prostatectomy. Anticancer Res. Oct 2015; 35(10):5679-5685.
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POLICY HISTORY:

Medical Policy Group, September 2005 (2)

Medical Policy Administration Committee, October 2005

Available for comment December 1, 2005-January 14, 2006

Medical Policy Group, October 2006 (1)

Medical Policy Group, October 2007 (1)

Medical Policy Group, February 2008 (2)

Medical Policy Administration Committee, February 2008

Medical Policy Group, December 2008 (2)

Medical Policy Group, September 2009 (3) new policy Biomarker Genes for Detection of Lymph Node Metastases in Breast Cancer (archived medical policy #385 August 2015)

Medical Policy Administration Committee, September 2009 presented new policy Biomarker Genes for Detection of Lymph Node Metastases in Breast Cancer (archived medical policy #385 August 2015)

Available for comment September 18-November 2, 2009 new policy Biomarker Genes for Detection of Lymph Node Metastases in Breast Cancer (archived medical policy #385 August 2015)

Medical Policy Group, December 2009 (1)

Medical Policy Group, June 2010 (1)

Medical Policy Group, January 2011 updated Key Points & References on policy Biomarker Genes for Detection of Lymph Node Metastases in Breast Cancer (archived medical policy #385 August 2015)

Medical Policy Group, July 2011 (1): Update to Description, Key Points and References

Medical Policy Group, November 2011 (1): Added 2012 CPT Codes Effective 1/1/12

Medical Policy Group, February 2012 (1): Deleted S3711 HCPCS Code effect 4/1/12

Medical Policy Group, June 2012 (1): 2012 Updates to Key Points and References

Medical Policy Group, November 2012: 2013 Coding Updates – Added 86152 & 86153

Medical Policy Group, January 2013 (1) Update to Coding on policy Biomarker Genes for Detection of Lymph Node Metastases in Breast Cancer (archived medical policy #385 August 2015)with addition of new codes 81479 and 81599 and deletion of code range 83890-83914; no change in policy statement

Medical Policy Group, February 2013 (1): policy Biomarker Genes for Detection of Lymph Node Metastases in Breast Cancer (archived medical policy #385 August 2015) Effective 02/01/2013 - Active Policy but no longer scheduled for regular literature reviews and updates.

Medical Policy Panel, June 2013

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

Medical Policy Panel, June 2014

Medical Policy Group, June 2014 (1): Update to Key Points and References; no change to policy statement

Medical Policy Panel, June 2015

Medical Policy Group, June 2015 (3): 2015 Update to Key Points & References; no change in policy statement

Medical Policy Group, August 2015 (3): incorporating pertinent information from policy #385 Biomarker Genes for Detection of Lymph Node Metastases in Breast Cancer and archiving medical policy #385; no change in policy statement – remains investigational

Medical Policy Group, November 2015: 2016 Annual Coding Update. Added CPT code 88346 and new CPT code 88350. Moved CPT 88347 from current coding to previous coding.

Medical Policy Panel, May 2016

Medical Policy Group, July 2016 (3): 2016 Incorporated Circulating Tumor DNA information. Update to Policy Title, Description, Key Points, Key Words, Approved by Governing Bodies & References. Policy statement- Circulating Tumor DNA added to policy statement as investigational. Removed HCPCS Code- S3711- deleted in 2012.

Medical Policy Panel, October 2016

Medical Policy Group, November 2016 (3): Added note in in policy statement: This policy does not address the use of blood-based testing for EGFR mutations. For blood-based testing for EGFR mutations, refer to medical policy, Expanded Molecular Panel Testing of Cancers to Identify Targeted Therapies. No change in intent; also removed CPT codes 88346 and 88350 from current coding; added clarifying statement to coding section on how this service might also be submitted; added note in Key Points - If a separate evidence review exists, then conclusions reached there supersede conclusions in this review.

Medical Policy Group, December 2016 (3): Added Guardant360 Panel to Governing Bodies, Key Words & References sections; no change in policy statement

Medical Policy Panel, May 2018

Medical Policy Group, June 2018 (2): 2018 Updates to Description, Key Points, and References; Policy statement remains unchanged – investigational.

Medical Policy Panel, December 2018

Medical Policy Group, January 2019 (9): 2018 Updates to Description, Key Points, and References; no change in policy statement intent, clarifying edit to policy statement made: added wording ‘reviewed herein’ to stress that other indications are reviewed in separate policies.

Medical Policy Group, February 2019 (9): updates made to Key Points for clarification purposes.

Medical Policy Group, June 2019: July 2019 quarterly coding update. Added new CPT code 0091U to current coding. Added Key Word FirstSight.

Medical Policy Panel, July 2019

Medical Policy Group, July 2019 (9): 2019 Updates to Description, Key Points, and References. Added key word: FoundationOne. No change to policy statement.

Medical Policy Group, September 2019 (9): Policy statement updated to open up coverage for liquid biopsy for EGFR mutations in patients who meet criteria. Updated Key Points, Description, Approved by Governing Bodies, and References. Information regarding NSCLC incorporated into this policy. Created previous coding section, moved CPT code 0091U to previous coding section. Added key words: plasma genotyping, EGFR, TKI, tyrosine kinase inhibitor, Cobas, Cobas EGFR Mutation Test v2, Guardant 360 test, Oncobeam Test, NSCLC, non-small cell lung cancer, Guardant Health, Roche Molecular Systems, Sysmex, PCR test.

Available for comment September 6, 2019 through October 31, 2019.

Medical Policy Administration Committee, September 2019.

Medical Policy Panel, October 2019

Medical Policy Group, October 2019 (9): 2019 Updates to Description, Key Points, References. Added key words: InVisionFirst-Lung test, InVisionFirst, osimertinib, EGFR T7900 resistant variant, EGFR T7900, resistant variant. No change to policy statement or intent.


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.