Populations	Interventions	Comparators	Outcomes
Individuals: With advanced cancer	Interventions of interest are: Testing of circulating tumor DNA to select targeted treatment	Comparators of interest are: Using tissue biopsy to select treatment	Relevant outcomes include: Overall survival Disease-specific survival Test validity Morbid events Medication use
Individuals: With advanced cancer	Interventions of interest are: Testing of circulating tumor cells to select targeted treatment	Comparators of interest are: Using tissue biopsy to select treatment	Relevant outcomes include: Overall survival Disease-specific survival Test validity Morbid events Medication use
Individuals: With cancer	Interventions of interest are: Testing of circulating tumor DNA to monitor treatment response	Comparators of interest are: Standard methods for monitoring treatment response	Relevant outcomes include: Overall survival Disease-specific survival Test validity Morbid events Medication use
Individuals: With cancer	Interventions of interest are: Testing of circulating tumor cells to monitor treatment response	Comparators of interest are: Standard methods for monitoring treatment response	Relevant outcomes include: Overall survival Disease-specific survival Test validity Morbid events Medication use
Individuals: Who have received curative treatment for cancer	Interventions of interest are: Testing of circulating tumor DNA to predict risk of relapse	Comparators of interest are: Standard methods for predicting relapse	Relevant outcomes include: Overall survival Disease-specific survival Test validity Morbid events Medication use
Individuals: Who have received curative treatment for cancer	Interventions of interest are: Testing of circulating tumor cells to predict risk of relapse	Comparators of interest are: Standard methods for predicting relapse	Relevant outcomes include: Overall survival Disease-specific survival Test validity Morbid events Medication use
Individuals: Who are asymptomatic and at high risk of developing cancer	Interventions of interest are: Testing of circulating tumor DNA to screen for cancer	Comparators of interest are: Standard screening methods	Relevant outcomes include: Overall survival Disease-specific survival Test validity
Individuals: Who are asymptomatic and at high risk of developing cancer	Interventions of interest are: Testing of circulating tumor cells to screen for cancer	Comparators of interest are: Standard screening methods	Relevant outcomes include: Overall survival Disease-specific survival Test validity

Background

Liquid biopsy refers to the analysis of circulating tumor DNA (ctDNA) or circulating tumor cells (CTCs) as methods of noninvasive 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. 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.^1, Unlike apoptosis, necrosis is considered a pathologic process and generates larger DNA fragments due to 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 (1-2 hours), and CTCs are cleared through extravasation into secondary organs.^1, Most assays detect CTCs through the use of surface epithelial markers such as EpCAM and cytokeratins. The primary reason for in detecting CTCs is prognostic, 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 cell-free DNA. 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 (eg BEAMing [which combines emulsion polymerase chain reaction with magnetic beads and flow cytometry] and digital polymerase chain reaction) 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 by biologic properties (expression of protein markers) or physical properties (size, density, electric charge). CTCs can then be detected using immunologic, molecular, or functional assays.^1,

Note that targeted therapy in non-small-cell lung cancer and 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.

Regulatory Status

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. 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.

In 2004, the CellSearch® System (Janssen Diagnostics, formerly Veridex) was cleared by the Food and Drug Administration 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. Food and Drug Administration product code: NQI.

Related Policies

• Miscellaneous Genetic and Molecular Diagnostic Tests (Policy #114 in the Pathology Section)
• Genetic and Protein Biomarkers for the Diagnosis and Cancer Risk Assessment of Prostate Cancer (Policy #030 in the Pathology Section)
• KRAS, NRAS, and BRAF Variant Analysis in Metastatic Colorectal Cancer (Policy #023 in the Pathology Section)
• Genetic Cancer Susceptibility Panels Using Next Generation Sequencing (Policy #084 in the Pathology Section)
• Gene Expression Profiling and Protein Biomarkers for Prostate Cancer Management (Policy #096 in the Pathology Section)
• Expanded Molecular Panel Testing of Cancers to Identify Targeted Therapies (Policy #105 in the Pathology Section)
• Circulating Tumor DNA for Management of Non-Small-Cell-Lung Cancer (Liquid Biopsy) (Policy #136 in the Pathology Section)

For members enrolled in a Fully Integrated Dual Eligible Special Needs Plan (FIDE-SNP): (1) to the extent the service is covered under the Medicare portion of the member’s benefit package, the above Medicare Coverage statement applies; and (2) to the extent the service is not covered under the Medicare portion of the member’s benefit package, the above Medicaid Coverage statement applies.

Policy Guidelines: (Information to guide medical necessity determination based on the criteria contained within the policy statements above.)

This policy does not address the use of blood-based testing for “driver mutations” to select therapy in non-small-cell lung cancer or metastatic colorectal cancer, use of blood-based testing for use of liquid biopsy for detection or risk assessment of prostate cancer or the use of AR-V7 circulating tumor cells for metastatic prostate cancer.


[RATIONALE: This policy was created in 2009 and has been updated regularly with searches of the MEDLINE database. The most recent literature update was performed through May 29, 2019.

Evidence reviews assess whether a medical test is clinically useful. A useful test provides information to make a clinical management decision that improves the net health outcome. That is, the balance of benefits and harms is better when the test is used to manage the condition than when another test or no test is used to manage the condition.

The first step in assessing a medical test is to formulate the clinical context and purpose of the test. The test must be technically reliable, clinically valid, and clinically useful for that purpose. Evidence reviews assess the evidence on whether a test is clinically valid and clinically useful. Technical reliability is outside the scope of these reviews, and credible information on technical reliability is available from other sources.

This policy evaluates uses for liquid biopsies not addressed in other reviews. If a separate policy exists, then conclusions reached there supersede conclusions here. The main criterion for inclusion in this review is the limited evidence on the clinical validity. The use of liquid biopsy for non-small-cell lung cancer is addressed in a separate policy on 'Circulating Tumor DNA for Management of Non-Small-Cell-Lung Cancer (Liquid Biopsy)' - Policy #136 in the Pathology Section. The use of liquid biopsy for metastatic colorectal cancer (CRC) will be addressed in 'KRAS, NRAS, and BRAF Variant Analysis in Metastatic Colorectal Cancer' - Policy #023 in the Pathology Section with an upcoming update. The use of liquid biopsy for detection or risk assessment of prostate cancer is addressed in 'Genetic and Protein Biomarkers for the Diagnosis and Cancer Risk Assessment of Prostate Cancer' - Policy #030 in the Pathology Section. The use of AR-V7 CTC liquid biopsy for metastatic prostate cancer is addressed in 'Gene Expression Profiling and Protein Biomarkers for Prostate Cancer Management' - Policy #096 in the Pathology Section.

Selecting Treatment in Advanced Cancer

Clinical Context and Test Purpose

Treatment selection is informed by tumor type, grade, stage, patient performance status and preference, prior treatments, and the molecular characteristics of the tumor such as the presence of driver mutations. One purpose of liquid biopsy testing of patients who have advanced cancer is to inform a decision regarding treatment selection (e.g., whether to select a targeted treatment or standard treatment).

The question addressed in this policy is: Does use of circulating tumor DNA (ctDNA) or circulating tumor cells (CTCs) testing to select treatment in patients with cancer to improve the net health outcome compared with standard tissue testing? Note that the use of a liquid biopsy to select therapy for non-small-cell lung cancer is addressed in 2.04.143, to select therapy for metastatic CRC is addressed in 2.04.53 and to select therapy in metastatic prostate cancer is addressed in 2.04.111.

The following PICOs were used to select literature to inform this policy.

Patients

The relevant population of interest are patients with advanced cancer for whom the selection of treatment depends on the molecular characterization of the tumor(s).

The setting of interest is oncology care.

Interventions

The test being considered is liquid biopsy using either ctDNA or CTCs. Both targeted polymerase chain reaction-based assays and broad next-generation sequencing-based approaches are available. Patients with negative liquid biopsy results should be reflexed to tumor biopsy testing if they are able to undergo tissue biopsy.^2,

Comparators

For patients who are able to undergo a biopsy, molecular characterization of the tumor is performed using standard tissue biopsy samples. Patients unable to undergo a biopsy generally receive standard therapy.

Outcomes

Liquid biopsies are easier to obtain and less invasive than tissue biopsies. True-positive liquid biopsy test results lead to the initiation of appropriate treatment (e.g., targeted therapy) without a tissue biopsy. False-positive liquid biopsy test results lead to the initiation of inappropriate therapy, which could shorten progression-free survival.

In patients able to undergo a tissue biopsy, negative liquid biopsies reflex to tissue testing. In patients unable to undergo a tissue biopsy, a negative liquid biopsy result would not change empirical treatment. Therefore, health outcomes related to negative test results do not differ between liquid biopsy and tissue biopsy.

The timing of interest for survival outcomes varies by type of cancer.

Technically Reliable

Assessment of technical reliability focuses on specific tests and operators and requires a review of unpublished and often proprietary information. Review of specific tests, operators, and unpublished data are outside the scope of this policy, and alternative sources exist. This policy focuses on the clinical validity and clinical utility.

Clinically Valid

A test must detect the presence or absence of a condition, the risk of developing a condition in the future, or treatment response (beneficial or adverse).

Circulating Tumor DNA

The American Society of Clinical Oncology and College of American Pathologists jointly convened an expert panel to review the current evidence on the use of ctDNA assays.^2, The literature review included a search for publications on the use of ctDNA assays for solid tumors in March 2017 and covers several different indications for the use of liquid biopsy. The search identified 1338 references to which an additional 31 references were supplied by the expert panel. Seventy-seven articles were selected for inclusion. The summary findings are discussed in the following sections, by indication.

Much of the literature to date on the use of ctDNA to guide treatment selection is for non-small-cell lung cancer, which is addressed in 2.04.143 and metastatic CRC, which is addressed in 2.04.53 and are not discussed here. Merker et al (2018) concluded that while a wide range of ctDNA assays has been developed to detect driver mutations, there is limited evidence of the clinical validity of ctDNA analysis in tumor types outside of lung cancer and CRC. Preliminary clinical studies of ctDNA assays for detection of potentially targetable variants in other cancers such as BRAF variants in melanoma^3, and PIK3CA and ESR1 variants in breast cancer were identified.^4,5,

Since the end date of the searches conducted by Merkel et al (2018), 4 observational studies of the clinical validity of FoundationOne Liquid (formerly FoundationACT) have been published (Table 1). All four studies compared liquid biopsy to tissue biopsy with FoundationOne comprehensive genomic testing. Test characteristics are shown in Table 2. Relevance, design, and conduct Imitations of these studies are summarized in Tables 3 and 4.

Table 1. Study Characteristics of the Clinical Validity of FoundationOne Liquid

Study	Study Population	Design	Reference Standard	Timing of Reference and Index Tests	Blinding of Assessors
Clark et al (2018)6,	Patients with advanced cancer	Retrospective (tissue) and prospective (liquid biopsy)	Tissue biopsy (FoundationOne)	0 to 60 days	Not stated
Zhou et al (2018)7,	Patients with locally advanced or metastatic solid tumors	Retrospective	Tissue biopsy (FoundationOne)	Not reported; only considered patient with no intervening treatment between liquid and tissue biopsy	Not stated
Chung et al (2017)8,	Women with estrogen receptor-positive breast cancer	Retrospective	Tissue biopsy  (FoundationOne)	0 to 60 days	Not stated
Kim et al (2017)9,	Women with measurable, inoperable, locally advanced or metastatic TNBC previously untreated with systemic therapy	Patients were enrolled in a Phase II RCT of Ipatasertib plus paclitaxel versus placebo plus paclitaxel	Tissue biopsy (FoundationOne)	Not reported	Not stated

RCT: randomized controlled trial; TNBC: triple-negative breast cancer.

Table 2. Clinical Validity of FoundationOne Liquid

Study	Initial N	Final N	PPA	Sensitivity (95% CI)	Specificity (95% CI)	PPV (95% CI)	NPV (95% CI)
Clark et al (2018)6,	NR	36
Overall	NR	36	75%	--	--	--	--
Base substitutions/ indels	NR	36		82.7% (69.7-91.8)	97.5% (95.9-98.5)	72.9% (59.7-83.6)	98.6% (97.3-99.4)
Rearrangements	NR	36		100% (15.8-100)	99.1% (94.3-100)	66.7% (9.4-99.2)	100% (96.5-100)
Amplifications	NR	36		38.5% ( 13.9-68.4)	100% (98.5-100	100% (47.8-100)	96.8% (93.6-98.6)
Zhou et al (2018)7,
Overall	NR	42	82%
Base substitutions	NR	42		77.2% (66.4-85.9)	96.0% (94.6-97.1)	59.2% (49.1-68.8)	98.3% (97.3-99.0)
Insertions/ deletions	NR	42		7.1% (0.9-23.5)	98.2% (95.5-99.5)	33.3% (4.3-77.7)	89.4% (84.9-93)
Amplifications	NR	42		23.7% (11.4-40.2)	99.8% (98.8-100)	90.0% (53.2-100)	94.1% (91.7-96)
Rearrangements or fusions	NR	42		100.0% (39.8-100)	97.6% (93.9-99.3)	50.0% (15.7-84.3)	100.0% (97.7-100
Chung et al (2017)8,
Short variants	NR	14	89%	89.5% (66.9-98.7)	92.4% (84.0-97.3)	73.9% (51.6-89.8)	97.3% (90.2-99.8)
Amplifications	NR	14	27%	27.3% (6.0-61)	100% (95.1-100	100% (29.2-100)	90.1% (81.5-95.6)
Kim et al (2017)9,
PIK3CA and AKT1	NR	72	100%	100% (93.4-100)	100% (81.5-100)	100% (47.8-100)	96.8% (93.6-98.6)

CI: confidence interval; PPA: positive percent agreement; PPV: positive predictive value; NPV: negative predictive value; NR: not reported

Table 3. Relevance Limitations of Clinical Validity Studies of FoundationOne Liquid

Study	Populationa	Interventionb	Comparatorc	Outcomesd	Duration of Follow-Upe
Clark et al (2018)6,	1. Included patients with a range of cancers	Earlier version of test used (FoundationACT)	2. FoundationOne tissue biopsy
Zhou et al (2018)7,	1.Included patients with a range of cancers	Earlier version of test used (FoundationACT)	2. FoundationOne tissue biopsy
Chung et al (2017)8,		Earlier version of test used (FoundationACT)	2. FoundationOne tissue biopsy
Kim et al (2017)9,		Earlier version of test used (FoundationACT)	2. FoundationOne tissue biopsy

The study limitations stated in this table are those notable in the current review; this is not a comprehensive limitations assessment.

^a Population key: 1. Intended use population unclear; 2. Clinical context is unclear; 3. Study population is unclear; 4. Study population not representative of intended use.

^bIntervention key: 1. Classification thresholds not defined; 2. Version used unclear; 3. Not intervention of interest.

^c Comparator key: 1. Classification thresholds not defined; 2. Not compared to credible reference standard; 3. Not compared to other tests in use for same purpose.

^d Outcomes key: 1. Study does not directly assess a key health outcome; 2. Evidence chain or decision model not explicated; 3. Key clinical validity outcomes not reported (sensitivity, specificity and predictive values); 4. Reclassification of diagnostic or risk categories not reported; 5. Adverse events of the test not described (excluding minor discomforts and inconvenience of venipuncture or noninvasive tests).

^e Follow-Up key: 1. Follow-up duration not sufficient with respect to natural history of disease (true-positives, true-negatives, false-positives, false-negatives cannot be determined).

Study	Selectiona	Blindingb	Delivery of Testc	Selective Reportingd	Data Completenesse	Statisticalf
Clark et al (2018)6,	2. convenience sample	1. Blinding unclear	1. Timing of liquid and tissue biopsy varied (0-60 days)		1. No description of indeterminate and missing samples
Zhou et al (2018)7,	2. convenience sample	1. Blinding unclear	1. Timing of liquid and tissue biopsy not reported		1. No description of indeterminate and missing samples-
Chung et al (2017)8,	2. convenience sample	1. Blinding unclear	1. Timing of liquid and tissue biopsy varied (0-60 days)		1. No description of indeterminate and missing samples
Kim et al (2017)9,	2. convenience sample	1. Blinding unclear	1. Timing of liquid and tissue biopsy not reported		1. No description of indeterminate and missing samples

^a Selection key: 1. Selection not described; 2. Selection not random or consecutive (i.e., convenience).

^bBlinding key: 1. Not blinded to results of reference or other comparator tests.

^cTest Delivery key: 1. Timing of delivery of index or reference test not described; 2. Timing of index and comparator tests not same; 3. Procedure for interpreting tests not described; 4. Expertise of evaluators not described.

^d Selective Reporting key: 1. Not registered; 2. Evidence of selective reporting; 3. Evidence of selective publication.

^e Data Completeness key: 1. Inadequate description of indeterminate and missing samples; 2. High number of samples excluded; 3. High loss to follow-up or missing data.

^f Statistical key: 1. Confidence intervals and/or p values not reported; 2. Comparison with other tests not reported.

In breast cancer, observations that estrogen receptor-positive tumors can harbor estrogen receptor-negative CTCs,[67] that overt distant metastases and CTCs can have discrepant human epidermal growth factor receptor 2 status compared with the primary tumor,^10,11,12, and that the programmed death-ligand 1 is frequently expressed on CTCs in patients with hormone receptor-positive, HER2-negative breast cancer^13, have suggested that trials investigating whether CTCs can be used to select targeted treatment are needed.

The clinical validity of each commercially available CTC test must be established independently.

Clinically Useful

A test is clinically useful if the use of the results informs management decisions that improve the net health outcome of care. The net health outcome can be improved if patients receive correct therapy, or more effective therapy, or avoid unnecessary therapy, or avoid unnecessary testing.

Circulating Tumor DNA

Direct Evidence

Direct evidence of clinical utility is provided by studies that have compared health outcomes for patients managed with and without the test. Because these are intervention studies, the preferred evidence would be from randomized controlled trials (RCTs).

Merker et al (2018) concluded that no such trials have been reported for ctDNA tests.^2,

Chain of Evidence

To develop a chain of evidence or a decision model requires explication of the elements in the model and evidence that is sufficient to demonstrate each of the links in the chain of evidence or the validity of the assumptions in the decision model.

A chain of evidence for ctDNA tests could be established if the ctDNA test has a high agreement with standard tissue testing (clinical validity) for identifying driver mutations and the standard tissue testing has proven clinical utility with high levels of evidence. A chain of evidence can also be demonstrated if the ctDNA test is able to detect driver mutations when standard methods cannot, and the information from the ctDNA test leads to management changes that improve outcomes.

The evidence is insufficient to demonstrate test performance for currently available ctDNA tests except for lung cancer (see 2.04.143); therefore, no inferences can be made about clinical utility.

Circulating Tumor Cells

Direct Evidence

Direct evidence of clinical utility is provided by studies that have compared health outcomes for patients managed with and without the test. Because these are intervention studies, the preferred evidence would be from RCTs.

Trials of using CTCs to select treatment are ongoing (see Table 5 in Supplemental Information).

Chain of Evidence

Indirect evidence on clinical utility rests on clinical validity. If the evidence is insufficient to demonstrate test performance, no inferences can be made about clinical utility.

The evidence is insufficient to demonstrate test performance for currently available CTC tests; therefore, no inferences can be made about clinical utility.

Section Summary: Selecting Treatment in Advanced Cancer

Circulating Tumor DNA

For indications reviewed herein, there is no direct evidence that selecting targeted treatment using ctDNA improves the net health outcome compared with selecting targeted treatment using tumor tissue testing. Given the breadth of methodologies available to assess ctDNA, the clinical validity of each commercially available test must be established independently. The evidence is insufficient to demonstrate test performance for currently available ctDNA tests that are reviewed herein; therefore, no inferences can be made about clinical utility through a chain of evidence.

Circulating Tumor Cells

For indications reviewed herein, there is no direct evidence that selecting targeted treatment using CTCs improves the net health outcome compared with selecting targeted treatment using tumor tissue testing. Trials are ongoing. 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 evidence is insufficient to demonstrate test performance for currently available CTC tests that are reviewed herein; therefore, no inferences can be made about clinical utility through a chain of evidence.

Monitoring treatment response in cancer

Clinical Context and Test Purpose

Monitoring of treatment response in cancer may be performed using tissue biopsy or imaging methods. Another proposed purpose of liquid biopsy testing in patients who have advanced cancer is to monitor treatment response, which could allow for changing therapy before clinical progression and potentially improve outcomes.

The question addressed in this policy is: Does ctDNA or CTC testing to monitor treatment response in patients with cancer improve the net health outcome?

The following PICOs were used to select literature to inform this policy.

Patients

The relevant population of interest are patients who are being treated for cancer.

The setting of interest is oncology care.

Interventions

The test being considered is liquid biopsy using either ctDNA or CTCs. For ctDNA tests, the best unit for quantifying DNA burden has not been established.^2,

Comparators

Standard monitoring methods for assessing treatment response are tissue biopsy or imaging methods

Outcomes

The outcome of primary interest is progression-free survival.

The timing of interest for survival outcomes varies by type of cancer.

Technically Reliable

Assessment of technical reliability focuses on specific tests and operators and requires a review of unpublished and often proprietary information. Review of specific tests, operators, and unpublished data are outside the scope of this policy, and alternative sources exist. This policy focuses on the clinical validity and clinical utility.

Clinically Valid

Circulating Tumor DNA

Merker et al (2018) identified several proof-of-principle studies demonstrating correlations between changes in ctDNA levels and tumor response or outcomes as well as studies demonstrating that ctDNA can identify the emergence of resistant variants.^2, However, they reported a lack of rigorous, prospective validation studies of ctDNA-based monitoring and concluded that clinical validity had not been established.

Circulating Tumor Cells

Systematic reviews and meta-analyses describing an association between CTCs and poor prognosis have been reported for metastatic breast cancer,^14,15,16,17, CRC,^18,19, hepatocellular cancer,^20, prostate cancer,^21,22,23, head and neck cancer,^24, and melanoma.^25,

The clinical validity of each commercially available CTC test must be established independently.

Clinically Useful

Circulating Tumor DNA

Direct Evidence

Direct evidence of clinical utility is provided by studies that have compared health outcomes for patients managed with and without the test. Because these are intervention studies, the preferred evidence would be from RCTs .

Merker et al (2018) concluded there is no evidence that changing treatment before clinical progression, at the time of ctDNA progression, improves patient outcomes.^2,

Chain of Evidence

Indirect evidence on clinical utility rests on clinical validity. If the evidence is insufficient to demonstrate test performance, no inferences can be made about clinical utility.

The evidence is insufficient to demonstrate test performance for currently available ctDNA tests for monitoring treatment response; therefore, no inferences can be made about clinical utility.

Circulating Tumor Cells

Direct Evidence

Direct evidence of clinical utility is provided by studies that have compared health outcomes for patients managed with and without the test. Because these are intervention studies, the preferred evidence would be from RCTs. Smerage et al (2014) reported on the results of anRCT of patients with metastatic breast cancer and persistently increased CTC levels to test whether changing chemotherapy after 1 cycle of first-line therapy could improve overall survival (OS; the primary study outcome).^26,Patients who did not have increased CTC levels at baseline remained on initial therapy until progression (arm A), patients with initially increased CTC levels that decreased after 21 days of therapy remained on initial therapy (arm B), and patients with persistently increased CTC levels after 21 days of therapy were randomized to continue initial therapy (arm C1) or change to an alternative chemotherapy (arm C2). There were 595 eligible and evaluable patients, 276 (46%) of whom did not have increased CTC levels (arm A). Of patients with initially increased CTC levels, 31 (10%) were not retested, 165 were assigned to arm B, and 123 were randomized to arms C1 or C2. There was no difference in median OS between arms C1 (10.7 months) and C2 12.5 months; p=0.98). CTC levels were strongly prognostic, with a median OS for arms A, B, and C (C1 and C2 combined) of 35 months, 23 months, and 13 months, respectively (p<0.001). This trial showed the prognostic significance of CTCs in patients with rests on clinical validity. If the evidence is insufficient to demonstrate test performance, no inferences can be made about clinical utility.

The evidence is insufficient to demonstrate test performance for currently available CTC tests; therefore, no inferences can be made about clinical utility through a chain of evidence.

Section Summary: Monitoring Treatment Response in Cancer

Circulating Tumor DNA

For indications reviewed herein, there is no direct evidence that using ctDNA to monitor treatment response improves the net health outcome compared with standard methods. 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. The evidence is insufficient to demonstrate test performance for currently available ctDNA tests that are reviewed herein; therefore, no inferences can be made about clinical utility through a chain of evidence.

Circulating Tumor Cells

For indications reviewed herein, there is no direct evidence that using CTCs to monitor treatment response improves the net health outcome compared with standard methods. 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 evidence is insufficient to demonstrate test performance for currently available CTC tests that are reviewed herein; therefore, no inferences can be made about clinical utility through a chain of evidence.

Predicting Risk of Relapse

Clinical Context and Test Purpose

Monitoring for relapse after curative therapy in patients with cancer may be performed using imaging methods and clinical examination. Another proposed purpose of liquid biopsy testing in patients who have cancer is to detect and monitor for residual tumor, which could lead to early treatment that would eradicate residual disease and potentially improve outcomes.

The question addressed in this policy is: Does ctDNA or CTC testing to predict the risk of relapse in patients with cancer improve the net health outcome?

The following PICOs were used to select literature to inform this policy.

Patients

The relevant population of interest are patients who have received curative treatment for cancer.

The setting of interest is oncology care.

Interventions

The test being considered is liquid biopsy using either ctDNA or CTCs.

Comparators

Standard monitoring methods for detecting relapse are imaging methods and clinical examination.

Outcomes

The outcome of primary interest is progression-free survival.

The timing of interest for survival outcomes varies by type of cancer.

Technically Reliable

Assessment of technical reliability focuses on specific tests and operators and requires a review of unpublished and often proprietary information. Review of specific tests, operators, and unpublished data are outside the scope of this policy, and alternative sources exist. This policy focuses on the clinical validity and clinical utility.

Clinically Valid

Circulating Tumor DNA

Merker et al (2018) identified several proof-of-principle studies demonstrating an association between persistent detection of ctDNA after local therapy and high-risk of relapse.^2, However, current studies are retrospective and have not systematically confirmed that ctDNA is being detected before the metastatic disease has developed. They concluded that the performance characteristics had not been established for any assays.

Circulating Tumor Cells

Rack et al (2014) published the results of a large multicenter study in which CTCs were analyzed in 2026 patients with early breast cancer before adjuvant chemotherapy and in 1492 patients after chemotherapy using the CellSearch System.^27, After chemotherapy, 22% of patients were CTC-positive, and CTC positivity was negatively associated with prognosis.

Smaller studies demonstrating associations between persistent CTCs and relapse have been published in prostate cancer,^28,CRC^29, bladder cancer,^30,31, liver cancer,^32, and esophageal cancer.^33,

The clinical validity of each commercially available CTC test must be established independently.

Clinically Useful

The evidence is insufficient to demonstrate test performance for currently available ctDNA and CTC tests for predicting relapse; therefore, no inferences can be made about clinical utility.

Circulating Tumor DNA and Circulating Tumor Cells

Direct Evidence

Direct evidence of clinical utility is provided by studies that have compared health outcomes for patients managed with and without the test. Because these are intervention studies, the preferred evidence would be from RCTs .

Merker et al (2018) concluded that there is no evidence that early treatment before relapse, based on changes in ctDNA, improves patient outcomes.^2, Similarly, no trials were identified demonstrating that treatment before relapse based on changes in CTCs improves patient outcomes.

Chain of Evidence

Indirect evidence on clinical utility rests on clinical validity. If the evidence is insufficient to demonstrate test performance, no inferences can be made about clinical utility.

A chain of evidence to demonstrate clinical utility requires an evidence-based management pathway. There is not an explicated, evidence-based management pathway for the use of ctDNA or CTCs to guide early treatment before relapse.

Section Summary: Predicting Risk of Relapse

Circulating Tumor DNA

For indications reviewed herein, there is no direct evidence that using ctDNA to predict the risk of relapse improves the net health outcome compared with standard methods. 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. The evidence is insufficient to demonstrate test performance for currently available CTC tests that are reviewed herein; therefore, no inferences can be made about clinical utility through a chain of evidence.

Circulating Tumor Cells

For indications reviewed herein, there is no direct evidence that using CTCs to predict the risk of relapse improves the net health outcome compared with standard methods. 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 evidence is insufficient to demonstrate test performance for currently available CTC tests that are reviewed herein; therefore, no inferences can be made about clinical utility through a chain of evidence.

Screening for cancer in asymptomatic individuals

Clinical Context and Test Purpose

It has also been proposed that liquid biopsies could be used to screen asymptomatic patients for early detection of cancer, which could allow for initiating treatment at an early stage, potentially improving outcomes.

The question addressed in this policy is: Does ctDNA or CTC testing to screen for cancer in asymptomatic individuals improve the net health outcome?

The following PICOs were used to select literature to inform this policy.

Patients

The relevant population of interest are asymptomatic individuals.

The setting of interest is primary care or oncology care.

Interventions

The test being considered is liquid biopsy using either ctDNA or CTCs.

Comparators

Outcomes

The outcome of primary interest is progression-free survival.

The timing of interest for survival outcomes varies by type of cancer.

Diagnosis of cancer that is not present or would not have become clinically important (false-positives and overdiagnosis) would lead to unnecessary treatment and treatment-related morbidity.

Technically Reliable

Assessment of technical reliability focuses on specific tests and operators and requires a review of unpublished and often proprietary information. Review of specific tests, operators, and unpublished data are outside the scope of this policy, and alternative sources exist. This policy focuses on the clinical validity and clinical utility.

Clinically Valid

Circulating Tumor DNA

Merker et al (2018) reported there is no evidence of clinical validity for the use of ctDNA in asymptomatic individuals.^2,

Circulating Tumor Cells

Systematic reviews with meta-analyses have evaluated the diagnostic accuracy of CTCs in patients with gastric and bladder/urothelial cancer.^34,35, Reported sensitivity was low in both cancers (42% and 35%) overall. Sensitivity was lower in patients with early-stage cancer, suggesting that the test would not be useful as an initial screen.

The clinical validity of each commercially available CTC test must be established independently.

Clinically Useful

A test is clinically useful if the use of the results informs management decisions that improve the net health outcome of care. The net health outcome can be improved if patients receive correct therapy, or more effective therapy, or avoid unnecessary therapy, or avoid unnecessary testing.

Circulating Tumor DNA and Circulating Tumor Cells

Direct Evidence

Direct evidence of clinical utility is provided by studies that have compared health outcomes for patients managed with and without the test. Because these are intervention studies, the preferred evidence would be from RCTs .

To evaluate the utility of the tests for screening, guidelines would be needed to establish criteria for screening intervals and appropriate follow-up for positive tests. After such guidelines are established, studies demonstrating the liquid biopsy test performance as a cancer screening test would be needed.

Chain of Evidence

Indirect evidence on clinical utility rests on clinical validity. If the evidence is insufficient to demonstrate test performance, no inferences can be made about clinical utility. Also, a chain of evidence requires an evidence-based management pathway. There is not an explicated, evidence-based management pathway for the use of ctDNA or CTCs for the screening of asymptomatic patients.

The evidence is insufficient to demonstrate test performance for currently available ctDNA and CTC tests as a screening test for cancer; therefore, no inferences can be made about clinical utility through a chain of evidence.

Section Summary: Screening for Cancer in Asymptomatic Individuals

Circulating Tumor DNA

For indications reviewed herein, there is no direct evidence that using ctDNA to screen for cancer in asymptomatic individuals improves the net health outcome compared with standard methods. 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. The evidence is insufficient to demonstrate test performance for currently available CTC tests that are reviewed herein; therefore, no inferences can be made about clinical utility through a chain of evidence.

Circulating Tumor Cells

For indications reviewed herein, there is no direct evidence that using CTCs to screen for cancer in asymptomatic individuals improves the net health outcome compared with standard methods. 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 evidence is insufficient to demonstrate test performance for currently available CTC tests that are reviewed herein; therefore, no inferences can be made about clinical utility through a chain of evidence.

Summary of Evidence

The ctDNA and 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 policy evaluates uses for liquid biopsies not addressed in a separate review. If a separate policy 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. The relevant outcomes are OS , disease-specific survival, test 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 the 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. The relevant outcomes are OS , 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. The relevant outcomes are OS, 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 an RCT, observational studies, and systematic reviews of observational studies. The relevant outcomes are OS , 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 RCT found no effect on OS when patients with persistently increased CTC levels after first-line chemotherapy were switched to 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 the risk of relapse, the evidence includes observational studies. The relevant outcomes are OS , 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 the risk of relapse, the evidence includes observational studies. The relevant outcomes are OS , 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. The relevant outcomes are OS , 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. The relevant outcomes are OS , 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.

 SUPPLEMENTAL INFORMATION

Practice Guidelines and Position Statements

National Comprehensive Cancer Network (v.1.2019) guidelines for breast cancer state that the use of circulating tumor cells in metastatic breast cancer is not yet included in algorithms for disease assessment and monitoring.^36, 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.'^37,

U.S. Preventive Services Task Force Recommendations

Not applicable.

Ongoing and Unpublished Clinical Trials

Some currently ongoing and unpublished trials that might influence this policy are listed in Table 5.

Table 5. Summary of Key Trials

NCT No.	Trial Name	Planned Enrollment	Completion Date
Ongoing
NCT02140463	Next generation personalized therapy with plasma DNA Trial 2 in refractory solid tumors (The NEXT-2 Trial)	260	Dec 2020
NCT02035813	DETECT IV - A Prospective, Multicenter, Open-label, Phase II Study in Patients With HER2-negative Metastatic Breast Cancer and Persisting HER2-negative Circulating Tumor Cells (CTCs).	520	Dec 2019
NCT01619111	DETECT III - A Multicenter, Randomized, Phase III Study to Compare Standard Therapy Alone Versus Standard Therapy Plus Lapatinib in Patients With Initially HER2-negative Metastatic Breast Cancer and HER2-positive Circulating Tumor Cells	120	Mar 2020
NCT03182634	A Multiple Parallel Cohort, Multi-centre Phase IIa Trial Aiming to Provide Proof of Principle Efficacy for Designated Targeted Therapies in Patients With Advanced Breast Cancer Where the Targetable Mutation is Identified Through ctDNA	1000	Nov 2023
NCT02889978	The Circulating Cell-free Genome Atlas Study	15000	Mar 2024
NCT03079011	Randomized, Open-Label, Multicentric Phase III Trial to Evaluate the Safety and Efficacy of Palbociclib in Combination With HT driven by ctDNA ESR1 Mutation Monitoring in ER+, HER2-negative Metastatic Breast Cancer Patients	800	Apr 2024
Unpublished
NCT01701050	COMETI Phase 2: Characterization of Circulating Tumor Cells (CTC) From Patients With Metastatic Breast Cancer Using the CTC-Endocrine Therapy Index	121	Nov 2016 (completed)
NCT02612350	Utility of Plasma Circulating Tumor DNA (ctDNA) in Asymptomatic Subjects for the Detection of Neoplastic Disease	1106	Aug 2017
NCT01349842	CirCe01 Study: Evaluation of the Use of Circulating Tumour Cells to Guide Chemotherapy From the 3rd Line of Chemotherapy for Metastatic Breast Cancer	265	Jan 2018
NCT01710605	Randomized Trial to Evaluate the Medico-economic Interest of Taking Into Account Circulating Tumor Cells (CTC) to Determine the Kind of First Line Treatment for Metastatic, Hormone-receptors Positive, Breast Cancers.	800	Sep 2018

NCT: national clinical trial.]
________________________________________________________________________________________

Horizon BCBSNJ Medical Policy Development Process:

This Horizon BCBSNJ Medical Policy (the “Medical Policy”) has been developed by Horizon BCBSNJ’s Medical Policy Committee (the “Committee”) consistent with generally accepted standards of medical practice, and reflects Horizon BCBSNJ’s view of the subject health care services, supplies or procedures, and in what circumstances they are deemed to be medically necessary or experimental/ investigational in nature. This Medical Policy also considers whether and to what degree the subject health care services, supplies or procedures are clinically appropriate, in terms of type, frequency, extent, site and duration and if they are considered effective for the illnesses, injuries or diseases discussed. Where relevant, this Medical Policy considers whether the subject health care services, supplies or procedures are being requested primarily for the convenience of the covered person or the health care provider. It may also consider whether the services, supplies or procedures are more costly than an alternative service or sequence of services, supplies or procedures that are at least as likely to produce equivalent therapeutic or diagnostic results as to the diagnosis or treatment of the relevant illness, injury or disease. In reaching its conclusion regarding what it considers to be the generally accepted standards of medical practice, the Committee reviews and considers the following: all credible scientific evidence published in peer-reviewed medical literature generally recognized by the relevant medical community, physician and health care provider specialty society recommendations, the views of physicians and health care providers practicing in relevant clinical areas (including, but not limited to, the prevailing opinion within the appropriate specialty) and any other relevant factor as determined by applicable State and Federal laws and regulations.

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Index:
Circulating Tumor DNA and Circulating Tumor Cells for Cancer Management (Liquid Biopsy)
Detection of Circulating Tumor Cells in the Management of Patients with Cancer
Breast Cancer, Circulating Tumor Cells
Cell Search
Circulating Tumor Cells, Breast Cancer
Tumor DNA, Circulating for Cancer Management
Liquid Biopsy
Oncotype SEQ (Genomic Health)
Genomic Health Oncotype SEQ
Circulogene Liquid Biopsy
Pathway Genomics Cancer Intercept
Biocept Inc.
Foundation ACT
CellSearch® System

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8. Chung, JJ, Pavlick, DD, Hartmaier, RR, Schrock, AA, Young, LL, Forcier, BB, Ye, PP, Levin, MM, Goldberg, MM, Burris, HH, Gay, LL, Hoffman, AA, Stephens, PP, Frampton, GG, Lipson, DD, Nguyen, DD, Ganesan, SS, Park, BB, Vahdat, LL, Leyland-Jones, BB, Mughal, TT, Pusztai, LL, O'Shaughnessy, JJ, Miller, VV, Ross, JJ, Ali, SS. Hybrid capture-based genomic profiling of circulating tumor DNA from patients with estrogen receptor-positive metastatic breast cancer. Ann. Oncol., 2017 Sep 26;28(11). PMID 28945887.

9. Kim, SS, Dent, RR, Wongchenko, MM, Singel, SS, Baselga, JJ. Concordance between plasma-based and tissue-based next-generation sequencing in LOTUS. Lancet Oncol., 2017 Dec 7;18(11). PMID 29208392.

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12. Riethdorf S, Muller V, Zhang L, et al. Detection and HER2 expression of circulating tumor cells: prospective monitoring in breast cancer patients treated in the neoadjuvant GeparQuattro trial. Clin Cancer Res. May 1 2010;16(9):2634-2645. PMID 20406831.

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23. de Bono J., Scher HI, Montgomery RB, et al. Circulating tumor cells predict survival benefit from treatment in metastatic castration-resistant prostate cancer. Clin Cancer Res. 2008;14(19):6302-6309. PMID.

24. Sun T, Zou K, Yuan Z, et al. Clinicopathological and prognostic significance of circulating tumor cells in patients with head and neck cancer: a meta-analysis. Onco Targets Ther. Jun 2017;10:3907-3916. PMID 28831265.

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27. Rack B, Schindlbeck C, Juckstock J, et al. Circulating tumor cells predict survival in early average-to-high risk breast cancer patients. J Natl Cancer Inst. May 15 2014;106(5). PMID 24832787.

28. 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. PMID 26408743.

29. Deneve E, Riethdorf S, Ramos J, et al. Capture of viable circulating tumor cells in the liver of colorectal cancer patients. Clin Chem. Sep 2013;59(9):1384-1392. PMID 23695297.

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31. Gazzaniga P, de Berardinis E, Raimondi C, et al. Circulating tumor cells detection has independent prognostic impact in high-risk non-muscle invasive bladder cancer. Int J Cancer. Oct 15 2014;135(8):1978-1982. PMID 24599551.

32. Schulze K, Gasch C, Staufer K, et al. Presence of EpCAM-positive circulating tumor cells as biomarker for systemic disease strongly correlates to survival in patients with hepatocellular carcinoma. Int J Cancer. Nov 2013;133(9):2165-2171. PMID 23616258.

33. Vashist YK, Effenberger KE, Vettorazzi E, et al. Disseminated tumor cells in bone marrow and the natural course of resected esophageal cancer. Ann Surg. Jun 2012;255(6):1105-1112. PMID 22580852.

34. Msaouel P, Koutsilieris M. Diagnostic value of circulating tumor cell detection in bladder and urothelial cancer: systematic review and meta-analysis. BMC Cancer. Aug 4 2011;11:336. PMID 21816094.

35. Tang L, Zhao S, Liu W, et al. Diagnostic accuracy of circulating tumor cells detection in gastric cancer: systematic review and meta-analysis. BMC Cancer. Jun 27 2013;13:314. PMID 23806209.

36. National Comprehensive Cancer Network (NCCN). NCCN Clinical Practice Guidelines in Oncology: Breast Cancer. Version 1.2019. https://www.nccn.org/professionals/physician_gls/default.aspx#breast. Accessed June 21, 2019.

37. National Comprehensive Cancer Network (NCCN). NCCN Clinical Practice Guidelines in Oncology: Melanoma. Version 2.2019. https://www.nccn.org/professionals/physician_gls/pdf/cutaneous_melanoma.pdf. Accessed June 21, 2019.

38. Palmetto GBA. Local Coverage Determination (LCD): MolDX: Circulating Tumor Cell Marker Assays (L35071). 2018; https://www.cms.gov/medicare-coverage-database/details/lcd- details.aspx?LCDId=35071&ver=10&Date=&DocID=L35071&bc=iAAAABAAAAAA&. Accessed June 21, 2019.

Codes:
(The list of codes is not intended to be all-inclusive and is included below for informational purposes only. Inclusion or exclusion of a procedure, diagnosis, drug or device code(s) does not constitute or imply authorization, certification, approval, offer of coverage or guarantee of payment.)

CPT*

86152
86153