Coding
The use of circulating tumor DNA and/or circulating tumor cells is considered investigational for all indications (see Table 1 for examples of liquid biopsy tests).
Code Description CPT
81479 Unlisted molecular pathology procedure
86152 Cell enumeration using immunologic selection and identification in fluid specimen (eg, circulating tumor cells in blood);
86153 Cell enumeration using immunologic selection and identification in fluid specimen (eg, circulating tumor cells in blood); physician interpretation and report, when required
Circulating Tumor DNA and Circulating Tumor Cells for Cancer Management (Liquid Biopsy)
Introduction
Liquid biopsy is a when a blood sample (rather than a piece of tissue) is used to test for cancer cells or small genetic cancer pieces mixing in the blood. The blood sample is taken from the arm and is tested for cells or genetic pieces that cancers shed into the bloodstream. Identifying tumor cell material in the blood might help to diagnose cancer, track changes in a cancer over time or help select the right type of cancer treatment. However, there is not enough information from clinical studies to be certain that this works as well as a tissue biopsy in most people, because we don’t yet know that this works as well as tissue biopsy. This treatment is not yet proven.
Note: The Introduction section is for your general knowledge and is not to be taken as policy coverage criteria. The rest of the policy uses specific words and concepts familiar to medical professionals. It is intended for providers. A provider can be a person, such as a doctor, nurse, psychologist, or dentist. A provider also can be a place where medical care is given, like a hospital, clinic, or lab. This policy informs them about when a service may be covered.
Policy Coverage Criteria
Procedure Investigational
Circulating Tumor DNA, Circulating Tumor Cells
Related Information
This policy does not address the use of blood-based testing for epidermal growth factor receptor variants in non-small-cell lung cancer or the use of AR-V7 circulating tumor cells for metastatic prostate cancer.
Description
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 policy evaluates uses for liquid biopsies not addressed in a separate policy. If a separate policy exists, then conclusions reached there supersede conclusions here.
Background
Liquid biopsy refers to 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). cfDNA 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 incomplete and random digestion of genomic DNA. The length or integrity of the circulating DNA can potentially distinguish between apoptotic and necrotic origin. ctDNA 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.
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 approaches="" are="" cfdna.="" eg="" methods="" more="" nbsp="" needed.="" of="" p="" sanger="" sensitive="" sequencing="" standard="" than="" the="" therefore="" total="">
Highly sensitive and specific methods have been developed to detect ctDNA, for both singlenucleotide mutations (eg, 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 mutant 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.
Summary of Evidence
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. 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, diseasespecific 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, diseasespecific survival, test accuracy, and test validity. Published data on clinical validity and clinical
