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 circulating tumor DNA (ctDNA) to select targeted treatment, the evidence includes observational studies. Relevant outcomes are overall survival (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 for the indications covered in this review. The clinical validity of FoundationOne Liquid compared to tissue biopsy with FoundationOne comprehensive genetic profiling was evaluated in 4 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 that the technology results in an improvement in the net health outcome.
For individuals who have advanced cancer who receive testing of circulating tumor cells (CTCs) to select targeted treatment, the evidence includes observational studies. 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 that the technology results in an improvement in the net health outcome.
For individuals who have cancer who receive testing of ctDNA to monitor treatment response, the evidence includes observational studies. 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 that the technology results in an improvement in the net health outcome.
For individuals who have cancer who receive testing of CTCs to monitor treatment response, the evidence includes a single randomized controlled trial (RCT) , observational studies, and systematic reviews of observational studies. 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 that the technology results in an improvement in the net health outcome.
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. 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 that the technology results in an improvement in the net health outcome.
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. 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 that the technology results in an improvement in the net health outcome.
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 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 that the technology results in an improvement in the net health outcome.
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 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 that the technology results in an improvement in the net health outcome.
This policy is designed to address medical guidelines that are appropriate for the majority of individuals with a particular disease, illness, or condition. Each person's unique clinical circumstances may warrant individual consideration, based on review of applicable medical records.
The use of circulating tumor DNA and/or circulating tumor cells is considered investigational for all indications reviewed herein (see Policy Guidelines).
| CPT | 81400-81408 | Molecular pathology analyte testing code range |
| 81479 | Unlisted molecular pathology procedure | |
| 86152 | Cell enumeration using immunologic selection and identification in fluid specimen (eg, circulating tumor cells in blood); | |
| 86153 | physician interpretation and report, when required | |
| 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 | |
| 0242U | Targeted genomic sequence analysis panel, solid organ neoplasm, cell free circulating DNA analysis of 55-74 genes, interrogation for sequence variants, gene copy number amplifications, and gene rearrangements | |
| 0338U | Oncology (solid tumor), circulating tumor cell selection, identification, morphological characterization, detection and enumeration based on differential EpCAM, cytokeratins 8, 18, and 19, and CD45 protein biomarkers, and quantification of HER2 protein biomarker–expressing cells, peripheral blood |
| ICD-10-CM | Investigational for all relevant diagnoses | |
| C00.0-C96.9 | Malignant neoplasms code range |
This policy does not address the use of blood-based testing (liquid biopsy) to select targeted treatment for breast cancer, non-small cell lung cancer, melanoma/glioma, ovarian cancer, pancreatic cancer, and prostate cancer, the use of liquid biopsy to select immune checkpoint inhibitor therapy, tumor-Informed circulating tumor DNA testing for cancer management, comprehensive genomic profiling for selecting targeted cancer therapies, the use of blood-based testing for detection or risk assessment of prostate cancer; or the use of AR-V7 circulating tumor cells for metastatic prostate cancer. Refer to the following related policies for indications not covered here:
2.04.033 - Genetic and Protein Biomarkers for the Diagnosis and Cancer Risk Assessment of Prostate Cancer
2.04.053 Somatic Biomarker Testing (Including Liquid Biopsy) for Targeted Treatment and Immunotherapy in Metastatic Colorectal Cancer (KRAS, NRAF, BRAF, MMR/MSI, HER2, and TMB)
2.04.061 Gene Expression Profile Testing and Circulating Tumor DNA Testing for Predicting Recurrence in Colon Cancer
2.04.077 Somatic Genetic Testing to Select Individuals with Melanoma or Glioma for Targeted Therapy (BRAF)
2.04.111 Gene Expression Profiling and Protein Biomarkers for Prostate Cancer Management
2.04.115 - Comprehensive Genomic Profiling for Selecting Targeted Cancer Therapies
2.04.151 Biomarker Testing (Including Liquid Biopsy) for Targeted Treatment and Immunotherapy in Breast Cancer
2.04.153 Tumor-Informed Circulating Tumor DNA Testing for Cancer Management
2.04.155 Germline and Somatic Biomarker Testing (Including Liquid Biopsy) for Targeted Treatment and Immunotherapy in Prostate Cancer (BRCA1/2, Homologous Recombination Repair Gene Alterations, Microsatellite Instability/Mismatch Repair, Tumor Mutational Burden)
2.04.156 Germline and Somatic Biomarker Testing (Including Liquid Biopsy) for Targeted Treatment and Immunotherapy in Ovarian Cancer (BRCA1, BRCA2, Homologous Recombination Deficiency, Tumor Mutational Burden, Microsatellite Instability/Mismatch Repair)
2.04.157 Somatic Biomarker Testing for Immune Checkpoint Inhibitor Therapy (BRAF, MSI/MMR, PD-L1, TMB)
Plans may need to alter local coverage medical policy to conform to state law regarding coverage of biomarker testing.
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.
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.
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 to 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 epithelial cell adhesion molecules (EpCAM) and cytokeratins. The primary reason for detecting CTCs is prognostic, through quantification of circulating levels.
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 (eg, 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.
Circulating tumor cell 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). Circulating tumor cells 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.
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 (FDA) has chosen not to require any regulatory review of this test.
Certain liquid biopsy-based assays have been cleared or approved by the FDA as companion diagnostic tests (Table 1).2, These indication are addressed in other evidence opinions and are listed here for information only. Refer to the associated evidence opinion (Column 5) for details.
| Diagnostic Name (Manufacturer) | Indication | Biomarker | Drug Trade Name (Generic) | Related Evidence Opinion |
| Agilent Resolution ctDx FIRST assay | NSCLC | KRAS | Krazati (adagrasib) | 2.04.45 |
| cobas EGFR Mutation Test v2 (Roche Molecular Systems, Inc.) | NSCLC | EGFR (HER1) | Tagrisso (osimertinib) | 2.04.45 |
| NSCLC | EGFR (HER1) | Iressa (gefitinib) | 2.04.45 | |
| NSCLC | EGFR (HER1) | Tarceva (erlotinib) | 2.04.45 | |
| NSCLC | EGFR (HER1) | Gilotrif (afatinib) | 2.04.45 | |
| FoundationOne Liquid CDx (Foundation Medicine, Inc.) | NSCLC | EGFR (HER1) | Exkivity (mobocertinib) | 2.04.45 |
| NSCLC | EGFR (HER1) | Iressa (gefitinib) | 2.04.45 | |
| NSCLC | EGFR (HER1) | Tagrisso (osimertinib) | 2.04.45 | |
| NSCLC | EGFR (HER1) | Tarceva (erlotinib) | 2.04.45 | |
| NSCLC | MET | Tabrecta (capmatinib) | 2.04.45 | |
| NSCLC | ROS1 | Rozlytrek (entrectinib) | 2.04.45 | |
| NSCLC | ALK | Alecensa (alectinib) | 2.04.45 | |
| Ovarian Cancer | BRCA1 and BRCA2 | Rubraca (rucaparib) | 2.04.156 | |
| Solid Tumors | ROS1 | Rozlytrek (entrectinib) | 5.01.31 | |
| Breast Cancer | PIK3CA | Piqray (alpelisib) | 2.04.151 | |
| Metastatic Castrate Resistant Prostate Cancer | BRCA1,BRCA2 and ATM | Lynparza (olaparib) | 2.04.155 | |
| Metastatic Castrate Resistant Prostate Cancer | BRCA1 and BRCA2 | Rubraca (rucaparib) | 2.04.155 | |
| Guardant360 CDx (Guardant Health, Inc.) | NSCLC | EGFR (HER1) | Tagrisso (osimertinib) | 2.04.45 |
| NSCLC | EGFR (HER1) | Rybrevant (amivantamb) | 2.04.45 | |
| NSCLC | KRAS | Lumakras (sotorasib) | 2.04.45 | |
| NSCLC | ERBB2 | ENHERTU (fam-trastuzumab deruxtecan-nxki) | 2.04.45 | |
| Breast Cancer | ESR1 ERB2 |
Orserdu (elacestrant) ENHERTU (fam-trastuzumab deruxtecan-nxki) |
2.04.151 In development for 2.04.151 |
|
| therascreen PIK3CA RGQ PCR Kit (QIAGEN GmbH) | Breast Cancer | PIK3CA | Piqray (alpelisib) | 2.04.151 |
Source: FDA (2023)2,
FDA: US Food and Drug Administration; NSCLC: non-small cell lung cancer
