Medical Policy: 02.04.16 

Original Effective Date: March 2008 

Reviewed: September 2018 

Revised: September 2018 

 

Benefit Application:

Benefit determinations are based on the applicable contract language in effect at the time the services were rendered. Exclusions, limitations or exceptions may apply. Benefits may vary based on contract, and individual member benefits must be verified. Wellmark determines medical necessity only if the benefit exists and no contract exclusions are applicable. This medical policy may not apply to FEP. Benefits are determined by the Federal Employee Program.

 

This Medical Policy document describes the status of medical technology at the time the document was developed. Since that time, new technology may have emerged or new medical literature may have been published. This Medical Policy will be reviewed regularly and be updated as scientific and medical literature becomes available.

 

Description:

This policy does not address EGFR testing, for EGFR testing see medical policy 02.04.055 Epidermal Growth Factor Receptor (EGFR) Testing.

 

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.

 

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 (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 (circulating tumor cells). 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 (ctDNA) can be used for genomic characterization of the tumor.

 

Intact circulating tumor cells (CTCs) are released from a primary tumor and/or 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 detecting CTCs is prognostic, through quantification of circulating levels which could potentially provide information that could guide treatment decisions or aid in the monitoring of response to treatment.

 

Circulating tumor DNA (ctDNA) and circulating tumor cells (CTCs) are being performed in certain types of advanced cancers including but not limited to breast, prostate, lung, colorectal, liver (hepatocellcular carcinoma), head and neck, bladder, esophageal, gastric and pancreas for screening, selecting treatment, treatment monitoring and residual disease detection; the largest body of data comes from studies of geno typical women with metastatic breast cancer. CTCs and ctDNA have also been investigated as an additional prognostic factor in non-metastatic breast cancer and could be used to determine the need for additional adjuvant chemotherapy. Circulating tumor DNA (ctDNA) and circulating tumor cells (CTCs) potentially offer a noninvasive alternative to tissue biopsy.

 

Detecting Circulating Tumor DNA (ctDNA) and Circulating Tumor Cells (CTCs)
Detection of circulating tumor DNA (ctDNA) is challenging because ctDNA is diluted by nonmalignant circulating DNA and usually represents a small fraction (<1%) of total cell-free DNA (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 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 and next generation sequencing.

 

Circulating tumor cells (CTCs) 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.

 

Examples of Circulating Tumor DNA (ctDNA) and Circulating Tumor Cells (CTCs) (Liquid biopsy) tests
TestManufacturerType of Liquid Biopsy
CancerIntercept: Breast, ovarian, lung, colorectal, melanoma, head and neck, pancreatic, thyroid, prostate, stomach. Pathway Genomics ctDNA Circulating Tumor DNA
CellMax-CRC Colorectal Cancer Early Detection Test: used as a screening test for colorectal cancer. Detects pre-cancer and early stage cancer. CellMax Life CTC Circulating Tumor Cells
CellMax-LBx Liquid Biopsy: Diagnosed solid tumor for targeted therapy selection. CTC Circulating Tumor Cells plus ctDNA Circulating Tumor DNA
CellMax-PanCa Monitoring Test: Diagnosed solid tumor for treatment effectiveness and early recurrence. CTC Circulating Tumor Cells
CellMax-Prostate Cancer Test: To reduce unnecessary biopsies in PSA gray zone patients. CTC Circulating Tumor Cells
CellSearch System: Aids in the monitoring of patients with metastatic breast, prostate or colorectal cancer and allows assessment of patient prognosis and is predictive of progression-free survival and overall survival. Informs clinical decision making. Janssen Diagnostics formerly Veridex CTC Circulating Tumor Cells
Circulogene: Provides information on current FDA-approved treatment options for the tumor DNA identified. Doctor can monitor tumor responsiveness and adjust treatment protocols. Theranostics ctDNA Circulating Tumor DNA
ClearID Biomarker Expression Assays: For Pl-L1 and HER2. Cynvenio CTC Circulating Tumor Cells plus ctDNA Circulating Tumor DNA
ClearID Breast Cancer: Optimized for breast cancer, also used for stomach, skin and prostate cancer. CTC Circulating Tumor Cells plus ctDNA Circulating Tumor DNA
ClearID Lung Cancer: Optimized for non-small cell lung cancer, also used for head and neck cancers, and other thoracic cancers CTC Circulating Tumor Cells plus ctDNA Circulating Tumor DNA
ClearID Solid Tumor Panel: Optimized for colon and bladder cancer, also used for other solid tumor cancers.
Note: ClearID test results are summarized in an actionable genomic report containing clinical interpretations of the identified biomarkers and variants, their associations with drugs, related clinical trials, and experimental therapies that can help guide physicians, oncologists, and pathologists in making treatment decisions.
CTC Circulating Tumor Cells plus ctDNACirculating Tumor DNA
Colvera: Identifies the presence of two methylated genes, BCAT1 and IKZF1, when present show a high concordance of colorectal cancer recurrence. Clinical Genomics ctDNA Circulating Tumor DNA
FoundationACT (FoundationOne Liquid): Provides targeted gene and microsatellite instability (MSI) results that can help direct therapy selection and clinical trial options for advanced stage cancer patients. Foundation Medicine ctDNA Circulating Tumor DNA
Guardant360: For advanced solid tumors, does not predict chemotherapy response but provides information on the genomic alterations known to respond to specific targeted therapies to the doctor the opportunity to tailor treatment to the individual cancer. Guardant Health ctDNA Circulating Tumor DNA
IVDiagnostics: Used for patients with metastatic advanced staged cancers: breast, lung, ovarian, prostate, colorectal, kidney, melanoma, and pancreatic. Detect and monitor for circulating tumor cells that can cause metastases to rapidly detect and monitor for these cells to inform therapeutic approaches. Velox CTC Circulating Tumor Cells
LiquidGx: Solid tumor therapies, monitoring for drug resistance markers. Admera Health ctDNA Circulating Tumor DNA
OncoBEAM for Colorectal Cancer: To assist in treatment decisions for metastatic colorectal cancer. Sysmex Inostics ctDNA Circulating Tumor DNA
OncoBEAM for Lung Cancer: To assist in treatment decisions for non-small cell lung cancer. ctDNA Circulating Tumor DNA
OncoBEAM for Melanoma: To assist in treatment decisions for melanoma. ctDNA Circulating Tumor DNA
PlasmaSelect 64: Multiple cancer types, provides clinical explanation of all reported alterations, including FDA approved therapies, clinical trials and published literature. Personal Genome Diagnostics ctDNA Circulating Tumor DNA
Target Selector: For breast, colorectal, gastric, prostate, lung, and melanoma to assist the doctor in understanding the status of the patients disease to make decisions about current and future therapy. Biocept ctDNA Circulating Tumor DNA

 

Selecting Treatment in Advanced Cancers

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 the liquid biopsy testing of patients who have advanced cancer is to inform a decision regarding treatment selection (e.g. whether to select a targeted a treatment or standard treatment).

 

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

 

Clinically Valid

Circulating Tumor DNA (ctDNA)

Much of the literature to date on the use of circulating tumor DNA (ctDNA) to guide treatment selection is for non-small cell lung cancer, which is addressed in medical policy 02.04.55 Epidermal Growth Factor Receptor (EGFR) Testing and is not discussed here.

 

Merker et. al (2018) the American Society of Clinical Oncology (ASCO) and College of American Pathologists jointly convened a panel to review the current evidence on the use of circulating tumor DNA (ctDNA) in patients with cancer. The literature search identified 1,338 references to which an additional 31 references were supplied by the expert panel. There were 77 articles selected for inclusion. Their analysis on the evidence on the use of ctDNA assays for treatment selection in advanced cancers found while a wide range of ctDNA assays have been developed to detect driver mutations, there is limited evidence of the clinical validity of ctDNA analysis in tumor types outside of lung cancer. Preliminary clinical studies of ctDNA assays for detection of potentially targetable variants in other cancers such as BRAF variants in melanoma and PIK3CA and ESR1 variants in breast cancer were identified. The authors concluded that future research studies to establish clinical validity and utility of ctDNA assays are needed and should include a patient cohort that matches the intended use population as closely as possible and samples collected from a prospective study with defined entry criteria. Data will most frequently come from a phase II or phase III study in the patient population where it is anticipated the assay would be used in subsequent clinical practice, with the frequency of the variant under study approximately equal to that in an unselected clinical population. In prospective studies of targeted therapies, the entry criteria should allow inclusion of patients in which the variant under study is observed in the plasma, but not in the tissue analysis, to evaluate the treatment response of this population with discordant genotype results.

 

In 2017, Vidal et. al. evaluated the clinical validity of the OncoBEAM CRC colorectal cancer assay in a retrospective-prospective study in two Spanish institutions from June 2009 to August 2016 which included 115 patients with histologically confirmed metastatic colorectal cancer (CRC) that were anti-EGFR treatment naive. Blood samples were collected in all patients before the administration of anti-EGFR treatment. OncoBEAM CRC assay was used to detect RAS mutations in plasma and RAS mutation detection in tissue samples were carried out according to standard of care procedures validated by each hospital. The median time from tumor tissue specimen collection to ctDNA collection was 47.5 days (range 0-1783 days). Of the 115 patients included in the study, 55 (47.8%) and 59 (51.3%) were shown to have RAS mutations in their tumor samples as detected by standard of care RAS tissue testing and as detected in ctDNA by OncoBEAM assay and standard techniques for tissue analysis was 93% (107/115 patients), kappa index 0.844 (95% CI 0.746-0.914). There were several limitations to this study to include the retrospective analysis, longitudinal blood extractions were only carried out in limited number of patients and given the low number of patients with specific clinic-pathological characteristics the inferences from associations with P-values marginally <0.05% should be cautiously interpreted. While this study was promising clinical validity data needs replicated.

 

Circulating Tumor Cells (CTCs)

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

 

The clinical validity of each commercially available ctDNA and CTC test must be established independently. Indirect evidence on clinical utility rests on clinical validity. If the evidence is insufficient to demonstrate test performance, no conclusion can be made about clinical utility.

 

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 testing. Direct evidence of clinical utility is provided by studies that have compared health outcomes for patients managed with and without the test. The preferred evidence would be from randomized controlled trials.

 

Merker et. al. 2018 concluded that no such trials for clinical utility have been reported for circulating tumor DNA (ctDNA).

Trials of using circulating tumor cells (CTCs) to select treatment are ongoing (current unpublished trials), the evidence is insufficient to demonstrate clinical utility.

 

Summary

There is no direct evidence that selecting targeted treatment using circulating tumor DNA (ctDNA) or circulating tumor cells (CTCs) improves the net health outcome compared with selecting targeted treatment using tumor tissue testing. Given the different methodologies available to assess ctDNA and 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 ctDNA and CTCs tests and therefore, no conclusion can be made about the clinical utility through a chain of evidence. Further high quality, well designed, large prospective studies are needed to explore and establish whether individualized therapeutic decisions based on ctDNA and CTC assays would improve net health outcomes. Per the 2018 joint review by the American Society of Clinical Oncology (ASCO) and College of American Pathologists on the clinical use of circulating tumor DNA in patients with cancer, the authors concluded future research studies to establish clinical validity and utility of ctDNA assays are needed.

 

Monitoring Treatment Response in Cancer

Monitoring of treatment response in cancer may be performed by 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 outcome of primary interest is progression-free survival.

 

Clinically Valid

Circulating Tumor DNA (ctDNA)

Merker et. al (2018) the American Society of Clinical Oncology (ASCO) and College of American Pathologists jointly convened a panel to review the current evidence on the use of circulating tumor DNA (ctDNA) in patients with cancer. The literature search identified 1,338 references to which an additional 31 references were supplied by the expert panel. There were 77 articles selected for inclusion. Their analysis on the evidence on the use of ctDNA assays for detection and monitoring of residual disease identified several proof-of-principal 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 resistance variants. 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 (CTCs)

Systematic reviews and meta-analysis describing an association between circulating tumor cells (CTCs) and poor prognosis have been reported for metastatic breast cancer (MBC), colorectal cancer (CRC), hepatocellular cancer (HCC), prostate cancer, head and neck cancer and melanoma and are described below.

 

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

 

Metastatic Breast Cancer

In 2015, Zhang et. al. conducted a systematic review and meta-analysis of published literature on the prognostic relevance of circulating tumor cells (CTCs), including patients with early and advanced breast cancer. Forty-nine eligible studies enrolling 6,825 patients were identified. The presence of CTC was significantly associated with shorter survival in the total population. The prognostic value of CTC was significant in both early (DFS: HR, 2.86; 95% CI, 2.19-3.75; OS: HR, 2.78; 95% CI, 2.22-3.48) and metastatic breast cancer (PFS: HR, 1.78; 95% CI, 1.52-2.09; OS: HR, 2.33; 95% CI, 2.09-2.60). Further subgroup analyses showed that our results were stable irrespective of the CTC detection method and time point of blood withdrawal. The authors concluded the present meta-analysis indicates that the detection of CTC is a stable prognosticator in patients with early stage and metastatic breast cancer. However, further studies are required to explore the clinical utility of CTC in breast cancer.

 

In 2016, LV et. al. conducted a systematic review and meta-analysis to clarify the correlation between circulating tumor cells (CTCs) and the clinicopathological features and prognosis of metastatic breast cancer (MBC). This meta-analysis included 24 studies (3701 MBC patients), 13 prospective studies and 11 retrospective studies. We found that CTCs were more frequently detected with HER2 positive primary tumors (pooled RR = 0.73, 95 % CI = 0.63-0.84). Additionally, higher CTC numbers indicated a worse treatment response (RR = 0.56, 95 % CI = 0.40-0.79), poorer PFS (RR = 0.64, 95 % CI = 0.56-0.73) and poorer OS (RR = 0.69, 95 % CI = 0.64-0.75) in MBC patients.

 

In 2017, Wang et. al. conducted a systematic review and meta-analysis to determine the prognostic value of HER2-positive circulating tumor cells (CTCs) in patients with breast cancer. Four studies with a total of 550 patients with stage I to IV breast cancer were included. HER2-positive CTCs were not associated with worse overall survival (OS [overall survival]; HR [hazard ratio], 1.489, 95% confidence interval [CI], 0.873-2.540, P = .144) or progression-free survival (PFS; HR, 1.543; 95% CI, 0.636-3.744; P = .338). In patients without metastasis, HER2-positive CTCs were associated with worse OS (HR, 2.273; 95% CI, 1.340-3.853; P = .002) and worse PFS (HR, 2.870; 95% CI, 1.298-6.343; P = .009). There was no significant relationship between HER2-positive CTCs and survival in subgroups of patients with metastasis.

 

Colorectal Cancer

Koerkamp et. al. (2013) performed a systematic review and meta-analysis to investigate the prognostic value of tumor cells in blood circulating tumor cells (CTCs) or bone marrow (BM) (disseminated tumor cells) of patients with resectable colorectal liver metastases or widespread metastatic colorectal cancer (CRC). The following databases were searched in May 2011: MEDLINE, EMBASE, Science Citation Index, BIOSIS, Cochrane Library. Studies that investigated the association between tumor cells in blood or BM and long-term outcome in patients with metastatic CRC were included. Hazard ratios (HRs) and confidence intervals (CIs) were extracted from the included studies and performed random-effects meta-analyses for survival outcomes. The literature search yielded 16 studies representing 1,491 patients. The results of 12 studies representing 1,329 patients were suitable for pooled analysis. The overall survival (HR, 2.47; 95 % CI 1.74-3.51) and progression-free survival (PFS) (HR, 2.07; 95 % CI 1.44-2.98) were worse in patients with CTCs. The subgroup of studies with more than 35 % CTC-positive patients was the only subgroup with a statistically significant worse PFS. All eight studies that performed multivariable analysis identified the detection of CTCs as an independent prognostic factor for survival.

 

In 2014, Huang et. al. conducted a meta-analysis to assess the prognostic and predictive value of circulating tumor cells (CTCs) in patients with colorectal cancer treated with chemotherapy. A comprehensive literature search for relevant studies was conducted in PubMed, Embase, the Cochrane Database, the Science Citation Index and the Ovid Database, up to April, 2014. Using the random-effects model in Stata software, version 12.0, the meta-analysis was performed using odds ratios (ORs), risk ratios (RRs), hazard ratios (HRs) and 95% confidence intervals (CIs) as effect measures. Subgroup and sensitivity analyses were also performed. Thirteen eligible studies were included. Our meta-analysis indicated that the disease control rate was significantly higher in CRC patients with CTC-low compared with CTC-high (RR = 1.354, 95% CI [1.002–1.830], p = 0.048). CRC patients in the CTC-high group were significantly associated with poor progression-free survival (PFS; HR = 2.500, 95% CI [1.746–3.580], p < 0.001) and poor overall survival (OS; HR = 2.856, 95% CI [1.959–4.164], p < 0.001). Patients who converted from CTC-low to CTC-high or who were persistently CTC-high had a worse disease progression (OR = 27.088, 95% CI [4.960–147.919], p < 0.001), PFS (HR = 2.095, 95% CI [1.105–3.969], p = 0.023) and OS (HR = 3.604, 95% CI [2.096–6.197], p < 0.001) than patients who converted from CTC-high to CTC-low. This meta-analysis included several limitations: it was not conclusive regarding when CTCs should be evaluated after the initiation of chemotherapy and what levels of CTCs would be useful for clinical prognostication; this was a retrospective study and was based on published data from the studies included; several studies did not provider hazard ratios (HRs) directly and were estimated from the published data; although the meta-regression showed that sampling time and detection method were the sources of heterogeneity, heterogeneity could not be eliminated because of patient characteristics, chemotherapy strategies, and heterogeneous CTC populations; and most of the studies included did not comprehensively report patient status regarding surgery or neoadjuvant chemotherapy and could not conduct an in-depth subgroup analysis that adjusted for these factors. The authors concluded that further high-quality, well-designed, large-scale multicenter studies are required to explore whether an individualized therapeutic decision based on CTC levels would improve the prognosis of CRC patients.

 

Hepatocellular Cancer (HCC)

In 2015, Fan et. al. conducted a meta-analysis of available studies to assess the prognostic value of circulating tumor cells (CTCs) in patients diagnosed with hepatocellular carcinoma (HCC). Medline, Ovid Database, Embase, The Science Citation Index, and Cochrane library, search was conducted on all studies reporting the outcomes of interest. The studies were set up according to the inclusion/exclusion criteria. Using a random-effects model, meta-analysis was performed using hazard ratio (HR), risk ratio (RR) and their 95% confidence intervals (95% CIs) as effect measures. Heterogeneity of the studies was tested for each pooled analysis. Subgroup and sensitivity analyses were also performed. Twenty-three published studies that matched the selection criteria were included in this meta-analysis. CTC positivity was significantly associated with relapse free survival (RFS) (HR 3.03, 95% CI: [1.89-4.86]; p<0.00001) and Overall survival (OS) (HR 2.45, 95% CI: [1.73-3.48]; p<0.00001). CTC positivity were also significantly associated with TNM Stage (RR 1.30, 95% CI: [1.02-1.65]; p=0.03), Tumor size (RR 1.36, 95% CI: [1.09-1.69]; p=0.006), Vascular invasion (RR 1.99, 95% CI: [1.43-2.77]; p<0.0001), Portal vein tumor thrombus (RR 1.73, 95% CI: [1.42-2.11]; p=0.0001), Serum alpha-fetoprotein (AFP) level (RR 2.05, 95% CI: [1.18-3.54]; p=0.01). The authors concluded that the results support the notion of a strong prognostic value of CTC in HCC. CTC could be useful as an effective indicator to evaluate the poor clinicopathological prognostic factors in the progression of HCC. However, further well-designed, large-scale detailed and accurate studies are required to explore CTC predictive value for the prognosis of patients with HCC.

 

Prostate Cancer

Wang et. al. (2011) performed a meta-analysis on the most recently reported circulating tumor cells (CTCs) to assess its prognostic effect and to determine whether its detection in the peripheral blood of patients diagnosed with metastatic, castration-resistant prostate cancer (CPRC) and hormone refractory prostate cancer (HRPC) can be used as a prognostic factor for survival. Science Direct, EMBASE, PubMed, and Cell Research databases were searched for studies that assessed the prognostic relevance of the presence number of circulating tumor cells (CTC) detection in the peripheral blood (PB). A fixed effects model with relative risk (RR) and 95% confidence interval (95% CI) was used for analysis. A total of 4 studies, including 486 patients, were eligible for final analysis. Pooled analysis indicated the presence number of CTC per 7.5 ml peripheral blood is associated with a poor survival rate (RR=2.51, 95% CI 1.96-3.21). The authors concluded, the results of this study suggest that presence of unfavorable numbers of CTCs is associated with a relatively shorter survival in patients with prostate cancer. However, this data does not establish CTC as a true surrogate of outcome, in order to establish that CTC can be used a surrogate for survival benefit it will require further evaluation in multiple prospective, randomized phase 3 therapeutic trials powered on survival end points on CTC as a biomarker, with meta-analytic analyses.

 

In 2014, Ma et. al. conducted a systematic review and meta-analysis for the prognostic role of circulating tumor cells (CTCs) and disseminated tumor cells (DTCs) in patients with prostate cancer. Relevant literature was searched in Pubmed and Embase. Survival data of included study were extracted. Forrest plots were used to estimate the effect of CTCs/DTCs on the survival of patients. Publication bias was evaluated using Begg's test.  The estimated HRs and 95 % confidence interval for the effect of CTCs/DTCs on overall survival (OS) and biochemical relapse-free survival (bRFS) or disease-free survival (DFS) were 2.43 [2.07, 2.86] (p<0.00001) and 2.15 [1.69, 2.73] (p<0.00001), respectively. Subgroup analysis revealed that CTCs were also relevant to poor prognosis (hazard ratio (HR) 2.43 [2.05, 2.89] for OS, HR 2.46 [2.08, 2.90] for bRFS/DFS). A similar result was yielded in DTCs (1.47 [1.21, 1.80] for DFS). CTCs/DTCs could also predict poor OS in metastatic prostate cancer (2.37 [1.99, 2.82], p<0.00001) and in localized stage (HR 1.84 [1.47, 2.28], p<0.00001). In addition, CTCs/DTCs detected by different methods, especially by CellSearch system (HR for OS 2.36 [1.95, 2.85] and HR for bRFS/DFS 2.53 [1.66, 3.85]), were relevant to poor prognosis. Available evidence supported the notion of the strong prognostic value of CTCs.

 

Head and Neck Cancer

Sun et. al (2017) conducted a meta-analysis of clinicopathological and prognostic significance of circulating tumor cells (CTCs) in patients with head and neck cancer.  PubMed, MEDLINE, EMBASE, Science Citation Index Expanded and Cochrane Library were searched up to February 2017. The estimated hazard ratio (HR), risk ratio (RR) and their 95% confidence intervals (95% CIs) were set as effect measures. All analyses were performed by STATA 12.0.A total of 17 studies were included in this meta-analysis. Positive CTCs were significantly associated with poor overall survival (HR =2.80, 95% CI: 1.34-5.86), disease-free survival (HR =3.86, 95% CI: 2.03-7.36) and progression-free survival (HR =3.31, 95% CI: 1.71-6.42). CTC-positive patients tend to have higher recurrence (RR =2.13, 95% CI: 1.26-3.59) and regional lymph node metastasis (RR =1.18, 95% CI: 1.02-1.36) rate and a more advanced tumor stage (RR =1.16, 95% CI: 1.03-1.32). Limitations of this meta-analysis included: the use of extracted data and not original data; limited studies were used for the prognostic value, and the heterogeneity was relatively obvious; the results may be influenced by accidental factor; and multiple CTC detection methods were involved. The authors concluded CTC detection has a great potential application in head and neck cancer. Positive CTCs in patients with head and neck cancer can predict the poor prognosis and the high recurrence and tumor progression rate. However, future large-scale multicenter studies are needed using the same standardized detection platforms to reduce inconsistencies across studies to further assess CTCs in patients with head and neck cancer.

 

Melanoma

Mocellin et. al. (2006) performed a systematic review and meta-analysis regarding the prognostic value clinical of circulating tumor cells (CTCs) in patients with melanoma. Fifty-three studies enrolling 5,433 patients were reviewed. Correlation of CTC status with tumor-node-metastasis disease stage and patients overall (OS) and progression-free (PFS) survival was assessed by means of association statistics and meta-analysis, respectively. CTC status correlated with both tumor-node-metastasis stage (stage I, 32%; stage II, 41.7%; stage III, 41.1%; stage IV, 47.4%; Ptrend < 0.0001) and survival (OS: hazard ratio, 2.42; 95% confidence interval, 1.7-3.45, P < 0.0001; PFS: hazard ratio, 2.45; 95% confidence interval, 1.78-3.38; P < 0.0001). However, statistical heterogeneity was significant for both OS and PFS, likely underscoring the wide variability in study design. Furthermore, CTC positivity rates in early stages were higher and in the metastatic setting were lower than expected, which indicates an unsatisfactory accuracy of currently available CTC detection assays. The authors concluded the available evidence is not sufficient to conclude that circulating melanoma cells are a biomarker reliable enough to be clinically implemented in the therapeutic decision making process. Further large multicenter prospective studies are needed.

 

Clinically Useful

Direct evidence of clinical utility is provided by studies that have compared health outcomes for patients managed with and without the test. The preferred evidence would be from randomized controlled trials.

 

Circulating Tumor DNA (ctDNA)

Merker et. al (2018) the American Society of Clinical Oncology (ASCO) and College of American Pathologists jointly convened a panel to review the current evidence on the use of circulating tumor DNA (ctDNA) in patients with cancer. The literature search identified 1,338 references to which an additional 31 references were supplied by the expert panel. There were 77 articles selected for inclusion. They concluded that there is no evidence that changing treatment before clinical progression, at the time of ctDNA progression improves patient outcomes.

 

Circulating Tumor Cells

In 2014, Smerage et. al. reported on the results of a randomized controlled trial of patients with metastatic breast cancer (MBC) and persistently increased circulating tumor cell (CTC) levels to test whether changing chemotherapy after 1 cycle of first-line therapy could improve overall survival (OS) the primary study outcome. Patients with MBC who did not have increased CTCs at baseline remained on initial therapy until progression (arm A). Patients with initially increased CTCs that decreased after 21 days of therapy remained on initial therapy (arm B). Patients with persistently increased CTCs after 21 days of therapy were randomly assigned to continue initial therapy (arm C1) or change to an alternative chemotherapy (arm C2). Of 595 eligible and evaluable patients, 276 (46%) did not have increased CTCs (arm A). Of those with initially increased CTCs, 31 (10%) were not retested, 165 were assigned to arm B, and 123 were randomly assigned to arm C1 or C2. No difference in median OS was observed between arm C1 and C2 (10.7 and 12.5 months, respectively; P = .98). CTCs were strongly prognostic. Median OS for arms A, B, and C (C1 and C2 combined) were 35 months, 23 months, and 13 months, respectively (P < .001). The authors concluded this trial showed the prognostic significance of CTCs in patients with metastatic breast cancer receiving first-line chemotherapy. For patients with persistently increased CTCs after 21 days of first-line chemotherapy, early switching to an alternate chemotherapy was not effective in prolonging overall survival (OS). For this population, there is a need for more effective treatment than standard chemotherapy.

 

Trials demonstrating that use of CTCs to monitor treatment for the purpose of making treatment changes are needed to demonstrate clinical utility.

 

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

 

Summary

There is no direct evidence that using circulating tumor DNA (ctDNA) or circulating tumor cells (CTCs) to monitor treatment response improves the net health outcome compared with standard methods. Given the different methodologies available to assess ctDNA and 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 ctDNA and CTCs tests and therefore, no conclusion can be made about the clinical utility through a chain of evidence. . Further high quality, well designed, large prospective studies are needed to explore and establish whether individualized therapeutic decisions based on ctDNA and CTC assays would improve net health outcomes. Per the 2018 joint review by the American Society of Clinical Oncology (ASCO) and College of American Pathologists on the clinical use of circulating tumor DNA in patients with cancer, the authors concluded future research studies are needed to establish the clinical validity and utility of ctDNA assays.

 

Predicting Risk of Relapse

Monitoring for relapse after curative therapy in patients with cancer may be performing 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 outcome of primary interest is progression-free survival.

 

Clinically Valid

Circulating Tumor DNA (ctDNA)

Merker et. al (2018) the American Society of Clinical Oncology (ASCO) and College of American Pathologists jointly convened a panel to review the current evidence on the use of circulating tumor DNA (ctDNA) in patients with cancer. The literature search identified 1,338 references to which an additional 31 references were supplied by the expert panel. There were 77 articles selected for inclusion. They identified several proof-of-principle studies demonstrating an association between persistent detection of ctDNA after local therapy and high risk of relapse. 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 (CTCs)

In 2014, Rack et. al. published results of a large multicenter study in which circulating tumor cells (CTCs) were analyzed in 2026 patients with early breast cancer before adjuvant chemotherapy and in 1492 patients after chemotherapy using the CellSearch System. After immuno-magnetic enrichment for cells expressing the epithelial-cell adhesion molecule, CTCs were defined as nucleated cells expressing cytokeratin and lacking CD45. The patients were followed for a median of 35 months (range = 0-54). Kaplan-Meier analyses and the log-rank test were used for survival analyses. All statistical tests were two-sided. Before chemotherapy, CTCs were detected in 21.5% of patients (n = 435 of 2026), with 19.6% (n = 136 of 692) of node-negative and 22.4% (n = 299 of 1334) of node-positive patients showing CTCs (P < .001). No association was found with tumor size, grading, or hormone receptor status. After chemotherapy, 22.1% of patients (n = 330 of 1493) were CTC positive. The presence of CTCs was associated with poor disease-free survival (DFS; P < .0001), distant DFS (P < .001), breast cancer-specific survival (P = .008), and overall survival (OS; P = .0002). CTCs were confirmed as independent prognostic markers in multivariable analysis for DFS (hazard ratio [HR] = 2.11; 95% confidence interval [CI] = 1.49 to 2.99; P < .0001) and OS (HR = 2.18; 95% CI = 1.32 to 3.59; P = .002). The prognosis was worst in patients with at least five CTCs per 30 mL blood (DFS: HR = 4.51, 95% CI = 2.59 to 7.86; OS: HR = 3.60, 95% CI = 1.56 to 8.45). The presence of persisting CTCs after chemotherapy showed a negative influence on DFS (HR = 1.12; 95% CI = 1.02 to 1.25; P = .02) and on OS (HR = 1.16; 95% CI = 0.99 to 1.37; P = .06). Although the presence of persisting CTCs after chemotherapy was associated with worse outcomes, survival of patients without CTCs before chemotherapy was the same irrespective of CTC status after chemotherapy. Limitations of this study included: the short median follow-up of 35 months; the number of cells detected by the CellSearch system is relatively low and limited to cells with expression of Epcam and cytokeratin; and CTCs with decreased epithelial marker expression as a result of the epithelial-mesenchymal transition could be missed by the CellSearch Methodology. The authors concluded, that the data offers support for the clinical potential of CTCs to assess the individual risk of patients at the time of primary diagnosis and may be used for treatment tailoring in the absence of other strong quantitative markers.

 

Smaller studies demonstrating association between persistent circulating tumor cells (CTCs) and relapse have been published in prostate cancer, colorectal cancer (CRC), bladder cancer, liver cancer (hepatocellular cancer HCC), and esophageal cancer and are described below.

 

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

 

Prostate Cancer

Thalgott et. al. (2015) reported on a study regarding circulating tumor cells (CTCs) possibly being prognostic for biochemical recurrence-free survival (bRFS) in patients with locally advanced high-risk prostate cancer (LAPC) undergoing neoadjuvant chemotherapy (NCHT) and radical prostatectomy (RP). CTCs were detected before and after NCHT, after RP and at follow-up using the CellSearch System for 59 blood samples (20 ml) from patients with LAPC (n=15) and, additionally, for 15 control samples. The median 5-year progression risk was 90%. CTCs (≥1/20 ml) were detected in 53.3% of patients, with a detection rate of 18.6% in sample-adjusted analysis. CTCs were detected at baseline in 20% of patients with LAPC and 6.7% of controls (p=0.6). CTC findings displayed no association with clinicopathological characteristics. The median bRFS of CTC-negative versus CTC-positive patients was 43.7 (95% confidence interval not reached) vs. 29.2 months (95% confidence interval=26.8-60.6 months), without statistical significance (p=0.76).

 

Colorectal Cancer

In 2013, Deneve et. al. reported on a study related to the capture of viable circulating tumor cells (CTCs) in the liver of colorectal cancer patients (CRC). The incidence and number of circulating tumor cells (CTCs) in the peripheral blood of colorectal cancer patients are lower than in other cancer types, which may point to a particular biology of colorectal cancer affecting CTC detection. They detected CTCs in the peripheral and mesenteric blood of colorectal cancer patients by use of 2 independent technologies on the basis of different biological properties of colon cancer cells. Seventy-five patients diagnosed with localized (M0, n = 60) and metastatic (M1, n = 15) colorectal cancer were included. Peripheral and mesenteric blood samples were collected before tumor resection. We performed CTC enumeration with an EpCAM-independent enrichment method followed by the Epispot assay that detected only viable CK19-releasing CTCs. In parallel, we used the FDA-cleared EpCAM-dependent CellSearch as the reference method. The enumeration of CK19-releasing cells by the CK19-Epispot assay revealed viable CTCs in 27 of 41 (65.9%) and 41 of 74 (55.4%) (P = 0.04) patients in mesenteric and peripheral blood, respectively, whereas CellSearch detected CTCs in 19 of 34 (55.9%) and 20 of 69 (29.0%) (P = 0.0046) patients. In mesenteric blood, medians of 4 (range 0-247) and 2.7 CTCs (range 0-286) were found with Epispot and CellSearch (P = 0.2), respectively, whereas in peripheral blood, Epispot and CellSearch detected a median of 1.2 (range 0-92) and 0 CTCs (range 0-147) (P = 0.002). A considerable portion of viable CTCs detectable by the Epispot assay are trapped in the liver as the first filter organ in CRC patients. The authors concluded, future investigations should focus on defining the best markers of the subpopulation of functional CTCs that are the metastasis initiating cells, defining the role of EpCAM in liver metastases formation, and identifying factors from colon CTCs able to induce the prometastatic microenvironment of the liver.

 

Bladder Cancer

Rink et. al. (2012) prospectively analyzed the prognostic role and HER2 expression of circulating tumor cells (CTCs) in peripheral blood of patients prior to radical cystectomy with clinically non-metastatic urothelial carcinoma of the bladder (UCB). Blood samples from 100 consecutive UCB patients treated with radical cystectomy (RC) were investigated for the presence (CellSearch system) of CTC and their HER2 expression status (immunohistochemistry). HER2 expression of the corresponding primary tumors and lymph node metastasis were analyzed using fluorescence in situ hybridization. Blood samples were taken preoperatively. Patients underwent RC with lymphadenectomy. Outcomes were assessed according to CTC status. HER2 expression of CTC was compared with that of the corresponding primary tumor and lymph node metastasis.  CTC were detected in 23 of 100 patients (23%) with non-metastatic UCB (median: 1; range: 1-100). Presence, number, and HER2 status of CTC were not associated with clinicopathologic features. CTC-positive patients had significantly higher risks of disease recurrence and cancer-specific and overall mortality (p values: ≤ 0.001). After adjusting for effects of standard clinicopathologic features, CTC positivity remained an independent predictor for all end points (hazard ratios: 4.6, 5.2, and 3.5, respectively; p values ≤ 0.003). HER2 was strongly positive in CTC from 3 of 22 patients (14%). There was discordance between HER2 expression on CTC and HER2 gene amplification status of the primary tumors in 23% of cases but concordance between CTC, primary tumors, and lymph node metastases in all CTC-positive cases (100%). The study was limited by its sample size.

 

In 2014, Gazzaniga et. al. performed study to investigate whether the presence of circulating tumor cells (CTCs) may improve prognostication in a large population of patients with Stage I bladder cancer who were all candidates for conservative surgery. A prospective single center trial was designed to correlate the presence of CTC to local recurrence and progression of disease in high-risk T1G3 bladder cancer. One hundred two patients were found eligible, all candidate to transurethral resection of the tumor followed by endovesical adjuvant immunotherapy with BCG. Median follow-up was 24.3 months (minimum-maximum: 4-36). The FDA-approved CellSearch System was used to enumerate CTC. Kaplan-Meier methods, log-rank test and multivariable Cox proportional hazard analysis was applied to establish the association of circulating tumor cells with time to first recurrence (TFR) and progression-free survival. CTC were detected in 20% of patients and predicted both decreased TFR (log-rank p < 0.001; multivariable adjusted hazard ratio [HR] 2.92 [95% confidence interval: 1.38-6.18], p = 0.005), and time to progression (log-rank p < 0.001; HR 7.17 [1.89-27.21], p = 0.004).

 

Liver Cancer

Schulze et. al. (2013) investigated the prognostic relevance of EpCAM-positive circulating tumor cells (CTCs) in patients with HCC. Current imaging technologies do not sufficiently detect micrometastasis and therefore do not allow adequate stratification of patients with hepatocellular carcinoma (HCC) for curative or systemic therapy. Blood from 78 patients (19 patients in the control cohort and 59 patients with HCC) was tested for CTCs with the CellSearch system. Correlation analysis to overall survival (OS), the Barcelona Clinic Liver Cancer (BCLC) staging system, macroscopic and microscopic vascular invasion and alpha-fetoprotein (AFP) levels were performed. They detected ≥1 CTC in 18/59 HCC patients and in 1/19 patients with cirrhosis or benign hepatic tumor (p = 0.026). OS was significantly shorter (460 vs. 746 days) in the CTC-positive cohort (p = 0.017). Comparing BCLC stages, significant differences in CTC detection rates were also observed: BCLC stages A 1/9, B 6/31 and C 11/19 (p = 0.006). Ten of 18 patients with macroscopic and 10/16 patients with microscopic vascular invasion exhibited positive findings in CTC testing (p = 0.004 and p = 0.006). The authors concluded, CTC results correlated to AFP (cutoff > 400 ng/mL) levels (p = 0.050). The study demonstrates frequent presence of EpCAM-positive CTC in patients with intermediate or advanced HCC and its prognostic value for OS with possible implications for future treatment stratification.

 

Esophageal Cancer

In 2012, Vashist et. al. assessed the impact of disseminated tumor cells (DTC) in bone marrow on recurrence and survival in complete resected esophageal cancer (EC) in prospective study. Current modalities to predict tumor recurrence and survival in EC are insufficient. They enrolled 370 consecutive EC patients (1995-2009). All tumors, 189 squamous cell carcinomas and 181 adenocarcinomas, were completely surgically resected (R0), and patients received neither neoadjuvant nor adjuvant therapy. Disseminated tumor cells were detected by an immunocytochemical cytokeratin assay in preoperatively taken bone marrow aspirates. The results were correlated with clinic-pathological parameters and clinical outcome. Overall 120 (32.4%) patients harbored DTC in their bone marrow. Presence of DTC significantly correlated with aggressive tumor biology as indicated by increased tumor size (P = 0.026), regional (P = 0.002) and distant (P = 0.012) lymph node metastases, and higher relapse rate (P < 0.001, χ test). A gradual decrease in disease-free (P < 0.001) and overall (P < 0.001, log-rank test) survival was observed between DTC-negative and DTC-positive patients and was evident in subgroup analysis stratified for nodal status, lymph node yield, lymph node ratio, and tumor subtypes. Disseminated tumor cells were identified as a strong independent prognosticator of tumor recurrence (hazard ratio [HR] 4.0, 95% confidence interval [CI]: 2.96-5.45, P < 0.001) and overall survival (HR 3.1, 95% CI: 2.37-4.09, P < 0.001, Cox regression analysis).

 

Clinically Useful

Circulating Tumor DNA (ctDNA) and Circulating Tumor Cells (CTCs)

Direct evidence of clinical utility is provided by studies that have compared health outcomes for patients managed with and without the test. The preferred evidence would be from randomized controlled trials.

 

Merker et. al. (2018) concluded that there is no evidence that early treatment before relapse, based on changes in circulating tumor DNA (ctDNA), improves patient outcomes.

 

No trials were identified demonstrating that treatment before relapse based on changes in circulating tumor cells (CTCs) improves patient outcomes.

 

The evidence is insufficient to demonstrate test performance (clinical validity) for currently available ctDNA and CTC tests for predicting relapse, therefore, no conclusions can be made about clinical utility. Also, a chain of evidence to demonstrate clinical utility requires an evidence based management pathway. There is not a clear evidence-based management pathway for the use of ctDNA or CTCs to guide early treatment before relapse.

 

Summary

There is no direct evidence that using circulating tumor DNA (ctDNA) or circulating tumor cells (CTCs) to predict the risk of relapse improves the net health outcome compared with standard methods. Given the different methodologies available to assess ctDNA and 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 ctDNA and CTCs tests and therefore, no conclusion can be made about the clinical utility through a chain of evidence. Further high quality, well designed, large prospective studies are needed to explore and establish whether individualized therapeutic decisions based on ctDNA and CTC assays would improve net health outcomes. Per the 2018 joint review by the American Society of Clinical Oncology (ASCO) and College of American Pathologists on the clinical use of circulating tumor DNA in patients with cancer, the authors concluded future research studies are needed to establish the clinical validity and utility of ctDNA assays.

 

Screening for Cancer in Asymptomatic Individuals

It has 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 outcome of primary interest is progression-free survival.

 

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

 

In 2011, Msaouel et. al. performed a systematic review and meta-analysis to consolidate current evidence regarding the use of circulating tumor cell (CTC) detection assays to diagnose bladder and other urothelial cancers and the association of CTC positivity with advanced, remote disease. Studies that investigated the presence of CTCs in the peripheral blood of patients with bladder cancer and/or urothelial cancer were identified and reviewed. Sensitivities, specificities, and positive (LR+) and negative likelihood ratios (LR-) of CTC detection in individual studies were calculated and meta-analyzed by random effects model. Overall odds ratio of CTC positivity in patients with advanced disease versus those with organ-confined cancer was also calculated. Overall sensitivity of CTC detection assays was 35.1% (95%CI, 32.4-38%); specificity, LR+, and LR- was 89.4% (95%CI, 87.2-91.3%), 3.77 (95%CI, 1.95-7.30) and 0.72 (95%CI, 0.64-0.81). CTC-positive patients were significantly more likely to have advanced (stage III-IV) disease compared with CTC-negative patients (OR, 5.05; 95%CI, 2.49-10.26). The authors concluded due to the low overall sensitivity, CTC detection assays should not be used as initial screening tests.

 

In 2013, Tang et. al. completed a systematic review and meta-analysis to evaluate the accuracy of circulating tumor cells (CTCs) for diagnosing gastric cancer. The pooled sensitivity (SEN), specificity (SPE), positive and negative likelihood ratios (PLR and NLR, respectively), diagnostic odds ratio (DOR) and summary receiver operating characteristic (sROC) curve were calculated to evaluate the overall test performance. Twenty studies were included. The diagnostic value of CTCs detection for the gastric cancer was calculated to evaluate the overall test performance. The summary estimates of The pooled sensitivity, specificity, positive and negative likelihood ratios, diagnostic odds ratio were 0.42 (95% confidence interval (CI), 0.21-0.67), 0.99 (95% CI, 0.96-1.00), 58.2 (95% CI, 9.8-345.9), 0.58 (95% CI, 0.38-0.89), and 100 (95% CI, 15–663), respectively. The summary receiver operating characteristic curve was 0.97 (95% CI, 0.95–0.98). Deek’s funnel plot asymmetry test found no evidence of study publication bias in the current study (P = 0.49). The authors concluded this systemic review suggests that CTCs detection alone cannot be recommended as a screening test for gastric cancer.

 

Merker et. al (2018) the American Society of Clinical Oncology (ASCO) and College of American Pathologists jointly convened a panel to review the current evidence on the use of circulating tumor DNA (ctDNA) in patients with cancer. The literature search identified 1,338 references to which an additional 31 references were supplied by the expert panel. There were 77 articles selected for inclusion. In regard to the evidence on the use of ctDNA assays in screening for cancer in asymptomatic individuals the panel concluded the following: Given that ctDNA can be detected in some patients diagnosed with early stage cancer, there is a substantial interest in the potential of using ctDNA in early detection of cancer in asymptomatic individuals and populations. Case reports of detection of cancer during maternal cell free DNA testing, to detect fetal DNA aneuploidy, raise the potential of this approach. However, at this time there are no data on clinical validity in this setting and no evidence of clinical utility. The extent to which assays may have false positive test results (both technical and biologic), diagnosing the presence of cancer in a patient without cancer, and determining tissue of origin, have not been established. It is also possible that circulating genomic variants could arise in cells that have taken the first step toward transformation but were never destined to become clinically important. This form of biologic false positive, commonly termed over-diagnosis has been well documented in breast cancer with mammographic screening and prostate cancer with prostate-specific antigen screening.

 

Summary

There is no direct evidence that using circulating tumor DNA (ctDNA) and circulating tumor cells (CTCs) to screen for cancer in asymptomatic individuals improves the net health outcomes compared with standard methods. Given the different methodologies available to assess ctDNA and 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 ctDNA and CTCs tests and therefore, no conclusion can be made about the clinical utility through a chain of evidence. Per the 2018 joint review by the American Society of Clinical Oncology (ASCO) and College of American Pathologists on the clinical use of circulating tumor DNA in patients with cancer, the authors concluded there is no evidence of clinical validity or clinical utility to suggest that ctDNA assays are useful for cancer screening, outside of a clinical trial.

 

Summary of Evidence

For individuals who have advanced cancer who receive testing of circulating tumor DNA (ctDNA) to select targeted treatment, the evidence includes observational studies. Given the different 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 net health outcomes.

 

For individuals who have advanced cancer who receive testing of circulating tumor cells (CTCs) to select targeted treatment, the evidence includes observational studies. Given the different 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 net health outcomes.

 

For individuals who have cancer who receive testing of circulating tumor DNA (ctDNA) to monitor treatment response, the evidence includes observational studies. Given the different 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 net health outcomes.

 

For individuals who have cancer who receive testing of circulating tumor cells (CTCs) to monitor treatment response, the evidence includes a randomized controlled trial, observational studies, and systematic reviews of observational studies. Given the different 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 net health outcomes.

 

For individuals who have received curative treatment for cancer who receive testing of circulating tumor DNA (ctDNA) to predict risk of relapse, the evidence includes observational studies. Given the different 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 net health outcomes.

 

For individuals who have received curative treatment for cancer who receive testing of circulating tumor cells (CTCs) to predict risk of relapse, the evidence includes observational studies. Given the different 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 net health outcomes.

 

For individuals who are asymptomatic and at high risk for cancer who receive testing of circulating tumor DNA (ctDNA) to screen for cancer, no evidence was identified. Published data on clinical validity and clinical utility are lacking. The evidence is insufficient to determine the effects of the technology on net health outcomes.

 

For individuals who are asymptomatic and at high risk for cancer who receive testing of circulating tumor cells (CTCs) to screen for cancer, the evidence includes observational studies. Given the different 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 net health outcomes.

 

Practice Guidelines and Position Statements

American Society of Clinical Oncology (ASCO):

In 2015, the American Society of Clinical Oncology (ASCO) updated their guideline, use of biomarkers to guide decisions on systemic therapy for women with metastatic breast cancer: American Society of Clinical Oncology Clinical Practice Guideline which states: “Recommendations for circulating tumor markers: In patients already receiving systemic therapy for metastatic breast cancer, decisions on changing to a new drug or regimen or discontinuing treatment should be based on clinical evaluation, judgment of disease progression or response, and the patient’s goals for care. There is no evidence at this time that changing therapy based solely on circulating biomarkers results improves health outcomes, quality of life or cost effectiveness.” (Type: evidence based. Evidence quality: intermediate. Strength of recommendation: moderate)

 

In 2017, the American Society of Clinical Oncology (ASCO) issued a focused update on the use of biomarkers to guide decisions and adjuvant systemic therapy for women with early stage invasive breast cancer which included the following recommendation: “The clinician should not use CTCs to guide decisions for adjuvant systemic therapy.” (Type: Evidence based; Evidence quality: Intermediate; Strength of recommendation: Strong)

 

In 2018, the American Society of Clinical Oncology (ASCO) and College of American Pathologists issued a joint review on circulating tumor DNA in patients with cancer which states: “There is no evidence of clinical utility and little evidence of clinical validity of circulating tumor DNA (ctDNA) assays in early stage cancer, treatment monitoring or residual disease detection. There is no evidence of clinical validity and clinical utility to suggest that ctDNA assays are useful for cancer screening, outside of a clinical trial. Robust research is needed to enable development of clinical practice recommendations.”

 

National Comprehensive Care Network (NCCN)

Breast Cancer Version 1.2018

Discussion Section: Monitoring Metastatic Disease: The clinical use of circulating tumor cells (CTC) in metastatic breast cancer is not yet included in the NCCN guidelines for Breast Cancer for disease assessment and monitoring. Patients with persistently increased CTC after 3 weeks of first line chemotherapy have a poor PFS (progressive free survival) and OS (overall survival). In spite of its prognostic ability, CTC count has failed to show a predictive value. A prospective, randomized phase 3 trials (SWOG S0500) evaluated the clinical utility of serial enumeration of CTC in patients with metastatic breast cancer. According to the study results, switching to an alternative cytotoxic therapy after 3 weeks of first line chemotherapy in patients with persistently increased CTC did not affect either PFS (progressive free survival) or OS (overall survival).

 

Bladder Cancer Version 5.2018

The clinical use of circulating tumor cells (CTC) and circulating tumor DNA (ctDNA) in bladder cancer is not yet included in this NCCN guideline.

 

Colon Cancer Version 2.2017

The clinical use of circulating tumor cells (CTC) and circulating tumor DNA (ctDNA) in colon cancer is not yet included in this NCCN guideline.

 

Rectal Cancer Version 3.2018

The clinical use of circulating tumor cells (CTC) and circulating tumor DNA (ctDNA) in rectal cancer is not yet included in this NCCN guideline.

 

Esophogeal and Esophagogastric Junction Cancers Version 2.2018

The clinical use of circulating tumor cells (CTC) and circulating tumor DNA (ctDNA) in esophageal and esophagogastric junction cancer is not yet included in this NCCN guideline

 

Gastric Cancer Version 2.2018

The clinical use of circulating tumor cells (CTC) and circulating tumor DNA (ctDNA) in gastric cancer is not yet included in this NCCN guideline.

 

Hepatobiliary Cancers Version 3.2018

The clinical use of circulating tumor cells (CTC) and circulating tumor DNA (ctDNA) in hepatobiliary cancers, particularly hepatocellular carcinoma (HCCH) is not yet included in this NCCN guideline.

 

Kidney Cancer Version 1.2019

The clinical use of circulating tumor cells (CTC) and circulating tumor DNA (ctDNA) in kidney cancer is not yet included in this NCCN guideline.

 

Non-Small Cell Lung Cancer Version 8.2017

The guideline discusses liquid biopsy or plasma biopsy in a few instances. One statement reads: “if repeat biopsy is not feasible, plasma biopsy should be considered,” but it is not stated to which biomarkers this statement apply. In the text discussion of osimertinib, a study cited supporting the use of plasma biopsy if tissue biopsy is not feasible.

 

Ovarian Cancer Including Fallopian Tube Cancer and Primary Peritoneal Cancer Version 2.2018

The clinical use of circulating tumor cells (CTC) and circulating tumor DNA (ctDNA) in ovarian cancer is not yet included in this NCCN guideline.

 

Pancreatic Adenocarcinoma Version 2.2018

The clinical use of circulating tumor cells (CTC) and circulating tumor DNA (ctDNA) in pancreatic adenocarcinoma is not yet included in this NCCN guideline.

 

Prostate Cancer Version 4.2018

Discussion Section: Progression after Enzalutamide and Abiraterone
No randomized trials that compare taxane chemotherapies versus novel hormonal therapies in this setting have been reported, and some data suggest cross-resistance between abiraterone and enzalutamide. One molecular biomarker that may aid appropriate selection of therapy after progression on abiraterone or enzalutamide is the presence of androgen receptor splice variant 7 (AR-V7) in circulating tumor cells (CTCs). Lack of response of men with metastatic CRPC to abiraterone and enzalutamide was associated with detection of AR-V7 mRNA in CTCs using an RNA based polymerase chain reaction (PCR) assay. AR-V7 presence did not preclude clinical benefit from taxane chemotherapies (docetaxel and cabazitaxel). Men with AR-V7 positive CTCs exhibited superior progression-free survival with taxanes compared to novel hormonal therapies (abiraterone and enzalutamide); the two classes of agents resulted in comparable progression-free survival in men with AR-V7 negative CTCs. A confirmatory study used a different CTC assay that detected nuclear localized AR-V7 protein using immunofluorescence. Men with AR-V7 positive CTCs had superior OS with taxanes versus abiraterone or enzalutamide, whereas OS was not different between the two classes of agents among patients with AR-V7 negative CTCs.

 

These single center clinical experiences suggest that AR-V7 assays are promising predictors of abiraterone and enzalutamide resistance, but they have not yet been validated prospectively and externally. Furthermore, the prevalence of AR-V7 positivity is only 3% in patients prior to treatment with enzalutamide, abiraterone and taxanes, so the panel believes AR-V7 detection would not be useful to inform treatment decisions in the naïve setting. On the other hand, the prevalence of AR-V7 positivity is higher after progression on abiraterone or enzalutamide (19% or 39%) but data have already shown that abiraterone/enzalutamide crossover therapy is rarely effective and taxanes are more effective in this setting. Therefore, the Panel does not recommend use of these tests to determine treatment selection as this time.

 

Thyroid Carcinoma Version 1.2018

The clinical use of circulating tumor cells (CTC) and circulating tumor DNA (ctDNA) in thyroid carcinoma is not yet included in this NCCN guideline.

 

Regulatory Status

The CellSearch™ system (Janssen Diagnostics, formerly Veridex) is the only U.S. Food and Drug Administration (FDA) approved device for monitoring patients with metastatic disease and CTCs. In 2004, the CellSearch™ system was cleared by the 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 (Cell Tracks® AutoPrep) and analysis (CellSpotterAnalyzer®), together with supplies, reagents, and epithelial cell control kits manufactured by Veridex.

 

Clinical laboratories may develop and validate tests in-house and market them as a laboratory service; laboratory developed tests (LDTs) must meet the general regulatory standards of the Clinical Laboratory Improvement Amendments (CLIA). Laboratories that offer LDTs must be licensed by CLIA 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.

 

Prior Approval:

Not applicable

 

Policy:

See related medical policies

  • This policy does not address EGFR testing, see medical policy 02.04.55 Epidermal Growth Factor Receptor (EGFR)
  • 02.04.63 Expanded Genetic Panels to Identify Targeted Cancer Therapy

 

The use of circulating tumor DNA (ctDNA) and/or circulating tumor cells (CTCs) (liquid biopsy) is considered investigational for all indications, including but not limited to the following:

  • Cancer Intercept
  • CellMax - CRC Colorectal Cancer Early Detection Test
  • CellMax – LBx Liquid Biopsy
  • CellMax – PanCa Monitoring Test
  • CellMax – Prostate Cancer Test
  • CellSearch
  • Circulogene
  • ClearID Biomarker Expression Assays
  • ClearID Breast Cancer
  • ClearID Lung Cancer
  • ClearID Solid Tumor Panel
  • Colvera
  • FoundationACT (FoundationOne Liquid)
  • Guardant 360
  • IVDiagnostics
  • LiquidGx
  • OncoBEAM for Colorectal Cancer
  • OncoBEAM for Lung Cancer
  • OncoBEAM for Melanoma
  • PlasmaSelect64
  • Target Selector

 

For individuals who have cancer who receive testing of circulating tumor DNA (ctDNA) and/or circulating tumor cells (CTCs) to select targeted treatment, monitor treatment response, or predict relapse; and in individuals who are asymptomatic at high risk for cancer for screening purposes, the evidence includes observational studies, randomized controlled trials, systematic reviews and meta-analysis. Given the different methodologies available to assess circulating tumor DNA (ctDNA) and circulating tumor cells (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. Per the 2018 joint review by the American Society of Clinical Oncology (ASCO) and College of American Pathologists on the clinical use of circulating tumor DNA (ctDNA) in patients with cancer, the authors concluded there is no evidence of clinical validity or clinical utility to suggest that circulating tumor DNA (ctDNA) assays are useful in the management of cancer for any indication or are they useful for cancer screening outside of a clinical trial. NCCN guidelines also do not recommend the use of circulating tumor DNA (ctDNA) or circulating tumor cell (CTC) assays in the management of cancer. The evidence is insufficient to determine the effects for the technology on net health outcomes.

 

Procedure Codes and Billing Guidelines:

To report provider services, use appropriate CPT* codes, Modifiers, Alpha Numeric (HCPCS level 2) codes, Revenue codes, and/or diagnosis codes.

  • 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.
  • 81479 Unlisted molecular pathology procedure

 

Selected References:

  • Cristofanilli M, Budd GT, Ellis MJ et al. Circulating tumor cells, disease progression and survival in metastatic breast cancer. NEJM 2004; 351:781-91.
  • Harris L, Fritsche H, Mennel R et al. American Society of Clinical Oncology 2007 Update of Recommendations for the Use of Tumor Markers in Breast Cancer. J Clin Oncol. 2007 Nov 20;25(33):5287-312.
  • Budd GT, Cristofanilli M, Ellis MJ et al. Circulating tumor cells versus imaging-predicting overall survival in metastatic breast cancer. Clin Cancer Res. 2006  Nov 1;12(21):6321-2.
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  • UpToDate. Prostate Cancer: Risk Stratification and Choice of Initial Treatment. Eric A. Klein, M.D. Topic last updated August 8, 2017.
  • National Comprehensive Cancer Network (NCCN): Breast Cancer Version 1.2018 
  • National Comprehensive Cancer Network (NCCN): Colon cancer Version 3.2018
  • National Comprehensive Cancer Network (NCCN) Rectal Cancer Version 3.2018.
  • National Comprehensive Cancer Network (NCCN) Melanoma Version 3.2018.
  • National Comprehensive Cancer Network (NCCN): Prostate Cancer Version 4.2018.
  • National Comprehensive Cancer Network (NCCN) Non-Small Cell Lung Cancer Version 6.2018.
  • National Comprehensive Cancer Network (NCCN) Hepatobiliary Cancers Version 3.2018.
  • National Comprehensive Cancer Network (NCCN) Head and Neck Cancers Version 2.2018.
  • National Comprehensive Cancer Network (NCCN) Bladder Cancer Version 5.2018.
  • National Comprehensive Cancer Network (NCCN) Esophageal and Esophagogastric Junction Cancers Version 2.2018.
  • National Comprehensive Cancer Network  (NCCN) Gastric Cancer Version 2.2018.
  • National Comprehensive Cancer Network (NCCN) Pancreatic Adenocarcinoma Version 2.2018.
  • National Comprehensive Cancer Network (NCCN) Ovarian Cancer Including Fallopian Tube Cancer and Primary Peritoneal Cancer Version 2.2018.
  • National Comprehensive Cancer Network (NCCN) Kidney Cancer Version 1.2019.
  • National Comprehensive Cancer Network (NCCN) Thyroid Carcinoma Version 1.2018. 
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  • UpToDate. Initial Staging and Evaluation of Men with Newly Diagnosed Prostate Cancer. Philp W. Kantoff M.D., Mary-Ellen Taplin M.D., Joseph A. Smith M.D.. Topic last updated April 14, 2017.
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Policy History:

  • September 2018 - Annual Review, Policy Revised
  • September 2017 - Annual Review, Policy Renewed
  • September 2016 - Annual Review, Policy Renewed
  • October 2015 - Annual Review, Policy Renewed
  • November 2014 - Annual Review, Policy Revised
  • January 2014 - Annual Review, Policy Renewed
  • January 2013 - Annual Review, Policy Renewed
  • January 2012 - Annual Review, Policy Renewed
  • January 2011 - Annual Review, Policy Renewed

Wellmark medical policies address the complex issue of technology assessment of new and emerging treatments, devices, drugs, etc.   They are developed to assist in administering plan benefits and constitute neither offers of coverage nor medical advice. Wellmark medical policies contain only a partial, general description of plan or program benefits and do not constitute a contract. Wellmark does not provide health care services and, therefore, cannot guarantee any results or outcomes. Participating providers are independent contractors in private practice and are neither employees nor agents of Wellmark or its affiliates. Treating providers are solely responsible for medical advice and treatment of members. Our medical policies may be updated and therefore are subject to change without notice.

 

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