Medical Policy

Policy Num:      11.003.136
Policy Name:    Tumor-informed Circulating Tumor DNA Testing for Cancer Management
Policy ID:          [11.003.136]  [Ac / B / M- / P-]  [2.04.153]

Last Review:      October 15, 2024
Next Review:      October 20, 2025
 

Related Policies: 

11.003.089 - Circulating Tumor DNA and Circulating Tumor Cells for Cancer Management (Liquid Biopsy)
11.003.135 - Germline and Somatic Biomarker Testing (Including Liquid Biopsy) for Targeted Treatment and Immunotherapy in Breast Cancer
11.003.009 - Somatic Biomarker Testing (Including Liquid Biopsy) for Targeted Treatment and Immunotherapy in Non-Small-Cell Lung Cancer (EGFR, ALK, BRAF, ROS1, RET, MET, KRAS, HER2, PD-L1, TMB)
11.003.004 - Somatic Biomarker Testing (Including Liquid Biopsy) for Targeted Treatment in Metastatic Colorectal Cancer (KRAS, NRAS, BRAF, and HER2)

Tumor-informed Circulating Tumor DNA Testing for Cancer Management

Summary

Description

This evidence review addresses the use of tumor-informed circulating tumor DNA (ctDNA) testing for cancer management. The purpose of tumor-informed ctDNA testing in individuals with cancer is to predict disease course to inform treatment decisions and to monitor for recurrence following treatment.

Summary of Evidence

For individuals with colorectal cancer (CRC) who receive tumor-informed circulating tumor DNA (ctDNA) testing with Signatera to guide treatment decisions and monitor for recurrence, the evidence includes a systematic review, 4 noncomparative studies (N = 1449), and 1 retrospective comparative study (N = 48). Relevant outcomes are overall survival, disease-specific survival, test validity, other test performance measures, change in disease status, morbid events, functional outcomes, health status measures, quality of life, and treatment-related mortality. The systematic review and nonrandomized studies have reported an association between ctDNA results measured at diagnosis, following surgery, during adjuvant therapy, and during surveillance after curative treatment and prognosis, but these studies are limited by a lack of comparison to tests used for the same purpose, imprecise estimates due to small sample sizes, and clinical heterogeneity of study populations. No study reported management changes made in response to ctDNA test results. A retrospective observational study found no advantage to surveillance with Signatera compared to standard surveillance conducted according to National Comprehensive Cancer Network (NCCN) guidelines (p>.99 for sensitivity and specificity compared to imaging). There is no direct evidence that the use of the test improves health outcomes, and indirect evidence is not sufficient to draw conclusions about clinical validity. The evidence is insufficient to determine that the technology results in an improvement in the net health outcome.

For individuals with breast cancer who receive tumor-informed ctDNA testing with Signatera to guide treatment decisions and monitor for recurrence, the evidence includes 2 noncomparative studies (N = 133). Relevant outcomes are overall survival, disease-specific survival, test validity, other test performance measures, change in disease status, morbid events, functional outcomes, health status measures, quality of life, and treatment-related mortality. One study evaluated Signatera testing for disease surveillance following primary treatment, and 1 reported the association of test results at different timepoints with response to neoadjuvant chemotherapy. Although the studies found an association of test results with prognosis, the studies are limited by a lack of comparison to tests used for the same purpose, imprecise estimates due to small sample sizes, and clinical heterogeneity of study populations. No study reported management changes made in response to ctDNA test results. There is no direct evidence that the use of the test improves health outcomes, and indirect evidence is not sufficient to draw conclusions about clinical validity. The evidence is insufficient to determine that the technology results in an improvement in the net health outcome.

For individuals with bladder cancer who receive tumor-informed ctDNA testing with Signatera to guide treatment decisions and monitor for recurrence, the evidence includes 1 uncontrolled prospective cohort study (N = 68), 1 retrospective cohort study (N = 102), and 1 retrospective subgroup analysis from a randomized controlled trial (N = 581). Relevant outcomes are overall survival, disease-specific survival, test validity, other test performance measure, change in disease status, morbid events, functional outcomes, health status measures, quality of life, and treatment-related mortality. The prospective study reported an association between Signatera test results at diagnosis, during chemotherapy treatment, and during surveillance following cystectomy to prognosis. The retrospective study reported an association between Signatera test results at diagnosis and during surveillance following cystectomy to prognosis; patients in this study did not receive chemotherapy. The retrospective subgroup analysis reported an association between test results and response to atezolizumab treatment. Study limitations, including a lack of comparison to tests used for the same purpose preclude drawing conclusions about clinical validity and usefulness. No study reported management changes made in response to ctDNA test results. There is no direct evidence that the use of the test improves health outcomes, and indirect evidence is not sufficient to draw conclusions about clinical validity. The evidence is insufficient to determine that the technology results in an improvement in the net health outcome.

For individuals with non-small cell lung cancer (NSCLC) who receive tumor-informed ctDNA testing with Signatera to guide treatment decisions and monitor for recurrence, the evidence includes 1 subgroup analysis of participants enrolled in a prospective observational study (N = 24). Relevant outcomes are overall survival, disease-specific survival, test validity, other test performance measures, change in disease status, morbid events, functional outcomes, health status measures, quality of life, and treatment-related mortality. Of 14 individuals with confirmed relapse, 13 (93%) had a positive ctDNA test (defined as at least 2 single-nucleotide variants detected). Of 10 individuals with no relapse after a median follow up of 775 days, (range 688 to 945 days), 1 had a positive ctDNA test (10%). This study’s small sample size and lack of a comparator preclude drawing conclusions about clinical validity. There is no direct evidence that the use of the test improves health outcomes, and indirect evidence is not sufficient to draw conclusions about clinical validity. The evidence is insufficient to determine that the technology results in an improvement in the net health outcome.

For individuals with esophageal cancer who receive tumor-informed ctDNA testing with Signatera to guide treatment decisions and monitor for recurrence, the evidence includes 1 noncomparative, retrospective study (N = 17). Relevant outcomes are overall survival, disease-specific survival, test validity, other test performance measure, change in disease status, morbid events, functional outcomes, health status measures, quality of life, and treatment-related mortality. Patients who were ctDNA-positive before surgery had significantly poorer disease-free survival (DFS) (p<.042), with a median DFS of 32.0 months versus 63.0 months in ctDNA-negative preoperative patients. This study was limited by its small number sample size and retrospective design. There is no direct evidence that the use of the test improves health outcomes. Due to the study's limitations and lack of additional supporting studies, the evidence is not sufficient to draw conclusions on clinical validity. Additionally, the management pathway for Signatera testing in esophageal cancer has not been clearly defined. The evidence is insufficient to determine that the technology results in an improvement in the net health outcome.

For individuals with solid tumors who receive tumor-informed ctDNA testing with Signatera to monitor response to immunotherapy, the evidence includes a subgroup analysis of individuals enrolled in a nonrandomized trial of pembrolizumab (N = 106). Relevant outcomes are overall survival, disease-specific survival, test validity, other test performance measures, change in disease status, morbid events, functional outcomes, health status measures, quality of life, and treatment-related mortality. The subgroup analysis evaluated Signatera testing to monitor response to immunotherapy in individuals with advanced solid tumors who were enrolled in a Phase II clinical trial of pembrolizumab. Lower-than-median ctDNA levels at baseline were associated with improved overall survival (adjusted hazard ratio [HR], 0.49; 95% confidence interval [CI], 0.29 to 0.83) and progression-free survival (adjusted HR, 0.54; 95% CI, 0.34 to 0.85). The study was limited by a small sample size, variability in results across different tumor types, and lack of a comparison to standard methods of monitoring response to treatment. There is no direct evidence that the use of the test improves health outcomes, and indirect evidence is not sufficient to draw conclusions about clinical validity. Additionally, the management pathway for Signatera testing for monitoring response to immunotherapy has not been clearly defined. The evidence is insufficient to determine that the technology results in an improvement in the net health outcome.

Additional Information

Not applicable.

Objective

The objective of this evidence review is to determine whether using tumor-informed circulating tumor DNA (ctDNA) testing improves the net health outcome in individuals with bladder, breast, colorectal, esophageal, or non-small cell lung cancer, or in individuals with solid tumors who are receiving immunotherapy.

Policy Statements

Tumor-informed circulating tumor DNA testing (e.g., Signatera) is considered investigational for all indications.

Policy Guidelines

Coding

See the Codes table for details.

Benefit Application

BlueCard/National Account Issues

Some Plans may have contract or benefit exclusions for genetic testing.

Benefits are determined by the group contract, member benefit booklet, and/or individual subscriber certificate in effect at the time services were rendered.  Benefit products or negotiated coverages may have all or some of the services discussed in this medical policy excluded from their coverage.

Background

The purpose of tumor-informed circulating tumor DNA (ctDNA) testing in individuals with cancer is to predict disease course to inform treatment decisions and to monitor for recurrence following treatment.

Signatera

Signatera is a tumor-specific ctDNA test. Tumor tissue obtained from either a diagnostic biopsy or surgically resected tissue is used to identify 16 single nucleotide variants found in the tumor but not in normal tissue and are likely to be present in all tumor cells regardless of tumor evolution. A custom assay of 16 tumor-specific clonal, somatic variants is generated for the individual and the resulting tumor signature can be monitored throughout the individual’s disease course. When the test is used for detection of recurrence following curative treatment, plasma samples with 2 or more out of these 16 variants detected above a predefined confidence threshold are deemed to be ctDNA-positive. When the test is used to monitor treatment response, evaluation is based on whether ctDNA levels increase or decrease from a baseline measurement. The test is intended to be used in conjunction with radiological assessment.

Regulatory Status

Signatera is a laboratory developed test regulated under CLIA. Signatera has been developed and its performance characteristics determined by Natera, the CLIA-certified laboratory performing the test. The test has not been cleared or approved by the US Food and Drug Administration (FDA), but has received 3 Breakthrough Device Designations from FDA:

• In May 2019, Signatera was granted a Breakthrough Device Designation (BDD) for the detection of ctDNA in localized or advanced colorectal cancer patients to optimize the use of chemotherapy alone or in combination with durvalumab.

• A March 2021 press release announced that FDA granted 2 additional BDDs covering new intended uses.^1,

Rationale

This evidence review was created in April 2022 with a search of the PubMed database. The most recent literature update was performed through July 23, 2024.

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

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 individuals receive correct therapy, or more effective therapy, or avoid unnecessary therapy, or avoid unnecessary testing.

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

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

Promotion of greater diversity and inclusion in clinical research of historically marginalized groups (e.g., People of Color [African-American, Asian, Black, Latino and Native American]; LGBTQIA (Lesbian, Gay, Bisexual, Transgender, Queer, Intersex, Asexual); Women; and People with Disabilities [Physical and Invisible]) allows policy populations to be more reflective of and findings more applicable to our diverse members. While we also strive to use inclusive language related to these groups in our policies, use of gender-specific nouns (e.g., women, men, sisters, etc.) will continue when reflective of language used in publications describing study populations.

Population Reference No. 1

Tumor-Informed Circulating Tumor DNA Testing with Signatera in Individuals with Colorectal Cancer

Clinical Context and Test Purpose

The purpose of Signatera testing in individuals who have colorectal cancer (CRC) is to inform treatment decisions and to monitor for recurrence following curative treatment.

The following PICO was used to select literature to inform this review.

Populations

The relevant populations of interest are individuals:

• With stage II or III CRC who have undergone surgical resection, or

• Who are being monitored for relapse following treatment for stage II or III CRC , or

• With metastatic (stage IV) CRC who have undergone surgical resection and are being evaluated for adjuvant chemotherapy and/or targeted therapy.

Interventions

The test being considered is circulating tumor DNA (ctDNA) testing with Signatera:

• Following surgery, to inform decisions about adjuvant chemotherapy or targeted therapy, or

• During disease surveillance after curative treatment, to identify metastatic relapse at an early timepoint, and aid in the selection of individuals who may benefit from early/adjuvant treatment.

Comparators

For individuals with stage II CRC , the current standard of care is not to routinely administer adjuvant chemotherapy. However, current National Comprehensive Cancer Network (NCCN) guidelines are that adjuvant chemotherapy can be considered in individuals with stage II CRC , using clinicopathologic characteristics to identify individuals who might benefit.

For individuals with stage III CRC , the current standard of care is to administer adjuvant chemotherapy routinely.

For individuals who are being monitored for relapse following treatment for stage II or III CRC , guidelines suggest monitoring carcinoembryonic antigen (CEA) every 3 to 6 months for 2 years, then every 6 months for a total of 5 years, as well as imaging every 6 to 12 months for 5 years.

For individuals with metastatic CRC who have undergone surgical resection, the current standard of care is routine individual checkups, periodic computed tomography scans, and monitoring of CEA level.

Outcomes

The general outcomes of interest are disease-specific survival, test accuracy and validity, and change in disease status. Specific outcomes of interest are recurrence risk, recurrence-free survival (RFS), and overall survival at follow-up.

Given that the majority of CRC recurrences occur within the first 3 years after surgical resection of the primary tumor and approximately 95% in the first 5 years, the timepoint of interest to assess recurrence is 3 to 5 years following surgical resection.

For individuals with stage II CRC who are being evaluated for adjuvant chemotherapy, given that the test will be used to rule-in stage II individuals for adjuvant chemotherapy, the performance characteristics of most interest are positive predictive value and specificity.

For individuals with stage III CRC who are being evaluated for adjuvant chemotherapy, given that the test will be used to rule-out individuals for adjuvant chemotherapy, the performance characteristics of most interest are negative predictive value and sensitivity. However, since the test would be used to select individuals who would not receive category 1 recommended treatment, direct evidence of improvement in outcomes is required. For individuals who are being monitored for relapse following treatment for CRC , recurrence at 3 to 5 years should be assessed.

Study Selection Criteria

For the evaluation of clinical validity of the Signatera test, studies that meet the following eligibility criteria were considered:

• Reported on the accuracy of the marketed version of the technology

• Included a suitable reference standard

• Individual/sample clinical characteristics were described

• Individual/sample selection criteria were described.

Systematic Reviews

Chidharla et al (2023) published a systematic review of 23 studies (N = 3568) investigating the use of ctDNA as a biomarker for minimal residual disease in patients with CRC after curative-intent surgery; only 3 of the included studies used the Signatera ctDNA assay and are described in more detail in the section below (Henriksen et al [2022]; Loupakis et al [2021]; Kotani et al [2023]).^2, The results of this analysis demonstrated that ctDNA positivity after surgery was associated with a significantly higher risk of recurrence, with a pooled hazard ratio (HR) of 7.27 for all stages of CRC. Furthermore, post-adjuvant chemotherapy ctDNA positivity was associated with an even higher risk of recurrence (pooled HR, 10.59).

Nonrandomized Trials

Five nonrandomized studies, 4 of which were noncomparative, examined the association of Signatera testing to prognosis in individuals with CRC (Table 1). They differed in their study designs, populations (e.g., stage of disease), frequency and timing of standard care, outcome measures, and timing of follow up. Three studies evaluated the association between positive ctDNA results and prognosis in CRC (Table 2). These studies did not provide comparisons of ctDNA testing to standard methods of risk stratification for therapy selection, monitoring response to therapy, or early relapse detection. One retrospective study compared Signatera testing to other surveillance strategies in individuals with resected CRC.^3, There are no RCTs, and no studies in which Signatera testing was used to guide treatment decisions.

Reinert et al (2019) enrolled 125 individuals with stage I to III CRC in a validation study of the Signatera assay.^4, Plasma samples were collected before surgery, at 30 days following surgery, and every 3 months for up to 3 years. The recurrence rate at 3 years was 70% in individuals with a positive ctDNA test (7 of 10) compared to 11.9% (10 of 84) of those with a negative ctDNA test. In multivariate analyses, ctDNA status was associated with recurrence after adjusting for clinicopathological risk factors including stage, lymphovascular invasion, and microradical resection status.

Henriksen et al (2022) assessed the added benefit of serial ctDNA analysis; with samples taken at diagnosis, following surgery, during adjuvant therapy, and at follow up.^5,

Loupakis et al (2021) evaluated the association of ctDNA with Signatera on survival outcomes in 112 individuals who had undergone resection for metastatic (stage IV) CRC.^6, The study included an analysis of the sensitivity of Signatera testing to digital droplet polymerase chain reaction (PCR) testing but not to standard methods to identify recurrence, such as CEA and imaging.

Fakih et al (2022) directly compared Signatera testing to other surveillance strategies in individuals with resected CRC in a retrospective observational study (Table 3).^3, This study was unique in that it used NCCN recommended guidelines for surveillance and ctDNA testing was performed at the same interval as standard surveillance with CEA and imaging. Test characteristics for Signatera were not significantly different from standard imaging techniques. Estimates were imprecise, with wide confidence intervals.

Kotani et al (2023) analyzed presurgical and postsurgical ctDNA levels in a large (N = 1039) prospective study that included patients with stage II to IV resectable CRC.^7, After a median follow-up of 16.74 months, postsurgical ctDNA positivity at 4 weeks after surgery was associated with a significantly higher risk of recurrence (HR, 10.0; 95% CI, 7.7 to 14; p<.0001), and identified patients with high-risk stage II or III CRC who derived a benefit from adjuvant chemotherapy (HR, 6.59; 95% CI, 3.53 to 12.3; p<.0001). For both outcomes, trends were observed across all pathological stages evaluated.

Study limitations are shown in Tables 4 and 5. Major limitations include a lack of comparison to tests used for the same purpose, imprecise estimates due to small sample sizes, and clinical heterogeneity of study populations.

Table 1. Nonrandomized Studies of Signatera Testing in Colorectal Cancer - Study Characteristics

Table 3. Retrospective Comparison of Signatera to Other Surveillance Strategies in Resected Colorectal Cancer

Table 5. Study Design and Conduct Limitations

Section Summary: Tumor-Informed Circulating Tumor DNA Testing with Signatera in Individuals with Colorectal Cancer

For individuals with CRC who receive tumor-informed ctDNA testing with Signatera to guide treatment decisions and monitor for recurrence, the evidence includes a systematic review and 4 noncomparative studies (N = 1,449 ) and 1 retrospective comparative study (N = 48). The systematic review and nonrandomized studies have reported an association between ctDNA results measured at diagnosis, following surgery, during adjuvant therapy, and during surveillance after curative treatment and prognosis, but these studies are limited by a lack of comparison to tests used for the same purpose, imprecise estimates due to small sample sizes, and clinical heterogeneity of study populations. No study reported management changes made in response to ctDNA test results. A retrospective observational study found no advantage to surveillance with Signatera compared to standard surveillance conducted according to NCCN guidelines (p>.99 for sensitivity and specificity compared to imaging). There is no direct evidence that the use of the test improves health outcomes, and indirect evidence is not sufficient to draw conclusions about clinical validity.

For individuals with colorectal cancer (CRC) who receive tumor-informed circulating tumor DNA (ctDNA) testing with Signatera to guide treatment decisions and monitor for recurrence, the evidence includes a systematic review, 4 noncomparative studies (N = 1449), and 1 retrospective comparative study (N = 48). Relevant outcomes are overall survival, disease-specific survival, test validity, other test performance measures, change in disease status, morbid events, functional outcomes, health status measures, quality of life, and treatment-related mortality. The systematic review and nonrandomized studies have reported an association between ctDNA results measured at diagnosis, following surgery, during adjuvant therapy, and during surveillance after curative treatment and prognosis, but these studies are limited by a lack of comparison to tests used for the same purpose, imprecise estimates due to small sample sizes, and clinical heterogeneity of study populations. No study reported management changes made in response to ctDNA test results. A retrospective observational study found no advantage to surveillance with Signatera compared to standard surveillance conducted according to NCCN guidelines (p>.99 for sensitivity and specificity compared to imaging). There is no direct evidence that the use of the test improves health outcomes, and indirect evidence is not sufficient to draw conclusions about clinical validity. The evidence is insufficient to determine that the technology results in an improvement in the net health outcome.

 Population Reference No. 2

Tumor-Informed Circulating Tumor DNA Testing with Signatera in Individuals with Breast Cancer

Clinical Context and Test Purpose

The purpose of Signatera testing in individuals with breast cancer is to predict disease course (e.g., aggressiveness, risk of recurrence, death) and inform treatment decisions, and to monitor for recurrence following curative treatment.

The following PICO was used to select literature to inform this review.

Populations

The population of interest is individuals with breast cancer, or those who have been treated for breast cancer and are being monitored for recurrence.

Interventions

The test being considered is ctDNA testing with Signatera:

• At diagnosis to inform decisions about neoadjuvant chemotherapy, or

• After surgery to inform decisions about adjuvant treatment, or

• Following curative treatment, to monitor for recurrence.

Comparators

• Decisions about neoadjuvant and adjuvant chemotherapy are based on clinicopathological risk factors.

• Guidelines for disease surveillance following breast cancer treatment recommend regular imaging and physical examinations, and additional testing upon presentation of symptoms.

Outcomes

The general outcomes of interest are disease-specific survival, test accuracy and validity, and change in disease status. Specific outcomes of interest are recurrence risk, RFS, and overall survival at follow-up.

The specific outcomes of interest depend on the proposed purpose of testing in individuals with breast cancer.

• If used for risk stratification to rule-out individuals for neoadjuvant chemotherapy at diagnosis or adjuvant treatment following surgery, the performance characteristics of most interest are negative predictive value and sensitivity.

• If used for risk stratification to to rule-in individuals for neoadjuvant chemotherapy at diagnosis or adjuvant treatment following surgery, the performance characteristics of most interest are positive predictive value and specificity.

If used for disease surveillance following primary treatment, beneficial outcomes of a true positive test would be earlier detection of metastasis and initiation of treatment. Harmful outcomes of a false positive test would be undergoing unnecessary or incorrect treatment, and experiencing adverse effects of such treatment.

See also Evidence review 2.04.36 for additional discussion of outcomes in breast cancer risk assessment studies.

Study Selection Criteria

For the evaluation of clinical validity of the Signatera test, studies that meet the following eligibility criteria were considered:

• Reported on the accuracy of the marketed version of the technology

• Included a suitable reference standard

• Individual/sample clinical characteristics were described

• Individual/sample selection criteria were described.

Nonrandomized Trials

Two noncomparative studies reported the association of Signatera testing with survival outcomes in breast cancer (Table 6). There are no RCTs, and no studies in which Signatera testing was used to guide treatment decisions.

Coombes et al (2019) evaluated Signatera for disease surveillance in 49 individuals who had received surgery and adjuvant therapy for stage I to III breast cancer of various subtypes.^8, Signatera detected ctDNA in 16 of 18 individuals who subsequently relapsed, and the presence of ctDNA test was associated with poorer prognosis (Table 7).

Magbanua et al (2021) evaluated ctDNA clearance as a predictor of response to neoadjuvant chemotherapy (NAC) in 84 individuals with nonmetastatic breast cancer who were enrolled in the I-SPY2 trial.^9, In the population as a whole, ctDNA positivity decreased during the course of NAC, from 73% before treatment (T0), to 35% at 3 weeks (T1), to 14% at the inter-regimen time point (T2), and down to 9% after NAC (T3). Hazard ratios for recurrence at each of these timepoints are shown in Table 7 and indicate that positive predictive value increased over time.

Study limitations are shown in Tables 8 and 9. Major limitations of both studies include a lack of comparison to standard methods of monitoring, and heterogeneity in the study populations.

Table 6. Nonrandomized Studies of Signatera Testing in Breast Cancer - Study Characteristics

Table 9. Study Design and Conduct Limitations

Section Summary: Tumor-Informed Circulating Tumor DNA Testing with Signatera in Individuals with Breast Cancer

For individuals with breast cancer who receive tumor-informed ctDNA testing with Signatera to guide treatment decisions and monitor for recurrence, the evidence includes 2 noncomparative studies (N = 133). One study evaluated Signatera testing for disease surveillance following primary treatment, and 1 reported the association of test results at different timepoints with response to neoadjuvant chemotherapy. Although the studies found an association of test results with prognosis, the studies are limited by a lack of comparison to tests used for the same purpose, imprecise estimates due to small sample sizes, and clinical heterogeneity of study populations. No study reported management changes made in response to ctDNA test results. There is no direct evidence that the use of the test improves health outcomes, and indirect evidence is not sufficient to draw conclusions about clinical validity.

For individuals with breast cancer who receive tumor-informed ctDNA testing with Signatera to guide treatment decisions and monitor for recurrence, the evidence includes 2 noncomparative studies (N = 133). Relevant outcomes are overall survival, disease-specific survival, test validity, other test performance measures, change in disease status, morbid events, functional outcomes, health status measures, quality of life, and treatment-related mortality. One study evaluated Signatera testing for disease surveillance following primary treatment, and 1 reported the association of test results at different timepoints with response to neoadjuvant chemotherapy. Although the studies found an association of test results with prognosis, the studies are limited by a lack of comparison to tests used for the same purpose, imprecise estimates due to small sample sizes, and clinical heterogeneity of study populations. No study reported management changes made in response to ctDNA test results. There is no direct evidence that the use of the test improves health outcomes, and indirect evidence is not sufficient to draw conclusions about clinical validity. The evidence is insufficient to determine that the technology results in an improvement in the net health outcome. 

Population Reference No. 3

Tumor-Informed Circulating Tumor DNA Testing with Signatera in Individuals with Bladder Cancer

Clinical Context and Test Purpose

The purpose of Signatera testing in individuals with bladder cancer is to predict disease course to inform treatment decisions and to monitor for recurrence following curative treatment.

The following PICO was used to select literature to inform this review.

Populations

The relevant population of interest is individuals with bladder cancer, or those who have been treated for bladder cancer and are being monitored for recurrence.

Interventions

The test being considered is ctDNA testing with Signatera:

• At diagnosis, to identify individuals at low risk of recurrence after cystectomy who may be eligible for cystectomy without neoadjuvant chemotherapy, or

• After chemotherapy before cystectomy, to determine treatment response and inform treatment decisions (e.g., additional cycles of chemotherapy or other therapeutic strategies), or

• During disease surveillance after cystectomy, to identify metastatic relapse after cystectomy at an early time point, and aid in the selection of individuals who may benefit from early/adjuvant treatment. For individuals with bladder cancer who are being evaluated for adjuvant chemotherapy, given that the test will be used to rule-in individuals for adjuvant chemotherapy, the performance characteristics of most interest are positive predictive value and specificity.

Comparators

• Urine testing, cystoscopy, and radiographic imaging are used for disease monitoring in individuals with bladder cancer.

• Detection of relapse and monitoring of response to treatment in the metastatic setting is performed by standard computed tomography scan.

Outcomes

The general outcomes of interest are disease-specific survival, test accuracy and validity, and change in disease status. Specific outcomes of interest are recurrence risk, RFS, and overall survival at follow-up.

If used to rule in individuals with bladder cancer who would be likely to benefit from adjuvant chemotherapy, the performance characteristics of most interest are positive predictive value and specificity.

If used to rule out patients with bladder cancer who could forego adjuvant chemotherapy, the performance characteristics of most interest are negative predictive value and sensitivity. However, since the test would be used to select individuals who would not receive category 1 recommended treatment, direct evidence of improvement in outcomes is required.

Study Selection Criteria

For the evaluation of clinical validity of the Signatera test, studies that meet the following eligibility criteria were considered:

• Reported on the accuracy of the marketed version of the technology

• Included a suitable reference standard

• Individual/sample clinical characteristics were described

• Individual/sample selection criteria were described.

Nonrandomized Trials

Two nonrandomized studies have reported an association between Signatera testing and prognosis in bladder cancer (Tables 10 and 11).

Christensen et al (2019) assessed the association of ctDNA with prognosis in 68 individuals with localized advanced bladder cancer who were receiving neoadjuvant chemotherapy before cystectomy (median follow-up of 21 months).^10, Data from a 68-month follow-up of this cohort were reported by Lindskrog et al (2023).^11, Additionally, Lingskrog et al (2023) reported on the association of ctDNA with prognosis in a separate cohort of 102 patients who did not receive neoadjuvant chemotherapy and had ctDNA testing before and after cystectomy (median follow-up of 72 months). Results demonstrated that ctDNA was prognostic regardless of whether or not patients received neoadjuvant chemotherapy before cystectomy.

Powles et al (2021) reported the association of a positive Signatera test to treatment response in 581 individuals who had undergone surgery for urothelial cancer and were enrolled in a RCT of atezolizumab versus observation.^12, Study participants who were positive for ctDNA had improved disease-free survival (DFS) and overall survival in the atezolizumab arm versus the observation arm (DFS HR, 0.58 [95% CI, 0.43 to 0.79]; p=.0024 and overall survival HR, 0.59 [95% CI, 0.41 to 0.86]). No difference in DFS or overall survival between treatment arms was noted for patients who were negative for ctDNA. At 2-year follow up, ctDNA status remained prognostic and no relapses were observed in the ctDNA-negative patients at baseline and after neoadjuvant therapy.^13,

The major limitation of these studies was lack of comparison to other tests used for the same purpose (Tables 12 and 13).

Table 10. Nonrandomized Studies of Signatera Testing in Bladder Cancer - Study Characteristics

Table 13. Study Design and Conduct Limitations

Section Summary: Tumor-Informed Circulating Tumor DNA Testing with Signatera in Individuals with Bladder Cancer

For individuals with bladder cancer who receive tumor-informed ctDNA testing with Signatera to guide treatment decisions and monitor for recurrence, the evidence includes 1 uncontrolled prospective cohort study (N = 68), 1 retrospective cohort study (N = 102), and 1 retrospective subgroup analysis from a RCT (N = 581). The prospective study reported an association between Signatera test results at diagnosis, during chemotherapy treatment, and during surveillance following cystectomy to prognosis. The retrospective study reported an association between Signatera test results at diagnosis and during surveillance following cystectomy to prognosis; patients in this study did not receive chemotherapy. The retrospective subgroup analysis reported an association between test results and response to atezolizumab treatment. Study limitations, including a lack of comparison to tests used for the same purpose preclude drawing conclusions about clinical validity and usefulness. No study reported management changes made in response to ctDNA test results. There is no direct evidence that the use of the test improves health outcomes, and indirect evidence is not sufficient to draw conclusions about clinical validity.

For individuals with bladder cancer who receive tumor-informed ctDNA testing with Signatera to guide treatment decisions and monitor for recurrence, the evidence includes 1 uncontrolled prospective cohort study (N = 68) and 1 retrospective subgroup analysis from a randomized controlled trial (N = 581). Relevant outcomes are overall survival, disease-specific survival, test validity, other test performance measure, change in disease status, morbid events, functional outcomes, health status measures, quality of life, and treatment-related mortality. The prospective study reported an association between Signatera test results at diagnosis, during chemotherapy treatment, and during surveillance following cystectomy to prognosis. The retrospective analysis reported an association between test results and response to atezolizumab treatment. Study limitations, including a lack of comparison to tests used for the same purpose preclude drawing conclusions about clinical validity and usefulness. No study reported management changes made in response to ctDNA test results. There is no direct evidence that the use of the test improves health outcomes, and indirect evidence is not sufficient to draw conclusions about clinical validity. The evidence is insufficient to determine that the technology results in an improvement in the net health outcome.

Population Reference No. 4 

Tumor-Informed Circulating Tumor DNA Testing with Signatera in Individuals with Non-Small Cell Lung Cancer

Clinical Context and Test Purpose

The purpose of Signatera testing in individuals with non-small cell lung cancer (NSCLC) is to predict disease course to inform treatment decisions and to monitor for recurrence following surgical resection.

The following PICO was used to select literature to inform this review.

Populations

The relevant population of interest is individuals with NSCLC, or those who have been treated for NSCLC and are being monitored for recurrence.

Interventions

The test being considered is ctDNA testing with Signatera following surgical resection, to identify metastatic relapse at an early time point, and aid in the selection of individuals who may benefit from early/adjuvant treatment.

Adjuvant platinum-based chemotherapy is not the standard of care following surgery for NSCLC; treatment improves cure rates after surgery in only 5% of patients, and 20% of patients receiving chemotherapy experience acute toxicities. Signatera testing is proposed to select patients who are very likely to relapse post-operatively and who might benefit from adjuvant treatment.

Comparators

Radiographic imaging is used for disease monitoring in individuals with NSCLC. Detection of relapse and monitoring of response to treatment in the metastatic setting is performed by standard computed tomography scan, with frequency and type of imaging depending on primary treatment and stage. For patients with stage I-II NSCLC following completion of definitive therapy, NCCN guidelines recommend history and physical and chest computed tomography every 6 months for 2 to 3 years, then annually. For patients with primary treatment that included radiotherapy, surveillance is recommended every 3 to 6 months for 3 years, and every 6 months for 2 years, then annually. Treatment options following recurrence include resection and/or systemic therapy.

Outcomes

The general outcomes of interest are disease-specific survival, test accuracy and validity, and change in disease status. Specific outcomes of interest are recurrence risk, RFS, and overall survival at follow-up.

Beneficial outcomes of a true positive test would be an individual undergoing potentially beneficial additional treatment such as chemotherapy at an earlier time point than if a relapse were identified clinically.

Harmful outcomes of a false positive test would be undergoing unnecessary or incorrect treatment, and experiencing adverse effects of such treatment.

Nonrandomized Trial

The evidence for the use of Signatera to detect relapse in NSCLC following surgery is limited to a subgroup analysis of 24 individuals enrolled in TRACERx, a longitudinal cohort study of tumor sampling and genetic analysis in individuals with NSCLC.^14, Of 14 individuals with confirmed relapse, 13 (93%) had a positive ctDNA test (defined as at least 2 single-nucleotide variants detected). Of 10 individuals with no relapse after a median follow up of 775 days, (range 688 to 945 days), 1 had a positive ctDNA test (10%).

Study limitations are shown in Tables 15 and 16. Major limitations include no comparison to standard surveillance methods and imprecise estimates due to the small sample size. Additionally, the commercially available Signatera has been updated since this publication.

Table 14. Nonrandomized Study of Signatera Testing in Non-Small Cell Lung Cancer

Table 16. Study Design and Conduct Limitations

Section Summary: Tumor-Informed Circulating Tumor DNA Testing with Signatera in Individuals with Non-Small Cell Lung Cancer

For individuals with NSCLC who receive tumor-informed ctDNA testing with Signatera to guide treatment decisions and monitor for recurrence, the evidence includes 1 subgroup analysis of participants enrolled in a prospective observational study (N = 24). Of 14 individuals with confirmed relapse, 13 (93%) had a positive ctDNA test (defined as at least 2 single-nucleotide variants detected). Of 10 individuals with no relapse after a median follow up of 775 days, (range 688 to 945 days), 1 had a positive ctDNA test (10%). This study’s small sample size and lack of a comparator preclude drawing conclusions about clinical validity. There is no direct evidence that the use of the test improves health outcomes, and indirect evidence is not sufficient to draw conclusions about clinical validity.

For individuals with NSCLC who receive tumor-informed ctDNA testing with Signatera to guide treatment decisions and monitor for recurrence, the evidence includes 1 subgroup analysis of participants enrolled in a prospective observational study (N = 24). Relevant outcomes are overall survival, disease-specific survival, test validity, other test performance measures, change in disease status, morbid events, functional outcomes, health status measures, quality of life, and treatment-related mortality. Of 14 individuals with confirmed relapse, 13 (93%) had a positive ctDNA test (defined as at least 2 single-nucleotide variants detected). Of 10 individuals with no relapse after a median follow up of 775 days, (range 688 to 945 days), 1 had a positive ctDNA test (10%). This study’s small sample size and lack of a comparator preclude drawing conclusions about clinical validity. There is no direct evidence that the use of the test improves health outcomes, and indirect evidence is not sufficient to draw conclusions about clinical validity. The evidence is insufficient to determine that the technology results in an improvement in the net health outcome.

Population Reference No. 5

Tumor-Informed Circulating Tumor DNA Testing with Signatera in Individuals with Esophageal Cancer

Clinical Context and Test Purpose

The purpose of Signatera testing in individuals with esophageal cancer is to detect minimal residual disease following surgical resection and to monitor for disease recurrence.

The following PICO was used to select literature to inform this review.

Populations

The relevant population of interest is individuals with esophageal cancer who have undergone surgical resection.

Interventions

The test being considered is ctDNA testing with Signatera:

• Following surgical resection, to detect minimal residual disease and aid in the selection of individuals who may benefit from early/adjuvant treatment, or

• For disease monitoring after curative treatment, to identify metastatic relapse at an early time point, and aid in the selection of individuals who may benefit from early/adjuvant treatment.

Comparators

Recommendations on surveillance and monitoring following esophageal cancer treatment include periodic upper endoscopy, laboratory tests, and imaging as indicated. Specific recommendations depend on tumor classification.

Outcomes

The general outcomes of interest are disease-specific survival, test accuracy and validity, and change in disease status. Specific outcomes of interest are recurrence risk, RFS, and overall survival at follow-up.

Beneficial outcomes of a true positive test would be an individual undergoing potentially beneficial additional treatment at an earlier time point than if a relapse were identified clinically.

Harmful outcomes of a false positive test would be undergoing unnecessary or incorrect treatment and experiencing adverse effects of such treatment.

Study Selection Criteria

For the evaluation of clinical validity of the Signatera test, studies that meet the following eligibility criteria were considered:

• Reported on the accuracy of the marketed version of the technology

• Included a suitable reference standard

• Individual/sample clinical characteristics were described

• Individual/sample selection criteria were described.

Nonrandomized Trial

One noncomparative retrospective study reported the association of Signatera testing measured before and after surgery with relapse and recurrence in 17 individuals with esophageal adenocarcinoma (Tables 17 and 18). Patients who were ctDNA-positive before surgery had significantly poorer DFS (p<.042), with a median DFS of 32.0 months vs. 63.0 months in ctDNA-negative preoperative patients. This study was limited by the very small number sample size, and its retrospective design (Tables 19 and 20).

Table 17. Nonrandomized Study of Signatera Testing to Predict Relapse in Esophageal Cancer - Study Characteristics

Table 18. Recurrence Rates by Risk Category in Nonrandomized Studies of Signatera in Resected Esophageal Cancer

Table 20. Study Design and Conduct Limitations

Section Summary: Tumor-Informed Circulating Tumor DNA Testing with Signatera in Individuals with Esophageal Cancer

For individuals with esophageal cancer who receive tumor-informed ctDNA testing with Signatera to guide treatment decisions and monitor for recurrence, the evidence includes 1 noncomparative, retrospective study (N = 17). Patients who were ctDNA-positive before surgery had significantly poorer DFS (p<.042), with a median DFS of 32.0 months versus 63.0 months in ctDNA-negative preoperative patients. This study was limited by its small number sample size and retrospective design. There is no direct evidence that the use of the test improves health outcomes. Due to the study's limitations and lack of additional supporting studies, the evidence is not sufficient to draw conclusions on clinical validity. Additionally, the management pathway for Signatera testing in esophageal cancer has not been clearly defined.

For individuals with esophageal cancer who receive tumor-informed ctDNA testing with Signatera to guide treatment decisions and monitor for recurrence, the evidence includes 1 noncomparative, retrospective study (N = 17). Relevant outcomes are overall survival, disease-specific survival, test validity, other test performance measure, change in disease status, morbid events, functional outcomes, health status measures, quality of life, and treatment-related mortality. Patients who were ctDNA-positive before surgery had significantly poorer disease-free survival (DFS) (p<.042), with a median DFS of 32.0 months versus 63.0 months in ctDNA-negative preoperative patients. This study was limited by its small number sample size and retrospective design. There is no direct evidence that the use of the test improves health outcomes. Due to the study's limitations and lack of additional supporting studies, the evidence is not sufficient to draw conclusions on clinical validity. Additionally, the management pathway for Signatera testing in esophageal cancer has not been clearly defined. The evidence is insufficient to determine that the technology results in an improvement in the net health outcome.

Population Reference No. 6

Tumor-Informed Circulating Tumor DNA Testing with Signatera in Individuals with Solid Tumors Receiving Immunotherapy

Clinical Context and Test Purpose

The purpose of Signatera testing in individuals with solid tumors who have received immunotherapy is to monitor treatment response and inform subsequent treatment decisions. Signatera is proposed as a method to stratify patients according to their likelihood of response to immunotherapy, to guide treatment decisions.

The following PICO was used to select literature to inform this review.

Populations

The relevant population of interest is individuals with solid tumors who have received immune checkpoint inhibitor (ICI) therapy.

Interventions

The test being considered is ctDNA testing with Signatera.

Comparators

For individuals with solid tumors receiving immunotherapy, treatment response is monitored by repeated radiographic evaluation of the tumor.

Outcomes

The general outcomes of interest are disease-specific survival, test accuracy and validity, and change in disease status. Specific outcomes of interest are recurrence risk, RFS, and overall survival at follow-up.

If the test is used to rule-in individuals with solid tumors who are likely to respond to immunotherapy, the performance characteristics of most interest are positive predictive value and specificity.

If the test is used to rule-out individuals with solid tumors who are unlikely to respond to immunotherapy, the performance characteristics of most interest are negative predictive value and sensitivity.

Study Selection Criteria

For the evaluation of clinical validity of the Signatera test, studies that meet the following eligibility criteria were considered:

• Reported on the accuracy of the marketed version of the technology

• Included a suitable reference standard

• Individual/sample clinical characteristics were described

• Individual/sample selection criteria were described.

Nonrandomized Trial

Bratman et al (2020) evaluated Signatera to predict treatment response in 106 individuals receiving pembrolizumab for solid tumors, including squamous cell cancer of head and neck, triple negative breast cancer, high-grade serous ovarian cancer, malignant melanoma, and mixed solid tumors (Tables 21 and 22).^16,

Lower-than-median ctDNA levels at baseline were associated with improved overall survival (adjusted HR , 0.49; 95% CI, 0.29 to 0.83) and progression-free survival (PFS) (adjusted HR, 0.54; 95% CI, 0.34 to 0.85). Among participants with at least 2 ctDNA measurements, any rise in ctDNA levels during surveillance above baseline was associated with rapid disease progression and poor survival (median overall survival, 13.7 months), whereas among 12 patients whose ctDNA cleared during treatment, overall survival was 100% at a median follow up of 25.4 months (range, 10.8 to 29.5 months) following the first clearance.

Study limitations are shown in Tables 23 and 24. This single-center study is limited by its small sample size and variability in results across different tumor types. The study did not include a comparison of monitoring with ctDNA to standard methods of monitoring response such as repeat imaging.

Table 21. Nonrandomized Study of Signatera Testing to Predict Response to Immunotherapy in Individuals with Solid Tumors - Study Characteristics

Table 24. Study Design and Conduct Limitations

Section Summary: Tumor-Informed Circulating Tumor DNA Testing with Signatera in Individuals with Solid Tumors Receiving Immunotherapy

For individuals with solid tumors who receive tumor-informed ctDNA testing with Signatera to monitor response to immunotherapy, the evidence includes a subgroup analysis of individuals enrolled in a nonrandomized trial of pembrolizumab (N = 106). The subgroup analysis evaluated Signatera testing to monitor response to immunotherapy in individuals with advanced solid tumors who were enrolled in a Phase II clinical trial of pembrolizumab. Lower-than-median ctDNA levels at baseline were associated with improved overall survival (adjusted HR, 0.49; 95% CI, 0.29 to 0.83) and PFS (adjusted HR, 0.54; 95% CI, 0.34 to 0.85). The study was limited by a small sample size, variability in results across different tumor types, and lack of a comparison to standard methods of monitoring response to treatment. There is no direct evidence that the use of the test improves health outcomes, and indirect evidence is not sufficient to draw conclusions about clinical validity. Additionally, the management pathway for Signatera testing for monitoring response to immunotherapy has not been clearly defined.

For individuals with solid tumors who receive tumor-informed ctDNA testing with Signatera to monitor response to immunotherapy, the evidence includes a subgroup analysis of individuals enrolled in a nonrandomized trial of pembrolizumab (N = 106). Relevant outcomes are overall survival, disease-specific survival, test validity, other test performance measures, change in disease status, morbid events, functional outcomes, health status measures, quality of life, and treatment-related mortality. The subgroup analysis evaluated Signatera testing to monitor response to immunotherapy in individuals with advanced solid tumors who were enrolled in a Phase II clinical trial of pembrolizumab. Lower-than-median ctDNA levels at baseline were associated with improved overall survival (adjusted hazard ratio [HR], 0.49; 95% confidence interval [CI], 0.29 to 0.83) and progression-free survival (adjusted HR, 0.54; 95% CI, 0.34 to 0.85). The study was limited by a small sample size, variability in results across different tumor types, and lack of a comparison to standard methods of monitoring response to treatment. There is no direct evidence that the use of the test improves health outcomes, and indirect evidence is not sufficient to draw conclusions about clinical validity. Additionally, the management pathway for Signatera testing for monitoring response to immunotherapy has not been clearly defined. The evidence is insufficient to determine that the technology results in an improvement in the net health outcome.

Supplemental Information

The purpose of the following information is to provide reference material. Inclusion does not imply endorsement or alignment with the evidence review conclusions.

Practice Guidelines and Position Statements

Guidelines or position statements will be considered for inclusion in ‘Supplemental Information' if they were issued by, or jointly by, a US professional society, an international society with US representation, or National Institute for Health and Care Excellence (NICE). Priority will be given to guidelines that are informed by a systematic review, include strength of evidence ratings, and include a description of management of conflict of interest.

American Society of Clinical Oncology

The American Society of Clinical Oncology (ASCO) 2022 guideline update on biomarkers for systemic therapy in metastatic breast cancer (MBC) does not recommend the use of circulating tumor DNA (ctDNA) as a biomarker to monitor the response to therapy (Type of recommendation: informal consensus-based; Quality of evidence: low; Strength of recommendation: moderate). The guidelines also provide the following recommendations:

• "Patients with locally recurrent unresectable or metastatic hormone receptor-positive and human epidermal growth factor receptor 2 (HER2)-negative breast cancer who are candidates for a treatment regimen that includes a phosphatidylinositol 3-kinase inhibitor and hormonal therapy should undergo testing for PIK3CA mutations using next-generation sequencing of tumor tissue or circulating tumor DNA (ctDNA) in plasma to determine their eligibility for treatment with the phosphatidylinositol 3-kinase inhibitor alpelisib plus fulvestrant. If no mutation is found in ctDNA, testing in tumor tissue, if available, should be used as this will detect a small number of additional patients with PIK3CA mutations (Type: evidence-based, benefits outweigh harms; Evidence quality: high; Strength of recommendation: strong)."

• "There are insufficient data at present to recommend routine testing for ESR1 mutations to guide therapy for hormone receptor-positive, HER2-negative MBC. Existing data suggest reduced efficacy of aromatase inhibitors (AIs) compared with the selective estrogen receptor degrader fulvestrant in patients who have tumor or ctDNA with ESR1 mutations (Type: informal consensus; Evidence quality: insufficient; Strength of recommendation: moderate)."

• "There are insufficient data to recommend routine use of ctDNA to monitor response to therapy among patients with MBC (Type: informal consensus; Evidence quality: low; Strength of recommendation: moderate)."

National Comprehensive Cancer Network

National Comprehensive Cancer Network (NCCN) guidelines either do not specifically address tumor-informed ctDNA testing for the cancer types included in this review, or do not provide specific recommendations for use.

The guideline on colon cancer states: "The panel believes that there are insufficient data to recommend the use of...post-surgical ctDNA to estimate risk of recurrence or determine adjuvant therapy...The NCCN Panel encourages enrollment in clinical trials to help with the generation of additional data on these assays."^17,

The guideline on breast cancer states that for recurrent/stage IV disease: "Tissue or plasma-based circulating tumor DNA (ctDNA) assays may be used and each of these have benefits and limitations for diagnosis and disease progression. Tissue-based assays have greater sensitivity, but ctDNA may reflect tumor heterogeneity more accurately. If one specimen is negative for actionable biomarkers, testing on the alternative specimen can be considered." Additionally, "For HR-positive/HER2-negative breast cancer, assess for PIK3CA mutations with tumor or liquid biopsy to identify candidates for alpelisib plus fulvestrant. PIK3CA mutation testing can be done on tumor tissue or ctDNA in peripheral blood (liquid biopsy). If liquid biopsy is negative, tumor tissue testing is recommended." The relevant discussion for these recommendations is pending an update.^18,

The guideline on esophageal and esophagogastric junction cancers states: "The genomic alterations of solid cancers may be identified by evaluating circulating tumor DNA (ctDNA) in the blood, hence a form of “liquid biopsy.” Liquid biopsy is being used more frequently in patients with advanced disease, particularly those who are unable to have a clinical biopsy for disease surveillance and management. The detection of mutations/alterations in DNA shed from esophageal and EGJ carcinomas can identify targetable alterations or the evolution of clones with altered treatment response profiles. Therefore, for patients who have metastatic or advanced esophageal/esophagogastric cancers who may be unable to undergo a traditional biopsy or for disease progression monitoring, testing using a validated NGS-based comprehensive genomic profiling assay performed in a CLIA-approved laboratory may be considered. A negative result should be interpreted with caution, as this does not exclude the presence of tumor mutations or amplifications."^19,

The guideline on non-small cell lung cancer (NSCLC) states the following in their section on molecular and biomarker analysis:^20,

• "ctDNA testing should not be used in lieu of a histologic tissue diagnosis.
• ctDNA is not routinely recommended in settings other than advanced/metastatic disease. For stages I–III, tissue-based testing is preferred. Metastatic disease confined to the thorax may have a higher yield with tissue-based testing.
• Studies have demonstrated ctDNA and tissue testing to have very high specificity. Both ctDNA and tissue testing have appreciable false-negative rates, supporting the complementarity of these approaches, and data support complementary testing to reduce turnaround time and increase yield of targetable alteration detection.
• Limitations of ctDNA testing that can impact interpretation include:
  • Low tumor fraction/ctDNA; some assays include a measure of ctDNA fraction, which can aid in identification of situations in which low
    ctDNA fraction might suggest compromised sensitivity.
  • The presence of mutations from sites other than the target lesion, most commonly clonal hematopoiesis of indeterminate potential
    (CHIP) or post-chemotherapy marrow clones. KRAS and TP53 can be seen in either of these circumstances
  • The inherent ability of the assay to detect fusions or other genomic variation of relevance."

U.S. Preventive Services Task Force Recommendations

Not applicable.

Medicare National Coverage

There is no national coverage determination. In the absence of a national coverage determination, coverage decisions are left to the discretion of local Medicare carriers.

Ongoing and Unpublished Clinical Trials

Some currently unpublished trials that might influence this review are listed in Table 25.

Table 25. Summary of Key Trials

References

1. Natera. FDA Grants Two New Breakthrough Device Designations for Nateras Signatera MRD Test. March 24, 2021. https://www.natera.com/company/news/fda-grants-two-new-breakthrough-device-designations-for-nateras-signatera-mrd-test/. Accessed July 21, 2024
2. Chidharla A, Rapoport E, Agarwal K, et al. Circulating Tumor DNA as a Minimal Residual Disease Assessment and Recurrence Risk in Patients Undergoing Curative-Intent Resection with or without Adjuvant Chemotherapy in Colorectal Cancer: A Systematic Review and Meta-Analysis. Int J Mol Sci. Jun 16 2023; 24(12). PMID 37373376
3. Fakih M, Sandhu J, Wang C, et al. Evaluation of Comparative Surveillance Strategies of Circulating Tumor DNA, Imaging, and Carcinoembryonic Antigen Levels in Patients With Resected Colorectal Cancer. JAMA Netw Open. Mar 01 2022; 5(3): e221093. PMID 35258578
4. Reinert T, Henriksen TV, Christensen E, et al. Analysis of Plasma Cell-Free DNA by Ultradeep Sequencing in Patients With Stages I to III Colorectal Cancer. JAMA Oncol. Aug 01 2019; 5(8): 1124-1131. PMID 31070691
5. Henriksen TV, Tarazona N, Frydendahl A, et al. Circulating Tumor DNA in Stage III Colorectal Cancer, beyond Minimal Residual Disease Detection, toward Assessment of Adjuvant Therapy Efficacy and Clinical Behavior of Recurrences. Clin Cancer Res. Feb 01 2022; 28(3): 507-517. PMID 34625408
6. Loupakis F, Sharma S, Derouazi M, et al. Detection of Molecular Residual Disease Using Personalized Circulating Tumor DNA Assay in Patients With Colorectal Cancer Undergoing Resection of Metastases. JCO Precis Oncol. Jul 2021; 5. PMID 34327297
7. Kotani D, Oki E, Nakamura Y, et al. Molecular residual disease and efficacy of adjuvant chemotherapy in patients with colorectal cancer. Nat Med. Jan 2023; 29(1): 127-134. PMID 36646802
8. Coombes RC, Page K, Salari R, et al. Personalized Detection of Circulating Tumor DNA Antedates Breast Cancer Metastatic Recurrence. Clin Cancer Res. Jul 15 2019; 25(14): 4255-4263. PMID 30992300
9. Magbanua MJM, Swigart LB, Wu HT, et al. Circulating tumor DNA in neoadjuvant-treated breast cancer reflects response and survival. Ann Oncol. Feb 2021; 32(2): 229-239. PMID 33232761
10. Christensen E, Birkenkamp-Demtröder K, Sethi H, et al. Early Detection of Metastatic Relapse and Monitoring of Therapeutic Efficacy by Ultra-Deep Sequencing of Plasma Cell-Free DNA in Patients With Urothelial Bladder Carcinoma. J Clin Oncol. Jun 20 2019; 37(18): 1547-1557. PMID 31059311
11. Lindskrog SV, Birkenkamp-Demtröder K, Nordentoft I, et al. Circulating Tumor DNA Analysis in Advanced Urothelial Carcinoma: Insights from Biological Analysis and Extended Clinical Follow-up. Clin Cancer Res. Dec 01 2023; 29(23): 4797-4807. PMID 37782315
12. Powles T, Assaf ZJ, Davarpanah N, et al. ctDNA guiding adjuvant immunotherapy in urothelial carcinoma. Nature. Jul 2021; 595(7867): 432-437. PMID 34135506
13. Szabados B, Kockx M, Assaf ZJ, et al. Final Results of Neoadjuvant Atezolizumab in Cisplatin-ineligible Patients with Muscle-invasive Urothelial Cancer of the Bladder. Eur Urol. Aug 2022; 82(2): 212-222. PMID 35577646
14. Abbosh C, Birkbak NJ, Wilson GA, et al. Phylogenetic ctDNA analysis depicts early-stage lung cancer evolution. Nature. Apr 26 2017; 545(7655): 446-451. PMID 28445469
15. Ococks E, Sharma S, Ng AWT, et al. Serial Circulating Tumor DNA Detection Using a Personalized, Tumor-Informed Assay in Esophageal Adenocarcinoma Patients Following Resection. Gastroenterology. Nov 2021; 161(5): 1705-1708.e2. PMID 34284036
16. Bratman SV, Yang SYC, Iafolla MAJ, et al. Personalized circulating tumor DNA analysis as a predictive biomarker in solid tumor patients treated with pembrolizumab. Nat Cancer. Sep 2020; 1(9): 873-881. PMID 35121950
17. National Comprehensive Cancer Network. Guidelines on Colon Cancer. Version 4.2024. https://www.nccn.org/professionals/physician_gls/pdf/colon.pdf. Accessed July 21, 2024.
18. National Comprehensive Cancer Network. Guidelines on Breast Cancer Version 4.2024. www.nccn.org/professionals/physician_gls/pdf/breast.pdf. Accessed July 22, 2024.
19. National Comprehensive Cancer Network. Guidelines on Esophageal and Esophagogastric Junction Cancers Version 3.2024. www.nccn.org/professionals/physician_gls/pdf/esophageal.pdf. Accessed July 20, 2024.
20. National Comprehensive Cancer Network. Non-small cell lung cancer. Version 7.2024. https://www.nccn.org/professionals/physician_gls/pdf/nscl.pdf. Accessed July 23, 2024.

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