Medical Policy Medical Policy
Policy Num: 11.003.133
Policy Name: Serologic Genetic and Molecular Screening for Colorectal Cancer
Policy ID: [11.003.133] [Ac / B / M- / P-] [2.04.150 ]
Last Review: January 20, 2026
Next Review: January 20, 2027
Related Policies:
02.001.046 - Chromoendoscopy as an Adjunct to Colonoscopy
11.003.096 - Miscellaneous Genetic and Molecular Diagnostic Tests
11.003.032 - Analysis of Human DNA or RNA in Stool Samples as a Technique for Colorectal Cancer Screening
11.003.004 - Somatic Biomarker Testing (Including Liquid Biopsy) for Targeted Treatment in Metastatic Colorectal Cancer (KRAS, NRAS, BRAF, NTRK, RET and HER2)
11.003.015 - Gene Expression Profile Testing and Circulating Tumor DNA Testing for Predicting Recurrence in Colon Cancer
06.001.020 - Virtual Colonoscopy/Computed Tomography Colonography
| Population Reference No. | Populations | Interventions | Comparators | Outcomes |
| 1 | Individuals: · Who are being screened for colorectal cancer | Interventions of interest are: · SEPT9 methylated DNA testing | Comparators of interest are:
| Relevant outcomes include:
|
| 2 | Individuals: · Who are being screened for colorectal cancer | Interventions of interest are: · Gene expression profiling | Comparators of interest are:
| Relevant outcomes include:
|
| 3 | Individuals: · Who are being screened for colorectal cancer and are at average risk of colorectal cancer | Interventions of interest are: · Epigenomic and genomic cell-free DNA (cfDNA) blood-based testing | Comparators of interest are:
| Relevant outcomes include:
|
It is well established that early detection of colorectal cancer (CRC) reduces disease-related mortality. For patients at average risk for CRC, organizations such as the U.S. Preventive Services Task Force have recommended several options for colon cancer screening. Currently accepted screening options for CRC include colonoscopy or sigmoidoscopy, fecal occult blood testing, and fecal immunochemical testing. However, many individuals do not undergo recommended screening with fecal tests or colonoscopy. Approximately 75% of colorectal cancer deaths occur in people who are not up to date with cancer screening. A simpler screening blood test for genetic alterations associated with non-familial CRC may have the potential to encourage screening and decrease mortality if associated with increased screening compliance. Genetic testing is also being investigated to guide therapy.
For individuals who are being screened for CRC who receive SEPT9 methylated DNA screening for CRC, the evidence includes case-control, cross-sectional, and prospective diagnostic accuracy studies along with systematic reviews of those studies. Relevant outcomes are overall survival (OS), disease-specific survival, test accuracy and validity, change in disease status, and morbid events. The Evaluation of SEPT9 Biomarker Performance for Colorectal Cancer Screening (PRESEPT) prospective study estimated the sensitivity and specificity of Epi proColon detection of invasive adenocarcinoma at 48% and 92%, respectively. Other studies were generally low to fair quality. In systematic reviews, sensitivity ranged from 62% to 71% and pooled specificity ranged from 91% to 93%. Based on results from these studies, the clinical validity of Septin9 (SEPT9) methylated DNA screening is limited by the low sensitivity of the test. Optimal intervals for retesting are not known. The evidence is insufficient to determine that the technology results in an improvement in the net health outcome.
For individuals who are being screened for CRC who receive gene expression profiling screening for CRC, the evidence includes cross-sectional studies. Relevant outcomes are OS, disease-specific survival, test accuracy and validity, change in disease status, and morbid events. Sensitivity in the 2 cross-sectional studies of ColonSentry ranged from 61% to 72% and specificity for detecting CRC was 70% to 77%. Based on results from these studies, the clinical validity of gene expression screening is limited by low sensitivity and low specificity. No published peer-reviewed evidence was identified for BeScreened-CRC. Optimal intervals for retesting are not known. The evidence is insufficient to determine that the technology results in an improvement in the net health outcome.
For individuals at average risk of CRC who are being screened for CRC who receive epigenomic and genomic cell-free DNA (cfDNA) blood-based testing, the evidence includes cross-sectional studies. Relevant outcomes are OS, disease-specific survival, test accuracy and validity, change in disease status, and morbid events. For one screening period, the cfDNA test performance exceeded the predefined acceptance criteria for regulatory approval and predefined criteria for Centers for Medicare & Medicaid Services (CMS) coverage, with sensitivity for CRC of 83% and specificity for non-advanced neoplasia of 90%. Although the cfDNA test has not been compared head-to-head with stool-based tests, these overall estimates of sensitivity and specificity for CRC appear similar to stool-based tests. However, the cfDNA test has lower sensitivity (13%) than colonoscopy and some alternative stool-based tests for the detection of advanced adenomas. Modeling studies conclude that 'blood-based' testing meeting CMS criteria would be clinically effective compared to no screening, but less clinically effective compared to fecal immunochemical test, multi-target stool DNA, and colonoscopy. Modeling studies also identify the potential harm if test substitution is not offset by increased screening participation among individuals refusing other screening modalities. Data evaluating a screening interval of 3 years are being collected as part of the Post-approval Study requirements. The evidence is insufficient to determine that the technology results in an improvement in the net health outcome.
Not applicable
The objective of this evidence review is to determine whether serologic genetic or molecular screening for colorectal cancer improves the net health outcome.
SEPT9 methylated DNA testing (e.g., ColoVantage®, ColoHealth™) is considered investigational for colorectal cancer screening.
Gene expression profiling (e.g., ColonSentry®, BeScreened™ CRC ) is considered investigational for colorectal cancer screening.
Epigenomic and genomic cell-free DNA (cfDNA) blood-based testing with Guardant Shield is considered investigational for all indications (see Policy Guidelines).
Plans may need to alter local coverage medical policy to conform to state law regarding coverage of biomarker testing.
There may be individual exceptions whereby use of epigenomic and genomic blood-based cfDNA testing would be considered medically necessary (see Supplemental Information Section).
On a population level, it is imperative that use of epigenomic and genomic blood-based cfDNA testing be implemented in a manner that limits substitution. Substitution is shifting the screening method to epigenomic and genomic blood-based cfDNA testing among individuals who would be willing to use an established method, and could lead to more harm than benefit. Modeling studies of substitution effect assume 25-50% substitution, and suggest that epigenomic and genomic blood-based cfDNA testing would have to match the performance of established alternatives in order to avoid harms from significant substitution.1, Real world evidence and studies of patient adherence, however, suggest that substitution could be higher. 2,[Graham-Adderton C, Guerra CE, Ngo-Metzger Q, et al.... ov 08 2025: 1-6. PMID 41164862]Plans choosing to employ the use of epigenomic and genomic blood-based cfDNA testing are thereby encouraged to consider use for individuals where patient-provider shared decision-making identifies that the individual is counseled on limited performance compared to other screening modalities; is unwilling to undergo screening by any other testing modality; and is committed to follow-up colonoscopy when the blood test is abnormal. Further, testing should be offered as part of a comprehensive colon cancer screening program that optimizes follow-up including that programs offer such within 9 months and ensures that substitution is limited. (see Supplemental Information Section)
Cell-free DNA testing with Guardant Shield has not been directly compared with other colorectal cancer screening tests, but has sensitivity and specificity for the detection of CRC similar to stool-based tests and might be of higher uptake among individuals currently declining colorectal cancer screening (see Appendix Table 1). It is not known if higher uptake of a blood-based test will offset lower sensitivity for detection of advanced adenomas at a population level; yet, the right screening test is one that is utilized. Plans may thereby consider Guardant Shield as a screening technique for colorectal cancer, particularly for individuals declining other screening technologies, should they be amenable to receiving a diagnostic colonoscopy after a positive screen. That is, Shield needs to be offered as part of a comprehensive colon cancer screening program that optimizes follow-up of individuals choosing to use blood-based colorectal cancer screening (see Supplemental Information Section).
For the detection of precancerous adenomas or other polyps, technologies that allow visualization of the colorectal tract perform better than stool or blood-based tests. The performance of any liquid-based product is expected to be lower for the detection of precancerous lesions, as these early lesions generally do not release high amounts of DNA into the circulation. Other analytes outside of DNA-based markers may eventually prove to be useful for blood-based detection of precancerous lesions. Even for the stool-based tests, the majority of the test sensitivity comes from the fecal immunochemical component rather than the DNA contribution, indicating that other analytes outside of DNA may need to be assessed in future versions of tests.
The transformation of adenoma to carcinoma typically takes around 10 years, which is the basic screening interval for colonoscopy. However, other pathways of colorectal tumorigenesis have been described, such as the microsatellite instability pathway and the methylation pathway, and these do not have well-defined timeframes. A 3-year interval of the Guardant Shield test has been suggested in the publication of results of the pivotal study, but has not been tested.
Combination testing of blood-based cfDNA with other methods of colorectal cancer screening has not been studied.
The FDA-approved product label for the Shield test includes the following Precaution:
"Based on data from clinical studies, Shield has limited detection (55%-65%) of Stage I colorectal cancer and does not detect 87% of precancerous lesions. One out of 10 patients with a negative Shield result may have a precancer that would have been detected by a screening colonoscopy. Shield demonstrated high detection of Stages II, III, and IV colorectal cancer."
Other limitations listed in the label include, but are not limited to, the following:
See the Codes table for details.
Some Plans may have contract or benefit exclusions for genetic testing. Some Plans may have contract language that incorporates concepts of cost-effectiveness or “least costly alternative” which might limit use of cfDNA screening tests.
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.
As mandated by Law 79 of August 1st, 2020 medical necessity and coverage may be determined following NCCN Guidelines and/or Local/National Coverage Determinations superseeding this medical policy criteria.
For patients at average risk for colorectal cancer (CRC), organizations such as the U.S. Preventive Services Task Force have recommended several options for colon cancer screening. The diagnostic performance characteristics of the currently accepted screening options (i.e. colonoscopy, sigmoidoscopy, fecal tests) have been established using colonoscopy as the criterion standard. Modeling studies and clinical trial evidence on some of the screening modalities have allowed some confidence in the effectiveness of several cancer screening modalities. The efficacy of these tests is supported by numerous studies evaluating the diagnostic characteristics of the test for detecting cancer and cancer precursors, along with a well-developed body of knowledge on the natural history of the progression of cancer precursors to cancer. Early detection of CRC reduces disease-related mortality, yet many individuals do not undergo recommended screening with fecal occult blood test or colonoscopy. A simpler screening blood test may have the potential to encourage screening and decrease mortality if associated with increased screening compliance.
Clinical laboratories may develop and validate tests in-house and market them as a laboratory service; laboratory-developed tests must meet the general regulatory standards of the Clinical Laboratory Improvement Amendments. Genetic tests evaluated in this evidence review are available under the auspices of the Clinical Laboratory Improvement Amendments. Laboratories that offer laboratory-developed tests must be licensed under the Clinical Laboratory Improvement Amendments for high-complexity testing. To date, the U.S. FDA has chosen not to require any regulatory review of these tests.
The Epi proColon test is the only SEPT9 DNA test that has received FDA approval. It was approved in 2016 for use in average-risk patients who decline other screening methods. In 2024, the Epi proColon test was purchased by New Day Diagnostics and renamed ColoHealth™.
Guardant Health’s Shield™ Blood Test was approved by the FDA in July 2024 for colorectal cancer (CRC) screening in adults aged 45 and older who are at average risk for the disease. The Molecular and Clinical Genetics Panel of the FDA’s Medical Devices Advisory Committee reviewed evidence for Shield and voted on three questions regarding the use of Shield. They voted 8 to 1 favorably that there is reasonable assurance Shield is safe, 6 to 3 favorably that there is reasonable assurance Shield is effective, and 7 to 2 favorably that the benefits of Shield outweigh its risks. The labeled indication is 'Shield is intended for colorectal cancer screening in individuals at average risk of the disease, age 45 years or older. Patients with a positive result should follow up with a colonoscopy. Shield is not a replacement for diagnostic colonoscopy or for surveillance colonoscopy in high-risk individuals.' A prospective, longitudinal Post-Approval Study (PAS) to evaluate the longitudinal performance of Shield in an average risk population was required (NCT04136002).
This evidence in this review was initially contained in policy 02.001.046 (Miscellaneous Genetic and Molecular Diagnostic Tests). This policy was created in July 2020 and has been updated regularly with searches of the PubMed database. The most recent literature update was performed through October 23, 2025.
Evidence reviews assess whether a medical test is clinically useful. A useful test provides information to make a clinical management decision that improves the net health outcome. That is, the balance of benefits and harms is better when the test is used to manage the condition than when another test or no test is used to manage the condition.
The first step in assessing a medical test is to formulate the clinical context and purpose of the test. The test must be technically reliable, clinically valid, and clinically useful for that purpose. Evidence reviews assess the evidence on whether a test is clinically valid and clinically useful. Technical reliability is outside the scope of these reviews, and credible information on technical reliability is available from other sources.
The U.S. Preventive Services Task Force has recommended screening for colorectal cancer (CRC) starting at age 45 years and continuing until age 75 years but many adults do not receive screening for CRC.4,Approximately 75% of colorectal cancer deaths occur in people who are not up to date with cancer screening.5, It is thought that less burdensome methods of screening could increase the number of adults screened and thereby improve outcomes.
Serum biomarkers that are shed from colorectal tumors have been identified and include Septin9 (SEPT9) hypermethylated DNA. The Septin 9 protein is involved in cell division, migration, and apoptosis and acts as a tumor suppressor; when hypermethylated, expression of SEPT9 is reduced. ColonSentry is a polymerase chain reaction assay that uses a blood sample to detect the expression of 7 genes found to be differentially expressed in individuals with CRC compared with controls. The purpose of CRC screening using SEPT9 methylated DNA testing and gene expression profiling in individuals who are indicated for CRC screening is to provide a testing option that is an alternative to or an improvement on existing tests used to detect CRC.
The following PICO was used to select literature to inform this review.
The relevant population of interest is individuals who are at average risk for CRC who are being screened for CRC.
The incidence of CRC varies by sex and race. Males have a higher incidence than females. Non-Hispanic American Indian or Alaska Native persons and non-Hispanic Black persons have the highest incidence.6,
The interventions of interest are SEPT9 methylated DNA testing (eg, ColoVantage, Epi proColon/ColoHealth™), gene expression profiling (eg ColonSentry, BeScreened-CRC), and cfDNA testing.
ColoVantage (various manufacturers) blood tests for serum Septin9 (SEPT9) methylated DNA are offered by several laboratories (ARUP Laboratories, Quest Diagnostics, Clinical Genomics). Epi proColon (Epigenomics) received U.S. Food and Drug Administration (FDA) approval in April 2016 (Epi proColon is now marketed by New Day Diagnostics as ColoHealth™) Epigenomics has licensed its Septin 9 DNA biomarker technology to Polymedco and LabCorp. ColoVantage and Epi proColon/ColoHealth™ are both polymerase chain reaction (PCR) assays; however, performance characteristics vary across tests, presumably due to differences in methodology (eg, DNA preparation, PCR primers, probes).
ColonSentry (Stage Zero Life Sciences) is a PCR assay that uses a blood sample to detect the expression of 7 genes found to be differentially expressed in CRC patients compared with controls7,: ANXA3, CLEC4D, TNFAIP6, LMNB1, PRRG4, VNN1, and IL2RB. The test is intended to stratify average-risk adults who are non-compliant with colonoscopy and/or fecal occult blood testing. "Because of its narrow focus, the test is not expected to alter clinical practice for patients who comply with recommended screening schedules."8, BeScreened-CRC (Beacon Biomedical) is a PCR assay that uses a blood sample to detect the expression of 3 protein biomarkers: teratocarcinoma derived growth factor-1 (TDGF-1, Cripto-1); carcinoembryonic antigen, a well-established biomarker associated with CRC; and an extracellular matrix protein involved in early stage tumor stroma changes.9,
Shield™ (Guardant Health) is a cell-free DNA (cfDNA) test to detect genomic (somatic mutations) and epigenomic alterations (methylation and fragmentation patterns) associated with colorectal cancer from whole blood samples collected from individuals at average risk for CRC. The results are combined using proprietary bioinformatics algorithms to generate a final qualitative test result of “Positive” or “Negative”. Patients with a positive result may have CRC or advanced adenomas and should be followed by colonoscopy.10,
The Shield product label includes the following statements:
"The Shield test is not intended as a screening test for individuals who are at high risk for CRC."
"Patients with a positive result should be followed by colonoscopy."
"Patients with a negative result should continue participating in colorectal cancer screening programs, at the appropriate guideline recommended intervals."
"The benefits and risks of programmatic colorectal screening (i.e., repeated testing over an established period of time) with Shield has not been studied.
A 3-year screening interval has been proposed by the manufacturer.11,
Ideally, the comparator of interest is the standard of care CRC screening. Colonoscopy is considered the reference standard for calculating performance characteristics of CRC screening modalities. However, approximately 40% of eligible adults are not adherent with screening guidelines.12, For these adults, the comparator is realistically no screening.
Table 1 shows the NCCN descriptions of modalities for CRC screening.13,
| Screening Test | Recommended Testing Interval1 | Sensitivity | Specificity | ||
| Colon Cancer | Colon Cancer | ||||
| Colonoscopy | Every 10 years | 94.7% | 89%–95% (≥10 mm adenomas) 75%–93% (≥6 mm adenomas) | ---- | 89% (≥10 mm adenomas) 94% (≥6 mm adenomas) |
| Flexible sigmoidoscopy2 | Every 5–10 years | 58%–75% | 72%–86% | ---- | 92% |
| CT colonography | Every 5 years | 86%–100% | 89% (≥10 mm adenomas) 86% (≥6 mm adenomas) | ---- | 94% (≥10 mm adenomas) 88% (≥6 mm adenomas) |
| High-sensitivity guaiac-based test | Annually | 50%–75% | 7%–21% (advanced neoplasia) 6%–17% (advanced adenoma) | 96%–98% | 96%–99% (advanced neoplasia) 96%–99% (advanced adenoma) |
| Quantitative FIT3 (using OC-Sensor) | Annually | 74% | 25% (advanced neoplasia) 23% (advanced adenoma) | 94% | 96% (advanced neoplasia) 96% (advanced adenoma) |
| Quantitative FIT3 (using OC-Light) | Annually | 81% | 27% (advanced neoplasia) 28% (advanced adenoma) | 93% | 95% (advanced neoplasia) 94% (advanced adenoma) |
| mt-sDNA test | Every 3 years | 93% | 47% (advanced neoplasia) 43% (advanced adenoma) | 85% | 89% (advanced neoplasia) 89% (advanced adenoma) |
| mt-sRNA test | Every 3 years | 94% | 46% (advanced adenoma) | 86% (advanced adenoma) | |
| bb-cfDNA test | Every 3 years | 83% | 13% (advanced pre-cancerous lesions) | 90% | 90% (advanced pre-cancerous lesions) |
1Frequency based upon normal (negative) results. 2Data for the sensitivity and specificity of flexible sigmoidoscopy are for the entire colon and are based on the completion of colonoscopy for those found to have a distal colon lesion on flexible sigmoidoscopy. 3Optimal FIT thresholds will vary across screening programs, taking into consideration available colonoscopy resources to investigate abnormal results, including false positive tests.
The outcomes of interest are overall survival (OS), disease-specific survival, test accuracy and validity, change in disease status, and morbid events. The timing of follow-up for CRC screening is weeks for the diagnosis of CRC to years for survival outcomes.
For the evaluation of clinical validity of serologic genetic or molecular tests, studies that meet the following eligibility criteria were considered:
Reported on the accuracy of the marketed version of the technology (including any algorithms used to calculate scores)
Included a suitable reference standard
Patient/sample clinical characteristics were described
Patient/sample selection criteria were described.
A test must detect the presence or absence of a condition, the risk of developing a condition in the future, or treatment response (beneficial or adverse).
The diagnostic performance of SEPT9 methylation for colon cancer has been reported in meta-analyses. The systematic reviews identified from 2016 and 2017 included 14 to 39 studies (see Table 2). Pooled sensitivity ranged from 62% to 71% and pooled specificity ranged from 91% to 93% (see Table 3). The systematic review by Nian et al (2017) found that study designs (case-control vs cross-sectional), assays or kits used (Epi proColon vs other), country (Asia or other), sample sizes (n >300 or <300), and risk of bias of included studies all contributed to heterogeneity.14, Most included studies were case-control with the exclusion of difficult-to-diagnose patients, which may lead to a spectrum bias and overestimation of diagnostic accuracy. Reviewers included 20 studies of Epi proColon test 1.0, 2.0, or a combination of the 2. When only looking at studies of Epi ProColon 2.0, sensitivity was 75% compared with 71% in the overall analysis, with a specificity of 93% (see Table 3). Sensitivity and specificity may be additionally affected by the specific algorithm used, with the 1/3 algorithm resulting in higher sensitivity and the 2/3 algorithm resulting in higher specificity.15, A 2020 systematic review of Epi proColon 2.0 by Hariharan and Jenkins found high specificity (92%) and negative predictive value (NPV) (99.9%) for CRC, so that a negative test would rule out CRC.16, However, a test with a sensitivity of 69% would accurately diagnose only 21 of 30 CRC cases in a sample of 10,000 people at average risk. Sensitivity for precancerous lesions would be lower.
| Study | Studies Included | N | Study Designs Included | Study Reference Standards Included | 11-Item QUADAS Quality Assessment | ||
| No. of Studies Rated as High or Unclear Risk of Bias | |||||||
| No Domains | 1 to 2 Domains | >2 Domains | |||||
| Harihan and Jenkins (2020)16, | 19 | 7629 | CC | Colonoscopy | 6 | 8 | 5 |
| Nian et al (2017)14, | 25 | 9927 | CC and CS | Colonoscopy | 3 | 14 | 8 |
| Li et al (2016)17, | 39 | 3853 patients with CRC and 6431 controls | CC and CS | Colonoscopy | 6 | 12 | 21 |
| Yan et al (2016)18, | 14 | 9870 | CC and CS | Colonoscopy | 0 | 13 | 1 |
CC: case-control; CRC: colorectal cancer; CS: cross-sectional.
| Study | Test | Sensitivity (95% CI), % | Specificity (95% CI), % |
| Harihan and Jenkins (2020)16, | Epi Procolon 2.0 | 69 (62 to 75) | 92 (89 to 95) |
| Nian et al (2017)14, | Various | 71 (67 to 75) | 92 (89 to 94) |
| Nian et al (2017)14, | Epi Procolon 2.0 | 75 (67 to 77) | 93 (88 to 96) |
| Li et al (2016)17, | Various | 62 (56 to 67) | 91 (89 to 93) |
| Yan et al (2016)18, | Various | 66 (64 to 69) | 91 (90 to 91) |
| Yan et al (2016)18, | Epi Procolon | 63 (58 to 67) | 91 (90 to 92) |
CI: confidence interval.
The evidence review for the 2016 U.S. Preventive Services Task Force update on CRC screening included studies on blood tests for methylated SEPT9 DNA. The inclusion criteria were fair- or good-quality English-language studies, asymptomatic screening populations, age of 40 years or older, and at average risk for CRC or not selected for inclusion based on CRC risk factors. The only study found to meet these inclusion criteria was the Evaluation of SEPT9 Biomarker Performance for Colorectal Cancer Screening (PRESEPT) (described below).
PRESEPT (Church et al [2014]) was an international prospective screening study of the first-generation Epi proColon test (see Table 4).19, Of 1516 patients selected for laboratory analysis, colonoscopy identified 53 (3%) patients with invasive adenocarcinoma, 315 (21%) with advanced adenoma, and 210 (14%) with nonadvanced adenoma. The overall sensitivity, specificity, positive predictive value (PPV), and NPV for the detection of invasive adenocarcinoma are shown in Table 5. Sensitivity for any adenoma was 48% and for advanced adenoma was 11%.
| Study | Study Population | Design | Reference Standard | Timing of Reference and Index Tests | Blinding of Assessors |
| Church et al (2014)19, | Patients ≥50 y at average risk and scheduled for colonoscopy | Prospective random sampling from 7941 patients at 32 sites | Colonoscopy | 6 to 16 days before colonoscopy | Yes |
| Study | Initial N | Final N | Excluded Samples | Clinical Validity (95% Confidence Interval), % | |||
| Sensitivity | Specificity | PPV | NPV | ||||
| Church et al (2014)19, | 1516 | 1510 | 6 | 48.2 (32.4 to 63.6) | 91.5 (89.7 to 93.1) | 5 | 100 |
NPV: negative predictive value; PPV: positive predictive value.
Tables 6 and 7 display notable limitations identified in each study. This information is synthesized as a summary of the body of evidence following each table and provides the conclusions on the sufficiency of the evidence supporting the position statement.
| Study | Populationa | Interventionb | Comparatorc | Outcomesd | Duration of Follow-Upe |
| Church et al (2014)19, | 3. First-generation test |
The study limitations stated in this table are those notable in the current review; this is not a comprehensive gaps assessment. a Population key: 1. Intended use population unclear; 2. Clinical context is unclear; 3. Study population is unclear; 4. Study population not representative of intended use. b Intervention key: 1. Classification thresholds not defined; 2. Version used unclear; 3. Not intervention of interest. c Comparator key: 1. Classification thresholds not defined; 2. Not compared to credible reference standard; 3. Not compared to other tests in use for same purpose. d Outcomes key: 1. Study does not directly assess a key health outcome; 2. Evidence chain or decision model not explicated; 3. Key clinical validity outcomes not reported (sensitivity, specificity and predictive values); 4. Reclassification of diagnostic or risk categories not reported; 5. Adverse events of the test not described (excluding minor discomforts and inconvenience of venipuncture or noninvasive tests). e Follow-Up key: 1. Follow-up duration not sufficient with respect to natural history of disease (true-positives, true-negatives, false-positives, false-negatives cannot be determined).
| Study | Selectiona | Blindingb | Delivery of Testc | Selective Reportingd | Data Completenesse | Statisticalf |
| Church et al (2014)19, | 2. Not randomly sampled |
The study limitations stated in this table are those notable in the current review; this is not a comprehensive gaps assessment. a Selection key: 1. Selection not described; 2. Selection not random or consecutive (ie, convenience). b Blinding key: 1. Not blinded to results of reference or other comparator tests. c Test Delivery key: 1. Timing of delivery of index or reference test not described; 2. Timing of index and comparator tests not same; 3. Procedure for interpreting tests not described; 4. Expertise of evaluators not described. d Selective Reporting key: 1. Not registered; 2. Evidence of selective reporting; 3. Evidence of selective publication. e Data Completeness key: 1. Inadequate description of indeterminate and missing samples; 2. High number of samples excluded; 3. High loss to follow-up or missing data. f Statistical key: 1. Confidence intervals and/or p values not reported; 2. Comparison with other tests not reported
Song et al (2018) conducted a prospective study of the colorectal tumor detection rate from methylated SEPT9 levels by Epi proColon 2.0 using the 2/3 algorithm.20, All 1347 individuals who met the criteria and were to undergo colonoscopy provided a blood sample prior to evaluation of clinical status. The level of methylated SEPT9 increased as the severity of disease increased, and the detection rate increased with disease severity. The detection rate was less than 20% for serrated adenoma and tubular adenoma, 41% for tubulovillous adenoma, 54% for stage I CRC, and then increased to 84% as the stage of CRC increased to stage IV CRC. Results suggested potential utility for monitoring treatment response but limited utility as a screening tool.
A test is clinically useful if the use of the results informs management decisions that improve the net health outcome of care. The net health outcome can be improved if patients receive correct therapy, or more effective therapy, or avoid unnecessary therapy, or avoid unnecessary testing.
Direct evidence of clinical utility is provided by studies that have compared health outcomes for patients managed with and without the test. Because these are intervention studies, the preferred evidence would be from randomized controlled trials (RCTs).
Studies comparing survival outcomes in patients who undergo CRC screening with SEPT9 methylated DNA testing or with standard screening were not identified. Such comparative studies with clinically meaningful outcomes (eg, survival) are necessary to demonstrate incremental improvement in the net health outcome compared with current standard screening approaches (fecal immunochemical test, colonoscopy) and to address lead-time bias for cancers identified through the screening.
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.
Because the sensitivity of SEPT9 methylated DNA is low, a chain of evidence establishing the clinical utility of SEPT9 methylated DNA cannot be established.
The evidence for the clinical validity of CRC screening includes case-control studies and prospective screening studies. Systematic reviews have reported that the sensitivity of testing ranges from 62% to 75% and the specificity from 91% to 93%. Studies were generally of low to fair quality. The prospective PRESEPT study with average-risk patients scheduled for colonoscopy estimated the sensitivity of Epi proColon for detection of invasive adenocarcinoma to be 48% and for an advanced adenoma to be 11%. Based on results from these studies, the clinical validity of SEPT9 methylated DNA screening is limited by low sensitivity and low positive predictive value of the test.
Detection of only half of preclinical cancers and a small proportion of advanced adenomas limits the clinical utility of the test. There is a need for further studies evaluating survival outcomes in patients screened with SEPT9 methylated DNA testing (ColoVantage, Epi proColon) who have refused established screening methods. Because the evidence on clinical validity has reported that the test has a lower sensitivity than other screening methods, the clinical utility is uncertain. If the test is restricted only to patients who would otherwise not be screened, outcomes might be improved. However, if the test is used as a substitute for other screening tests that have higher sensitivity, outcomes may be worse.
For individuals who are being screened for CRC who receive SEPT9 methylated DNA screening for CRC, the evidence includes case-control, cross-sectional, and prospective diagnostic accuracy studies along with systematic reviews of those studies. Relevant outcomes are overall survival (OS), disease-specific survival, test accuracy and validity, change in disease status, and morbid events. The Evaluation of SEPT9 Biomarker Performance for Colorectal Cancer Screening (PRESEPT) prospective study estimated the sensitivity and specificity of Epi proColon detection of invasive adenocarcinoma at 48% and 92%, respectively. Other studies were generally low to fair quality. In systematic reviews, sensitivity ranged from 62% to 71% and pooled specificity ranged from 91% to 93%. Based on results from these studies, the clinical validity of Septin9 (SEPT9) methylated DNA screening is limited by the low sensitivity of the test. Optimal intervals for retesting are not known. The evidence is insufficient to determine that the technology results in an improvement in the net health outcome.
| Population Reference No. 1 Policy Statement | [ ] MedicallyNecessary | [X] Investigational |
Population Reference No. 2
A test must detect the presence or absence of a condition, the risk of developing a condition in the future, or treatment response (beneficial or adverse).
Two case-control studies have been identified with ColonSentry. Marshall et al (2010) conducted a genome-wide association study in 189 whole blood samples (98 controls, 91 patients with CRC) and identified 45 differentially expressed gene biomarker candidates using microarray hybridization.21, Through logistic regression and bootstrapping (subsampling with replacement) in a training set of 232 samples, 7 genes were selected for further development. In a subsequent test set of 410 samples (208 controls, 202 patients with CRC), sensitivity, specificity, PPV, and NPV were determined (see Tables 8 and 9). Yip et al (2010) conducted a similar cross-sectional study of 210 blood samples from patients in Malaysia.7, The Malaysian population has different ethnic groups with different CRC incidences and CRC in Asian populations is more likely to be nonpolypoid (ie, flat or depressed) compared with Western populations in whom the test was developed.
Sensitivity for the 2 studies ranged from 61% to 72% and specificity for detecting CRC were 70% to 77%. The area under the curve was 0.76 (95% confidence interval [CI], 0.70 to 0.82).
| Study | Study Population | Design | Reference Standard | Timing of Reference and Index Tests |
| Marshall et al (2010)21, | 202 patients with CRC and 208 controls | Case-control | NA | NA |
| Yip et al (2010)7, | 99 patients with CRC and 111 controls | Case-control | NA | NA |
CRC: colorectal cancer; NA: not applicable.
| Study | Initial N | Final N | Excluded Samples | AUC (95% CI) | Clinical Validity (95% CI), % | |||
| Sensitivity | Specificity | PPV | NPV | |||||
| Marshall et al (2010)21, | 410 | 0.80 (0.76 to 0.84) | 72 | 70 | 70 | 72 | ||
| Yip et al (2010)7, | 200 | 61 | 77 | |||||
AUC: area under the curve; CI: confidence interval; NPV: negative predictive value; PPV: positive predictive value.
Tables 10 and 11 display notable limitations in relevance and design and conduct. Because of its cross-sectional design, follow-up of controls to determine which strata developed CRC was not reported, limiting conclusions drawn about the accuracy of the test for risk prediction.
| Study | Populationa | Interventionb | Comparatorc | Outcomesd | Duration of Follow-Upe |
| Marshall et al (2010)21, | 4. Included patients with CRC and healthy controls | ||||
| Yip et al (2010)7, | 4. Included patients with CRC and healthy controls |
CRC: colorectal cancer. The study limitations stated in this table are those notable in the current review; this is not a comprehensive gaps assessment. a Population key: 1. Intended use population unclear; 2. Clinical context is unclear; 3. Study population is unclear; 4. Study population not representative of intended use. bIntervention key: 1. Classification thresholds not defined; 2. Version used unclear; 3. Not intervention of interest. c Comparator key: 1. Classification thresholds not defined; 2. Not compared to credible reference standard; 3. Not compared to other tests in use for same purpose. d Outcomes key: 1. Study does not directly assess a key health outcome; 2. Evidence chain or decision model not explicated; 3. Key clinical validity outcomes not reported (sensitivity, specificity and predictive values); 4. Reclassification of diagnostic or risk categories not reported; 5. Adverse events of the test not described (excluding minor discomforts and inconvenience of venipuncture or noninvasive tests). e Follow-Up key: 1. Follow-up duration not sufficient with respect to natural history of disease (true-positives, true-negatives, false-positives, false-negatives cannot be determined).
| Study | Selectiona | Blindingb | Delivery of Testc | Selective Reportingd | Data Completenesse | Statisticalf |
| Marshall et al (2010)21, | 2. Selection not random | |||||
| Yip et al (2010)7, | 2. Selection not random |
The study limitations stated in this table are those notable in the current review; this is not a comprehensive gaps assessment. a Selection key: 1. Selection not described; 2. Selection not random or consecutive (ie, convenience). bBlinding key: 1. Not blinded to results of reference or other comparator tests. cTest Delivery key: 1. Timing of delivery of index or reference test not described; 2. Timing of index and comparator tests not same; 3. Procedure for interpreting tests not described; 4. Expertise of evaluators not described. d Selective Reporting key: 1. Not registered; 2. Evidence of selective reporting; 3. Evidence of selective publication. e Data Completeness key: 1. Inadequate description of indeterminate and missing samples; 2. High number of samples excluded; 3. High loss to follow-up or missing data. f Statistical key: 1. Confidence intervals and/or p values not reported; 2. Comparison with other tests not reported.
A test is clinically useful if the use of the results informs management decisions that improve the net health outcome of care. The net health outcome can be improved if patients receive correct therapy, or more effective therapy, or avoid unnecessary therapy, or avoid unnecessary testing.
Direct evidence of clinical utility is provided by studies that have compared health outcomes for patients managed with and without the test. Because these are intervention studies, the preferred evidence would be from RCTs.
No studies examining the clinical utility of ColonSentry were identified.
Indirect evidence on clinical utility rests on clinical validity. If the evidence is insufficient to demonstrate test performance, no inferences can be made about clinical utility.
A chain of evidence supporting the use of ColonSentry for predicting CRC risk cannot be constructed due to lack of clinical validity.
ColonSentry is intended to stratify patients with average CRC risk who are averse to current screening approaches to identify those at increased risk and therefore choose a less-invasive screening method. However, 2 cross-sectional studies are insufficient to demonstrate the risk predictive ability of the test; ie, clinical validity has not been established. Sensitivity for the 2 studies ranged from 61% to 72% and specificity for detecting CRC was 70% to 77%. Based on results from these studies, the clinical validity of gene expression screening with ColonSentry is limited by low sensitivity and low specificity. Direct and indirect evidence of clinical utility is currently lacking.
A test must detect the presence or absence of a condition, the risk of developing a condition in the future, or treatment response (beneficial or adverse).
No published peer-reviewed evidence was identified.
A test is clinically useful if the use of the results informs management decisions that improve the net health outcome of care. The net health outcome can be improved if patients receive correct therapy, or more effective therapy, or avoid unnecessary therapy, or avoid unnecessary testing.
Direct evidence of clinical utility is provided by studies that have compared health outcomes for patients managed with and without the test. Because these are intervention studies, the preferred evidence would be from RCTs.
No studies examining the clinical utility of BeScreened-CRC were identified.
Indirect evidence on clinical utility rests on clinical validity. If the evidence is insufficient to demonstrate test performance, no inferences can be made about clinical utility.
A chain of evidence supporting the use of BeScreened-CRC for predicting CRC risk cannot be constructed due to lack of evidence.
BeScreened-CRC is intended for individuals who are averse to current screening approaches to identify those at increased risk and, therefore, choose a less invasive screening method. No published peer-reviewed evidence was identified; therefore, evidence of clinical validity and clinical utility is currently lacking.
For individuals who are being screened for CRC who receive gene expression profiling screening for CRC, the evidence includes cross-sectional studies. Relevant outcomes are OS, disease-specific survival, test accuracy and validity, change in disease status, and morbid events. Sensitivity in the 2 cross-sectional studies of ColonSentry ranged from 61% to 72% and specificity for detecting CRC was 70% to 77%. Based on results from these studies, the clinical validity of gene expression screening is limited by low sensitivity and low specificity. No published peer-reviewed evidence was identified for BeScreened-CRC. Optimal intervals for retesting are not known. The evidence is insufficient to determine that the technology results in an improvement in the net health outcome.
| Population Reference No. 2 Policy Statement | [ ] MedicallyNecessary | [X] Investigational |
Population Reference No. 3
A test must detect the presence or absence of a condition, the risk of developing a condition in the future, or treatment response (beneficial or adverse).
The pivotal study of the cfDNA test was described in the FDA Summary of Safety and Effectiveness document and a publication by Chung et al (2024).10,11, The ECLIPSE study was a multicenter (265 US sites), prospective, non-randomized, observational study including 7,861 participants ages 45 to 84 years who were of average risk for CRC. Individuals who were eligible for CRC screening and intended to undergo colonoscopy were enrolled in the study between 2019 and 2022. Blood samples were collected prior to the participant undergoing a standard-of-care colonoscopy. Central pathology reviews were conducted for lesion classification; the lesion of greatest clinical significance was used to classify into histopathology categories. The primary outcomes were sensitivity for CRC and specificity for non-advanced neoplasia compared to colonoscopy/histopathology. The predefined acceptance criteria were a lower bound of the 95% confidence interval of >65% for sensitivity and a lower bound for the 95% confidence interval of specificity of >85%. The secondary outcome was sensitivity for advanced adenoma.10,11,The test performance exceeded the predefined acceptance criteria for the primary outcomes with sensitivity for CRC of 83% and specificity for non-advanced neoplasia of 90%. The sensitivity for advanced adenoma was 13%. The reported performance characteristics are for one round of testing. Characteristics for repeated testing over time are unknown. ECLIPSE Study characteristics and results are shown in Tables 12 and 13. Study relevance and design and conduct limitations are shown in Tables 14 and 15. The FDA included a requirement for a Post-Approval study (PAS; NCT04136002) that will gather data on the cumulative false-positive and true-positive rates over 3 years, among other outcomes.
| Study | Study Population | Design | Reference Standard | Timing of Reference and Index Tests |
| ECLIPSE (2024)10,11, | Individuals 45 to 84 years of age who were of average risk for CRC Median age, 60y 54% female 7% Asian; 12% Black or African American; 79% White; 2.1% Other 13% Hispanic | Prospective, observational, multicenter study at 265 US sites, including primary care and endoscopy centers in academic and community-based institutions | Reference-standard screening colonoscopy with histopathological diagnosis | Participants provided a study blood sample for cfDNA testing before any medical preparation for colonoscopy |
CRC: colorectal cancer; NA: not applicable.
| Study | N | Clinical Validity (95% CI), % | |||
| ECLIPSE (2024)10,11, | 7,861 | Sensitivity CRC: 83% (72 to 90) Advanced adenoma: 13% (11 to 15) | Specificity Non-advanced neoplasia: 90% (89 to 90) | PPV CRC: 3% Advanced adenoma: 12% | NPV Non-advanced neoplasia: 90% |
CI: confidence interval; CRC: colorectal cancer; NPV: negative predictive value; PPV: positive predictive value.
| Study | Populationa | Interventionb | Comparatorc | Outcomesd | Duration of Follow-Upe |
| ECLIPSE (2024)10,11, | 4. Screening interval of 3 years has been proposed but not tested | 3. Performance characteristics for repeated testing were not reported |
CRC: colorectal cancer. The study limitations stated in this table are those notable in the current review; this is not a comprehensive gaps assessment. a Population key: 1. Intended use population unclear; 2. Clinical context is unclear; 3. Study population is unclear; 4. Study population not representative of intended use; 5. Other. bIntervention key: 1. Classification thresholds not defined; 2. Version used unclear; 3. Not intervention of interest; 4. Other. c Comparator key: 1. Classification thresholds not defined; 2. Not compared to credible reference standard; 3. Not compared to other tests in use for same purpose; 4. Other. d Outcomes key: 1. Study does not directly assess a key health outcome; 2. Evidence chain or decision model not explicated; 3. Key clinical validity outcomes not reported (sensitivity, specificity and predictive values); 4. Reclassification of diagnostic or risk categories not reported; 5. Adverse events of the test not described (excluding minor discomforts and inconvenience of venipuncture or noninvasive tests); 5. Other e Follow-Up key: 1. Follow-up duration not sufficient with respect to natural history of disease (true-positives, true-negatives, false-positives, false-negatives cannot be determined); 5. Other
| Study | Selectiona | Blindingb | Delivery of Testc | Selective Reportingd | Data Completenesse | Statisticalf |
| ECLIPSE (2024)10,11, |
The study limitations stated in this table are those notable in the current review; this is not a comprehensive gaps assessment. a Selection key: 1. Selection not described; 2. Selection not random or consecutive (ie, convenience). bBlinding key: 1. Not blinded to results of reference or other comparator tests. cTest Delivery key: 1. Timing of delivery of index or reference test not described; 2. Timing of index and comparator tests not same; 3. Procedure for interpreting tests not described; 4. Expertise of evaluators not described. d Selective Reporting key: 1. Not registered; 2. Evidence of selective reporting; 3. Evidence of selective publication. e Data Completeness key: 1. Inadequate description of indeterminate and missing samples; 2. High number of samples excluded; 3. High loss to follow-up or missing data. f Statistical key: 1. Confidence intervals and/or p values not reported; 2. Comparison with other tests not reported.
A test is clinically useful if the use of the results informs management decisions that improve the net health outcome of care. The net health outcome can be improved if patients receive correct therapy, or more effective therapy, or avoid unnecessary therapy, or avoid unnecessary testing.
Direct evidence of clinical utility is provided by studies that have compared health outcomes for patients managed with and without the test. Because these are intervention studies, the preferred evidence would be from RCTs.
No RCTs directly examining the clinical utility of the cfDNA test were identified.
Two modeling studies predicting clinical outcomes across CRC screening strategies, including blood-based tests, have been published. van den Puttelaar et al (2024) reported results of a modeling study commissioned by the National Cancer Institute. The authors modeled outcomes for a hypothetical blood test meeting the Centers for Medicare & Medicaid Services (CMS) criteria for coverage of blood tests for CRC screening (i.e., 74% sensitivity and 90% specificity) as well as a blood test with performance characteristics of the Shield cfDNA test.22, Similarly, Ladabaum et al (2024) also reported results of modeling of outcomes for a hypothetical test meeting CMS criteria.23, The authors of both publications came to the same conclusion that blood-based testing meeting CMS criteria would be clinically effective compared to no screening, but would be less clinically effective compared to fecal immunochemical test [FIT], multi-target stool DNA, and colonoscopy. The performance characteristics of the Shield test exceed the CMS minimum criteria.
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.
For one screening period, the cfDNA test performance exceeded the predefined acceptance criteria for regulatory approval and predefined criteria for CMS coverage, with sensitivity for CRC of 83% and specificity for non-advanced neoplasia of 90%. Individuals with a positive test should undergo a colonoscopy. Colonoscopy has been shown to improve health outcomes. Individuals with a negative result should be advised to continue standard screening. The cfDNA test has lower sensitivity than colonoscopy and some alternative stool-based tests for the detection of advanced adenomas, but may be a screening method for those individuals who do not have adequate access or are choosing not to obtain a colonoscopy or stool-based tests.
For one screening period, the cfDNA test performance exceeded the predefined acceptance criteria for regulatory approval and predefined criteria for CMS coverage, with sensitivity for CRC of 83% and specificity for non-advanced neoplasia of 90%. Although the cfDNA test has not been compared head-to-head with stool-based tests, these overall estimates of sensitivity and specificity for CRC appear similar to stool-based tests. However, the cfDNA test has lower sensitivity than colonoscopy and some alternative stool-based tests for the detection of advanced adenomas. The sensitivity for advanced adenoma for the cfDNA test was 13%, i.e., 87% of patients with advanced adenoma may be missed by the cfDNA test. The label recommends that individuals with negative cfDNA test results continue participating in screening programs. Modeling studies conclude that 'blood-based' testing meeting CMS criteria would be clinically effective compared to no screening, but less clinically effective compared to fecal immunochemical test [FIT], multi-target stool DNA, and colonoscopy. Therefore, the cfDNA test may be a screening method for those individuals who are unable to or are choosing not to obtain a colonoscopy or stool-based tests. The authors of the publication of the pivotal results have proposed a 3-year screening interval. Data evaluating the proposed screening interval are being collected as part of the Post-approval Study requirements.
For individuals at average risk of CRC who are being screened for CRC who receive epigenomic and genomic cell-free DNA (cfDNA) blood-based testing, the evidence includes cross-sectional studies. Relevant outcomes are OS, disease-specific survival, test accuracy and validity, change in disease status, and morbid events. For one screening period, the cfDNA test performance exceeded the predefined acceptance criteria for regulatory approval and predefined criteria for Centers for Medicare & Medicaid Services (CMS) coverage, with sensitivity for CRC of 83% and specificity for non-advanced neoplasia of 90%. Although the cfDNA test has not been compared head-to-head with stool-based tests, these overall estimates of sensitivity and specificity for CRC appear similar to stool-based tests. However, the cfDNA test has lower sensitivity (13%) than colonoscopy and some alternative stool-based tests for the detection of advanced adenomas. Modeling studies conclude that 'blood-based' testing meeting CMS criteria would be clinically effective compared to no screening, but less clinically effective compared to fecal immunochemical test, multi-target stool DNA, and colonoscopy. Modeling studies also identify the potential harm if test substitution is not offset by increased screening participation among individuals refusing other screening modalities. Data evaluating a screening interval of 3 years are being collected as part of the Post-approval Study requirements. The evidence is insufficient to determine that the technology results in an improvement in the net health outcome.
| Population Reference No. 3 Policy Statement | [ ] MedicallyNecessary | [X] Investigational |
The purpose of the following information is to provide reference material. Inclusion does not imply endorsement or alignment with the evidence review conclusions.
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.
In 2018, the American Cancer Society recommended that "adults aged 45 years and older with an average risk of CRC [colorectal cancer] undergo regular screening with either a high‐sensitivity stool‐based test or a structural (visual) examination, depending on patient preference and test availability. As a part of the screening process, all positive results on noncolonoscopy screening tests should be followed up with timely colonoscopy." 24, The stool-based tests listed as options are a fecal immunochemical test, fecal occult blood test, and multi-target stool DNA test. The Society noted that "…at this time, [methylated] SEPT9 [Septin9] is not included in this guideline as an option for routine CRC screening for average‐risk adults."
The American College of Gastroenterology published updated guidelines in 2021 on CRC screening recommendations.6, Regarding blood-based tests, they made a conditional recommendation based on very low-quality of evidence stating the following: "We suggest against Septin 9 for CRC screening."
In 2019, based on its review of U.S. guidelines, the American College of Physicians issued a guidance statement on screening for CRC in average-risk adults.25, For average-risk adults ages 50 to 75 years, the College recommended using a stool-based test, flexible sigmoidoscopy, or optical colonoscopy for screening. No recommendation for genetic or molecular testing of average-risk individuals was included. Updated guidance was issued in 2023, and recommended CRC tests mentioned were fecal immunochemical or high-sensitivity guaiac fecal occult blood tests, colonoscopy, flexible sigmoidoscopy, and fecal immunochemical tests.26, The College stated that "Clinicians should not use stool DNA, computed tomography colonography, capsule endoscopy, urine, or serum screening tests for colorectal cancer."
In 2025, the American Gastroenterological Association (AGA) published a clinical practice update focused on blood tests for CRC screening.27, The AGA notes that while such blood tests may increase screening participation due to their convenience, patients should know that a positive result necessitates a follow-up colonoscopy. Furthermore, although modeling shows that regular use of these tests is significantly better than no screening, they are less effective at preventing CRC and related deaths compared to standard screening methods. Therefore, these blood tests are best suited for individuals who decline standard CRC screening methods.
Current National Comprehensive Cancer Network (NCCN) (v.2.2025 ) guidelines on CRC screening state that blood-based screening modalities "should only be employed to screen individuals of average risk with the commitment to a follow-up colonoscopy for any abnormal result."13, Furthermore, blood-based cell-free DNA (bb-cfDNA)-based testing is recommended for every-3-year average-risk screening. The guideline also notes the following regarding bb-cfDNA testing:
The U.S. Multi-Society Task Force (MSTF) on Colorectal Cancer represents the American College of Gastroenterology, the AGA, and the American Society for Gastrointestinal Endoscopy.28, In 2017, the Task Force's clinical guidelines stated that the advantage of SEPT9 assays for CRC screening is convenience. The disadvantage is "markedly inferior performance characteristics compared with FIT [fecal immunochemical test]." The guidelines also stated that the best frequency for performing the test is unknown and that the task force recommended not using SEPT9 assays for CRC screening. The MSTF published a focused update of the guidance in 2022.29, The updated guidance suggested CRC screening in average-risk individuals ages 45 to 49. The updated guidance did not address SEPT9 assays.
In 2021, the U.S. Preventive Services Task Force (USPSTF) updated its recommendations for CRC screening in adults.30,31,4,It recommended screening for CRC starting at age 45 years and continuing until age 85 years. However, conclusions regarding the level of certainty and net benefit with screening varied by age groups. The USPSTF provided a Grade A recommendation for screening in adults aged 50 to 75 years (based on high certainty of a substantial net benefit), a Grade B recommendation for screening in adults aged 45 to 49 years (based on moderate certainty of a moderate net benefit), and a Grade C recommendation for selective screening in adults aged 76 to 85 years (based on moderate certainty of a small net benefit). The guideline states that "because of limited available evidence, the USPSTF recommendation does not include serum tests, urine tests, or capsule endoscopy for colorectal cancer screening." The evidence review supporting the recommendations included a search for studies of serum-based tests (eg, methylated SEPT9 DNA tests) but concluded that the strength of evidence was low, based on a single case-control study.
NCD 210.3 (Colorectal Cancer Screening Tests) refers to blood-based biomarker tests:32,
"Effective for dates of service on or after January 19, 2021, a blood-based biomarker test is covered as an appropriate colorectal cancer screening test once every 3 years for Medicare beneficiaries when performed in a Clinical Laboratory Improvement Act (CLIA)-certified laboratory, when ordered by a treating physician and when all of the following requirements are met:
The patient is:
The blood-based biomarker screening test must have all of the following:
Effective January 1, 2023, the minimum age for blood-based biomarker test is reduced to 45 years and older."
Some currently ongoing and unpublished trials that might influence this review are listed in Table 16.
| NCT No. | Trial Name | Planned Enrollment | Completion Date |
| Ongoing | |||
| NCT03218423a | Performance of Epi proColon in Repeated Testing in the Intended Use Population (PERT) | 4500 | Jan 2024 (unknown) |
NCT: national clinical trial. a Denotes industry-sponsored or cosponsored trial.
| Codes | Number | Description |
|---|---|---|
| CPT | 81327 | SEPT9 (Septin9) (eg, colorectal cancer) methylation analysis |
| 96041 | Medical genetics and genetic counseling services, each 30 minutes of total time provided by the genetic counselor on the date of the encounter | |
| 0163U | Oncology (colorectal) screening, biochemical enzyme-linked immunosorbent assay (ELISA) of 3 plasma or serum proteins (teratocarcinoma derived growth factor-1 [TDGF-1, Cripto-1], carcinoembryonic antigen [CEA], extracellular matrix protein [ECM]), with demographic data (age, gender, CRC-screening compliance) using a proprietary algorithm and reported as likelihood of CRC or advanced adenomas (BeScreened™–CRC test from Beacon Biomedical) | |
| 0537U | Oncology (colorectal cancer), analysis of cell-free DNA for epigenomic patterns, next-generation sequencing, >2500 differentially methylated regions (DMRs), plasma, algorithm reported as positive or negative (Shield™ by Guardant Health) | |
| HCPCS | G0327 | Colorectal cancer screening; blood-based biomarker |
| ICD-10-CM | Investigational for all relevant diagnoses | |
| ICD-10-PCS | Not applicable. ICD-10-PCS codes are only used for inpatient services. There are no ICD procedure codes for laboratory tests. | |
| Type of service | Laboratory/Pathology | |
| Place of service | Reference laboratory |
| Date | Action | Description |
|---|---|---|
| 01/20/2026 | Revision due to MPP | Policy updated with literature review through October 23, 2025; references added. PICOs separated and added separate PICO for Shield test. Position statement added: "Epigenomic and genomic cell-free DNA (cfDNA) blood-based testing with Guardant Shield is considered investigational for all indications (see Policy Guidelines). Added to benefit application statement related to Law 79 of August 1st, 2020, |
| 08/18/2025 | Annual Review | No changes. |
| 08/20/2024 | Annual Review | Policy updated with literature review through May 21, 2024; reference added. Policy statements unchanged. |
| 08/17/2023 | Annual Review | Policy updated with literature review through May 22, 2023; reference added. Policy statements unchanged. |
| 08/23/2022 | Annual Review | Policy updated with literature review through April 18, 2022; no references added. Policy statements unchanged. |
| 08/18/2021 | Annual Review | Policy updated with literature review .references added. Minor change to second gene expression profiling policy statement to add BeScreened™ as investigational. |
| 08/24/2020 | New Policy | Added to the laboratory/pathology section |
| Screening Test | Interval (NCCN Summary, if available) | Sensitivity CRC (NCCN Summary, if available) | Sensitivity Adenoma (NCCN Summary, if available) | Specificity CRC (NCCN Summary, if available) | Specificity Adenoma (NCCN Summary, if available) | Evidence (USPSTF summary, if available) | Considerations (USPSTF summary, if available) |
| Visualization | |||||||
| Colonoscopy | q10 yrs | 94.7 | 89–95(≥10 mm adenomas) 75–93(≥6 mm adenomas) | 89% (≥10 mm adenomas) 94% (≥6 mm adenomas) | Evidence from cohort studies that colonoscopy reduces colorectal cancer mortality· · Harms from colonoscopy include bleeding and perforation, which both increase with age | Screening and diagnostic follow-up of positive results can be performed during the same examination Requires less frequent screening Requires bowel preparation, anesthesia or sedation, and transportation to and from the screening examination | |
| Flex Sig | q5-10 yrs | 58–75 | 72–86 | 92 | Evidence from RCTs that flexible sigmoidoscopy reduces colorectal cancer mortality· · Risk of bleeding and perforation but less than risk with colonoscopy· · Modeling suggests that it provides fewer life-years gained alone than when combined with FIT or in comparison to other strategies | Additional harms may arise from colonoscopy to follow up abnormal flexible sigmoidoscopy results Test availability has declined in the US but may be available in some communities where colonoscopy is less available | |
| CT | q5 yrs | 86–100 | 89(≥10 mm adenomas) 86(≥6 mm adenomas) | 94(≥10 mm adenomas) 88(≥6 mm adenomas) | Evidence available that CT colonography has reasonable accuracy to detect colorectal cancer and adenomas· · No direct evidence evaluating effect of CT colonography on colorectal cancer mortality· · Limited evidence about the potential benefits or harms of possible evaluation and treatment of incidental extracolonic findings, which are common. Extracolonic findings detected in 1.3% to 11.4% of exams; <3% required medical or surgical treatment | Additional harms from screening with CT colonography arise from colonoscopy to follow up abnormal CT colonography results Requires bowel preparation Does not require anesthesia or transportation to and from the screening examination | |
| Stool based | |||||||
| High-sensitivity guaiac-based test | Annual | 50%–75% | 7–21 (advanced neoplasia) 6–17 (advanced adenoma) | 96–98 | 96–99 (advanced neoplasia) 96–99 (advanced adenoma) | Evidence from RCTs that gFOBT reduces colorectal cancer mortality· · High-sensitivity versions (eg, Hemoccult SENSA) have superior test performance characteristics than older tests (eg, Hemoccult II), although there is still uncertainty about the precision of test sensitivity estimates. Given this uncertainty, it is unclear whether high-sensitivity gFOBT can detect as many cases of advanced adenomas and colorectal cancer as other stool-based tests | Harms from screening with gFOBT arise from colonoscopy to follow up abnormal gFOBT results Requires dietary restrictions and three stool samples Requires good adherence over multiple rounds of testing Does not require bowel preparation, anesthesia, or transportation to and from the screening examination (test is performed at home) |
| Quantitative FIT (using OC-Sensor) | Annual | 74 | 25 (advanced neoplasia) 23 (advanced adenoma) | 94 | 96 (advanced neoplasia) 96 (advanced adenoma) | Evidence from 1 large cohort study that screening with FIT reduces colorectal cancer mortality· · Certain types of FIT have improved accuracy compared with gFOBT and HSgFOBT (20 μg hemoglobin per gram of feces threshold was used in the CISNET modeling) | Harms from screening with FIT arise from colonoscopy to follow up abnormal FIT results Can be done with a single stool sample Requires good adherence over multiple rounds of testing Does not require bowel preparation, anesthesia or sedation, or transportation to and from the screening examination (test is performed at home) |
| Quantitative FIT (using OC-Light) | Annual | 81 | 27 (advanced neoplasia) 28 (advanced adenoma) | 93 | 95 (advanced neoplasia) 94 (advanced adenoma) | ||
| Cologuard | q3 yrs | 93 | 47 (advanced neoplasia) 43 (advanced adenoma) | 85 | 89 (advanced neoplasia) 89 (advanced adenoma) | Systematic review conducted by Lin et al informed USPSTF recommendations; Imperiale 2014 study accounted for ≥80% of the data (n=9,989) Improved sensitivity compared with FIT per 1-time application of screening test· Specificity is lower than that of FIT, resulting in more false-positive results, more follow-up colonoscopies, and more associated adverse events per sDNA-FIT screening test compared with per FIT test· · Modeling suggests that screening every 3 y does not provide a favorable (ie, efficient) balance of benefits and harms compared with other stool-based screening options (ie, annual FIT or sDNA-FIT every 1 or 2 y)· · Insufficient evidence about appropriate longitudinal followup of abnormal findings after a negative follow-up colonoscopy· · No direct evidence evaluating the effect of sDNA-FIT on colorectal cancer mortality | Harms from screening with sDNA-FIT arise from colonoscopy to follow up abnormal sDNA-FIT results Can be done with a single stool sample but involves collecting an entire bowel movement Requires good adherence over multiple rounds of testing Does not require bowel preparation, anesthesia or sedation, or transportation to and from the screening examination (test is performed at home) |
| Cologuard Plus | 94 (87 to 98) | 43 (41 to 46) | 91(90 to 91) | Pivotal study: Imperiale T, et al. N Engl J Med (2024) (n=20,176 ) USPSTF summary not yet available | USPSTF summary not available Data limited on screening period, although could reasonably extrapolate from data on Cologuard | ||
| ColoSense | q3 yrs | 94% | 46% (advanced adenoma) | 86% (advanced adenoma) | Pivotal study: Barnell EK, et al. JAMA. 2023 (n=7,763) USPSTF summary not yet available | USPSTF summary not available Screening interval not determined; biologically plausible to be similar to Cologuard; very similar performance characteristics would suggest modeling studies for Cologuard would be applicable for Colosense | |
| Blood-based | |||||||
| Epi pro | 75 | 48.2 (32.4 to 63.6) | 93 | 91.5 (89.7 to 93.1) | USPSTF summary not yet available | USPSTF summary not yet available | |
| ColonSentry | 61 to 72 | 70 to 77 | USPSTF summary not yet available 2 cross-sectional studies | USPSTF summary not yet available | |||
| BeScreened-CRC | USPSTF summary not yet available No published evidence | USPSTF summary not yet available | |||||
| Shield | 83 | 13 (advanced pre-cancerous lesions) | 90 | 90 (advanced pre-cancerous lesions) | 1 well designed study (n=7,861) USPSTF summary not yet available | USPSTF summary not yet available Screening interval not determined; CMS coverage will be q3 yrs | |
CISNET: Cancer Intervention and Surveillance Modeling Network; CMS: Centers for Medicare & Medicaid Services; CT: computed tomography; FIT: fecal immunochemical test; HSgFOBT: high-sensitivity guaiac fecal occult blood test; NCCN: National Comprehensive Cancer Network; sDNA: stool DNA; USPSTF: U.S. Preventive Services Task Force. 1Additional information available in NCCN and USPSTF colorectal cancer screening guidelines.