Screening for Colorectal Cancer-Non-Invasive Biomarker Tests

The Centers for Medicare & Medicaid Services (CMS) proposes changes to NCD (210.3) colorectal cancer screening tests according to the provisions in sections I.B. and I.C. below.

B.              Coverage Criteria

We propose that non-invasive biomarker colorectal cancer screening tests are covered once every three years for Medicare beneficiaries when ordered by the physician, physician assistant, nurse practitioner, or clinical nurse specialist who will use the results in the management of the patient and when all the following conditions are met:

a.                Patient Criteria

1. Age 45 to 85 years, and,
2. Asymptomatic (no signs or symptoms of colorectal disease including but not limited to lower gastrointestinal pain, blood in stool, positive guaiac fecal occult blood test (gFOBT) or fecal immunochemical test (FIT)), and,
3. At average risk of developing colorectal cancer (no personal history of adenomatous polyps, colorectal cancer, or inflammatory bowel disease, including Crohn’s Disease and ulcerative colitis; no family history of colorectal cancers or adenomatous polyps, familial adenomatous polyposis, or hereditary nonpolyposis colorectal cancer).

b.                Test Criteria

1. The test must be Food and Drug Administration (FDA) market authorized and indicated for colorectal cancer screening; and,
2. The test must achieve the requirements of the FDA-required post-approval study as specified in the Safety and Effectiveness Data (SSED) to continue coverage; and
3. The test must be processed in a CLIA certified laboratory; and,
4. The test must demonstrate performance characteristics that meet EITHER Criteria 1, a sensitivity of greater than or equal to 90% and a specificity greater than or equal to 87%, OR Criteria 2, a sensitivity of greater than or equal to 79% and a specificity of greater than or equal to 90% in the detection of colorectal cancer compared to the recognized standard (accepted as colonoscopy at this time), based on the FDA labeling.

All other indications for colorectal cancer screening not otherwise specified in the Act and regulations, or otherwise specified above, remain nationally non-covered.

See Appendix A for proposed Medicare National Coverage Determinations Manual language.

CMS is seeking comments on our proposed decision. We will respond to public comments in a final decision memorandum, as required by §1862(l)(3) of the Act.

Table of Contents

1. Proposed Decision
   1. Proposed Decision
   2. Coverage Criteria
      1. Patient Criteria
      2. Test Criteria
   3. Other Uses of Colorectal Cancer Screening Biomarker Tests
2. Clinical Review
   1. Background
   2. Food and Drug Administration Status
3. Evidence
   1. Evidence Questions
   2. Technology Assessments
   3. Medicare Evidence Development and Coverage Advisory Committee (MEDCAC)
   4. Clinical Literature Search
      1. Summary of Evidence
   5. Assessment of the Evidence
      1. RNA-based stool tests
      2. DNA-based stool tests
      3. DNA-based blood-based tests
      4. Limitations
      5. Relevance and generalizability to Medicare beneficiaries
      6. Evidence from systematic reviews and meta-analyses
   6. Evidence-Based Guidelines
   7. Professional Society Recommendations / Consensus Statements / Other Expert Opinion
   8. Appropriate Use Criteria
   9. Public Comments
4. CMS Coverage Analysis
   1. CMS Coverage Authority
   2. CMS Analysis for Coverage of CRC screening
      1. Rationale for Coverage Requirements for CRC screening
      2. Evidence Questions – Answered
   3. Benefit Category
5. History of Medicare Coverage
   1. Current National Coverage Request
   2. Timeline of NCA Milestones
6. Appendices
   Appendix A: Proposed Medicare National Coverage Determinations Manual Language
   Appendix B: Referenced Materials
Bibliography

Abbreviations used throughout the Proposed Decision Memorandum for Colorectal Cancer Screening Non-Invasive Biomarker Tests

AA – Advanced adenoma
ACG – American College of Gastroenterology
ACS – American Cancer Society
BBB – Blood-based biomarker
bb-cf DNA — Blood-based cell-free DNA
cfDNA – Cell-free DNA (deoxyribonucleic acid)
CI – Confidence interval
CMS – Centers for Medicare and Medicaid Services
CRC – Colorectal cancer
CTC – CT colonography
ct-DNA – Circulating tumor DNA
DNA – Deoxyribonucleic acid
fDNA – Fecal deoxyribonucleic acid
FOBT – Fecal occult blood test
FDA – United States Food & Drug Administration
FIT – Fecal immunoassay test or Fecal immunochemical test; also known as iFOBT (Immunochemical Fecal Occult Blood Test)
gFOBT – Guaiac fecal occult blood test
HGD — High-grade dysplasia
iFOBT – Fecal immunochemical test or Immunochemical Fecal Occult Blood Test, also known as FIT (Fecal Immunochemical Test)
mt-sDNA – Multi-target stool DNA (deoxyribonucleic acid)
mt-sRNA – Multi-target stool RNA (ribonucleic acid)
NCI – National Cancer Institute
NPV – Negative predictive value
PPV – Positive predictive value
RCT – Randomized control trial
RNA – Ribonucleic acid
sDNA – Stool deoxyribonucleic acid
SEER – Surveillance, Epidemiology, and End Results
SSA – Sessile serrated adenoma
SSED – Summary of Safety and Effectiveness Data
SSP – Sessile serrated polyps
USPSTF – United States Preventive Services Task Force

I.                 Proposed Decision

The Centers for Medicare & Medicaid Services (CMS) proposes changes to NCD (210.3) colorectal cancer screening tests according to the provisions in sections I.B. and I.C. below.

B.              Coverage Criteria

We propose that non-invasive biomarker colorectal cancer screening tests are covered once every three years for Medicare beneficiaries when ordered by the physician, physician assistant, nurse practitioner, or clinical nurse specialist who will use the results in the management of the patient and when all the following conditions are met:

a.                Patient Criteria

1. Age 45 to 85 years, and,
2. Asymptomatic (no signs or symptoms of colorectal disease including but not limited to lower gastrointestinal pain, blood in stool, positive guaiac fecal occult blood test (gFOBT) or fecal immunochemical test (FIT)), and,
3. At average risk of developing colorectal cancer (no personal history of adenomatous polyps, colorectal cancer, or inflammatory bowel disease, including Crohn’s Disease and ulcerative colitis; no family history of colorectal cancers or adenomatous polyps, familial adenomatous polyposis, or hereditary nonpolyposis colorectal cancer).

b.                Test Criteria

1. The test must be Food and Drug Administration (FDA) market authorized and indicated for colorectal cancer screening; and,
2. The test must achieve the requirements of the FDA-required post-approval study as specified in the Safety and Effectiveness Data (SSED) to continue coverage; and
3. The test must be processed in a CLIA certified laboratory; and,
4. The test must demonstrate performance characteristics that meet EITHER Criteria 1, a sensitivity of greater than or equal to 90% and a specificity greater than or equal to 87%, OR Criteria 2, a sensitivity of greater than or equal to 79% and a specificity of greater than or equal to 90% in the detection of colorectal cancer compared to the recognized standard (accepted as colonoscopy at this time), based on the FDA labeling.

All other indications for colorectal cancer screening not otherwise specified in the Act and regulations, or otherwise specified above, remain nationally non-covered.

See Appendix A for proposed Medicare National Coverage Determinations Manual language.

CMS is seeking comments on our proposed decision. We will respond to public comments in a final decision memorandum, as required by §1862(l)(3) of the Act.

II.              Clinical Review

A.              Background

Colorectal cancer (CRC) is the fourth most common cancer and the second leading cause of cancer deaths in the United States (Siegel et al., 2024). In 2025, the National Cancer Institute (NCI) estimated that there would be over 154,270 new cases of colorectal cancer in the United States with the highest percentage of cases (25.8%) in ages 65 to 74 years and a median age at diagnosis of 66 years (NCI/SEER, 2025). Primary prevention, early detection and early treatment have contributed to declining overall mortality rates for CRC over the past decade. However, CRC was estimated to account for over 52,000 deaths in 2025, with a median age at death of 72 years (NCI/SEER, 2025).

Early detection and removal of large pre-cancerous adenomas helps prevent the progression of these noncancerous tumors to cancerous tissue (carcinoma), reducing the incidence of colorectal cancer and improving mortality (American Cancer Society, 2024). If cancerous cells spread beyond where they started (localized versus regional or distant), it can negatively affect a person’s survival (NCI/SEER, 2025). While the screening rate of CRC has increased, there are still missed opportunities as the screening rate in adults aged 45-75 years (63%) remains below the Healthy People 2030 goal of 72.8% (US HHS, 2024). Colonoscopy is the gold standard for CRC screening.

Constant colorectal epithelial tissue renewal occurs in the colon epithelium, in which cells migrate to surface levels and then undergo apoptosis (normal programmed cell death) and are shed into the colon lumen. Normal systems that regulate DNA repair and healthy cell proliferation (e.g., suppressor genes, oncogenes, DNA repair genes) become damaged by cellular mutations as adenomas form (Nguyen et al., 2020). Sequential alterations in growth regulatory genes and progressive cellular tissue changes can occur via multiple pathways, but specific gene mutations must occur for these cells to become malignant (Nguyen et al., 2020). Testing of stool for fecal DNA or RNA aims to detect molecular biomarkers of altered genetic material that are contained in the cells shed by CRC and pre-malignant colorectal epithelial neoplasia into the lumen of the large bowel (Gómez-Molina et al., 2024).

Genetic biomarkers are released regularly and continuously, due to the constant sloughing of the colorectal epithelial cells lining the bowel lumen and end up in the stool stream. Using selective enrichment and amplification techniques, multitarget stool DNA (mt-sDNA) and multitarget stool RNA (mt-sRNA) tests are designed to detect very small amounts of genetic biomarkers to identify pre-malignant colorectal neoplasia (including advanced adenomas [AAs]) and CRC.

Altered genetic material shed by cancerous cells can also be released into the bloodstream and potentially be identified with “liquid biopsies” or blood serum samples, including tests that examine non-genetic cell-free DNA (cfDNA) biomarkers (Mannucci & Goel, 2024). Multitarget blood-based tests are designed to detect the presence of cancer-derived signals based on different profiles and combinations of the circulating cfDNA.

B.              Food and Drug Administration Status

On August 11, 2014, the FDA approved the Cologuard® premarket approval (PMA) application (P130017). Cologuard® is intended for the qualitative detection of colorectal neoplasia associated with DNA markers and for the presence of occult hemoglobin in human stool and is indicated as a screening test for adults, 45 years or older, who are at typical average-risk for CRC.

The Cologuard® post-approval study (PAS) is a prospective longitudinal study to assess the impact of repeat Cologuard® testing at 3 years in average risk patients.

On May 3, 2024, the FDA approved the ColoSense® PMA application (P230001).  ColoSense® is intended for the qualitative detection of colorectal neoplasia associated RNA markers and for the presence of occult hemoglobin in human stool and is indicated as a screening test for adults, 45 years of age or older, who are at typical average-risk for developing CRC.

The ColoSense® PAS is a prospective study. The primary objective is to continue to evaluate the clinical effectiveness of ColoSense® by obtaining at least 23 CRC cases (23 cases in addition to the 27 obtained in CRC-PREVENT for a total of 50 CRC cases) to have an adequate number of CRC subjects that are part of the intended use population (average risk) to provide more certainty in the test performance. The secondary objective of this PAS is to further define sensitivity for CRC, AAs, and serrated precancerous lesions and specificity for negative findings on a colonoscopy for Geneoscopy’s mt-sRNA test (ColoSense®), using colonoscopy as the reference method.

On July 26, 2024, the FDA approved the Shield™ PMA application (P230009). Shield™ is a qualitative, in vitro diagnostic test intended to detect colorectal cancer derived alterations in cfDNA from blood collected in the Guardant Shield Blood Collection Kit and is intended for screening in individuals at average risk of the disease, age 45 years or older.

The Shield™ PAS is a prospective, longitudinal study supplemented with Real World Evidence (RWE) to evaluate the longitudinal performance of Shield™ in an average risk population at a second round of testing for individuals between the ages of 45 and 81 at average risk of CRC using colonoscopy as the reference method.

On October 3, 2024, the FDA approved the Cologuard Plus™ PMA application (P230043). Cologuard Plus™ is a qualitative in vitro diagnostic test intended for the detection of colorectal neoplasia associated DNA markers and for the presence of occult hemoglobin in human stool and is indicated to screen adults 45 years or older, who are at average risk for CRC.

The FDA PAS Database can be accessed at: https://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfPMA/pma_pas.cfm. 

III.           Evidence

This section provides a summary of the evidence considered during this review.  The evidence presented here includes the pertinent published clinical research on CRC screening. This proposed NCD addresses CRC screening biomarker tests. It does not address the long-standing policy on fecal occult blood tests (FOBT).

A detailed account of the methodological principles of study design that the Agency utilizes to assess the relevant literature can be found in the CMS National Coverage Analysis Evidence Review Guidance Document, published August 7, 2024.

A.              Evidence Questions

The following questions guide our review and analysis of the evidence on the clinical utility of CRC non-invasive biomarker screening tests:

Question 1: Is the evidence sufficient to determine that screening for colorectal cancer with non-invasive biomarker tests is reasonable and necessary for the prevention or early detection of illness or disability?

Question 2: Is the evidence sufficient to determine that screening for colorectal cancer with non-invasive biomarker tests is appropriate for Medicare beneficiaries?

B.               Technology Assessments

CMS did not request an external technology assessment on this topic.

C.              Medicare Evidence Development and Coverage Advisory Committee (MEDCAC)

A MEDCAC meeting was not convened on this topic.

D.              Clinical Literature Search

A systematic literature review was undertaken to address the evidence questions defined above. Literature searches were conducted in PubMed and Embase focusing on non-invasive biomarker CRC screening tests. The database searches were conducted using structured vocabulary terms and included key words centered on non-invasive CRC screening multi-targeted stool RNA or DNA and blood-based tests (molecular biomarkers). The review included published English language literature from 2021 to present. The literature search excluded abstracts from presentations at meetings and animal studies.

A supplementary search was conducted specifically targeting blood-based CRC screening tests. The original database searches included the term “non-invasive” and would potentially exclude tests utilizing a patient peripheral venous blood draw.

The literature searches were originally conducted on December 19, 2024. Additional literature was submitted during the initial 30-day comment period and included in the evidence review.

This review identified 9 studies that met the inclusion criteria, only one of which was a randomized controlled trial. Five studies were observational prospective cohort designs including two stool RNA, two stool DNA, and one blood-based DNA study. One study was a retrospective cohort study of a stool-based DNA test in hemorrhoid patients, one study used a retrospective comparison design to compare a stool-based DNA test to CT colonography (CTC), and one study was a prospective comparative trial of two new stool-based DNA tests versus a FIT test.

We note that two publications were published shortly prior to posting of this proposed decision memorandum. While they have not been summarized in detail here, we will include them in the final decision memorandum. The results of the recent publications do not change our proposed decision.

Table 1 (Appendix B) provides an overview of studies included in this systematic review.

Table 2 (Appendix B) outlines the CRC specificity & sensitivity primary outcomes for each study included in the report.

E.                Assessment of the Evidence

1.     RNA-Based Stool Tests

Barnell et al., 2021 assessed the ability for the stool-based RNA-FIT test to detect advanced neoplasias (CRC and AA), examining sensitivity for highly aggressive precancerous adenomas (AAs with high-grade dysplasia (HGD), carcinoma in situ, or villous/tubulovillous architecture). One thousand three hundred five (1,305) participants were split into a 939-patient screening model development training set, and then the model was used on a 366-patient hold out testing set, with 22 samples also obtained from patients after diagnosis of CRC or AA. The RNA-FIT assay demonstrated 95% sensitivity for CRC detection and 85% specificity for no findings on a colonoscopy in a geographically diverse, predominantly White participant sample. Along with high sensitivity, the test was able to detect 62% of all AAs and 25% of other non-advanced adenomas (non-AA). The authors speculate that the RNA-FIT assay reduction in specificity relative to existing screening alternatives may have been partially attributable to missed adenomas on colonoscopy considering this increased test sensitivity for both AA and non-AA. Overall, the authors concluded that the RNA-FIT test was able to demonstrate clinically relevant detection by the RNA-FIT screening test of all grades of colorectal neoplasia, including carcinomas, AAs, and other non-AAs (ONAs).

Barnell et al., 2023 was a phase III pivotal clinical trial (CRC-PREVENT) to evaluate the sensitivity and specificity of a noninvasive, mt-sRNA test (ColoSense®) compared with results from a colonoscopy. The study sample was also geographically diverse across the US, although only 4.7% of participants were enrolled in rural settings and participants were predominantly White, recruited from an online social media platform through a decentralized recruitment effort. The mt-sRNA test demonstrated 94.4% sensitivity for CRC detection and 45.9% for AA. The mt-sRNA test sensitivity for CRC detection (94.4% vs 77.8%; McNemar p = .01) and AA detection (45.9% vs 28.9%; McNemar p < .001) was significantly higher when compared to the FIT test. The mt-sRNA test specificity for no findings on a colonoscopy was 86.9%, and 95.4% (95% confidence interval [CI]: 95 to 96) for the FIT test. The FIT test specificity for no lesions on colonoscopy was also higher than the mt-sRNA test (95.7% vs 87.9%; p < .001). When examining test performance by age group, results indicated a sensitivity of 87.5% (n=7/8) for CRC and 49.6% (n=61/123) for AA in adults 65 years of age or older. Specificity in this age group for no findings was 85.2% (n=588/690). FIT test performance in this age group was not reported.

2.     DNA-Based Stool Tests

Imperiale et al., 2021 sought to quantify the specificity and sensitivity of a mt-sDNA test for CRC and advanced precancerous lesions (APL) in average-risk 45–49-year-olds who were interested in having a screening colonoscopy. No participants had CRC or HGD, and the large sample size required to estimate sensitivity in a low prevalence population precluded the feasibility of estimating mt-sDNA test sensitivity. The mt-sDNA test sensitivity for APL detection was 32.7%, but there was a lack of HGD identified in the participants. The specificity for no findings (either nonadvanced neoplasia or negative findings) was 95.2% and 96.3% for only negative findings. The authors noted that the higher specificity likely reflects the expected lower prevalence of any colorectal neoplasia, lesions that cause bleeding, and lower background methylation in stool samples in a younger age group.

Imperiale et al., 2024 conducted a large prospective pivotal study (BLUE-C trial) on a new mt-sDNA screening test, identified as a 2.0 next-generation test being developed by Exact Sciences, that used the same principle of operation as the prior FDA-approved Cologuard® test. However, the new version includes an optimized methylation marker panel, a newly formulated hemoglobin sample stability buffer, and removes the KRAS mutation detection (Imperiale et al., 2024). The researchers indicated these changes were aimed at increasing test specificity and increasing the time between collection and testing, while maintaining or increasing the CRC and AA sensitivity. The FDA approved this test as “Cologuard Plus™” in October 2024, and became publicly available in 2025, based upon the results of this trial. The study recruited participants aged 40 and above, though only 59 of the 20,176 enrolled, evaluable participants were 40 to 44 years of age. Only 60.1% of participants identified as White (not Hispanic or Latino) in the study conducted at 186 sites across the US. The test sensitivity for CRC detection was 93.9% and sensitivity for APL was 43.4%. The specificity for nonneoplastic findings or negative colonoscopy was 92.7% and the specificity for AA was 90.6%.

Deiss-Yehiely et al., 2022 compared noninvasive screening detection of high-risk Sessile Serrated Lesions (SSLs) between the mt-sDNA test and CTC in separate electronic medical record cohorts at one large institution. Participants selected for the study with a negative test result would not have typically followed up with a colonoscopy, preventing the researchers from determining a sensitivity and specificity for detection of high-risk SSLs. Unlike mt-sDNA and other stool-based tests that yield binary results (e.g., positive, negative), CTC provides information on polyp size and morphology and can be stratified by size thresholds for test positivity (e.g., small polyps: 6–9 mm, large polyps: ≥ 10 mm, or frank masses concerning for CRC) and diagnostic confidence. Results indicated that CTC at both thresholds had significantly higher yield (6-mm= 1.7%; 10-mm: 1.6%) for high-risk SSLs compared with mt-sDNA (0.7%) detection rate (p<0.001). Similarly, there were significant differences (p<0.001) for the positive predictive value (PPV) of mt-sDNA for high-risk SSLs (5.5%) compared with CTC at the 6-mm threshold (14.4%) and CTC with the 10-mm threshold (25.9%). Age (63.8 vs. 56.2 years) and gender (females: 64% vs 54%; males: 36% vs 46%) were significantly different in this retrospective cohort study between the mt-sDNA and CTC groups (both p <0.001).

Ebner et al., 2023 conducted a retrospective study of participants from the DeeP-C Trial (Original study: Imperiale et al., 2014) to evaluate the effect of hemorrhoids on noninvasive mt-sDNA stool test performance for CRC screening. The DeeP-C study took place from 2011 to 2013 and was the trial to support the safety and effectiveness of the mt-sDNA Cologuard® test as a screening device for the detection of markers associated with the presence of CRC and AA. The mt-sDNA specificity for the detection of advanced neoplasia was 86.4% in patients without hemorrhoids versus 86.7% in those with hemorrhoids (p=67). The mt-sDNA sensitivity for CRC detection was 92.9% in patients with hemorrhoids and 91.9% in those without. Overall, the authors reported that none of the mt-sDNA test characteristics differed significantly on the basis of hemorrhoid status.

Jin et al., 2022 tested two new stool-based DNA tests against a FIT test for CRC screening to estimate the sensitivity and specificity of the tests to detect CRC. The tests were developed and offered to outpatient adults because the mt-sDNA Cologuard® test was not available in China. The specificities for a negative colonoscopy result for the stool DNA test-I (91.4%) and test-II (93.3%) were significantly lower (both p < 0.001 by McNemar test) than the FIT (96.8%). The sensitivity for CRC detection for stool-based DNA test-I (90.5%) was not significantly different from a FIT test (88.1%) adjusted to match the specificity of the DNA test. Likewise, the test-II (92.9%) sensitivity did not differ from an adjusted FIT test (88.1%). Although the two types of stool-based DNA tests demonstrated adequate sensitivity and specificity for CRC screening, there was no significant advantage compared with FIT.

3.     DNA-Based Blood Tests

Coronado et al., 2024 was the only RCT identified and examined whether adherence to CRC screening recommendations in an organized FIT screening program could be improved by integrating a blood-based testing option opportunistically as part of standard health encounters. The primary outcome was receipt of any CRC screening test (blood draw or FIT or FIT-DNA or flexible sigmoidoscopy or colonoscopy) within 3 months of eligibility determination. Participants were randomly assigned to receive either the Guardant Health cfDNA blood test or standard of care, which included point-of-care reminders to complete FIT testing. A total of 30.5% underwent CRC screening blood test, FIT, or colonoscopy and 13% of the usual care group completed a FIT or colonoscopy. Further, 10.4% had abnormal results with the blood test, leading to a follow-up colonoscopy in 50% of cases. In comparison to cfDNA blood test, 4.7% had abnormal results on FIT test and 70% of these had a follow-up colonoscopy. The authors reported an increase in CRC screening of 17.5% when adding the option of a blood test. Hence, adding cfDNA as an additional screening tool with FIT for CRC screening might increase CRC screening among an average risk population.

Chung et al., 2024 conducted the ECLIPSE Study (Evaluation of the ctDNA [circulating tumor DNA] LUNAR Test in an Average Patient Screening Episode) to assess the performance characteristics of a cfDNA blood-based test in a population eligible for CRC screening. All patients underwent cfDNA testing followed by colonoscopy.  The cfDNA test demonstrated a sensitivity of 83.1% for detecting CRC, with varying sensitivities by different stages (Stage I: 65%, Stage II: 100%, Stage III: 100% and Stage IV: 100%). The specificity for no neoplasia was 89.9%, with a false positive rate of 10.1%. Exploratory analyses examined PPV and negative predictive value (NPV) for several lesions. Overall, PPV (CRC) was 3.2%, PPV (advanced cancerous lesions) was 12.9% and NPV (no CRC) was 99.9%. The study further reports sensitivity across tumor sizes, tumor grade, as well as histopathology diagnosis and demographic characteristics including age, race, gender, and tobacco use. The authors reported that there were no unanticipated adverse device events observed across the 22,877 enrolled subjects. Of the 43 reported adverse events, 30 (70%) were minor related to phlebotomy and 13 (30%) were unrelated to the study intervention, including the two reported serious adverse events. Key possible adverse events related to the device/ screening technique included bruising and swelling at the site of blood collection, dizziness, syncope, emesis, fainting, hematoma, nausea and vomiting, and vasovagal episode. The study suggested the potential utility of the cfDNA blood test as a non-invasive screening tool to increase adherence for CRC detection in the average risk population.

4.     Limitations

The reviewed evidence had several limitations.

• All studies of commercially available CRC tests (Cologuard®, ColoSense®, Shield™) were supported by the companies that developed the tests.
• While utilizing multiple recruitment sites may potentially benefit the generalizability of the study findings, it also may lead to differing standard colonoscopy protocols (e.g., scheduling, bowel preparation, reporting practices, pathology reports) and practitioners with varying experience and skill levels. The variability in both aspects of the study may affect colonoscopy withdrawal times and adenoma detection rates, potentially increasing the variability of results and the false-positive and false-negative result rate of the mt-sRNA, mt-sDNA, and blood-based biomarker (BBB) tests (Barnell et al., 2021; Barnell et al., 2023; Chung et al., 2024; Imperiale et al., 2024).
• Non-randomly selected or non-randomly assigned study designs have the potential for participant self-selection bias, which are open to confounding factors that may be controlled with randomization strategies.
• The retrospective study designs have inherent weaknesses, such as the potential for confounding and bias, leading to limits to the study’s internal validity (Deiss-Yehiely et al., 2022; Ebner et al., 2023).
• The comparative mt-sDNA vs CTC study conducted by Deiss-Yehiely et al., 2022 did not match participants by age, sex, or propensity score and reported a significant difference in age and sex between the groups. Differential health behavior, CRC risk and prevalence associated with age and gender may impact study findings.
• Ebner et al., 2023 retrospectively studied the effect of hemorrhoids on a mt-sDNA test from study data that was not collected for this purpose and did not control for other non-neoplastic factors (e.g., angioectasias, diverticulum) that may have potentially influenced the result of the mt-sDNA test.
• Imperiale et al., 2021 studied a mt-sDNA test in an average-risk screening population of 45- to 49-year-olds; however, none of the study participants were found to have CRC or HGD, potentially inhibiting performance for CRC detection and limiting the interpretation of the APL sensitivity.
• Furthermore, cross-sectional designs and randomized trials with short follow-up duration preclude accurate assessment of long-term benefits in clinical outcomes. No study reported adverse events, except for Chung et al. (2024), or morbidity or mortality-related outcomes.
• Study cohorts reported enrollment of predominantly White participants; the majority of participants in all studies were female.

5.     Relevance and Generalizability to Medicare Beneficiaries

Although CRC screening is recommended to begin for adults well below the age of most Medicare beneficiaries, guidelines recommend screening continue until at least age 75 years. The risk of CRC increases with age and continues in older adult populations, with the number of colon cancer cases increasing from 34.3–62.5 per 100,000 between ages of 50–64 years to 92.6–212.2 per 100,000 between 65–85 years (Mattiuzzi et al., 2019). CRC incidence rates increase by approximately 80% to 100% with each 5-year age group until 50 years of age and then by 20% to 30% from ages 55-59 years upward (ACS, 2023). Routine screening for CRC continues to be an important part of health and wellness, and disease prevention in the Medicare population.

In terms of applicability of study findings, consideration of multiple study design and participant sample characteristics help determine whether the findings from these studies are applicable to other populations (i.e., Medicare beneficiaries). The studies reviewed for this report had few exclusion criteria, other than exclusion criteria for a history of colorectal neoplasia, digestive cancer, or inflammatory bowel disease, indicators of a high-risk population. The studies recruited and enrolled asymptomatic, average-risk participants. The studies varied in the reporting of other demographic information (e.g., income, health, body mass index [BMI], geographic location, colonoscopy testing setting).

All but two reviewed studies (Deiss-Yehiely et al., 2022; Imperiale et al., 2021) reported age groups for participant samples in order to identify the number of older adults enrolled. One study only enrolled participants 45-49 years old (Imperiale et al., 2021) and only approximately 4% of participants in the mt-sRNA test study by Barnell et al. (2021) were adults over 65 years of age. All other studies reporting age groups reported older adult (greater than age 60 or 65) enrollment of 25-50% of the studied sample. Three studies reported CRC test performance results by age group, specifically in adults 60 or 65 years or older (Barnell et al., 2023; Chung et al., 2024; Imperiale et al., 2024). These three studies covered the three FDA-cleared screening tests (mt-sRNA, mt-sDNA, mt-cfDNA).

Considering the many clinical sites, large sample sizes, and lack of restrictive exclusion criteria, the study findings are likely to be applicable to a Medicare population. However, there was a general lack of diversity in racial and ethnic participant characteristics, potentially limiting the applicability of study results to some population subgroups.

6.    Evidence from Systematic Reviews and Meta-Analyses

The systematic reviews and meta-analyses captured by the searches conducted for this report were closely reviewed for any potential studies that may meet the report’s inclusion criteria and did not yield additional qualifying studies. Some of the key ongoing and emerging research summarized in the reviews are outlined below.

Biomarkers associated with methylation processes are a common focus of research, including methylated circulating tumor DNA (ctDNA), white blood cell DNA, and panels of methylated genes (Khabbazpour et al., 2024). As a biochemical epigenetic process, methylation occurs when a methyl group is added to a protein, DNA, or another molecule, signaling a potential alteration in gene expression (Ferrari et al., 2021; Goyal et al., 2023; Khabbazpour et al., 2024). Genetic alterations can also be detected in RNA, micro-RNA (miRNA), and Piwi-Interacting RNA (piRNA) that serve important regulatory functions related to cell differentiation, development, and growth (Ferrari et al., 2021; Goyal et al., 2023; Zakari et al., 2024; Zhao et al., 2021). The FDA-cleared available stool and blood-based tests include processes to identify methylated genes, and more work is being conducted to identify other potential genetic biomarkers or panels of these biomarkers that may have increased sensitivity and specificity for CRC. Alterations in circulating blood lipids and elevated levels of various panels of proteins (e.g., carcinoembryonic antigen, carbohydrate antigen 19-9) are also being studied as blood-based biomarkers to detect CRC (Ferrari et al., 2021). Many of the potential protein CRC biomarkers can also be present or elevated with inflammatory processes present in other non-cancerous conditions, confounding progress for this work.

In a recent novel approach, researchers sponsored by Freenome Holdings have developed and tested a blood-based CRC screening test that combines multiple technologies, such as computational biology, machine learning, and multiple data types (RNA, DNA, proteins). The company has utilized multi-omics (i.e., using data from different research areas such as genomics, epigenomics, transcriptomics, proteomics, metabolomics) as the basis for developing the CRC screening test and has conducted a large prospective cohort clinical trial (PREEMPT CRC) in average-risk, asymptomatic adults aged 45-85 years (Shaukat et al., 2025). The trial enrolled 48,995 participants (27,010 were evaluated) across more than 200 research sites, using virtual and traditional recruitment methods to reach underserved communities and ensure a representative population (Shaukat et al., 2025). The study found that the blood-based CRC screening method demonstrated a CRC sensitivity in detecting colorectal cancer of 79.2% (Stage I: 57.1%, Stage II: 100%, Stage III: 82.4%, Stage IV: 100%) and a 91.5% specificity for non-advanced colorectal neoplasia (Shaukat et al., 2025). The company has indicated that it will continue to optimize the testing method for CRC sensitivity and AA detection.

Along with altered RNA and DNA, other potential stool-based biomarkers include an isoenzyme (M2-PK) and differential gut microbiota have been identified in some CRC patients (Ferrari et al., 2021; Song et al., 2023). Recent reviews of the potential use of gut microbiota as a CRC screening modality concluded that there were conflicting results related to a high level of heterogeneity in inclusion criteria and study methodology, and no consensus on common markers among the studies (Lișcu et al., 2024; Zwezerijnen-Jiwa et al., 2023).

Overall, ten systematic reviews were screened for applicable noninvasive CRC stool or blood-based screening tests. As noted, a large body of work exists for emerging CRC screening biomarkers, though the consensus from these reviews suggests limited reliability and generalizability despite advances in CRC biomarker research. Specifically, the studies lack standardized protocols for biomarker detection and quantification methods, resulting in high variability of results across studies, as well as a lack of sufficient validation in large, diverse patient populations (Goyal et al., 2023; Laugsand et al., 2021; Mannucci & Goel, 2024; Zakari et al., 2024). As with studies of existing FDA-cleared CRC screening tests, trials will need to conduct direct performance comparisons FIT tests that use colonoscopy as the gold standard comparator and evaluate their combined use for advanced pre-cancerous lesion screening (Goyal et al., 2023).

F.               Evidence-Based Guidelines

We identified four evidence-based professional society guidelines (ACG, ACS, ACP, NCCN) relevant to CRC screening. A complete summary of these guidelines is included in Table 3 (Appendix B).

In 2025, the NCCN published an update (Version 2.2025 – June 24, 2025) to their 2024 CRC screening guidelines and added mt-sRNA and bb-cfDNA tests as recommended stool-based and blood-based, respectively, colorectal cancer screening strategies, in addition to the currently NCCN recommended mt-sDNA-based testing, for average risk individuals (NCCN, 2025).

G.             Professional Society Recommendations / Consensus Statements / Other Expert Opinion

We identified one evidence-based professional society recommendation (USPSTF) relevant to CRC screening. A complete summary of this recommendation is included in Table 3 (Appendix B).

H.              Appropriate Use Criteria

There are no relevant, published appropriate use criteria.

I.                  Public Comment

CMS uses the initial public comments to inform its proposed decision.  Public comments that cite published clinical evidence give CMS useful information.  Public comments that contain information on unpublished evidence such as the results of individual practitioners or patients are less rigorous and therefore less useful for making a coverage determination.

First Comment Period: 9/10/2025-10/10/2025

During the first 30-day public comment period CMS received 47 comments. Some commenters expressed support for mt-sRNA screening tests and recommended they be covered, while other commenters expressed concerns about the evidentiary base for mt-sRNA screening tests. A few commenters recommended removing or lessening ordering requirements. Some commenters noted that colonoscopy is the gold standard of colorectal cancer screening. All comments that were submitted during the comment period without personal health information may be viewed by using the following link https://www.cms.gov/medicare-coverage-database/view/ncacal-public-comments.aspx?ncaid=319.

The majority of comments were provided by professional societies and advocacy groups, as well as many physicians and professors. There were also comments by healthcare systems and test manufacturers, including the requestor, Geneoscopy. Six comments were provided by national associations/professional organizations the National Comprehensive Cancer Network (NCCN), the American Gastroenterological Association (AGA), the American Society for Gastrointestinal Endoscopy (ASGE), American Cancer Society Cancer Action Network (ACS CAN), the American College of Radiology (ACR), and the National Center for Health Research (NCHR).

Numerous commenters provided references for our deliberation of this NCA. We appreciate this information. All such references were assessed for inclusion in our evidence review.

Second Comment Period: 03/10/2026 - 04/09/2026

Publication of this proposed decision initiates the second 30-day public comment period.  CMS will summarize and provide detailed responses to the public comments when issuing the final decision memorandum.

IV.         CMS Coverage Analysis

A.              CMS Coverage Authority

National coverage determinations (NCDs) are determinations by the Secretary with respect to whether or not a particular item or service is covered nationally by Medicare (§ 1869(f)(1)(B) of the Act).  In order to be covered by Medicare, an item or service must fall within one or more benefit categories contained within Part A or Part B and must not be otherwise excluded from coverage.  Moreover, with limited exceptions, items or services must be reasonable and necessary for the diagnosis or treatment of illness or injury or to improve the functioning of a malformed body member (§ 1862(a)(1)(A) of the Act).  Congress has specifically authorized coverage of certain screening tests under Part B of the Medicare program.  CRC screening tests have a benefit category under §1832, §1861(s)(2)(R) and §1861(pp) of the Act.  Specifically, we are using the NCD authority under section 1861(pp)(1)(D) (and implementing regulations at 42 CFR 410.37(a)(1)(v)) to determine whether the scope of the CRC screening benefit should be expanded.

B.              CMS Analysis for Coverage of CRC screening

This section includes CMS’ analysis of the evidence related to the use of non-invasive biomarker tests for CRC screening. Relevant details from studies listed in Tables 1 and 2 (Appendix B) are provided in context when key study findings or limitations are discussed with respect to coverage.

The overall objective for the critical appraisal of the evidence is to determine to what degree we are confident that the specific assessment questions raised in a National Coverage Analysis (NCA) can be answered conclusively. When conducting NCAs for an item or service under the reasonable and necessary statute, CMS generally makes three kinds of assessments: (1) The quality of relevant individual studies; (2) What conclusions can be drawn from the body of the evidence on the direction and magnitude of the intervention’s potential harms and benefits; and (3) The generalizability of findings from relevant studies to the Medicare beneficiary population.  (See CMS’ Evidence Review Guidance Document).

1.                 Rationale for Coverage Requirements for CRC screening

CMS proposes to cover CRC screening according to the provisions in section I.B (Coverage Criteria) under the Proposed Decision section of this document, which are explained below.

1. Patient Criteria:

1. Age 45 to 85 years, and,  
2. Asymptomatic (no signs or symptoms of colorectal disease including but not limited to lower gastrointestinal pain, blood in stool, positive gFOBT or FIT) and,
3. At average risk of developing CRC (no personal history of adenomatous polyps, CRC, or inflammatory bowel disease, including Crohn’s Disease and ulcerative colitis; no family history of CRCs or adenomatous polyps, familial adenomatous polyposis, or hereditary nonpolyposis CRC).

Rationale for patient criteria:
Age Range (45 to 85 years): A number of professional societies and organizations have developed guidelines for CRC screening using non-invasive CRC screening tests.  The American Cancer Society (ACS) recommends screening at age 45 years to age 85 years (Wolf, 2018). The American College of Gastroenterology (ACG) recommends CRC screening at 45 years to 75 years old (Shaukat, 2021).  The 2021 USPSTF recommends CRC screening at 45 years to 85 years (Davidson, 2021).

The 2025 NCCN Guidelines recommend screening for individuals age 45 years to 75 years (NCCN, 2025).  They further recommend that the decision to screen between ages 76–85 years should be individualized and include a discussion of the risks and benefits based on comorbidity status and estimated life expectancy (NCCN, 2025).

Since the methodology and analytic approach for CRC screening tests have been used consistently for past considerations, we determined that the age range for screening will remain as 45 years to 85 years for non-invasive CRC screening tests.

Asymptomatic: Preventive services are generally for individuals without symptoms of the disease being screened.

At average risk of developing colorectal cancer: Preventive services help prevent illness, detect health conditions early when they are most treatable, and manage disease to avoid complications.  Individuals at high risk require a more focused, intensive approach for screening.

2.     Test Criteria

1. The test must be FDA market authorized and indicated for CRC screening; and,
2. The test must achieve the requirements of the FDA-required post-approval study as specified in the SSED to continue coverage; and,
3. The test must demonstrate performance characteristics that meet EITHER Criteria 1, a sensitivity of greater than or equal to 90% and a specificity greater than or equal to 87%, OR Criteria 2, a sensitivity of greater than or equal to 79% and a specificity of greater than or equal to 90% in the detection of colorectal cancer compared to the recognized standard (accepted as colonoscopy at this time), based on the FDA labeling.
   

   	Test Performance Criteria 1	Test Performance Criteria 2
   Sensitivity	≥ 90%	≥ 79%
   Specificity	≥ 87%	≥ 90%

Rationale for test criteria:
FDA market authorized and indicated: The non-invasive CRC screening test must follow the FDA-approved label indication for colorectal cancer screening.

FDA-required post-approval study: Non-invasive CRC screening tests often include the requirement for a post-approval study in the FDA approval documentation and labeling. Since this means that the manufacturer must continue to collect and submit data on the test’s performance post-market to ensure its continued safety and effectiveness, we propose this as a requirement for continued reasonable and necessary coverage. The test must complete the post-approval study, and the FDA specified results must be achieved.

CLIA certified laboratory: The non-invasive CRC screening test must be performed in a CLIA certified laboratory to ensure the accuracy, reliability, and timeliness of the patient test results.

Sensitivity and specificity criteria: Parameters of Test Criteria

Our framework for specifying two sets (Criteria 1 or Criteria 2) of cut points for both sensitivity and specificity uses an evidence-based approach, provides continuity of coverage for tests currently covered by Medicare, provides coverage predictability for tests coming onto the market and covers a range of tests (across non-invasive biomarker) so the patient and their practitioner can select the test that is most appropriate for the patient and that the patient is willing to complete. This proposal also offers innovators more flexibility to improve the overall performance of CRC screening tests. Given the inverse relationship between sensitivity and specificity, we believe that having the “or” statement could allow for innovation in the development of non-invasive CRC screening tests. If the test manufacturer decided to increase screening test sensitivity, then it is likely that specificity would decrease for the screening test. If the test manufacturer decided to increase screening test specificity, then it is likely that sensitivity would decrease.

The non-invasive CRC screening test must fulfill ONE of the test performance criteria to meet the test criteria for coverage.

Test performance criteria 1:

If the test has a sensitivity that is greater than or equal to 90%, then the specificity must be greater than or equal to 87%.

Test performance criteria 2:

If the test has a specificity that is greater than or equal to 90%, then the sensitivity must be greater than or equal to 79%.

The cut points allow for a balance of the false positive rate against the false negative rate. We were concerned about the tradeoff relationship between low sensitivity and high false negative rate, leading to incorrectly informing a patient that they do not have cancer resulting in missing individuals with CRC. Additionally, we acknowledge the tradeoff between low specificity and a high false positive rate, leading to incorrectly telling a patient that they have cancer when they do not, resulting in unnecessary follow up procedures (colonoscopy) and emotional stress. It is important to note that colonoscopy is the gold standard for diagnosing CRC. While we are interested in decreasing the false positive rate, having a highly sensitive test decreases the false negative rate.  We have a focus on improving the false negative rate out of concern over minimizing the possibility of incorrectly telling a patient that they do not have CRC and reducing the opportunity of missing cases of CRC. The test performance criteria as proposed would yield the most reasonable balance of the benefits and harms of the non-invasive CRC screening test based on the evidence available.

Test performance characteristics that allow some flexibility could encourage innovation and promote competition to develop better tests and will encourage manufacturers to develop screening tests with sensitivities and specificities above the proposed cut points.

This proposed approach will also allow sponsors to develop non-invasive screening tests with higher sensitivity and specificity for AA. While we acknowledge the utility and potential clinical benefit of screening for AAs, there is very limited available evidence on the accuracy of non-invasive screening tests to detect AAs and the sensitivity of FIT for AA is low (Imperiale, 2019), which we further discuss in the section on AA. Thus, we do not include point sensitivity or specificity to screen for AA in the decision.

This proposed NCD outlines coverage criteria for any current or future noninvasive biomarker FDA approved/cleared screening tests. We believe non-invasive stool-based and blood-based screening tests and potential future non-invasive biomarker screening tests should be considered using the same proposed methodology. Further, published evidence demonstrates that non-invasive CRC screening tests that meet these criteria would improve health outcomes for Medicare patients. Therefore, by establishing criteria in the proposed NCD that is not test-specific but rather across non-invasive biomarker tests, the NCD will not require reconsideration as new tests come to market.

In past NCDs on screening FIT, stool DNA tests (Cologuard®), and BBB tests, we determined test performance criteria that would improve health outcomes (early diagnosis, reduced mortality).  The methodology proposed in this NCD builds upon prior work and better serves beneficiaries be eliminating delays to coverage as new tests meet the CMS criteria.

The following table reviews the sensitivity and specificity of CRC screening tests currently on the market.

Table 5. Sensitivity and Specificity by Test from Key Pivotal Studies and SSED

*Because the SSED and the publication of the results of the pivotal trial occur at different times, the sensitivity shown in the SSED might be somewhat different from the sensitivity shown in the published Imperiale (2024) pivotal trial results, as seen in Table 5.  For example, in the study of Cologuard Plus™, the analysis in the Imperiale (2024) study had a slightly larger study population and had 98 CRC cases which is 13 more CRC cases when compared to the Cologuard Plus™ SSED which had 85 CRC cases.

To reduce the burden on providers and to streamline implementation of the NCD, we are clarifying the parameters of the test criteria for the analytic comparison.  It will be necessary to demonstrate at least equivalent test performance of a new stool-based or blood-based CRC screening test. In the BBB screening test NCD, we established the specific threshold relative to FIT since it has been shown to prevent CRC and improve health outcomes for patients with early-stage CRC. We recognize the importance of test performance and note that there may be harms associated with utilizing a screening test with lower performance. As noted in the background, there has been a steady decline in CRC mortality due in large part to cancer prevention (removal of large or AAs before large adenomas progress to cancer) and detection of cancer at an early stage where treatments are most effective in improving survival.  In a scenario where a test does not detect large adenomas or early cancer as well as currently covered tests, there may be detriments to patients since the opportunity for cancer prevention may have been missed or cancer treatments may be initiated at a later stage when health outcomes may be reduced.  For the parameters of the test criteria, we will select minimum upper bound and minimum lower bound cut points for specificity and sensitivity.

Specificity

Specificity Criteria 1

We are using a different approach for selecting the proposed specificity minimum for Criteria 1.  We selected the lowest point from across the range of estimates for specificity. In Table 5 above, the lowest specificity among the recent key pivotal studies is 87.9% (we excluded the specificity (86.6%) for the original mt-sDNA test since that test has been replaced by a newer generation). The results of the pivotal study for the mt-sRNA test published in the Barnell (2023) study reported a specificity of 87.9%, which was the lowest specificity for no lesions on colonoscopy. The specificity of 86.9% was excluded because this was the specificity for no findings. Therefore, the proposed specificity is 87% which we propose is an acceptable bound when coverage is driven by a high sensitivity (Criteria 1 sensitivity ≥90%).

Specificity Criteria 2

We base the proposed specificity on the BBB test cut point (established in a prior NCD) at 90%.  CMS did not identify a compelling reason to change this cut point when test characteristics are driven by higher specificity.

Specificity Definitions

The use of specificity was inconsistent across publications. Table 6 (Appendix B) provides the test result histopathological classification system shown in the SSED for the mt-sRNA test (ColoSense®). As seen in Table 6, specificity can be defined as test results with negative findings which include categories 3.1 to 6.2.  Other definitions for specificity include non-advanced precancerous lesions (NAPL) defined as category 3 to 5. Alternatively, specificity can be defined as negative (NEG) findings consisting of category 6 which includes category 6.1 and 6.2, as shown in the Imperiale (2024) study.

Table 7 (Appendix B) from the SSED for ColoSense® is based on the specificity test result histopathological classification system, NAPL (category 3 to 5) and NEG findings (category 6.

In Table 8 (Appendix B) from the Barnell (2023) publication on CRC-PREVENT which examined the mt-sRNA test, specificity was defined in several ways including medium-risk adenomas, low risk adenomas, and no findings, with each category including several subcategories. The specificity reported in the SSED is different from the specificity reported in the Barnell (2023) publication on CRC-PREVENT which examined the same mt-sRNA test but used different definitions for specificity, such as medium-risk adenoma, low-risk adenoma, and no findings.

In Table 9 (Appendix B) from the Imperiale (2024) study on the next-generation Cologuard Plus™ test, the authors reported on three definitions of specificity based on the specificity test result histopathological classification system which were categories 3 through 6, category 6 (6.1 or 6.2), and category 6.2.

The sensitivity and specificity for the mt-sDNA, mt-sRNA, and the BBB (bb-cf-DNA) tests are shown in Table 10 (Appendix B) from the NCCN 2025 guidelines.  For the mt-sRNA test, the sensitivity for colon cancer is reported to be 94% but no specificity for colon cancer is shown.

A pivotal study on the circulating tumor DNA-based blood-based (ct-DNA) test SimpleScreen™ was recently published (Shaukat, 2025). Table 11 (Appendix B) reported the specificity for a ct-DNA-based blood-based test which was defined in several different ways including no findings (category 4.4) with category 4.4 defined as “no findings on colonoscopy, no histopathological review” (Shaukat, 2025). The definition of specificity used in the ct-DNA-based blood-based test clinical trial appears to be different from how specificity was defined in the specificity test result histopathological classification system used in the SSED for ColoSense® (mt-sRNA).

In the NCCN Colorectal Cancer Screening Clinical Practice Guidelines (NCCN, 2025), how specificity was defined depended on how it was reported in each test’s publication.  For instance, “the specificity for nonneoplastic findings with next-generation mt-sDNA” was reported (NCCN, 2025).  However, for the mt-sRNA test, “the specificity for no lesions on colonoscopy” was reported (NCCN, 2025).

Given that there is no standardized uniform method for reporting specificity, we clarify specificity for the purposes of this NCD as negative colonoscopy (no findings on a colonoscopy) which may (but does not necessarily) crosswalk to numeric categories as they may differ across studies. Further, we could not find any consensus statement on how to report specificity using a uniform methodology.

Sensitivity

Sensitivity Criteria 1

Instead of selecting from across the range of estimates of point threshold levels for sensitivity, since many of the point estimates clustered above 90%, we averaged the point levels for sensitivity to come up with an arithmetic mean sensitivity that can be used as a sensitivity bound. We used the sensitivity for the next-generation mt-sDNA test published in the Imperiale (2024) study because it is the updated version of the mt-sDNA test that was published in the earlier Imperiale (2014) study. The arithmetic mean sensitivity among the key pivotal studies in Table 5 above is (94.4% [mt-sRNA] + 93.9% [only next generation mt-sDNA] + 83.1% [BBB] / 3) 90.46%.  The proposed sensitivity minimum upper bound is 90%.

Sensitivity Criteria 2

The lowest overall sensitivity among the publications in the table of key pivotal studies in Table 5 above is 79.2% which is the sensitivity of the ct-DNA blood test. The proposed sensitivity minimum lower bound is 79%.  This appropriately will allow continuity of coverage of a blood-based screening test and pairs this sensitivity with a high specificity of ≥ 90%.

Advanced Adenomas

While we acknowledge the utility and potential clinical benefit of screening for AAs, the definitions for AAs have been used inconsistently.

In the SSED for ColoSense®, AA was defined in three different categories (Table 6-Appendix B) as Category 2.1 HGD or ≥ 10 adenomas, any size; Category 2.2 Tubulovillous adenoma, any size; or Category 2.3 Tubular adenoma, > 10 millimeters (mm).  In addition, a positive test result was defined as a Serrated Precancerous Lesions (SPL) (Category 2.4).

In the Barnell (2023) study on the mt-sRNA test, lesions within the AAs category were defined as at least 10 adenomas of any size or lesions with HGD, tubulovillous adenomas (TVA); any size, or traditional serrated adenomas (TSA) or tubular adenomas (TA); ≥10 mm.

In the Imperiale (2024) study on the next-generation mt-sDNA test, the authors reported on APLs defined as adenomas and sessile serrated lesions (SSL) (including large, hyperplastic polyps) that were at least one (1) centimeter (cm) in the longest dimension, lesions with villous histologic features, or HGD.

The NCCN CRC Screening Clinical Practice Guidelines glossary (NCCN, 2025), defined advanced precancerous lesion as AA or sessile serrated polyp (SSP) / SSL ≥ 1 cm and / or containing dysplasia.

The general term “polyp” is an abnormal growth of tissue that protrudes from the surface of an organ, like the large intestines of the gastrointestinal (GI) tract.  The term “polyp” in the practice guidelines refers to both polyps (polypoid lesions) and nonpolypoid (flat) lesions.  The guidelines define polypoid lesion as a lesion protruding from the surface of the GI mucosa into the lumen that is ≥ 2.5 millimeters (mm).

The term “adenomas” is used synonymously with “adenomatous polyps”, which are most often found to be tubular. Adenoma is defined as noninvasive neoplastic lesion of the columnar epithelium. AA is defined as an adenoma that is ≥ 1 cm or has villous or tubulovillous histology, or HGD. TVAs are comprised mostly of tubular glands and have <25% villous features. Villous adenomas have high risk features such as a polyp/adenoma with > 75% villous structures (long finger-like or leaf-like projections on the surface). TVAs have high risk features such as a polyp/adenoma with 25%-75% villous histology.  HGD has high risk features and refers to the distribution of nuclei within the cells.

The three main subtypes of serrated polyps (SPs), another precursor lesion of colorectal cancer, are SSP / SSLs, traditional serrated adenomas (TSAs), and hyperplastic polyps. It is noted that the classification systems for serrated lesions continue to evolve.

In the 2021 USPSTF CRC screening recommendation statement, in four studies on Cologuard® (n = 12,424) reporting the accuracy of sDNA- FIT (now designated as mt-sDNA in this proposed decision memo), pooled sensitivity for CRC detection was 0.93 (95% confidence interval [CI], 0.87-1.0) and pooled specificity was 0.84 (95% CI, 0.84-0.86), with a lower pooled sensitivity for detecting AAs (0.43 [95% CI, 0.40-0.46]) but higher pooled specificity (0.89 [95% CI, 0.86-0.92]).  It appears that in these studies of sDNA-FIT, the pooled sensitivity for detecting AAs was 43%.

There appears to be an inconsistent use of definitions for AAs. We could not find a standardized uniform methodology or a consensus statement for reporting AAs. The sensitivity for detecting AAs remains around 40% to 43%. While we acknowledge the utility and potential clinical benefit of screening for AAs, there continues to be limited available evidence on the accuracy of non-invasive screening tests to detect AAs and the sensitivity for detecting AA is low (Imperiale, 2019). We did not include point sensitivity or specificity to screen for AA in the proposed test performance criteria.

Implementation of Threshold Test Performance Criteria

In determining the performance characteristics for any test, we suggest using the sensitivity and specificity data published in the FDA label. Because the FDA label includes the results from the pivotal study, the sensitivity and specificity of the new screening test can be compared to CMS’ proposed Criteria 1 and Criteria 2 cut points.  The analysis of sensitivity and specificity will be valid as long as the pivotal study incorporates colonoscopy as the gold standard comparator to the new CRC screening test.  If the pivotal study does not estimate the sensitivity and specificity of the new non-invasive CRC screening test, then the test performance characteristics may come from another published comparative clinical study that has colonoscopy as the gold standard comparator. We expect the results of new non-invasive CRC screening tests to be generalizable to the Medicare population.

To further demonstrate clinical utility of this type of screening test, if applicable, the non-invasive CRC screening test must achieve the requirements of the FDA-required PAS as specified in the SSED to continue coverage. In the PAS, the screening test must achieve the study objectives and the study endpoints as specified in the SSED.  Failure to comply with post-approval requirements as stated in the FDA approval letter will result in noncoverage.

• Ordering Requirements

Non-invasive CRC screening tests must be ordered by the physician, physician assistant, nurse practitioner, or clinical nurse specialist who will use the results in the management of the patient.

Rationale for ordering practitioner:

We do not believe there is an evidentiary reason to limit the ordering of non-invasive CRC screening test to physicians and are proposing to allow physicians, physician assistants, nurse practitioners, or clinical nurse specialists who will use the results in the management of the patient to order these tests.

We encourage a discussion between the patient and their practitioner to include the balance of benefits and harms of CRC screening, along with the patient’s health status, including life expectancy and comorbid conditions; prior screening status; family history; and individual patient preferences. Clinicians and patients may consider a variety of factors in deciding which screening test may be best for each individual. For example, each test requires different frequencies of screening, location of screening (home or office), methods of screening (stool-based or blood-based, or direct visualization), preprocedural bowel preparation, anesthesia or sedation, and follow-up for abnormal findings (USPSTF, 2021). We believe the consultation should also include a discussion of the importance of adherence to non-invasive CRC screening frequency guidelines, the impact of comorbidities, and ability or willingness to undergo follow-up colonoscopy for diagnosis and treatment, since these concepts are an integral and important component of the benefit and harm discussion around non-invasive CRC screening and a positive screening test should result in a timely follow-up colonoscopy. Discussion of these considerations with a patient may help better identify CRC screening tests that are more likely to be completed by a given individual.

• Frequency of testing

Non-invasive biomarker CRC screening tests are covered once every three years.

Rationale for testing frequency:
A number of professional societies and organizations have developed guidelines for CRC screening using non-invasive CRC screening tests. The ACG recommends the mts-DNA test every three years (Shaukat, 2021), the ACS recommends the mt-sDNA test every three years (Wolf, 2018), and the USPSTF in 2021 recommends the mt-sDNA every one to three years (Davidson, 2021)

In 2025, the National Comprehensive Cancer Network (NCCN) published an update (as Colorectal Cancer Screening, Version 2.2025 – June 24, 2025, NCCN Clinical Practice Guidelines in Oncology [NCCN Guidelines]) to their 2024 colorectal cancer screening guidelines and added mt-sRNA and bb-cfDNA tests as recommended stool-based and blood-based, respectively, CRC screening strategies, in addition to the currently NCCN recommended mt-sDNA-based testing, for average risk individuals (NCCN, 2025). For mt-sDNA and mt-sRNA testing, the recommended frequency is for every three years for average risk for CRC individuals (NCCN, 2025). For bb-cfDNA-based testing (or BBB test for this proposed decision memo), the recommended frequency is testing every three years for average risk individuals, but the NCCN only recommends this test for individuals who are not willing to undergo colon cancer screening through another modality (NCCN, 2025).

This approach is consistent with the past NCDs on both stool-based and blood-based non-invasive CRC screening tests.

2.                 Evidence Questions – Answered

Our review of the evidence on the clinical utility of CRC screening for Medicare beneficiaries was guided by two general questions.

Question 1: Is the evidence sufficient to determine that screening for colorectal cancer with non-invasive biomarker tests is reasonable and necessary for the prevention or early detection of illness or disability?

Yes - The evidence demonstrates that screening in Medicare beneficiaries using a non-invasive CRC screening test is suitable for prevention or early detection of CRC. The published evidence shows that the tests we reviewed that met either Category 1 or Category 2 criteria improve health outcomes for Medicare beneficiaries.

The key pivotal studies for the mt-sDNA test, the mt-sRNA test, and the BBB test provided the evidence for the analysis of sensitivity. The sensitivity for the FIT test is used as a comparator, since there is a large evidence base that was available on the accuracy of FIT. In the USPSTF CRC screening recommendation for FIT, the pooled sensitivity for detection of CRC was 74% and pooled specificity was 94% (USPSTF, 2021). Among the key pivotal studies, sensitivity is higher than 74% for the BBB test (83.1%; Chung, 2024), the next-generation mt-sDNA test (93.9%; Imperiale, 2024), and the mt-sRNA test (94.4%; Barnell, 2023). With the ct-DNA-based blood-based test included in the analysis, the sensitivity (79.2%; Shaukat, 2025) is also greater than the sensitivity for FIT.

The key pivotal studies for the mt-sDNA test, the mt-sRNA test, and the BBB test provide the evidence for the analysis of specificity. The comparator for specificity of 90% is used which was the test performance criterion for the specificity cut point from the Screening for Colorectal Cancer - Blood-Based Biomarker Tests (CAG-00454N) decision memo (CMS, 2021). Among the key pivotal studies, specificity was found to be higher than 90% for the next-generation mt-sDNA test (93.4%; Imperiale, 2024). The specificity for the ct-DNA blood-based test (91.5%; Shaukat, 2025) is also greater than the specificity of 90%.

As noted in the Screening for Colorectal Cancer - Stool DNA Testing (CAG-00440N) decision memo (CMS, 2014), like other non-invasive, stool-based CRC screening tests (FOBT, FIT), the harms from the mt-sDNA, and, for this proposed decision memo, the mt-sRNA test are likely to be small. The associated harms lie in the downstream risks from diagnostic and therapeutic colonoscopy after a positive mt-sDNA test or positive mt-sRNA test. The harms from colonoscopy have been well documented and are generally considered low.

The primary harms from stool-based screening tests are thought to come from false-positive and false-negative results and from harms of workup of positive screening test results, such as colonoscopy. Serious harms from colonoscopy to follow-up positive screening results are estimated to be 17.5 serious bleeding events and 5.4 perforations per 10,000 colonoscopies (USPSTF, 2021). Rates of serious bleeding events and perforations are lower with screening colonoscopy than with colonoscopy performed following positive stool-based screening test results (presumably because of fewer biopsies and adenoma removals), with 14.6 major bleeding events per 10,000 colonoscopies and 3.1 perforations per 10,000 colonoscopies (USPSTF, 2021).

If sedation is used during colonoscopy, cardiopulmonary events may rarely occur, although the precise frequency of occurrence is not known. Other serious reported harms include infection and other gastrointestinal events (besides bleeding and perforation). Bowel preparation for colonoscopy may lead to dehydration or electrolyte imbalances, particularly in older adults or persons with comorbid conditions, but accurate estimates of the rates of these events were not available (USPSTF, 2021).

Overall, the mt-sDNA test, the mt-sRNA test, and the BBB test are suitable screening tests for CRC with a higher sensitivity compared to another currently covered stool-based screening test, FIT. For the mt-sDNA test, this is consistent with the ACG (Shaukat, 2021), the 2021 USPSTF (Davidson, 2021), the ACS (Wolf, 2018), and the 2025 NCCN (NCCN, 2025) recommendations for the mt-sDNA test as a suitable for CRC screening. For the mt-sRNA test, the NCCN published an update (as Colorectal Cancer Screening, Version 2.2025 – June 24, 2025, NCCN Clinical Practice Guidelines in Oncology [NCCN Guidelines]) to their 2024 CRC screening guidelines and added mt-sRNA as a recommended stool-based CRC screening strategy (NCCN, 2025). As noted in the previous BBB NCD (CAG-00454N; CMS, 2021), the BBB test is suitable for CRC screening. Relevant to this proposed decision, the NCCN includes the BBB test (bb-cf-DNA) as a suitable modality for CRC screening (Chung, 2024; in NCCN, 2025).

The benefits outweigh the harms for using non-invasive tests to screen for CRC. As a suitable screening test likely to lead to improvements in health outcomes, the evidence is sufficient to conclude that CRC screening in Medicare beneficiaries using the mt-sDNA test, the mt-sRNA test, and the BBB test are suitable for prevention or early detection of CRC.

We will apply the same approach to determine which CRC screening tests are appropriate to include in the Medicare program as used with previous non-invasive CRC screening tests. Previous NCAs discussed appropriate test performance criteria such as point sensitivity and specificity compared to colonoscopy. We note that the determination of appropriateness is similar to the consideration of what is appropriate for a device to be, “at least as beneficial as an existing and available medically appropriate alternative.”

Sensitivity and specificity measure the accuracy of the test to assess clinical validity of the test. These outcomes assess the ability of the test to accurately identify CRC in patients screened for cancer. Sensitivity and specificity do not provide direct evidence on net health outcomes. Mortality is direct evidence of the net health outcome of the CRC screening test. Mortality, or survival, measures the impact of the screening test on health outcomes to assess clinical utility of the test and is dependent on the detection of large adenomas and early-stage cancer where treatments have been shown to be more effective. Mortality is a health outcome relevant to Medicare beneficiaries being screened for CRC.

Through the evaluation of evidence from published studies, the clinical data for the test must reach the threshold for being appropriate. The direct evidence by Shaukat, et al. (2013) and Levin et al. (2018) suggests that there is clinical utility in using FOBT and FIT for early detection of CRC because these tests reduce mortality of the disease. In the USPSTF systematic review of observational studies, receipt of screening colonoscopy or FIT was associated with lower risk of CRC mortality, in addition to similar results for randomized clinical trials of flexible sigmoidoscopy and gFOBT (USPSTF, 2021). Conversely, there is no direct evidence on outcomes such as mortality for newer stool-based or BBB tests used in screening for CRC. USPSTF notes that “newer screening tests with similar sensitivity may result in CRC mortality reductions similar to reductions shown in existing trials. If sensitivity is better, without a trade-off in specificity (e.g., various FITs), mortality reductions could be greater” (USPSTF, 2021). Therefore, we assessed whether there was supporting indirect evidence from studies that used FOBT or FIT as comparators to establish a link to the screening test under consideration. By comparing the test performance characteristics, defined as sensitivity and specificity, of new screening tests to FOBT or FIT, we can assess whether other, newer stool-based and blood-based tests might translate into similar reductions in disease mortality for Medicare beneficiaries. Thus, if the sensitivity and specificity of the new screening tests are as good as or better than the sensitivity and specificity of FOBT or FIT, then we have indirect evidence suggesting that the new stool-based or BBB tests may reduce CRC mortality.

As suggested by Cochrane and Holland (1971), test performance characteristics are defined as sensitivity and specificity. However, the validation of a screening test does not include an assessment of adherence or compliance with CRC screening guidelines (Cochrane & Holland, 1971). Level 2 diagnostic accuracy efficacy, or test performance characteristics, is defined as sensitivity and specificity in a defined clinical problem setting, not compliance with screening guidelines (Fryback & Thornbury, 1991).

Question 2: Is the evidence sufficient to determine that screening for colorectal cancer with non-invasive biomarker tests is appropriate for Medicare beneficiaries?

Yes - The published evidence demonstrates that the available mt-sDNA test, mt-sRNA test, and the BBB screening test will identify CRC biomarkers sufficiently early to perform interventions to prevent progression of AAs to cancer or to improve health outcomes for patients found to have CRC during screening. To provide clarity to innovators and to reduce burden of a reconsideration of this NCD, we provide a direct pathway for coverage of appropriate mt-sDNA, mt-sRNA, and BBB CRC screening tests when the criteria are met.

Among the cited key pivotal studies, individuals at least 65 years of age were included in the study populations.  Both men and women were adequately represented in the evidence base, especially among the key pivotal studies.

C.              Benefit Category

Medicare is a defined benefit program.  For an item or service to be covered by the Medicare program, it must fall within one of the statutorily defined benefit categories outlined in the Social Security Act. Congress has specifically authorized coverage of certain screening tests under Part B of the Medicare program. CRC screening tests have a benefit category under §1832, §1861(s)(2)(R) and §1861(pp) of the Act. Specifically, we are using the NCD under section 1861(pp)(1)(D) (and implementing regulations at 42 CFR 410.37(a)(1)(v)) to determine the details of the proposed changes to NCD (210.3) Colorectal Cancer Screening Tests.

For an item or service to be covered by the Medicare program, it must fall within one of the statutorily defined benefit categories outlined in §1812 (Scope of Part A); §1832 (Scope of Part B); or §1861(s) (Definition of Medical and Other Health Services) of the Act.

CRC screening tests qualify as:

• Colorectal Cancer Screening Tests

Note: This may not be an exhaustive list of all applicable Medicare benefit categories for this item or service.

V.            History of Medicare Coverage

A.              Current National Coverage Request

This is a reconsideration of NCD (210.3) Colorectal Cancer Screening Tests. This reconsideration was externally initiated. CMS received a complete, formal request to open a reconsideration of the topic from Geneoscopy, Inc. The request letter is available at https://www.cms.gov/files/document/id319.pdf.

B.              Timeline of NCA Milestones

VI.         Appendices

Appendix A:  Proposed Medicare National Coverage Determinations Manual Language

Draft

We are seeking public comments on the proposed language that we would include in the Medicare National Coverage Determinations Manual. This proposed language does not reflect public comments that will be received on the proposed decision memorandum, and which may be revised in response to those comments.

Table of Contents
(Rev.)

210.3 – Colorectal Cancer Screening Tests

A. General

Sections 1861(s)(2)(R) and 1861(pp) of the Social Security Act (the Act) and regulations at 42 CFR 410.37 authorize Medicare coverage for screening colorectal cancer tests under Medicare Part B. The statute and regulations authorize the Secretary to add other tests and procedures (and modifications to tests and procedures for colorectal cancer screening) as the Secretary finds appropriate based on consultation with appropriate organizations.

B. Nationally Covered Indications

1. Fecal Occult Blood Tests (FOBT)

Fecal occult blood tests (FOBTs) are generally divided into two types: immunoassay and guaiac types. Immunoassay (or immunochemical) fecal occult blood tests (iFOBT) use “antibodies directed against human globin epitopes. While most iFOBTs use spatulas to collect stool samples, some use a brush to collect toilet water surrounding the stool. Most iFOBTs require laboratory processing.

Guaiac fecal occult blood tests (gFOBT) use a peroxidase reaction to indicate presence of the heme portion of hemoglobin. Guaiac turns blue after oxidation by oxidants or peroxidases in the presence of an oxygen donor such as hydrogen peroxide. Most FOBTs use sticks to collect stool samples and may be developed in a physician’s office or a laboratory. In 1998, Medicare began reimbursement for gFOBTs, but not immunoassay type tests for colorectal cancer screening. Since the fundamental process is similar for other iFOBTs, the Centers for Medicare & Medicaid Services evaluated colorectal cancer screening using immunoassay FOBTs in general.

Medicare covers one screening FOBT per annum for the early detection of colorectal cancer. This means that Medicare will cover one gFOBT or one iFOBT at a frequency of every 12 months; i.e., at least 11 months have passed following the month in which the last covered screening FOBT was performed, for beneficiaries aged 45 years and older. The beneficiary completes the existing gFOBT by taking samples from two different sites of three consecutive stools; the beneficiary completes the iFOBT by taking the appropriate number of stool samples according to the specific manufacturer’s instructions. This screening requires a written order from the beneficiary’s attending physician. (“Attending physician” means a doctor of medicine or osteopathy (as defined in §1861(r)(1) of the Act) who is fully knowledgeable about the beneficiary’s medical condition, and who would be responsible for using the results of any examination performed in the overall management of the beneficiary’s specific medical problem.)

The minimum age for FOBT is reduced to 45 years and older.

2. Non-Invasive Biomarker Tests

Biomarker testing detects molecular markers shed by colorectal cancer and pre- malignant colorectal epithelial neoplasia into blood, bodily secretions, or directly into the intestinal lumen. Through the use of selective enrichment and amplification techniques, tests are designed to detect very small amounts of markers to identify colorectal cancer or pre-malignant colorectal neoplasia.

Non-Invasive Biomarker tests are covered under the following conditions.

1.     Patient Criteria
   1.      Age 45 to 85 years, and,
   2.      Asymptomatic (no signs or symptoms of colorectal disease including but not limited to lower gastrointestinal pain, blood in stool, positive guaiac fecal occult blood test (gFOBT) or fecal immunochemical test (FIT)), and
   3.      At average risk of developing colorectal cancer (no personal history of adenomatous polyps, colorectal cancer, or inflammatory bowel disease, including Crohn’s Disease and ulcerative colitis; no family history of colorectal cancers or adenomatous polyps, familial adenomatous polyposis, or hereditary nonpolyposis colorectal cancer).

2.      Test Criteria
   1.       The test must be Food and Drug Administration (FDA) market authorized and indicated for colorectal cancer screening; and,
   2.       The test must achieve the requirements of the FDA-required post-approval study as specified in the Safety and Effectiveness Data (SSED) to continue coverage; and
   3.       The test must be processed in a CLIA certified laboratory; and,
   4.       The test must demonstrate performance characteristics that meet EITHER Criteria 1, a sensitivity of greater than or equal to 90% and a specificity greater than or equal to 87%, OR Criteria 2, a sensitivity of greater than or equal to 79% and a specificity of greater than or equal to 90% in the detection of colorectal cancer compared to the recognized standard (accepted as colonoscopy at this time), based on the FDA labeling.

Frequency Limits

• once every 3 years

Order Requirements

• ordered by the physician, physician assistant, nurse practitioner, or clinical nurse specialist who will use the results in the management of the patient

C. Nationally Non-Covered Indications

All other indications for colorectal cancer screening not otherwise specified in the Act and regulations, or otherwise specified above remain nationally non-covered.

D. Other

N/A

Appendix B: Referenced Materials

Table 1. Study outline for non-invasive CRC screening multi-targeted & other stool- & blood-based tests

Note: NR: Not reported; CRC: Colorectal Cancer; AA: Advanced Adenomas; non-AA or NAA or NA: Nonadvanced adenomas; APL: Advanced precancerous lesions; MRA: Medium-risk adenomas; LRA: Low-risk adenomas; PPV: Positive predictive value; NPV: Negative predictive value

Table 2. Specificity & sensitivity for non-invasive CRC screening multi-targeted stool- & blood-based tests

Note: NR: Not reported; CRC: Colorectal Cancer; AA: Advanced Adenomas; non-AA or NAA or NA: Nonadvanced adenomas; APL: Advanced precancerous lesions; MRA: Medium-risk adenomas; LRA: Low-risk adenomas

Table 3. Professional guidelines for CRC screening in asymptomatic average-risk adults

Note: ACS guidelines: strong recommendation conveys the consensus that the benefits of adherence to that intervention outweigh the undesirable effects that may result from screening. Qualified recommendations indicate there is clear evidence of benefit (or harm) of screening, but less certainty about the balance of benefits and harms or about patients’ values and preferences, which could lead to different decisions about screening. USPSTF guidelines: Evidence Grade A: The USPSTF recommends the service. There is high certainty that the net benefit is substantial. Offer or provide this service. Evidence Grade B: USPSTF recommends the service. There is high certainty that the net benefit is moderate, or there is moderate certainty that the net benefit is moderate to substantial. Offer or provide this service. Evidence Grade C: The USPSTF recommends selectively offering or providing this service to individual patients based on professional judgment and patient preferences. There is at least moderate certainty that the net benefit is small. Offer or provide this service for selected patients depending on individual circumstances.

Table 4 .  Sensitivities and Specificities of Stool-based CRC Screening Tests from Screening for Colorectal Cancer - Blood-Based Biomarker Tests (CAG-00454N; CMS, 2021)

Table 6.  FDA, Summary of Safety and Effectiveness Data (SSED) for Stool RNA-Based Colorectal Cancer Screening Test ColoSense® -(Table 11) Test Result Classification System by Histopathological Categories from Summary of Safety and Effectiveness Data (SSED) for Stool RNA-Based Colorectal Cancer Screening Test

Table 7. Summary of Safety and Effectiveness Data (SSED) for Stool RNA-Based Colorectal Cancer Screening Test-(Table 7) Secondary performance characteristics by colonoscopy categories-specificity

Table 8. Barnell (2023) publication on CRC-PREVENT which examined the multitarget stool RNA (mt-sRNA) test (Table 2) Sensitivity and Specificity of mt-SRNA and FIT

Table 9. Imperiale (2024) study on the next-generation multitarget stool DNA test (Table 1) Sensitivity and Specificity of mt-SDNA and FIT

Table 10.  2025 NCCN Guidelines

Table 11.  Shaukat (2025) study on Circulating Tumor DNA-Based Blood-Based (ct-DNA) Test (Table 2) Sensitivity and Specificity

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