Screening for Colorectal Cancer-Non-Invasive Biomarker Tests

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A. Decision Non-invasive biomarker tests for colorectal cancer screening are covered according to the provisions in sections I.B. and I.C. below. B. Coverage Criteria Non-invasive biomarker colorectal cancer screening tests are covered once every three years when all the following criteria are met: 1. Ordering Criteria When ordered by the physician, physician assistant, nurse practitioner, or clinical nurse specialist who will use the results in the management of the patient. 2. Patient Criteria Age 45 to 85 years; and, Asymptomatic (no signs or symptoms of colorectal disease including but not limited to lower gastrointestinal pain, blood in stool, positive non-invasive biomarker colorectal cancer screening test ); and, 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); and, Provided with information about the test performance and the importance of a follow-on colonoscopy if the test returns a positive result. 3. Test Criteria The test must be Food and Drug Administration (FDA) market authorized and indicated for colorectal cancer screening; and, 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 The test must be processed in a CLIA certified laboratory; and 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 for CRC ≥ 90% ≥ 79% Specificity for CRC ≥ 87% ≥ 90% C. Other Uses of Colorectal Cancer Screening Biomarker Tests All other indications for colorectal cancer screening not otherwise specified in the Act, regulations, or otherwise specified above, remain nationally non-covered. See Appendix A for Medicare National Coverage Determinations Manual language.

Decision Memo: June 8, 2026 Table of Contents Decision Decision Coverage Criteria Ordering Criteria Patient Criteria Test Criteria Other Uses of Colorectal Cancer Screening Biomarker Tests Clinical Review Background Food and Drug Administration Status Evidence Evidence Questions Technology Assessments Medicare Evidence Development and Coverage Advisory Committee (MEDCAC) Clinical Literature Search Summary of Evidence Assessment of the Evidence RNA-based stool tests DNA-based stool tests DNA-based blood-based tests Limitations Relevance and generalizability to Medicare beneficiaries Evidence from systematic reviews and meta-analyses Evidence-Based Guidelines Professional Society Recommendations / Consensus Statements / Other Expert Opinion Appropriate Use Criteria Public Comments CMS Coverage Authority CMS Coverage Authority CMS Analysis for Coverage of CRC screening Rationale for Coverage Requirements for CRC screening Evidence Questions - Answered Benefit Category History of Medicare Coverage Current National Coverage Request Timeline of NCA Milestones Appendices Appendix A: Proposed Medicare National Coverage Determinations Manual Language Appendix B: Referenced Materials Bibliography Abbreviations used throughout the 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. Decision A. Decision Non-invasive biomarker tests for colorectal cancer screening are covered according to the provisions in sections I.B. and I.C. below. B. Coverage Criteria Non-invasive biomarker colorectal cancer screening tests are covered once every three years when all the following criteria are met: 1. Ordering Criteria When ordered by the physician, physician assistant, nurse practitioner, or clinical nurse specialist who will use the results in the management of the patient. 2. Patient Criteria Age 45 to 85 years; and, Asymptomatic (no signs or symptoms of colorectal disease including but not limited to lower gastrointestinal pain, blood in stool, positive non-invasive biomarker colorectal cancer screening test ); and, 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); and, Provided with information about the test performance and the importance of a follow-on colonoscopy if the test returns a positive result. 3. Test Criteria The test must be Food and Drug Administration (FDA) market authorized and indicated for colorectal cancer screening; and, 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 The test must be processed in a CLIA certified laboratory; and 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 for CRC ≥ 90% ≥ 79% Specificity for CRC ≥ 87% ≥ 90% C. Other Uses of Colorectal Cancer Screening Biomarker Tests All other indications for colorectal cancer screening not otherwise specified in the Act, regulations, or otherwise specified above, remain nationally non-covered. See Appendix A for Medicare National Coverage Determinations Manual language. II. Clinical Review A. Background Colorectal cancer (CRC) is the third most common cancer in both women and men and the second leading cause of cancer deaths in the United States (Siegel et al., 2026). The American Cancer Society (ACS) estimated that, in 2026, there will be 158,850 new cases of CRC, and 55,230 people will die from these cancers (ACS, 2026). In 2025, the highest percentage of colorectal cancer cases (25.8%) was in ages 65 to 74 years and had 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 Summary of Safety and Effectiveness Data (SSED) can be accessed at: https://www.accessdata.fda.gov/cdrh_docs/pdf13/p130017b.pdf . The Cologuard® post-approval study (PAS) was 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 SSED can be accessed at: https://www.accessdata.fda.gov/cdrh_docs/pdf23/P230001B.pdf . 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 SSED can be accessed at: https://www.accessdata.fda.gov/cdrh_docs/pdf23/P230009B.pdf . 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 SSED can be accessed at: https://www.accessdata.fda.gov/cdrh_docs/pdf23/P230043B.pdf . 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 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. 1. Summary of Evidence Table 2 (Appendix B) provides an overview of studies included in this systematic review. Table 3 (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 lesions on a colonoscopy was 87.9%, and 95.7% (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 five evidence-based professional society guidelines (ACG, ACP, NCCN, ASGE, ACS) relevant to CRC screening. A complete summary of these guidelines is included in Table 4 (Appendix B). 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 4 (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: 3/10/2026-4/9/2026 During the second 30-day public comment period CMS received 95 comments. The majority of commenters supported efforts to modernize the coverage pathway and expand access to CRC screening to increase adherence. Commenters supported the expansion of the ordering requirements. While most commenters supported adding stool-based RNA screening tests as an additional screening option, some commenters believe it is an inferior test to current stool DNA tests. Many commenters noted concern for blood-based screening tests. Even though they have been a Medicare coverable test since 2021, many commenters requested test sensitivity criteria be included for detecting advanced adenomas and designate blood-based screening tests as a second line screening option. Many commenters supported the FDA post approval study requirement. All comments submitted during the comment period without personal health information may be viewed at: https://www.cms.gov/medicare-coverage-database/view/ncacal-public-comments.aspx?ncaid=319&ncacaldoctype=all&status=all&sortBy=status&bc=17 . The majority of comments were provided by physicians and other health care professionals. Comments were also received by five test manufacturers, including Abbott (previously Exact Sciences), CellMax Life, Freenome, Geneoscopy, and Guardant Health. Eleven comments were provided by national associations/professional organizations including the Advanced Medical Technology Association (AdvaMed), American Academy of Physician Associates (AAPA), the American Cancer Society and the Cancer Action Network (ACS CAN), the American Clinical Laboratory Association (ACLA), the American College of Gastroenterology (ACG), the American College of Radiology (ACR), the American Gastroenterological Association (AGA), the American Society for Gastrointestinal Endoscopy (ASGE), Association for Molecular Pathology (AMP), Medical Device Manufacturers Association (MDMA), and the National Comprehensive Cancer Network (NCCN). Fourteen comments were provided by advocacy organizations/coalitions including 60Plus Association, Action for Health, Alliance for Aging Research, Big Mike’s Bottom Line, the Blue Hat Foundation, Cheeky Charity, Coalition for 21 st Century Medicine (C21), Colon Cancer Coalition, Colon Cancer Prevention Project, Colon Cancer Stars, Colorectal Cancer Alliance, Fight CRC, Global Healthy Living Foundation, and One Cancer Place. Other comments were provided by professors, healthcare systems, a former Member of Congress, consultants, a regulatory quality coordinator, a regulatory attorney, and Medicare beneficiaries. Five comments did not provide their titles and/or organizations. Numerous commenters provided references for our deliberation of this NCA. All such references were assessed for inclusion in the evidence review. Screening Strategy Comment: The majority of commenters expressed support for broader Medicare coverage of non-invasive biomarker colorectal cancer screening tests. Many commenters stated that expanding access to additional screening options could improve screening uptake, facilitate earlier detection, and reduce colorectal cancer morbidity and mortality. Some commenters noted that broader access could help address barriers such as reluctance to undergo colonoscopy, difficulty with stool collection, transportation challenges, time away from work, and other practical concerns. Some commenters also believed broader access could improve screening participation in underserved populations and beneficiaries facing logistical, financial, or other barriers to care. Response: We thank commenters for highlighting these issues in support of the proposed NCD. Comment: Several commenters supported maintaining distinct coverage pathways for stool-based and blood-based CRC screening tests based on their differences in ability to detect colorectal cancer and advanced precancerous lesions. Some commenters believe this coverage approach does not align with the statutory requirement that NCDs address a “particular item or service” under § 1869(f)(1)(B) of the Social Security Act (the Act). They also cite 42 C.F.R. § 410.37 (k) for referencing “noninvasive stool-based colorectal cancer screening” and “blood-based biomarker colorectal cancer screening” as separate tests. Response: As noted in the Analysis under ‘Consistent CRC Detection Test Criteria for Stool-based and Blood-based Tests,’ the test performance coverage criteria for colorectal cancer detection for the stool-based tests and the blood-based tests are not separated. This approach standardizes coverage by applying consistent criteria across the testing modalities (e.g. stool-based, blood-based). We do not agree that this screening strategy for non-invasive biomarker CRC screening tests does not align with the statutory requirement that NCDs address a “particular item or service” under § 1869(f)(1)(B) of the Act. These class of tests are used for the same purpose of cancer detection and all use biomarkers. Test performance criteria were determined appropriate based on current FDA approved screening tests and currently covered Medicare screening tests; new tests within the space of non-invasive biomarker screening to detect colon cancer must meet the criteria to be eligible for coverage. This coverage approach, rather than test-specific, is also used in NCD 90.2 Next Generation Sequencing. 42 C.F.R. 410.37(k) defines a complete colorectal cancer screening to include a follow-on screening colonoscopy after a Medicare covered non-invasive stool-based CRC screening test or blood-based biomarker CRC screening test returns a positive result. Thank you for this comment as in the future we will consider making a conforming change to the regulatory language for consistency. Comment: A commenter suggested allowing Medicare Administrative Contractors (MAC) discretion for tests without FDA authorization. Response : MACs do not have authority to make Medicare coverage determinations with respect to expanding coverage for new colorectal cancer screening tests under § 1861(pp)(1)(D) of the Act. Screening Interval Comment: Some commenters stated that the rescreening interval should be test-specific and based on the evidence and FDA-authorized labeling for each modality, rather than applying a uniform three-year interval across all non-invasive biomarker tests. Response: As noted in the Analysis under ‘Frequency of testing’, the NCD is aligned with the most consistent screening frequency interval recommended across the NCCN, ACG, ACS, and USPSTF. The indications for use in the three SSEDs (mt-sDNA, Cologuard Plus, 2024; mt-sRNA, ColoSense, 2024; BBB, Shield, 2024) do not report a screening interval. Ordering Criteria Comment: Commenters supported expanding the list of clinicians who may order non-invasive colorectal cancer screening tests to include physician assistants, nurse practitioners, and clinical nurse specialists and consistency among all non-invasive screening tests. Some commenters recommended further broadening the language to include other nonphysician practitioners recognized under Medicare law or regulation, such as § 1861(s) of the Act or 42 CFR 410.32(a)(2). Response: We appreciate the suggestion to broaden the non-physician providers even further however, this expansion is in alignment with the ordering requirements for screening FOBT in 42 CFR §410.37(b). Comment: Some commenters recommended either deleting or revising the requirement that the ordering practitioner use the results “for” the management of the patient, rather than “in” the management of the patient to better define the role of the ordering provider in the screening process. The management of the patient that is needed following a positive result is referral to colonoscopy, and therefore the management falls to another provider. Response: The health care provider who orders the screening test is the person who receives the results of the screening test and who then recommends next steps in the management of the patient, which can include referral to another health care provider if the test is positive or a discussion with the patient of when the next screening test will occur if the test is negative. We consider these steps as described to be for the management of the patient. We are finalizing as proposed. Comment: While this NCA does not include a review of the long-standing coverage for fecal occult blood tests (FOBT), a commenter indicated that the ordering requirements for FOBT in NCD 210.3 are not in alignment with the colorectal cancer screening section of the CFR. Specifically, 42 CFR §410.37(b) authorizes payment of FOBT ordered by PAs, stating: “Condition for coverage of screening fecal-occult blood tests. Medicare Part B pays for a screening fecal-occult blood test if it is ordered in writing by the beneficiary's attending physician, physician assistant, nurse practitioner, or clinical nurse specialist.” Response: We appreciate the commenter bringing this to our attention. We will make a conforming change to the ordering requirements for FOBT in NCD 210.3 for consistency with the regulatory language in 42 CFR §410.37(b). Patient Criteria Comment: Two commenters noted the need for individualized screening decisions for adults ages 76 to 85, based on health status, prior screening history, life expectancy, and patient preference. Response: Consistent with current existing professional organization recommendations and coverage of other CRC screening tests, we are finalizing the age range of 45-85 years. The USPSTF currently recommends the decision to screen for colorectal cancer in adults aged 76 to 85 years should be an individual one, taking into account the patient’s overall health and prior screening history, and we agree this is appropriate. We further anticipate that ordering CRC screening tests may stem from a beneficiary’s Annual Wellness Visit and personalized prevention plan which should take into account the concerns identified by the commenter. Comment: One commenter suggested updating the “asymptomatic” and “average risk” patient criteria to align with the contraindications of recently approved tests and clinical guidelines. The longstanding definition for colorectal cancer screening defines asymptomatic as ‘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).” Response: Thank you for the comment. We agree that this should be expanded to include any positive non-invasive biomarker tests to align with new FDA market authorized non-invasive biomarker CRC screening tests that have come to market, including the mt-sDNA test, mt-sRNA test, and BBB test. It was an oversight that this was not updated to include mt-sDNA when BBB tests were added to the NCD in 2021. The final NCD reflects this change. The average risk definition is derived from 42 CFR §410.37(a)(3). It defines an individual at high risk for colorectal cancer to mean an individual with a close relative (sibling, parent, or child) who has had colorectal cancer or an adenomatous polyp; a family history of familial adenomatous polyposis; a family history of hereditary nonpolyposis colorectal cancer; a personal history of adenomatous polyps; a personal history of colorectal cancer, or inflammatory bowel disease, including Crohn’s Disease, and ulcerative colitis. Average risk defines an individual that does not meet the high-risk criteria. We are finalizing as proposed. Comment: Many commenters expressed the need for shared decision-making. They suggest that patients need to be educated about the available screening tests, their test performance and the completion of the full screening process if the test provides a positive result. While commenters support non-invasive screening tests they acknowledge there are performance differences between stool-based and blood-based tests and patients need to be educated to select the most appropriate test. Response: We appreci