557 Form

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Medical Policy Analysis of Human DNA or RNA in Stool Samples as a Technique for Colorectal Cancer Screening
Table of Contents • Policy: Commercial • Description
• Information Pertaining to All Policies
• Authorization Information • Policy History
• Endnotes • Coding Information • References

Policy Number: 557

BCBSA Reference Number: 2.04.29 (For Plan internal use only) Related Policies
None Policy1 Commercial Members: Managed Care (HMO and POS), PPO, and Indemnity

Cologuard, Cologuard Plus or Colosense, a multitarget stool DNA or RNA test, is considered MEDICALLY NECESSARY as a colorectal cancer screening test for asymptomatic, average risk individuals who meet all of the following 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 guaiac fecal occult blood test or fecal immunochemical 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).

All other DNA or RNA analysis of stool samples as a screening technique for colorectal cancer, in both individuals with average to moderate risk and individuals considered at high risk for colorectal cancer, is INVESTIGATIONAL.

Prior Authorization Information
Inpatient • For services described in this policy, precertification/preauthorization IS REQUIRED for all products if the procedure is performed inpatient.
Outpatient • For services described in this policy, see below for products where prior authorization might be required if the procedure is performed outpatient.

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Outpatient Commercial Managed Care (HMO and POS) Prior authorization is not required. Commercial PPO and Indemnity Prior authorization is not required. CPT Codes / HCPCS Codes / ICD Codes Inclusion or exclusion of a code does not constitute or imply member coverage or provider reimbursement. Please refer to the member’s contract benefits in effect at the time of service to determine coverage or non-coverage as it applies to an individual member.

Providers should report all services using the most up-to-date industry-standard procedure, revenue, and diagnosis codes, including modifiers where applicable.

The above medical necessity criteria MUST be met for the following codes to be covered for Commercial Members: Managed Care (HMO and POS), PPO, and Indemnity: CPT Codes
CPT codes: Code Description 81528 Oncology (colorectal) screening, quantitative real-time target and signal amplification of 10 dna markers (kras mutations, promoter methylation of ndrg4 and bmp3) and fecal hemoglobin, utilizing stool, algorithm reported as a positive or negative result 0464U Oncology (colorectal) screening, quantitative real-time target and signal amplification, methylated DNA markers, including LASS4, LRRC4 and PPP2R5C, a reference marker ZDHHC1, and a protein marker (fecal hemoglobin), utilizing stool, algorithm reported as a positive or negative result 0421U Oncology (colorectal) screening, quantitative real-time target and signal amplification of 8 RNA markers (GAPDH, SMAD4, ACY1, AREG, CDH1, KRAS, TNFRSF10B, EGLN2) and fecal hemoglobin, algorithm reported as a positive or negative for colorectal cancer risk

The following CPT code is considered investigational for Commercial Members: Managed Care (HMO and POS), PPO, Indemnity, Medicare HMO Blue and Medicare PPO Blue:

CPT Codes CPT codes:

Code Description 0501U Oncology (colorectal), blood, quantitative measurement of cell- free DNA (cfDNA)

The following HCPCS code is considered investigational for Commercial Members: Managed Care (HMO and POS), PPO, and Indemnity:

HCPCS Codes HCPCS codes:

Code Description G0327 Colorectal cancer screening; blood-based biomarker

DESCRIPTION Colorectal Cancer Several cellular genetic alterations have been associated with colorectal cancer (CRC). In the proposed multistep model of carcinogenesis, the tumor suppressor gene p53 and the proto-oncogene KRAS are most frequently altered. Variants in adenomatous polyposis coli genes and epigenetic markers (eg, hypermethylation of specific genes) have also been detected. CRC is also associated with DNA replication errors in microsatellite sequences (termed microsatellite instability) in patients with Lynch syndrome (formerly known as hereditary nonpolyposis CRC) and in subgroups of patients with sporadic

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colon carcinoma. Tumor-associated gene variants and epigenetic markers can be detected in exfoliated intestinal cells in stool specimens. Because cancer cells are shed into the stool, tests have been developed to detect these genetic alterations in the DNA from shed CRC cells isolated from stool samples.

FDA Approved Colorectal Cancer Screening Tests Evaluating DNA or RNA in Stool Samples Device Manufacturer Indication(s) Cologuard™

Exact Sciences Corporation

“Intended for the qualitative detection of colorectal neoplasia associated DNA markers and for the presence of occult hemoglobin in human stool. A positive result may indicate the presence of colorectal cancer (CRC) or advanced adenoma (AA) and should be followed by diagnostic colonoscopy. Cologuard is indicated to screen adults of either sex, 45 years or older, who are at typical average-risk for CRC. Cologuard is not a replacement for diagnostic colonoscopy or surveillance colonoscopy in high-risk individuals.”

Cologuard Plus™ Exact Sciences Corporation

“Intended for the detection of colorectal neoplasia-associated DNA markers and for the presence of occult hemoglobin in human stool. The Cologuard Plus test is performed on samples collected using the Cologuard Plus Collection Kit. A positive result may indicate the presence of colorectal cancer (CRC) or advanced precancerous lesions (APL) and should be followed by colonoscopy. The Cologuard Plus test is indicated to screen adults 45 years or older, who are at average risk for CRC. The Cologuard Plus test is not a replacement for diagnostic colonoscopy or surveillance colonoscopy in high-risk individuals.”

Colosense® Geneoscopy, Inc “Intended for the detection of colorectal neoplasia associated RNA markers and for the presence of occult hemoglobin in human stool. ColoSense is for use with the ColoSense Collection Kit, the ColoSense Test Kit, the ColoSense Software, and the following instruments: Polymedco Immunochemical Fecal Occult Blood Test (iFOBT) Analyzer; bioMerieux EMAG Nucleic Acid Extraction System; and Bio-Rad QXDx Droplet Digital Polymerase Chain Reaction (ddPCR) System. ColoSense is a single-site test performed at Geneoscopy, Inc. A positive ColoSense result may indicate the presence of colorectal cancer (CRC), advanced adenomas (AA) or serrated precancerous lesions (SPL) and should be followed by a colonoscopy. ColoSense is indicated as a screening test for adults, 45 years of age or older, who are at average-risk for developing CRC. ColoSense is not a replacement for diagnostic colonoscopy or surveillance colonoscopy in high-risk individuals.”

Summary Description Detection of DNA or RNA abnormalities associated with colorectal cancer (CRC) in stool samples has been proposed as a screening test for CRC. This technology is another potential alternative to currently available screening approaches such as fecal occult blood testing, fecal immunochemical testing (FIT), and colonoscopy. The currently available stool tests combine FIT and DNA or RNA analysis and are referred to as FIT-DNA or FIT-RNA in this review, though other publications use terms such as stool DNA (sDNA)-FIT multitarget stool DNA (mt-sDNA) or multitarget stool RNA (mt-sRNA) test.

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Summary of Evidence For individuals who are asymptomatic and at average risk of colorectal cancer (CRC) who receive fecal immunochemical testing (FIT)-DNA, the evidence screening studies comparing the original and next- generation version of the FIT-DNA (using colonoscopy as the reference standard) to FIT alone, 3 systematic reviews of screening studies, and modeling studies. Relevant outcomes are overall survival and disease-specific survival. The screening studies have reported that both the original and the next- generation FIT-DNA tests have higher sensitivity and lower specificity than FIT. There are no studies directly assessing health outcomes such as overall survival or disease-specific survival. The screening interval for the test has not been confirmed nor is there evidence on the adherence of the test at a recommended screening interval. Effective screening for CRC requires a screening program with established screening intervals and appropriate follow-up for positive tests. Clinical utility of FIT-DNA is based on modeling studies. These studies have demonstrated that the diagnostic characteristics of FIT- DNA are consistent with decreases in CRC mortality that are in the range of other accepted modalities. FIT- DNA every 3 years is less effective than most other accepted screening strategies, while FIT-DNA every year is close to the efficacy of colonoscopy every 10 years. The evidence is sufficient to determine that the technology results in an improvement in the net health outcome.

For individuals who are asymptomatic and at average risk of colorectal cancer (CRC) who receive fecal immunochemical testing (FIT)-RNA, the evidence includes a screening study comparing the FIT-RNA (using colonoscopy as the reference standard) to FIT alone. Relevant outcomes are overall survival and disease-specific survival. The screening study reported that the FIT-RNA test has higher sensitivity and lower specificity than FIT. There are no studies directly assessing health outcomes such as overall survival or disease-specific survival. The screening interval for the test has not been confirmed nor is there evidence on the adherence of the test at a recommended screening interval. Effective screening for CRC requires a screening program with established screening intervals and appropriate follow-up for positive tests. Clinical utility of FIT-RNA is based on the similar performance characteristics of FIT-RNA compared to FIT-DNA so that FIT-DNA modeling studies are also of relevance for FIT-RNA. The evidence is sufficient to determine that the technology results in an improvement in the net health outcome.

Policy History Date Action 2/2026 Annual policy review. Policy updated with literature review through October 23, 2025; references added. Policy statements unchanged.
6/2025 Policy clarified to specify Colosense to the policy statement. 5/2025 Annual policy review. Policy updated with literature review through September 12, 2024; references added. Cologuard Plus and Colosense added to evidence review and policy statements as medically necessary. Title expanded to include RNA tests. Clarified coding information. Effective 5/1/2025. 12/2024 Clarified coding information. 10/2024 Clarified coding information. 7/2024 Clarified coding information. 1/2024 Annual policy review. Description, summary, and references updated. Policy statements unchanged. 1/2023 Annual policy review. Minor editorial refinements to policy statements; intent unchanged. 1/2022 Annual policy review. Description, summary, and references updated. Policy statements unchanged. 7/2021 Clarified coding information 1/2021 Annual policy review. Description, summary, and references updated. Policy statements unchanged. 1/2021 Medicare information removed. See MP #132 Medicare Advantage Management for local coverage determination and national coverage determination reference.
1/2020 Annual policy review. Description, summary, and references updated. Policy statements unchanged. 1/2019 Annual policy review. Description, summary, and references updated. Policy statements unchanged.

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1/2018 Annual policy review. New references added. 12/2016 Annual policy review. New references added. 1/2016 Clarified coding information. 10/2015 New medically necessary statement added for commercial plans. Effective 10/1/2015. 1/2015 CMS decision memo for screening for colorectal cancer - stool DNA testing (CAG- 00440N) added. Clarified coding information. Effective 10/9/2014. 12/2014 Annual policy review. New references added. 2/2014 Annual policy review. New references added. 11/2011-4/2012 Medical policy ICD 10 remediation: Formatting, editing and coding updates. No changes to policy statements.
7/2011 Reviewed - Medical Policy Group – Hematology and Oncology. No changes to policy statements. 3/21/2011 New policy describing ongoing non-coverage. Information Pertaining to All Blue Cross Blue Shield Medical Policies Click on any of the following terms to access the relevant information: Medical Policy Terms of Use Managed Care Guidelines Indemnity/PPO Guidelines Clinical Exception Process Medical Technology Assessment Guidelines

References

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3. Food and Drug Administration. SUMMARY OF SAFETY AND EFFECTIVENESS DATA (SSED): Cologuard. August 2014. Accessed Oct 23, 2025.
4. Food and Drug Administration. SUMMARY OF SAFETY AND EFFECTIVENESS DATA (SSED): Cologuard Plus. October 2024. Accessed Oct 22, 2025.
5. Food and Drug Administration. SUMMARY OF SAFETY AND EFFECTIVENESS DATA (SSED): ColoSense. May 2024. Accessed Oct 21, 2025.
6. National Comprehensive Cancer Network (NCCN). NCCN Clinical Practice Guidelines in Oncology: Colorectal Cancer Screening. Version 2.2025. https://www.nccn.org/professionals/physician_gls/pdf/colorectal_screening.pdf. Accessed October 23,
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23. Berger BM, Kisiel JB, Imperiale TF, et al. Low Incidence of Aerodigestive Cancers in Patients With Negative Results From Colonoscopies, Regardless of Findings From Multitarget Stool DNA Tests. Clin Gastroenterol Hepatol. Apr 2020; 18(4): 864-871. PMID 31394289
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34. Issaka RB, Chan AT, Gupta S. AGA Clinical Practice Update on Risk Stratification for Colorectal Cancer Screening and Post-Polypectomy Surveillance: Expert Review. Gastroenterology. Nov 2023; 165(5): 1280-1291. PMID 37737817
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37. Centers for Medicare and Medicaid Services (CMS). Colorectal Cancer Screening Tests. 2023; https://www.cms.gov/medicare-coverage-database/view/ncd.aspx?ncdid=281&ncdver=7. Accessed October 23, 2025. Endnotes

    1 Based on Medicare Decision Memo for Screening for Colorectal Cancer - Stool DNA Testing (CAG- 00440N)