ModifiedBlue Cross Blue Shield - KansasPolicy N/A

Analysis of Human DNA or RNA in Stool Samples as a Technique for Colorectal Cancer Screening

This policy addresses use of stool-based testing that analyzes human DNA or RNA (FIT-DNA / FIT-RNA) as a screening technique for colorectal cancer in asymptomatic, average-risk adults and governs coverage determinations for Blue Cross Blue Shield of Kansas members.

Policy Summary

PayerBlue Cross Blue Shield - Kansas

PolicyAnalysis of Human DNA or RNA in Stool Samples as a Technique for Colorectal Cancer Screening

Policy CodePolicy N/A

Change TypeTitle and coding additionseligibility language updated

Effective DateMar 13, 2025

Next Review DateN/A

Key ActionOrder stool DNA/RNA testing only for asymptomatic, average-risk adults who have not undergone another colorectal cancer screening method within the last year and follow positive results with timely colonoscopy.

SourceLink

POLICY UPDATE CHANGES

Added RNA to the policy title 'Analysis of Human DNA or RNA in Stool Samples as a Technique for Colorectal Cancer Screening'.

Removed prior specific eligibility language that required no other colorectal cancer screening within specified prior intervals (e.g., colonoscopy within 10 years) as a condition for Cologuard coverage.

Added CPT/HCPCS code 0421U and later 0464U to the coding section.

45-84age range

q3ymt-sDNA interval

94%

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CRC sensitivity (Cologuard Plus)

91%specificity (Cologuard Plus)

81528,0421U,0464Ulisted codes

Coverage Criteria — When Stool DNA/RNA Screening Is Covered

inv-01: Medically necessary

Policy coverage statements

A. Medically necessary screening: DNA or RNA analysis of stool samples can be considered medically necessary as a screening technique for colorectal cancer in individuals at average risk of colorectal cancer who have not been screened by another colorectal cancer screening method within the last year.

Applies to asymptomatic, average‑risk adults (relevant population ages 45–84).

inv-02: Experimental / Investigational — 2 top-level nodes

B. Experimental/Investigational: Combination testing of DNA or RNA analysis of stool samples with other methods of colorectal cancer screening within a year is experimental/investigational.within 1 year

May lead to denial or noncoverage for combined tests billed within a 12‑month period.

C. Other indications: DNA or RNA analysis of stool samples is considered experimental/investigational for all other indications.

Includes uses beyond asymptomatic, average‑risk screening (eg, surveillance after CRC).

inv-03: Covered uses — average-risk screening; matches studied populations and recommended intervals

Covered when test use matches studied populations and recommended intervals

Age and population: Test is intended for asymptomatic, average‑risk adults beginning at age 45; pivotal studies and approvals include individuals aged 45 years and older (study populations include ages up to 84 years).age >=45

Aligned with USPSTF and FDA approvals for Cologuard/Cologuard Plus; population described in policy (ages 45–84).

Test‑specific interval: mt‑sDNA (eg, Cologuard and Cologuard Plus) and mt‑sRNA: repeat testing every 3 years when results are negative; quantitative FIT is recommended annually per guideline considerations.mt‑sDNA/mt‑sRNA: q3y; FIT: q1y

Intervals reflect regulatory approvals and guideline/modeling evidence reported in the document.

Specimen and reference standard alignment:

inv-04: Guideline-based contexts — guideline-aligned screening contexts where stool DNA/RNA testing is mentioned

Guideline-aligned screening contexts where stool DNA/RNA testing is mentioned:

Average‑risk screening inclusion: Major guideline sources (ACS, AGA, Multi‑Society Task Force, NCCN, USPSTF) include or discuss FIT‑DNA/FIT‑RNA as an option for colorectal cancer screening in average‑risk adults, with recommended intervals varying by guideline (commonly every 1–3 years for FIT‑DNA/FIT‑RNA or every 3 years in many statements).

References: ACS 2018, AGA updates, Multi‑Society Task Force, NCCN v2.2025, USPSTF 2021.

Age ranges: Guidelines generally recommend starting average‑risk screening at age 45 and continuing through age 75, with individualized decisions for ages 76–85 and not recommending screening after 85.

Aligns with USPSTF, ACS, and task force guidance summarized in the policy.

Follow‑up after positive test: NCCN recommends follow‑up colonoscopy within 9 months after a positive FIT‑DNA or FIT‑RNA test.

Specifies recommended diagnostic follow‑up interval after positive stool DNA/RNA testing.

inv-05: Medically necessary indication — Covered when ALL of the following are met

Covered when ALL of the following are met

Average‑risk individual and prior screening: Individual is at average risk for colorectal cancer and has not been screened by another colorectal cancer screening method within the last year.not screened within last year

This condition is required for DNA or RNA stool analysis to be considered medically necessary per the updated policy language.

inv-06: Experimental / Investigational — Not covered / Experimental when ANY of the following apply

Not covered / Experimental when ANY of the following apply

Combination testing within a year: Combination testing of DNA or RNA stool analysis with other colorectal cancer screening methods within a year is experimental/investigational.within 1 year

May result in noncoverage or denial if billed as medically necessary in combination with other screening tests within 12 months.

Other indications: DNA or RNA analysis of stool samples is considered experimental/investigational for all other indications beyond the specified average‑risk screening scenario.

Includes uses such as post‑colorectal cancer diagnosis surveillance and other non‑screening indications.

Use of DNA or RNA analysis of stool samples in combination with other colorectal cancer screening methods within a year is explicitly excluded and is considered experimental/investigational. This exclusion means combined stool-based testing plus any other CRC screening modality performed within a 12‑month period may be denied as not meeting medical necessity criteria.

The primary clinical evidence for stool DNA/RNA tests comes from studies of average‑risk, asymptomatic populations; several cohort studies excluded individuals with prior colorectal cancer screening or high‑risk conditions. Therefore, the supporting evidence and performance metrics apply to average‑risk cohorts rather than to individuals with prior screening, known polyps, or hereditary risk factors.

The American College of Physicians (ACP) 2023 guidance states that clinicians should not use stool DNA tests (and several other noninvasive modalities) for CRC screening in asymptomatic, average‑risk adults, and does not endorse FIT‑DNA or similar stool DNA/RNA tests as recommended screening options.

The policy reiterates that combination testing with other screening methods within one year is considered experimental/investigational. Tests billed as combined screening modalities within a 12‑month window do not meet the policy's medically necessary criteria and may be denied.

Individuals with an estimated life expectancy of less than 10 years should not be screened for colorectal cancer; screening in this population is not recommended by the policy.

Outside the specific asymptomatic average‑risk screening scenario described in the policy, DNA or RNA analysis of stool samples is considered experimental/investigational. This includes use for indications other than routine screening of average‑risk individuals who meet the policy conditions.

There are currently no randomized trials demonstrating that Cologuard or Cologuard Plus reduce colorectal cancer mortality. Direct evidence of mortality reduction from these tests is lacking; large prospective outcome studies (for example, Voyage) are ongoing but will not complete for several years.

The policy restates that DNA or RNA stool analysis is experimental/investigational for any indication that does not meet the specified screening criteria, i.e., uses beyond asymptomatic, average‑risk screening under the policy conditions are not covered.

Coding — Applicable CPT / HCPCS Codes

Covered CPT CodesCPT

No codes listed

Stool DNA screening codesCPT/HCPCSCovered

81528

Oncology (colorectal) screening, quantitative real-time target and signal amplification of 10 DNA markers and fecal hemoglobin, stool, algorithm reported as a positive or negative result.

Stool RNA screening codesCPT/HCPCSCovered

0421U

Oncology (colorectal) screening, quantitative real-time target and signal amplification of 8 RNA markers and fecal hemoglobin, algorithm reported as a positive or negative for colorectal cancer risk.

Additional stool DNA/methylation screening codesCPT/HCPCSCovered

0464U

Oncology (colorectal) screening, quantitative real-time target and signal amplification, methylated DNA markers and a protein marker (fecal hemoglobin), stool, algorithm reported as a positive or negative result.

Provider Actions — Documentation, Follow-up, and Billing

Documentation Required

Age and Interval Requirements

A. Age and interval requirements: DNA or RNA analysis of stool (eg, mt‑sDNA/FIT‑DNA or FIT‑RNA tests such as Cologuard, Cologuard Plus, Colosense) is indicated for average‑risk adults starting at age 45. When used for routine screening, repeat testing at intervals of every 3 years may be considered medically necessary (mt‑sDNA every 3 years). The tests are intended for average‑risk individuals who have not undergone another colorectal cancer screening method within the past year.

Age: ≥45 years for FDA‑approved tests (Cologuard, Cologuard Plus)
Interval: mt‑sDNA/FIT‑DNA every 3 years is the recommended rescreen interval after a negative test

Billing Rule

Code Applicability

Code applicability and billing note: The CPT/HCPCS codes listed in this policy are applicable only when the procedure is performed according to the policy criteria. Inclusion of a code does not guarantee coverage. Submit supporting documentation that demonstrates the member meets policy criteria to support medical necessity.

Background

Colorectal cancer arises from genetic and epigenetic alterations in colonic epithelial cells that can be shed into stool. Stool‑based assays detect these changes by combining fecal hemoglobin measurement (FIT) with molecular markers—such as methylated DNA, mutation markers, or stool RNA—from exfoliated intestinal cells. These biomarkers enable noninvasive detection of colorectal neoplasia and form the biological rationale for FIT‑DNA and FIT‑RNA screening tests.

Definitions and Test Descriptions

FIT-DNA / FIT-RNA — combined FIT with DNA/RNA markers — definition

TermFIT-DNA / FIT-RNA

DefinitionStool tests that combine fecal immunochemical testing (FIT) with analysis of DNA or RNA markers associated with colorectal neoplasia; also referred to as stool DNA (sDNA)-FIT, multitarget stool DNA (mt-sDNA) or multitarget stool RNA (mt-sRNA)

SpecimenStool sample collected at home in a manufacturer-supplied kit and shipped to a central laboratory for analysis

Cologuard / Cologuard Plus / ColoSense — FDA‑approved commercial tests

CologuardFIT + DNA markers including promoter methylation (NDRG4, BMP3), KRAS mutations, and fecal hemoglobin (occult blood)

Cologuard PlusNext-generation FIT-DNA test expanding methylated DNA marker panel (eg, LASS4, LRRC4, PPP2R5C, ZDHHC1) to improve specificity

Policy Summary

PayerBlue Cross Blue Shield - Kansas

PolicyAnalysis of Human DNA or RNA in Stool Samples as a Technique for Colorectal Cancer Screening

Policy CodePolicy N/A

Change TypeTitle and coding additionseligibility language updated

Effective DateMar 13, 2025

Next Review DateN/A

SourceLink

On This Page

Stool specimens should be collected consistent with study methods (eg, prior to screening colonoscopy, within study timeframes) with colonoscopy and histopathology as the reference standard for performance data.

pre‑colonoscopy specimen collection (eg, within 90 days)

Ensures test use matches clinical validity evidence from pivotal studies (BLUE‑C, Imperiale et al).

Relevant codes include 81528, 0421U, 0464U (see coding section)
Codes are medically necessary ONLY if performed per the Policy section

Denial Risk

Completion and Follow‑Up Risk

Completion and follow‑up risks: Real‑world studies report incomplete test completion and gaps in follow‑up after positive stool tests. Expect noncompletion of ordered mt‑sDNA tests (eg, ~37% not completed in one cohort) and that a substantial proportion of positive results may not receive timely colonoscopy; average time to colonoscopy after a positive result may be prolonged (eg, mean ~229 days) and many patients with positive tests do not proceed to colonoscopy.

Report and track test completion rates; document navigation efforts to obtain follow‑up colonoscopy
Average observed time from positive mt‑sDNA to colonoscopy in cohort: ~229 ± 273 days; only ~57% of positives had follow‑up colonoscopy in one study

Note

Prior Authorization — Not Specified

Not applicable statements in this document portion: Prior authorization requirement is not specified in this section. Provider should follow payer-specific prior authorization processes if applicable elsewhere in the member contract.

No explicit prior authorization requirement provided here

Documentation Required

Missing Supporting Documentation

Missing supporting documentation: If medical documentation is not provided to support medical necessity (eg, documentation of average‑risk status, absence of another screening test within the past year, or appropriate age), DNA/RNA stool testing (eg, Cologuard) may be considered not medically necessary or non‑covered. Ensure records include prior screening history, risk assessment, and ordering rationale.

Document average‑risk status and that no other screening was done in the prior year
Lack of documentation may result in denial or classification as not medically necessary

Documentation Required

Specimen Collection and Test Site

Specimen collection and test site: Stool specimens are collected at home by the patient using the manufacturer’s collection kit and shipped to the test manufacturer or designated laboratory for analysis.

Home‑collected stool sample in manufacturer kit
Samples are sent to the manufacturer’s laboratory for analysis

Documentation Required

Specimen Collection and Linkage to Reference

Specimen collection linkage to validation studies: In pivotal and validation studies, stool specimens were collected prior to colonoscopy—commonly within a defined window (eg, ≤90 days before colonoscopy) — and were linked to colonoscopy and central histopathology reports used as the reference standard.

Pivotal study collections: stool obtained ≤90 days before screening colonoscopy (Imperiale et al.)
Cologuard Plus (BLUE‑C) and other studies collected stool prior to colonoscopy with central review of pathology

Documentation Required

Reference Standard for Validation Studies

Reference standard for validation studies: Colonoscopy with histopathological review of biopsied or resected lesions (central pathology review in pivotal trials) was used as the reference standard for determining diagnostic performance (sensitivity, specificity) of stool DNA/RNA tests.

Colonoscopy findings ± centralized histopathology served as the reference standard in pivotal and cohort studies

Step Therapy

Step Therapy / Sequencing Note

Step‑therapy and sequencing note: Stool DNA/RNA testing is considered an acceptable alternative screening modality for individuals who have not been screened within the prior year or who decline colonoscopy; it is positioned as an alternative pathway rather than first‑line over colonoscopy. Combination testing with other screening methods within a 1‑year period is considered experimental/investigational and is not supported.

Stool DNA/RNA acceptable when no other screening in past year
Combination testing with other modalities within one year = experimental/investigational

Note

Colonoscopy vs Stool Tests and Screening Hierarchy

Consideration of colonoscopy versus stool‑based tests and screening hierarchy: Guideline task forces and modeling place colonoscopy every 10 years as first‑tier (highest priority) for average‑risk screening; stool tests (annual FIT or FIT‑DNA every 3 years) are alternative options for individuals who decline colonoscopy. Modeling suggests FIT‑DNA every 3 years yields life‑years gained within the range of other strategies but lower than colonoscopy; annual FIT or annual FIT‑DNA may offer higher effectiveness at the cost of more follow‑up colonoscopies.

Multi‑Society Task Force: colonoscopy every 10 years first‑tier; FIT annually as first‑tier alternative; FIT‑DNA every 3 years as second‑tier for those who refuse colonoscopy/FIT
Modeling: FIT‑DNA every 3 years has lower LYG than colonoscopy every 10 years but is in range of acceptable strategies

Note

Provider Actions — Not Specified

Provider action — not specified: Some operational provider actions (eg, specific prior authorization steps, payer‑specific forms, or provider denial triggers beyond documentation gaps and combination testing within one year) are not specified in this document portion. Providers should consult the payer contract and coding/billing guidance for any additional procedural requirements.

No explicit provider checklist or prior authorization workflow is provided here — follow payer contract and local billing rules

ColoSenseFIT combined with 8 stool-derived eukaryotic RNA (seRNA) markers plus FIT; single combined result reported based on RNA markers, hemoglobin, and smoking status

mt-sDNA / FIT-DNA — multitarget stool DNA definition

Termmt-sDNA / FIT-DNA (multitarget stool DNA)

DefinitionA multitarget stool DNA test that combines fecal immunochemical testing (FIT) with multiple molecular DNA markers to detect colorectal cancer and advanced precancerous lesions; example: Cologuard and Cologuard Plus

Performance notePivotal studies report high CRC sensitivity (eg, mt-sDNA ~93% and Cologuard Plus CRC sensitivity 94%) with lower specificity compared to FIT alone

Quantitative FIT — definition and examples

TermQuantitative FIT

DefinitionFecal immunochemical test measured quantitatively (examples: OC‑Sensor, OC‑Light) with program-specific thresholds and typically recommended at annual intervals

Performance examplesReported CRC sensitivity varies by device (eg, OC‑Light CRC sensitivity ~81%) and recommended testing interval commonly annual

FIT-DNA / multitarget stool DNA — explanatory definition

DefinitionFIT-DNA (multitarget stool DNA) combines FIT with molecular DNA markers to detect colorectal cancer and precancerous lesions; shows higher sensitivity but lower specificity than FIT alone

Clinical implicationModeling indicates FIT-DNA annual testing approaches but may not equal colonoscopy effectiveness; testing every 3 years is less effective than many alternatives

Specimen/reference standardDiagnostic performance assessed using stool collected prior to colonoscopy, with colonoscopy as the reference standard

FIT-RNA / stool RNA test (ColoSense) — definition and performance note

TermFIT-RNA / stool RNA test (ColoSense)

DefinitionStool test combining FIT with RNA-based molecular markers (seRNA) to detect colorectal cancer and advanced adenomas; ColoSense evaluates 8 RNA markers plus FIT

Performance noteProspective CRC-PREVENT data report FIT-RNA (ColoSense) CRC sensitivity ~94% with overall specificity ~87%; modeling studies incorporating FIT-RNA outcomes are pending

FIT-DNA — brief definition

TermFIT-DNA (brief)

Short definitionA stool-based screening test combining fecal hemoglobin measurement (FIT) with multiple DNA markers to detect colorectal neoplasia, with higher sensitivity and lower specificity than FIT alone

Typical intervalOften recommended every 1–3 years depending on guideline and test version (commonly every 3 years for mt-sDNA)

0421U (FIT-RNA) — CPT/HCPCS code definition and algorithm note

Code0421U

DescriptionOncology (colorectal) screening: quantitative real-time target and signal amplification of 8 RNA markers (GAPDH, SMAD4, ACY1, AREG, CDH1, KRAS, TNFRSF10B, EGLN2) plus fecal hemoglobin; algorithm reported as positive or negative for colorectal cancer risk

NoteTest algorithm yields a positive/negative result based on combined RNA marker amplification and fecal hemoglobin; inclusion in coding section reflects FDA-cleared FIT-RNA (ColoSense)