For patients at average risk for colorectal cancer (CRC), organizations such as the U.S Preventive Services Task Force have recommended several options for colon cancer screening. The diagnostic performance characteristics of the currently accepted screening options (ie, colonoscopy, sigmoidoscopy, fecal tests) have been established using colonoscopy as the criterion standard. Modeling studies and clinical trial evidence on some of the screening modalities have allowed some confidence in the effectiveness of several cancer screening modalities. The efficacy of these tests is supported by numerous studies evaluating the diagnostic characteristics of the test for detecting cancer and cancer precursors along with a well-developed body of knowledge on the natural history of the progression of cancer precursors to cancer. Early detection of colorectal cancer (CRC) reduces disease-related mortality, yet many individuals do not undergo recommended screening with fecal occult blood test or colonoscopy. A simpler screening blood test may have the potential to encourage screening and decrease mortality if associated with increased screening compliance.

SEPT9 Methylated DNA

ColoVantage (various manufacturers) blood tests for serum SEPT9 methylated DNA are offered by several laboratories (ARUP Laboratories, Quest Diagnostics, Clinical Genomics). Epi proColon (Epigenomics) received U.S. Food and Drug Administration approval in April 2016. Epigenomics has licensed its Septin 9 DNA biomarker technology to Polymedco and LabCorp. ColoVantage and Epi proColon are both PCR assays; however, performance characteristics vary across tests, presumably due to differences in methodology (eg, DNA preparation, PCR primers, probes).

Gene Expression Profiling

ColonSentry (Stage Zero Life Sciences) is a PCR assay that uses a blood sample to detect the expression of 7 genes found to be differentially expressed in CRC patients compared with controls^1,: ANXA3, CLEC4D, TNFAIP6, LMNB1, PRRG4, VNN1, and IL2RB. The test is intended to stratify average-risk adults who are non-compliant with colonoscopy and/or fecal occult blood testing. "Because of its narrow focus, the test is not expected to alter clinical practice for patients who comply with recommended screening schedules."^2,

Table 1 lists tests assessed in this policy.

Table 1. Genetic and Molecular Diagnostic Tests Assessed This Policy

Test Name	Manufacturer	Date Added	Diagnostic	Prognostic	Therapeutic	Future Risk
ColonSentry®	Stage Zero Life Sciences	Aug 2015
SEPT9 methylated DNAa	Severalb	Oct 2014

a. For example, ColoVantage® and Epi proColon®.
b. ARUP, Quest, Clinical Genomics and Epigenomics.

Regulatory Status

Clinical laboratories may develop and validate tests in-house and market them as a laboratory service; laboratory-developed tests must meet the general regulatory standards of the Clinical Laboratory Improvement Amendments. Genetic tests evaluated in this policy are available under the auspices of the Clinical Laboratory Improvement Amendments. Laboratories that offer laboratory-developed tests must be licensed under the Clinical Laboratory Improvement Amendments for high-complexity testing. To date, the U.S. Food and Drug Administration (FDA) has chosen not to require any regulatory review of these tests.

The Epi proColon test is the only SEPT9 DNA test that has received FDA approval. It was approved in 2016 for use in average-risk patients who decline other screening methods.

Related Policies

• Genetic Testing for Lynch Syndrome and Other Inherited Colon Cancer Syndromes (Policy #015 in the Pathology Section)
• Identification of Microorganisms Using Nucleic Acid Probes (Policy #074 in the Pathology Section)
• KRAS, NRAS, and BRAF Variant Analysis in Metastatic Colorectal Cancer (Policy #023 in the Pathology Section)
• General Approach to Genetic Testing (Policy #082 in the Pathology Section)
• General Approach to Evaluating the Utility of Genetic Panels (Policy #083 in the Pathology Section)
• Miscellaneous Genetic and Molecular Diagnostic Tests (Policy #114 in the Pathology Section)

For members enrolled in Medicaid and NJ FamilyCare plans, Horizon BCBSNJ applies the above medical policy.

FIDE SNP:

For members enrolled in a Fully Integrated Dual Eligible Special Needs Plan (FIDE-SNP): (1) to the extent the service is covered under the Medicare portion of the member’s benefit package, the above Medicare Coverage statement applies; and (2) to the extent the service is not covered under the Medicare portion of the member’s benefit package, the above Medicaid Coverage statement applies.

Policy Guidelines: (Information to guide medical necessity determination based on the criteria contained within the policy statements above.)

Genetic Counseling
Genetic counseling is primarily aimed at patients who are at risk for inherited disorders, and experts recommend formal genetic counseling in most cases when genetic testing for an inherited condition is considered. The interpretation of the results of genetic tests and the understanding of risk factors can be very difficult and complex. Therefore, genetic counseling will assist individuals in understanding the possible benefits and harms of genetic testing, including the possible impact of the information on the individual's family. Genetic counseling may alter the utilization of genetic testing substantially and may reduce inappropriate testing. Genetic counseling should be performed by an individual with experience and expertise in genetic medicine and genetic testing methods.


[RATIONALE: This policy was initially included in a separate policy on 'Miscellaneous Genetic and Molecular Diagnostic Tests' (Policy #114 in the Pathology Section). The evidence has been updated regularly with searches of the PubMed database. The most recent literature update was performed through June 17, 2020.

Evidence reviews assess whether a medical test is clinically useful. A useful test provides information to make a clinical management decision that improves the net health outcome. That is, the balance of benefits and harms is better when the test is used to manage the condition than when another test or no test is used to manage the condition.

The first step in assessing a medical test is to formulate the clinical context and purpose of the test. The test must be technically reliable, clinically valid, and clinically useful for that purpose. Evidence reviews assess the evidence on whether a test is clinically valid and clinically useful. Technical reliability is outside the scope of these reviews, and credible information on technical reliability is available from other sources.

Colorectal Cancer Screening

Clinical Context and Test Purpose

The U.S. Preventive Services Task Force has recommended screening for CRC starting at age 50 years and continuing until age 75 years but many adults do not receive screening for CRC.^3, It is thought that less burdensome methods of screening could increase the number of adults screened and thereby improve outcomes.

Serum biomarkers that are shed from colorectal tumors have been identified and include Septin 9 hypermethylated DNA (SEPT9). The Septin 9 protein is involved in cell division, migration, and apoptosis and acts as a tumor suppressor; when hypermethylated, expression of SEPT9 is reduced. ColonSentry is a PCR assay that uses a blood sample to detect the expression of 7 genes found to be differentially expressed in CRC patients compared with controls.

The question addressed in this policy is: Does CRC screening using the tests described below in individuals diagnosed with a disease improve the net health outcome?

The following PICO was used to select literature to inform this review.

Patients

The relevant population of interest is patients who are being screened for CRC.

Intervention

The interventions of interest are SEPT9 methylated DNA testing (eg, ColoVantage, Epi proColon) and gene expression profiling (eg ColonSentry).

Comparators

The comparator of interest is the standard of care without genetic screening.

Outcomes

The outcomes of interest are OS, disease-specific survival, test accuracy and validity, change in disease status, and morbid events. The timing of follow-up for CRC screening is weeks for the diagnosis of CRC to years for survival outcomes.

SEPT9 Methylated DNA With ColoVantage and Epi proColon

Technically Reliable

Assessment of technical reliability focuses on specific tests and operators and requires a review of unpublished and often proprietary information. Review of specific tests, operators, and unpublished data are outside the scope of this policy and alternative sources exist. This policy focuses on the clinical validity and clinical utility.

Clinically Valid

A test must detect the presence or absence of a condition, the risk of developing a condition in the future, or treatment response (beneficial or adverse).

Review of Evidence

The diagnostic performance of SEPT9 methylation for colon cancer has been reported in meta-analyses. The systematic reviews identified from 2016 and 2017 included from 14 to 39 studies (see Table 2). Pooled sensitivity ranged from 62% to 71% and pooled specificity ranged from 91% to 93% (see Table 3). The systematic review by Nian et al (2017) found that study designs (case-control vs cross-sectional), assays or kits used (Epi proColon vs other), country (Asia or other), sample sizes (>300 or <300), and risk of bias of included studies all contributed to heterogeneity.^4, Most included studies were case-control with the exclusion of difficult to diagnose patients, which may lead to a spectrum bias and overestimation of diagnostic accuracy. Reviewers included 20 studies of Epi proColon test 1.0, 2.0, or a combination of the 2. When only looking at studies of Epi ProColon 2.0, sensitivity was 75% compared with 71% in the overall analysis, with a specificity of 93% (see Table 3). Sensitivity and specificity may be additionally affected by the specific algorithm used, with the 1/3 algorithm resulting in higher sensitivity and the 2/3 algorithm resulting in higher specificity.^5,A 2020 systematic review of Epi proColon 2.0 by Hariharan and Jenkins found high specificity (92%) and NPV (99.9%) for CRC so that a negative test would rule out CRC.^6, However, a test with sensitivity of 69% would accurately diagnose only 21 of 30 CRC cases in a sample of 10,000 people at average risk. Sensitivity for precancerous lesions would be lower.

Table 2. Systematic Review Characteristics

Study	Studies Included	N	Study Designs Included	Study Reference Standards Included	11-Item QUADAS Quality Assessment
					No. of Studies Rated as High or Unclear Risk of Bias
					No Domains	1-2 Domains	>2 Domains
Harihan and Jenkins (2020)6,	19	7629	CC	Colonoscopy	6	8	5
Nian et al (2017)4,	25	9927	CC and CS	Colonoscopy	3	14	8
Li et al (2016)7,	39			Colonoscopy	6	12	21
Yan et al (2016)8,	14	9870	CC and CS	Colonoscopy	0	13	1

CC: case-control; CRC: colorectal cancer; CS: cross-sectional.

Table 3. Systematic Review Results

Study	Test	Sensitivity (95% CI), %	Specificity (95% CI), %
Harihan and Jenkins (2020)6,	Epi Procolon 2.0	69 (62 to 75)	92 (89 to 95)
Nian et al (2017)4,	Various	71 (67 to 75)	92 (89 to 94)
Nian et al (2017)4,	Epi Procolon 2.0	75 (67 to 77)	93 (88 to 96)
Li et al (2016)7,	Various	62 (56 to 67)	91 (89 to 93)
Yan et al (2016)8,	Various	66 (64 to 69)	91 (90 to 91)
Yan et al (2016)8,	Epi Procolon	63 (58 to 67)	91 (90 to 92)

CI: confidence interval.

The evidence review for the 2016 U.S. Preventive Services Task Force update on CRC screening included studies on blood tests for methylated SEPT9 DNA. The inclusion criteria were fair- or good-quality English-language studies, asymptomatic screening populations, age of 40 years or older, and at average risk for CRC or not selected for inclusion based on CRC risk factors. The only study found to meet these inclusion criteria was the Evaluation of SEPT9 Biomarker Performance for Colorectal Cancer Screening (PRESEPT) (described below).

PRESEPT (Church et al [2014]) was an international prospective screening study of the first-generation Epi proColon test (see Table 4).^9, Of 1516 patients selected for laboratory analysis, colonoscopy identified 53 (3%) patients with invasive adenocarcinoma, 315 (21%) with advanced adenoma, and 210 (14%) with nonadvanced adenoma. The overall sensitivity, specificity, positive predictive value, and negative predictive value for the detection of invasive adenocarcinoma are shown in Table 5. Sensitivity for any adenoma was 48% and advanced adenoma was 11%.

Table 4. Study Characteristics

Study	Study Population	Design	Reference Standard	Timing of Reference and Index Tests	Blinding of Assessors
Church et al (2014)9,	Patients ≥50 y at average risk and scheduled for colonoscopy	Prospective random sampling from 7941 patients at 32 sites	Colonoscopy	6-16 d before colonoscopy	Yes

Table 5. Study Results

Study	Initial N	Final N	Excluded Samples	Clinical Validity (95% Confidence Interval), %
				Sensitivity	Specificity	PPV	NPV
Church et al (2014)9,	1516	1510	6	48.2 (32.4 to 63.6)	91.5 (89.7 to 93.1)	5	100

NPV: negative predictive value; PPV: positive predictive value.

The purpose of the limitations tables (see Tables 6 and 7) is to display notable limitations identified in each study. This information is synthesized as a summary of the body of evidence following each table and provides the conclusions on the sufficiency of theevidence supporting the position statement.

Table 6. Study Relevance Limitations

Study	Populationa	Interventionb	Comparatorc	Outcomesd	Duration of Follow-Upe
Church et al (2014)9,		3. First-generation test

The study limitations stated in this table are those notable in the current review; this is not a comprehensive gaps assessment.
a Population key: 1. Intended use population unclear; 2. Clinical context is unclear; 3. Study population is unclear; 4. Study population not representative of intended use.
^b Intervention key: 1. Classification thresholds not defined; 2. Version used unclear; 3. Not intervention of interest.
^c Comparator key: 1. Classification thresholds not defined; 2. Not compared to credible reference standard; 3. Not compared to other tests in use for same purpose.
^d Outcomes key: 1. Study does not directly assess a key health outcome; 2. Evidence chain or decision model not explicated; 3. Key clinical validity outcomes not reported (sensitivity, specificity and predictive values); 4. Reclassification of diagnostic or risk categories not reported; 5. Adverse events of the test not described (excluding minor discomforts and inconvenience of venipuncture or noninvasive tests).
^e Follow-Up key: 1. Follow-up duration not sufficient with respect tonatural history of disease (true-positives, true-negatives, false-positives, false-negatives cannot be determined).

Table 7. Study Design and Conduct Limitations

Study	Selectiona	Blindingb	Delivery of Testc	Selective Reportingd	Data Completenesse	Statisticalf
Church et al (2014)9,	2. Not randomly sampled

The study limitations stated in this table are those notable in the current review; this is not a comprehensive gaps assessment.
^a Selection key: 1. Selection not described; 2. Selection not random or consecutive (ie, convenience).
^b Blinding key: 1. Not blinded to results of reference or other comparator tests.
^c Test Delivery key: 1. Timing of delivery of index or reference test not described; 2. Timing of index and comparator tests not same; 3. Procedure for interpreting tests not described; 4. Expertise of evaluators not described.
^d Selective Reporting key: 1. Not registered; 2. Evidence of selective reporting; 3. Evidence of selective publication.
^e Data Completeness key: 1. Inadequate description of indeterminate and missing samples; 2. High number of samples excluded; 3. High loss to follow-up or missing data.
^f Statistical key: 1. Confidence intervals and/or p values not reported; 2. Comparison with other tests not reported

Song et al (2018) conducted a prospective study of the colorectal tumor detection rate from methylated SEPT9 levels by Epi proColon 2.0 using the 2/3 algorithm.^10,All 1347 individuals who met criteria and were to undergo colonoscopy provided a blood sample prior to evaluation of clinical status. The level of methylated SEPT9 increased as the severity of disease increased, and the detection rate increased with disease severity. The detection rate was less than 20% for serrated adenoma and tubular adenoma, 41% for tubulovillous adenoma, 54% for stage I CRC, and then increased to 84% as the stage of CRC increased to stage IV CRC. Results suggested potential utility for monitoring treatment response but limited utility as a screening tool.

Clinically Useful

A test is clinically useful if the use of the results informs management decisions that improve the net health outcome of care. The net health outcome can be improved if patients receive correct therapy, or more effective therapy, or avoid unnecessary therapy, or avoid unnecessary testing.

Review of Evidence

Direct Evidence

Direct evidence of clinical utility is provided by studies that have compared health outcomes for patients managed with and without the test. Because these are intervention studies, the preferred evidence would be from RCTs.

Studies comparing survival outcomes in patients who undergo CRC screening with SEPT9 methylated DNA testing or with standard screening were not identified. Such comparative studies with clinically meaningful outcomes (eg, survival) are necessary to demonstrate incremental improvement in the net health outcome compared with current standard screening approaches (fecal immunochemical test, colonoscopy) and to address lead-time bias for cancers identified through the screening.

Chain of Evidence

Indirect evidence on clinical utility rests on clinical validity. If the evidence is insufficient to demonstrate test performance, no inferences can be made about clinical utility.

Because the sensitivity of SEPT9 methylated DNA is low, a chain of evidence establishing the clinical utility of SEPT9 methylated DNA cannot be established.

Subsection Summary: Colorectal Cancer Screening With SEPT9 Methylated DNA Testing

The evidence for the clinical validity of CRC screening includes case-control studies and prospective screening studies. Systematic reviews have reported that the sensitivity of testing ranges from 62% to 75% and the specificity from 91% to 93%. Studies were generally of low to fair quality. The prospective PRESEPT study with average-risk patients scheduled for colonoscopy estimated the sensitivity of Epi proColon for detection of invasive adenocarcinoma to be 48% and for an advanced adenoma to be 11%. Based on results from these studies, the clinical validity of SEPT9 methylated DNA screening is limited by low sensitivity and low positive predictive value of the test.

Detection of only half of preclinical cancers and a small proportion of advanced adenomas limits the clinical utility of the test. There is a need for further studies evaluating survival outcomes in patients screened with SEPT9 methylated DNA testing (ColoVantage, Epi proColon) who have refused established screening methods.. Because the evidence on clinical validity has reported that the test has a lower sensitivity than other screening methods, the clinical utility is uncertain. If the test is restricted only to patients who would otherwise not be screened, outcomes might be improved. However, if the test is used as a substitute for other screening tests that have higher sensitivity, outcomes may be worse.

Gene Expression Profiling With ColonSentry

Clinically Valid

Review of Evidence

Two case-control studies have been identified with ColonSentry. Marshall et al (2010) conducted a genome-wide association study in 189 whole blood samples (98 controls, 91 patients with CRC) and identified 45 differentially expressed gene biomarker candidates using microarray hybridization.^11, Through logistic regression and bootstrapping (subsampling with replacement) in a training set of 232 samples, 7 genes were selected for further development. In a subsequent test set of 410 samples (208 controls, 202 patients with CRC), sensitivity, specificity, PPV, and NPV were determined (see Tables 8 and 9). Yip et al (2010) conducted a similar cross-sectional study of 210 blood samples from patients in Malaysia.^1, The Malaysian population has different ethnic groups with different CRC incidences and CRC in Asian populations is more likely to be nonpolypoid (ie, flat or depressed) compared with Western populations in whom the test was developed.

Sensitivity for the 2 studies ranged from 61% to 72% and specificity for detecting CRC were 70% to 77%. The area under the curve was 0.76 (95% CI, 0.70 to 0.82).

Table 8. Study Characteristics

Study	Study Population	Design	Reference Standard	Timing of Reference and Index Tests
Marshall et al (2010)11,	202 patients with CRC and 208 controls	Case-control	NA	NA
Yip et al (2010)1,	99 patients with CRC and 111 controls	Case-control	NA	NA

CRC: colorectal cancer; NA: not applicable.

Table 9. Study Results

Study	Initial N	Final N	Excluded Samples	AUC (95% CI)	Clinical Validity (95% Confidence Interval), %
					Sensitivity	Specificity	PPV	NPV
Marshall et al (2010)11,	410			0.80 (0.76 to 0.84)	72	70	70	72
Yip et al (2010)1,	200				61	77

AUC: area under the curve; CI: confidence interval; NPV: negative predictive value; PPV: positive predictive value.

Limitations in relevance and design and conduct are shown in Tables 10 and 11. Because of its cross-sectional design, follow-up of controls to determine which strata developed CRC was not reported, limiting conclusions drawn about the accuracy of the test for risk prediction.

Table 10. Study Relevance Limitations

Study	Populationa	Interventionb	Comparatorc	Outcomesd	Duration of Follow-Upe
Marshall et al (2010)11,	4. Included patients with CRC and healthy controls
Yip et al (2010)1,	4. Included patients with CRC and healthy controls

The study limitations stated in this table are those notable in the current review; this is not a comprehensive gaps assessment.
CRC: colorectal cancer.
^a Population key: 1. Intended use population unclear; 2. Clinical context is unclear; 3. Study population is unclear; 4. Study population not representative of intended use.
^bIntervention key: 1. Classification thresholds not defined; 2. Version used unclear; 3. Not intervention of interest.
^c Comparator key: 1. Classification thresholds not defined; 2. Not compared to credible reference standard; 3. Not compared to other tests in use for same purpose.
^d Outcomes key: 1. Study does not directly assess a key health outcome; 2. Evidence chain or decision model not explicated; 3. Key clinical validity outcomes not reported (sensitivity, specificity and predictive values); 4. Reclassification of diagnostic or risk categories not reported; 5. Adverse events of the test not described (excluding minor discomforts and inconvenience of venipuncture or noninvasive tests).
^e Follow-Up key: 1. Follow-up duration not sufficient with respect to natural history of disease (true-positives, true-negatives, false-positives, false-negatives cannot be determined).

Table 11. Study Design and Conduct Limitations

Study	Selectiona	Blindingb	Delivery of Testc	Selective Reportingd	Data Completenesse	Statisticalf
Marshall et al (2010)11,	2. Selection not random
Yip et al (2010)1,	2. Selection not random

The study limitations stated in this table are those notable in the current review; this is not a comprehensive gaps assessment.
^a Selection key: 1. Selection not described; 2. Selection not random or consecutive (ie, convenience).
^bBlinding key: 1. Not blinded to results of reference or other comparator tests.
^cTest Delivery key: 1. Timing of delivery of index or reference test not described; 2. Timing of index and comparator tests not same; 3. Procedure for interpreting tests not described; 4. Expertise of evaluators not described.
^d Selective Reporting key: 1. Not registered; 2. Evidence of selective reporting; 3. Evidence of selective publication.
^e Data Completeness key: 1. Inadequate description of indeterminate and missing samples; 2. High number of samples excluded; 3. High loss to follow-up or missing data.
^f Statistical key: 1. Confidence intervals and/or p values not reported; 2. Comparison with other tests not reported.

Clinically Useful

A test is clinically useful if the use of the results informs management decisions that improve the net health outcome of care. The net health outcome can be improved if patients receive correct therapy, or more effective therapy, or avoid unnecessary therapy, or avoid unnecessary testing.

Review of Evidence

Direct Evidence

Direct evidence of clinical utility is provided by studies that have compared health outcomes for patients managed with and without the test. Because these are intervention studies, the preferred evidence would be from RCTs.

No studies examining the clinical utility of ColonSentry were identified.

Chain of Evidence

Indirect evidence on clinical utility rests on clinical validity. If the evidence is insufficient to demonstrate test performance, no inferences can be made about clinical utility.

A chain of evidence supporting the use of ColonSentry for predicting CRC risk cannot because constructed due to lack of clinical validity.

Subsection Summary: Colorectal Screening With ColonSentry

ColonSentry is intended to stratify patients with average CRC risk who are averse to current screening approaches to identify those at increased risk and therefore choose a less-invasive screening method. However, 2 cross-sectional studies are insufficient to demonstrate the risk predictive ability of the test; ie, clinical validity has not been established. Sensitivity for the 2 studies ranged from 61% to 72% and specificity for detecting CRC were 70% to 77%. Based on results from these studies, the clinical validity of gene expression screening is limited by low sensitivity and low specificity. Direct and indirect evidence of clinical utility is currently lacking.

Summary of Evidence

For individuals who are being screened for CRC who receive serologic molecular or genetic screening for colorectal cancer, the evidence includes case-control, cross-sectional, and prospective diagnostic accuracy studies along with systematic reviews of those studies. Relevant outcomes are OS, disease-specific survival, test accuracy and validity, change in disease status, and morbid events. The PRESEPT prospective study estimated the sensitivity and specificity of Epi proColon detection of invasive adenocarcinoma at 48% and 92%, respectively. Other studies were generally low to fair quality. In systematic reviews, sensitivity ranged from 62% to 71% and pooled specificity ranged from 91% to 93%. Based on results from these studies, the clinical validity of SEPT9 methylated DNA screening is limited by the low sensitivity of the test. Optimal intervals for retesting are not known. Sensitivity in the 2 cross-sectional studies of ColonSentry ranged from 61% to 72% and specificity for detecting CRC were 70% to 77%. Based on results from these studies, the clinical validity of gene expression screening is limited by low sensitivity and low specificity. The evidence is insufficient to determine the effects of the technologies on health outcomes.

SUPPLEMENTAL INFORMATION

Practice Guidelines and Position Statements

National Comprehensive Cancer Network

Current NCCN (v.2.2020) guidelines on colorectal cancer (CRC) screening state that "A blood test that detects circulating methylated SEPT9 DNA has been U.S. Food and Drug Administration approved for CRC screening for those who refuse other screening modalities. It is not recommended for routine screening. The interval for repeating testing is unknown".^12,

American Cancer Society

In 2018, the American Cancer Society has recommended that "adults aged 45 y and older with an average risk of CRC undergo regular screening with either a high‐sensitivity stool‐based test or a structural (visual) examination, depending on patient preference and test availability. As a part of the screening process, all positive results on noncolonoscopy screening tests should be followed up with timely colonoscopy." ^13, The stool-based tests listed as options are a fecal immunochemical test, fecal occult blood test, and multi-target stool DNA test. The College noted that "…at this time, mSEPT9 is not included in this guideline as an option for routine CRC screening for average‐risk adults."

American College of Physicians

In 2019, based on its review of U.S. guidelines, the American College of Physicians issued a guidance statement on screening for CRC in average risk adults.^14, For average-risk adults ages 50 to 75 years, the College recommended using a stool-based test, flexible sigmoidoscopy, or optical colonoscopy for screening. No recommendation for genetic or molecular testing of average-risk individuals was included.

U.S. Multi-Society Task Force on Colorectal Cancer

The U.S. Multi-Society Task Force on Colorectal Cancer represents the American College of Gastroenterology, the American Gastroenterological Association, and the American Society for Gastrointestinal Endoscopy.^15, In 2017, the Task Force's clinical guidelines stated that the advantage of SEPT9 assays for CRC screening is convenience. The disadvantage is "markedly inferior performance characteristics compared with FIT [fecal immunochemical test]." The guidelines also stated that the best frequency for performing the test is unknown and that the task force recommended not using SEPT9 assays for CRC screening.

U.S. Preventive Services Task Force Recommendations

In 2016, the U.S. Preventive Services Task Force updated its recommendations for CRC screening in adults.^3,16, It recommended screening for CRC starting at age 50 years and continuing until age 75 years. The 2016 recommendations differ from the 2008 recommendations in that current guidance does not emphasize specific screening approaches but highlights evidence that CRC screening substantially reduces deaths from the disease among adults ages 50 to 75 years and not enough adults in the U. S. are using effective preventive interventions. The evidence review supporting the recommendations included a search for studies of blood tests for methylated SEPT9 DNA but concluded that the test "currently has limited evidence evaluating its use."

Ongoing and Unpublished Clinical Trials

Some currently ongoing and unpublished trials that might influence this review are listed in Table 12.

Table 12. Summary of Key Trials

NCT No.	Trial Name	Planned Enrollment	Completion Date
Ongoing
NCT03598166	Assessing the Effect of Offering a Blood-based Colorectal Cancer Screening Test on Screening Adherence and Colonoscopy Completion in Patients Who Have Refused Colonoscopy and FIT	360	Dec 2020
NCT03218423a	Performance of Epi proColon in Repeated Testing in the Intended Use Population	4500	Jan 2022

NCT: national clinical trial.
^a Denotes industry-sponsored or cosponsored trial.]
________________________________________________________________________________________

Horizon BCBSNJ Medical Policy Development Process:

This Horizon BCBSNJ Medical Policy (the “Medical Policy”) has been developed by Horizon BCBSNJ’s Medical Policy Committee (the “Committee”) consistent with generally accepted standards of medical practice, and reflects Horizon BCBSNJ’s view of the subject health care services, supplies or procedures, and in what circumstances they are deemed to be medically necessary or experimental/ investigational in nature. This Medical Policy also considers whether and to what degree the subject health care services, supplies or procedures are clinically appropriate, in terms of type, frequency, extent, site and duration and if they are considered effective for the illnesses, injuries or diseases discussed. Where relevant, this Medical Policy considers whether the subject health care services, supplies or procedures are being requested primarily for the convenience of the covered person or the health care provider. It may also consider whether the services, supplies or procedures are more costly than an alternative service or sequence of services, supplies or procedures that are at least as likely to produce equivalent therapeutic or diagnostic results as to the diagnosis or treatment of the relevant illness, injury or disease. In reaching its conclusion regarding what it considers to be the generally accepted standards of medical practice, the Committee reviews and considers the following: all credible scientific evidence published in peer-reviewed medical literature generally recognized by the relevant medical community, physician and health care provider specialty society recommendations, the views of physicians and health care providers practicing in relevant clinical areas (including, but not limited to, the prevailing opinion within the appropriate specialty) and any other relevant factor as determined by applicable State and Federal laws and regulations.

___________________________________________________________________________________________________________________________

Index:
Serologic Genetic and Molecular Screening for Colorectal Cancer
SEPT9 Methylated DNA Testing
ColoVantage
Epi proColon
ColonSentry

References:
1. Yip KT, Das PK, Suria D, et al. A case-controlled validation study of a blood-based seven-gene biomarker panel for colorectal cancer in Malaysia. J Exp Clin Cancer Res. Sep 16 2010; 29: 128. PMID 20846378

2. Chao S, Ying J, Liew G, et al. Blood RNA biomarker panel detects both left- and right-sided colorectal neoplasms: a case-control study. J Exp Clin Cancer Res. Jul 23 2013; 32: 44. PMID 23876008

3. U.S. Preventive Services Task Force. Colorectal cancer: screening. 2016; https://www.uspreventiveservicestaskforce.org/Page/Document/UpdateSummaryFinal/colorectal-cancer- screening2. Accessed June 18, 2020.

4. Nian J, Sun X, Ming S, et al. Diagnostic Accuracy of Methylated SEPT9 for Blood-based Colorectal Cancer Detection: A Systematic Review and Meta-Analysis. Clin Transl Gastroenterol. Jan 19 2017; 8(1): e216. PMID 28102859

5. Song L, Jia J, Peng X, et al. The performance of the SEPT9 gene methylation assay and a comparison with other CRC screening tests: A meta-analysis. Sci Rep. Jun 08 2017; 7(1): 3032. PMID 28596563

6. Hariharan R, Jenkins M. Utility of the methylated SEPT9 test for the early detection of colorectal cancer: a systematic review and meta-analysis of diagnostic test accuracy. BMJ Open Gastroenterol. 2020; 7(1): e000355. PMID 32128229

7. Li B, Gan A, Chen X, et al. Diagnostic Performance of DNA Hypermethylation Markers in Peripheral Blood for the Detection of Colorectal Cancer: A Meta-Analysis and Systematic Review. PLoS ONE. 2016; 11(5): e0155095. PMID 27158984

8. Yan S, Liu Z, Yu S, et al. Diagnostic Value of Methylated Septin9 for Colorectal Cancer Screening: A Meta-Analysis. Med Sci Monit. Sep 25 2016; 22: 3409-3418. PMID 27665580

9. Church TR, Wandell M, Lofton-Day C, et al. Prospective evaluation of methylated SEPT9 in plasma for detection of asymptomatic colorectal cancer. Gut. Feb 2014; 63(2): 317-25. PMID 23408352

10. Song L, Wang J, Wang H, et al. The quantitative profiling of blood mSEPT9 determines the detection performance on colorectal tumors. Epigenomics. Dec 2018; 10(12): 1569-1583. PMID 30426784

11. Marshall KW, Mohr S, Khettabi FE, et al. A blood-based biomarker panel for stratifying current risk for colorectal cancer. Int J Cancer. Mar 01 2010; 126(5): 1177-86. PMID 19795455

12. National Comprehensive Cancer Network (NCCN). NCCN Clinical practice guidelines in oncology: colorectal cancer screening. Version 2.2020. https://www.nccn.org/professionals/physician_gls/pdf/colorectal_screening.pdf. Accessed June 18, 2020.

13. Wolf AMD, Fontham ETH, Church TR, et al. Colorectal cancer screening for average-risk adults: 2018 guideline update from the American Cancer Society. CA Cancer J Clin. Jul 2018; 68(4): 250-281. PMID 29846947

14. Qaseem A, Crandall CJ, Mustafa RA, et al. Screening for Colorectal Cancer in Asymptomatic Average-Risk Adults: A Guidance Statement From the American College of Physicians. Ann Intern Med. Nov 05 2019; 171(9): 643-654. PMID 31683290

15. Rex DK, Boland CR, Dominitz JA, et al. Colorectal Cancer Screening: Recommendations for Physicians and Patients from the U.S. Multi-Society Task Force on Colorectal Cancer. Am J Gastroenterol. Jul 2017; 112(7): 1016-1030. PMID 28555630

16. Bibbins-Domingo K, Grossman DC, Curry SJ, et al. Screening for Colorectal Cancer: US Preventive Services Task Force Recommendation Statement. JAMA. Jun 21 2016; 315(23): 2564-2575. PMID 27304597

Codes:
(The list of codes is not intended to be all-inclusive and is included below for informational purposes only. Inclusion or exclusion of a procedure, diagnosis, drug or device code(s) does not constitute or imply authorization, certification, approval, offer of coverage or guarantee of payment.)

CPT*

81327