Highmark Commercial Medical Policy - Pennsylvania
Medical Policy: L-208-002
Topic: Sept9 Methylation Analysis for Colorectal Cancer
Section: Laboratory
Effective Date: November 13, 2017
Issue Date: November 13, 2017
Last Reviewed: March 2017

Two tests designed to detect colorectal cancer by analyzing Sept9 methylation are Epi proColon and ColoVantage:

  • The Epi proColon Test (Epigenomics) is a Septin 9 assay that measures the presence of methylated Septin 9 DNA in a blood sample. It is intended to identify early stage colorectal cancer.  It offers an alternative to current screening options.
  • The ColoVantage Test (Quest Diagnostics) is a Septin 9 assay that measures the presence of methylated Septin 9 DNA in a blood sample.  This test “aids in the detection of colorectal cancer in patients non-adherent to current testing approaches.”

Both Epi proColon and ColoVantage are performed on a blood sample.  No bowel preparation or dietary or medication restrictions are required to complete either test.  Both tests measure methylation of Septin 9 DNA, which is increased in colorectal cancer.  Tumors often have increased methylation of Septin 9. When tumor DNA is shed into the bloodstream, this increase in methylation of Septin 9 can be found in the blood.  Epi proColon provides a qualitative result: positive or negative.

This policy is designed to address medical guidelines that are appropriate for the majority of individuals with a particular disease, illness, or condition. Each person's unique clinical circumstances may warrant individual consideration, based on review of applicable medical records.

Policy Position Coverage is subject to the specific terms of the member’s benefit plan.

Sept9 methylation analysis for colorectal cancer is considered experimental/investigational and therefore non-covered. 

Experimental/investigational molecular and genomic (MolGen) tests refer to assays involving chromosomes, DNA, RNA, or gene products that have insufficient data to determine the net health impact, which typically means there is insufficient data to support that a test accurately assesses the outcome of interest (analytical and clinical validity), significantly improves health outcomes (clinical utility), and/or performs better than an existing standard of care medical management option. 

Such tests are also not generally accepted as standard of care in the evaluation or management of a particular condition. In the case of MolGen testing, FDA clearance is not a reliable standard given the number of laboratory developed tests that currently fall outside of FDA oversight and FDA clearance often does not assess clinical utility.

Procedure Codes
81327

Professional Statements and Societal Positions

Guidelines and Evidence

There are currently no US guidelines that specifically address the use of either Epi proColon or ColoVantage testing.

Current CRC cancer screening guidelines from the U.S. Preventative Services Task Force (USPSTF, 2016) recommend the use of gFOBT, FIT, FIT-DNA, colonoscopy, CT colonography, and flexible sigmoidoscopy for individuals ages 50 years to 75 years at average risk of colorectal cancer.  These guidelines specifically state the following regarding Septin DNA testing:

  • “Although a serology test to detect methylated SEPT9 DNA was included in the systematic evidence review, this screening method currently has limited evidence evaluating its use (a single published test characteristic study met inclusion criteria, which found it had a sensitivity to detect colorectal cancer of<50%). It is therefore not included in this table.”

For other age groups, the USPSTF guidelines recommend the following:

  • “For older adults aged 76 to 85 years, the benefits of screening for colorectal cancer decline, and the risk of experiencing serious associated harms increases.  The most important consideration for clinicians and patients in this age group is whether the patient has previously been screened. Patients in this age group who have never been screened for colorectal cancer are more likely to benefit than those who have been previously screened.”
  • “Screening [in adults aged 76 to 85 years] would be most appropriate among adults who 1) are healthy enough to undergo treatment if colorectal cancer is detected and 2) do not have comorbid conditions that would significantly limit their life expectancy.”
  • “The USPSTF does not recommend routine screening for colorectal cancer in adults 86 years and older. In this age group, competing causes of mortality preclude a mortality benefit that would outweigh the harms.”

The U.S. Food and Drug Administration approved Epi proColon in 2016 as an in vitro diagnostic.

  • “The Epi proColon test is indicated to screen adults of either sex, 50 years or older, defined as average risk for CRC, who have been offered and have a history of not completing CRC screening.”
  • “The Epi proColon test is not intended to replace colorectal cancer screening tests that are recommended by appropriate guidelines (e.g., 2008 USPSTF guidelines) such as colonoscopy, sigmoidoscopy and high sensitivity fecal occult blood testing.”
  • “The Epi proColon test is not intended for patients who are willing and able to undergo routine colorectal cancer screening tests that are recommended by appropriate guidelines.” 
  • “Tests that are available and recommended in the USPSTF 2008 CRC screening guidelines should be offered and declined prior to offering the Epi proColon test.”

Epi proColon

  • “The performance of Epi proColon has been established in cross-sectional (i.e., single point in time) studies. Programmatic performance of Epi proColon (i.e., benefits and risks with repeated testing over an established period of time) has not been studied.  Performance has not been evaluated for patients who have been previously tested with Epi proColon. Non-inferiority of Epi proColon programmatic sensitivity as compared to other recommended screening methods for CRC has not been established.”
  • “Screening with Epi proColon in subsequent years following a negative test result should be offered only to patients who after counseling by their healthcare provider again decline CRC screening methods according to appropriate guidelines.  The screening interval for this follow-up has not been established.”
  • The frequency intervals that follow up when Epi proColon testing should be performed have yet to be established.
  • A large, prospective multicenter trial (PRESEPT) evaluated men and women between the ages of 50 to 85 years who were at average risk for colorectal cancer.
    • Clinical performance of the Epi proColon test in terms of sensitivity and specificity was based on 1544 samples from subjects whose colorectal cancer status was determined by colonoscopy. 
    • Sensitivity was determined to be 68.2% with a specificity of 78.8%. Positive predictive value (PPV) was 2.4% with a negative predictive value (NPV) of 99.7%.
  • In 6 clinical validation studies, values of sensitivity and specificity of the Epi proColon test were reported.  Sensitivity ranged from 72% to 79%, and specificity ranged from 82% to 96%.  One study showed increasing sensitivity for higher CRC stages (~89% at Stage IV).  In a comparative clinical validation trial, Epi proColon showed better sensitivity but worse specificity, when compared with gFOBT or FIT.  Another study showed that the performance of the test is negatively impacted by risk factors frequently observed in CRC screening populations, such as early-stage disease, age greater than 65 years, diabetes, arthritis, and arteriosclerosis.
  • Specifically, increased age was associated with increased rates of false positive and false negative results.
    • Results of a recent meta-analysis/systematic review indicate that the area under the receiver operating curve (AUC) for the pooled diagnostic accuracy results for Epi proColon test was 0.8709.  In head-to-head comparisons, the AUC of the combined results of 1) Epi proColon and mSEPT 9 tests and 2) FOBT for CRC diagnosis were 0.7857 and 0.6571, respectively.

ColoVantage
The analytical validity, clinical validity, and clinical utility of the ColoVantage test for detecting CRC has not been established.

  • ColoVantage Plasma is currently undergoing clinical trials in Australia.

Place of Service: Inpatient/Outpatient

Experimental/Investigational (E/I) services are not covered regardless of place of service.

Sept9 methylation analysis for colorectal cancer is typically an outpatient procedure which is only eligible for coverage as an inpatient procedure in special circumstances, including, but not limited to, the presence of a co-morbid condition that would require monitoring in a more controlled environment such as the inpatient setting.


The policy position applies to all commercial lines of business


Denial Statements

Services that do not meet the criteria of this policy will be considered experimental/investigational (E/I). A network provider can bill the member for the experimental/investigational service. The provider must give advance written notice informing the member that the service has been deemed E/I. The member must be provided with an estimate of the cost and the member must agree in writing to assume financial responsibility in advance of receiving the service. The signed agreement must be maintained in the provider’s records.

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