It is well established that early detection of colorectal cancer (CRC) reduces disease-related mortality. For patients at average risk for CRC, organizations such as the U.S. Preventive Services Task Force have recommended several options for colon cancer screening. Currently accepted screening options for CRC include colonoscopy or sigmoidoscopy, fecal occult blood testing, and fecal immunochemical testing. However, many individuals do not undergo recommended screening with fecal tests or colonoscopy. A simpler screening blood test for genetic alterations associated with non-familial CRC may have the potential to encourage screening and decrease mortality if associated with increased screening compliance. Genetic testing is also being investigated to guide therapy.
For individuals who are being screened for colorectal cancer (CRC) who receive serologic molecular or genetic screening for CRC, the evidence includes case-control, cross-sectional, and prospective diagnostic accuracy studies along with systematic reviews of those studies. Relevant outcomes are overall survival (OS), disease-specific survival, test accuracy and validity, change in disease status, and morbid events. The Evaluation of SEPT9 Biomarker Performance for Colorectal Cancer Screening (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 Septin9 (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. No published peer-reviewed evidence was identified for BeScreened-CRC. The evidence is insufficient to determine that the technology results in an improvement in the net health outcome.
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.
SEPT9 methylated DNA testing (e.g., ColoVantage®, Epi proColon®) is considered investigational for colorectal cancer screening.
Gene expression profiling (e.g., ColonSentry®, BeScreened™-CRC ) is considered investigational for colorectal cancer screening.
| CPT | 81327 | SEPT9 (Septin9) (eg, colorectal cancer) methylation analysis |
| 0163U | Oncology (colorectal) screening, biochemical enzyme-linked immunosorbent assay (ELISA) of 3 plasma or serum proteins (teratocarcinoma derived growth factor-1 [TDGF-1, Cripto-1], carcinoembryonic antigen [CEA], extracellular matrix protein [ECM]), with demographic data (age, gender, CRC-screening compliance) using a proprietary algorithm and reported as likelihood of CRC or advanced adenomas |
| HCPCS | G0327 | Colorectal cancer screening; blood-based biomarker |
| ICD-10-CM | Investigational for all relevant diagnoses |
Genetic counseling is primarily aimed at individuals 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.
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 (i.e. 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 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.
ColoVantage (various manufacturers) blood tests for serum Septin9 (SEPT9) methylated DNA are offered by several laboratories (ARUP Laboratories, Quest Diagnostics, Clinical Genomics). Epi proColon (Epigenomics) received U.S. Food and Drug Administration (FDA) approval in April 2016. Epigenomics has licensed its Septin 9 DNA biomarker technology to Polymedco and LabCorp. ColoVantage and Epi proColon are both polymerase chain reaction (PCR) assays; however, performance characteristics vary across tests, presumably due to differences in methodology (eg, DNA preparation, PCR primers, probes).
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 controls1,: 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, BeScreened-CRC (Beacon Biomedical) is a PCR assay that uses a blood sample to detect the expression of 3 protein biomarkers: teratocarcinoma derived growth factor-1 (TDGF-1, Cripto-1); carcinoembryonic antigen, a well-established biomarker associated with CRC; and an extracellular matrix protein involved in early stage tumor stroma changes.3,
Table 1 lists tests assessed in this evidence review.
| Test Name | Manufacturer | Date Added | Diagnostic | Prognostic | Therapeutic | Future Risk |
| BeScreened-CRC | Beacon Biomedical | May 2021 | ⚫ | |||
| 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.
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 evidence review 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. 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.
