SEPT9 Methylation Analysis for Colorectal Cancer - eviCore
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Lab Management Guidelines V2.0.2021
SEPT9 Methylation Analysis for
Colorectal Cancer
MOL.TS.164.A
v2.0.2021
Introduction
SEPT9 methylation analysis for colorectal cancer is addressed by this guideline.
Procedures addressed
The inclusion of any procedure code in this table does not imply that the code is under
management or requires prior authorization. Refer to the specific Health Plan's
procedure code list for management requirements.
Procedure addressed by this guideline Procedure code
SEPT9 Methylation Analysis 81327
What is SEPT9 methylation analysis for colorectal cancer
Definition
Colorectal cancer (CRC) is one of the most common types of cancers, with over
145,000 new cases identified each year in the United States. 1 It typically affects adults
over 55 years old, with a median age at diagnosis of 67 years. 1
Screening programs for CRC allow for its early detection. The earlier CRC is
caught, the better chance a person has of surviving. Five year survival rates are
89.9% for localized cancer, 71.3% for cancer that has spread regionally, and 14.2%
for CRC with distant metastasis.1
Standard recommended screening for CRC includes guaiac-based fecal occult
blood test (gFOBT), fecal immunochemical test (FIT), multitargeted stool DNA test
(FIT-DNA), colonoscopy, CT colonography, and flexible sigmoidoscopy. Screening
begins at age 50 years and continues until at least age 75 for people at average
risk for CRC.2
Although several screening tests have been endorsed and found to be cost-
effective, compliance with CRC screening recommendations is limited. According to
2010 data from the Centers for Disease Control and Prevention (CDC), the
percentage of adults over 50 years who reported their CRC screening was up to
date ranged from 58.92% to 75.03%, depending on the state. The CDC estimates
that 28 million Americans are not up-to-date on CRC screening. 3
Two tests designed to detect colorectal cancer by analyzing SEPT9 methylation will
be addressed in this guideline: Epi proColon and ColoVantage.
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Test information
Introduction
Epi proColon and ColoVantage measure the methylation status of circulating free
SEPT9 DNA in blood plasma.4,5 Tumors may have increased methylation of SEPT9.
When tumor DNA is shed into the bloodstream, this increase in methylation of SEPT9
may be found in the blood.4,6 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.4,5
SEPT9 Methylation Analysis for Colorectal Cancer
The Epi proColon Test (Epigenomics) and the ColoVantage Test (Quest Diagnostics)
are SEPT9 assays that measure the presence of methylated SEPT9 DNA in a blood
sample. Both are intended to identify early stage colorectal cancer and offer an
alternative to screening options.4,5 Theses tests may “aid in the detection of colorectal
cancer in patients non-adherent to current testing approaches.” 5
Results
A qualitative result of either positive or negative is reported. People who receive
positive results should be referred for a diagnostic colonoscopy. Those with negative
results can continue with standard CRC screening recommendations. 4-6
Guidelines and evidence
Introduction
This section includes guidelines and evidence pertaining to SEPT9 methylation
analysis for colorectal cancer. There are currently no US guidelines that specifically
address the use of either Epi proColon or ColoVantage testing.
Sept9 Methylation
National Comprehensive Cancer Network
The National Comprehensive Cancer Network (NCCN, 2020) guidelines on colorectal
cancer screening include the following footnote regarding methylated SEPT9 DNA
testing:7
"A blood test that detects circulating methylated SEPT9 DNA has been FDA-
approved for CRC screening for those who refuse other screening modalities. The
interval for repeating testing is unknown."
"The interval for repeat testing is uncertain and the NCCN Guidelines for CRC
Screening (see CSCR-3 and CSCR-4 in the algorithm) do not recommend the
SEPT9 DNA test for routine screening.”
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U.S. Food and Drug Administration
The U.S. Food and Drug Administration (FDA, 2016) approved Epi proColon as an in
vitro diagnostic.6 They state the following:
“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."
U.S. Preventive Services Task Force
The U.S. Preventive Services Task Force (USPSTF, 2016) published guidelines for
colorectal cancer screening.
For individuals 50 years to 75 years at average risk for colorectal cancer they
recommend the use of gFOBT, FIT, FIT-DNA, colonoscopy, CT colonography, and
flexible sigmoidoscopy. These guidelines specifically state the following regarding
SEPT9 testing:
o “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 ofLab Management Guidelines V2.0.2021
o “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.” 2
Selected Relevant Publications
Multiple peer reviewed publications address the analytical and clinical validity of Epi
proColon.9-32 The number of well-designed prospective multicenter studies evaluating
the test performance of Epi proColon in screening populations with average-risk CRC
is limited. The few available studies suggest a low rate of sensitivity to detect the
presence of CRC, a high rate of false positives, and a high rate of specificity to detect
the absence of disease. No clinical studies were identified that reported if use of Epi
proColon leads to reduction in disease-associated mortality or other meaningful health
outcomes in average-risk CRC populations. Thus, the clinical utility of Epi proColon
has not been established. The appropriate intervals for testing have not been
established.
Specifically regarding 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.” 7
“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.” 6
The frequency interval that follow up Epi proColon testing should be performed has
yet to be established.6,7
Sept9 Methylation
A large, prospective multicenter trial (PRESEPT) evaluated men and women over
the age of 50 years who were at average risk for colorectal cancer. 9
o 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.
o 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%.
Results of a 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
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results of 1) Epi proColon and mSEPT 9 tests and 2) FOBT for CRC diagnosis were
0.7857 and 0.6571, respectively.17
Specifically regarding ColoVantage:
The analytical validity, clinical validity, and clinical utility of the ColoVantage test for
detecting CRC has not been established.
Criteria
Epi proColon and ColoVantage testing are considered investigational and/or
experimental.
o Investigational and experimental (I&E) 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.
o 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
References
Introduction
This guideline cites the following references.
Sept9 Methylation
1. SEER Cancer Statistics Factsheets: Colon and Rectum Cancer. National Cancer
Institute. Bethesda, MD. Available at:
http://seer.cancer.gov/statfacts/html/colorect.html.
2. U.S. Preventive Services Task Force. Final Recommendation Statement:
Colorectal Cancer: Screening. June 2016. Available at
http://jama.jamanetwork.com/article.aspx?articleid=2529486
3. Centers for Disease Control and Prevention. Colorectal Cancer. Available at: http://
www.cdc.gov/cancer/colorectal/index.htm.
4. Epi proColon. Epi proColon website. Available at: http://www.epiprocolon.com/en/
5. About ColoVantage. Quest Diagnostics website. Available at:
https://testdirectory.questdiagnostics.com/test/test-detail/16983/colovantage-
methylated-septin-9?cc=MASTER
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6. US Food and Drug Administration. Approval Order Epi proColon: P130001.
Available at: http://www.accessdata.fda.gov/cdrh_docs/pdf13/P130001C.pdf and
http://www.accessdata.fda.gov/cdrh_docs/pdf13/P130001A.pdf.
7. National Comprehensive Cancer Network. NCCN Guidelines Version 2.2020:
Colorectal Cancer Screening. Available at:
https://www.nccn.org/professionals/physician_gls/pdf/colorectal_screening.pdf.
8. Nikolaou S, Qiu S, Fiorentino F, et al. Systematic review of blood diagnostic
markers in colorectal cancer. Tech Coloproctol. 2018;22(7):481-498. doi:
10.1007/s10151-018-1820- 3.
9. Epi proColon: Epi proColon Medical Professionals brochure. Epi proColon website.
Available at:
https://www.epiprocolon.com/wp-content/uploads/sites/3/2017/06/MKT_0026_Phys
ician_messaging_and_brochure_rev5.pdf https://www.epiprocolon.com/wp-content/
uploads/sites/3/2016/06/MKT0049EN-EpiproColon-2.0-CE-Med-Professional-
brochure.pdf
10. Potter NT, Hurban P, White MN, et al. Validation of a real-time PCR-based
qualitative assay for the detection of methylated SEPT9 DNA in human plasma.
Clin Chem. 2014;60(9):1183-1191.
11. Johnson DA, Barclay RL, Mergener K, et al. Plasma Septin9 versus fecal
immunochemical testing for colorectal cancer screening: a prospective multicentre
study. PLoS One. 2014;9(6):1-8.
12. Jin P, Kang Q, Wang X, et al. Performance of a second-generation methylated
SEPT9 test in detecting colorectal neoplasm. J Gastroenterol Hepatol. May
2015;30(5):830-833.
13. Orntoft MB, Nielsen HJ, Orntoft TF, Andersen CL. Performance of the colorectal
cancer screening marker Sept9 is influenced by age, diabetes and arthritis: a
nested case-control study. BMC Cancer. Oct 29 2015;15:819.
14. Song L, Li Y, Jia J, et al. Algorithm Optimization in Methylation Detection with
Multiple RT-qPCR. PloS One. 2016;11(11):e0163333.
Sept9 Methylation
15. Toth K, Sipos F, Kalmar A, et al. Detection of methylated SEPT9 in plasma is a
reliable screening method for both left- and right-sided colon cancers. PloS One.
2012;7(9):e46000.
16. Wu D, Zhou G, Jin P, et al. Detection of Colorectal Cancer Using a Simplified
SEPT9 Gene Methylation Assay Is a Reliable Method for Opportunistic Screening.
J Mol Diagn. Jul 2016;18(4):535-545.
17. Yan S, Liu Z, Yu S, Bao Y. Diagnostic Value of Methylated Septin9 for Colorectal
Cancer Screening: A Meta-Analysis. Med Sci Monit. Sep 25 2016;22:3409-3418.
18. Song L, Guo S, Wang J, et al. The blood mSEPT9 is capable of assessing the
surgical therapeutic effect and the prognosis of colorectal cancer. Biomark Med.
2018;12(9):961-973.
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400 Buckwalter Place Boulevard, Bluffton, SC 29910 (800) 918-8924 www.eviCore.comLab Management Guidelines V2.0.2021
19. Song L, Peng X, Li Y, et al. The SEPT9 gene methylation assay is capable of
detecting colorectal adenoma in opportunistic screening. Epigenomics.
2017;9(5):599-610.
20. Song L, Wang J, Wang H, et al. The quantitative profiling of blood mSEPT9
determines the detection performance on colorectal tumors. Epigenomics.
2018;10(12):1569-1583.
21. Song L, Jia J, Yu H, et al. The performance of the mSEPT9 assay is influenced by
algorithm, cancer stage and age, but not sex and cancer location. J Cancer Res
Clin Oncol. 2017;143(6):1093-1101.
22. Toth K, Patai AV, Kalmar A, et al. Circadian rhythm of methylated septin 9, cell-free
DNA amount and tumor markers in colorectal cancer patients. Pathol Oncol Res.
2017;23(3):699-706.
23. He N, Song L, Kang Q, et al. The pathological features of colorectal cancer
determine the detection performance on blood ctDNA. Technol Cancer Res Treat.
2018;17. doi: 10.1177/1533033818791794.
24. Leung WK, Shin VY, Law WL. Detection of methylated septin 9 DNA in blood for
diagnosis, prognosis, and surveillance of colorectal cancer. Hong Kong Med J.
2019;25 Suppl 9(6):32-34. doi.
25. 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 Gastroenterology. 2020;7(1):e000355. doi: 10.1136/bmjgast-
2019-000355.
26. Church TR, Wandell M, Lofton-Day C, et al. Prospective evaluation of methylated
SEPT9 in plasma for detection of asymptomatic colorectal cancer. Gut.
2014;63(2):317-325. doi: 10.1136/gutjnl-2012-304149.
27. Song L, Yu H, Jia J, et al. A systematic review of the performance of the SEPT9
gene methylation assay in colorectal cancer screening, monitoring, diagnosis and
prognosis. Cancer Biomark. 2017;18(4):425-432. doi: 10.3233/cbm-160321.
28. Song L JJ, Peng X, Xiao W, Li Y. The performance of the SEPT9 gene mehtylation
Sept9 Methylation
assay and a comparison with other CRC screening tests: a meta-analysis.
Scientific Reports 2016;7(3032). doi: 10.1038/s41598-017-03321-8.
29. Fu B, Yan P, Zhang S, et al. Cell-free circulating methylated SEPT9 for noninvasive
diagnosis and monitoring of colorectal cancer. Dis Markers. 2018;2018:6437104.
doi: 10.1155/2018/6437104.
30. Hu J, Hu B, Gui YC, et al. Diagnostic value and clinical significance of methylated
SEPT9 for colorectal cancer: A meta-analysis. Med Sci Monit. 2019;25:5813-5822.
doi: 10.12659/msm.915472.
31. Kim H, Lee JK, Hong YJ, et al. Detection of methylated SEPT9 in Korean
colorectal cancer patients: Comparison with previous studies. Clin Lab.
2018;64(9):1573-1579. doi: 10.7754/Clin.Lab.2018.180551.
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400 Buckwalter Place Boulevard, Bluffton, SC 29910 (800) 918-8924 www.eviCore.comLab Management Guidelines V2.0.2021
32. 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
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Sept9 Methylation
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