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A.2.04.61
Gene expression profile (GEP) and circulating tumor DNA (ctDNA) tests have been developed for use as prognostic markers of stage 2 or stage 3 colon cancer to help identify individuals who are at high-risk for recurrent disease and could be candidates for adjuvant chemotherapy.
Colon Cancer
According to estimates by the National Cancer Institute, in 2025 over 154,000 new cases of colorectal cancer will be diagnosed in the United States, and nearly 53,000 people will die of this cancer. Five-year survival estimates are around 65%. Disparities in colorectal cancer outcomes have been identified in different subgroup classifications based on race and ethnicity, age, socioeconomic status, insurance access, geography, and environmental exposures. For example, in the U.S. between 2012 and 2016, mortality rates were highest amongst non-Hispanic Black patients (incidence rate of 45.7 per 100,000), which were 20% and 50% higher than rates amongst non-Hispanic White and Asian patients, respectively. Additionally, non-Hispanic Black patients may have limited opportunities for therapeutic interventions due to experiencing higher inequities in comorbidities.
Colorectal cancer is classified as stage 2 (also called Dukes B) when it has spread outside the colon and/or rectum to nearby tissue, but is not detectable in lymph nodes (stage 3 disease, also called Dukes C) and has not metastasized to distant sites (stage 4 disease). Primary treatment is surgical resection of the primary cancer and colonic anastomosis. After surgery, the prognosis is good, with survival rates of 75% to 80% at 5 years. A 2008 review of 50 studies of adjuvant therapy versus surgery alone in stage 2 patients, found a small though statistically significant absolute benefit of chemotherapy for disease-free survival, but not for overall survival. Therefore, adjuvant chemotherapy with 5-fluorouracil (5-FU), capecitabine, CAPEOX (capecitabine and oxaliplatin) or FOLFOX (5-FU and oxaliplatin) is recommended only for resected patients, with high-risk stage 2 disease (i.e. those with poor prognostic features).
However, the clinical and pathologic features used to identify high-risk disease are not well-established, and the patients for whom the benefits of adjuvant chemotherapy would most likely outweigh harms cannot be identified with certainty. The current diagnostic system relies on a variety of factors, including tumor substage 2B (T4a tumors that invade the muscularis propria and extend into the surface of the visceral peritoneum) or 2C (T4B tumors that invade or are adherent to other organs or structures), obstruction or bowel perforation at initial diagnosis, an inadequately low number of sampled lymph nodes at surgery (<12), histologic features of aggressiveness, and indeterminate or positive resection margins. Gene expression profiling and circulating tumor DNA (ctDNA) tests are intended to facilitate identifying stage II patients most likely to experience recurrence after surgery and most likely to benefit from additional treatment.
Of interest, a 2010 review has noted that microsatellite instability and mismatch repair deficiency in colon cancer may represent confounding factors to be considered in treatment. These factors may identify a minority (15% to 20%) of the population with improved disease-free survival who may derive no benefit or may exhibit deleterious effects from adjuvant 5-fluorouracil plus leucovorin-based treatments. Patient microsatellite instability and mismatch repair status may be critically important in how to study, interpret, and use a particular gene expression profile test.
Clinical laboratories may develop and validate tests in-house and market them as a laboratory service; laboratory-developed tests (LDTs) must meet the general regulatory standards of the Clinical Laboratory Improvement Amendments. Multigene expression assay testing and circulating tumor DNA (ctDNA) testing for predicting recurrent colon cancer are available under the auspices of the Clinical Laboratory Improvement Amendments. Laboratories that offer laboratory-developed tests must be licensed by the Clinical Laboratory Improvement Amendments for high-complexity testing. To date, the U.S. Food and Drug Administration has chosen not to require any regulatory review of this test.
Gene expression profile and ctDNA tests for colon cancer that are currently commercially available include:
GeneFx® Colon (Helomics Therapeutics; also known as ColDx, Almac Diagnostics)
Oncotype DX® Colon Recurrence Score (Exact Sciences)
Colvera® ctDNA test (Clinical Genomics).
The Oncotype DX® breast cancer test is addressed in the Assays of Genetic Expression in Tumor Tissue as a Technique to Determine Prognosis in Patients with Breast Cancer medical policy.
Gene expression assays (Oncotype DX® colon cancer test) for determining the prognosis of stage 2 or stage 3 colon cancer following surgery are considered investigational.
Circulating tumor DNA assays for determining the prognosis of stage 2 or 3 colon cancer following surgery are considered investigational.
None
The coverage guidelines outlined in the Medical Policy Manual should not be used in lieu of the Member's specific benefit plan language.
Genetics Nomenclature Update
The Human Genome Variation Society nomenclature is used to report information on variants found in DNA and serves as an international standard in DNA diagnostics. It is being implemented for genetic testing medical evidence review updates starting in 2017 (see Table 1). The Society's nomenclature is recommended by the Human Variome Project, the HUman Genome Organization, and by the Human Genome Variation Society itself.
The American College of Medical Genetics and Genomics (ACMG) and the Association for Molecular Pathology (AMP) standards and guidelines for interpretation of sequence variants represent expert opinion from both organizations, in addition to the College of American Pathologists. These recommendations primarily apply to genetic tests used in clinical laboratories, including genotyping, single genes, panels, exomes, and genomes. Table 2 shows the recommended standard terminology—"pathogenic," "likely pathogenic," "uncertain significance," "likely benign," and "benign"—to describe variants identified that cause Mendelian disorders.
Table 1. Nomenclature to Report on Variants Found in DNA
Previous | Updated | Definition |
Mutation | Disease-associated variant | Disease-associated change in the DNA sequence |
Variant | Change in the DNA sequence | |
Familial variant | Disease-associated variant identified in a proband for use in subsequent targeted genetic testing in first-degree relatives |
Table 2. ACMG-AMP Standards and Guidelines for Variant Classification
Variant Classification | Definition |
Pathogenic | Disease-causing change in the DNA sequence |
Likely pathogenic | Likely disease-causing change in the DNA sequence |
Variant of uncertain significance | Change in DNA sequence with uncertain effects on disease |
Likely benign | Likely benign change in the DNA sequence |
Benign | Benign change in the DNA sequence |
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.
Investigative is defined as the use of any treatment procedure, facility, equipment, drug, device, or supply not yet recognized as a generally accepted standard of good medical practice for the treatment of the condition being treated and; therefore, is not considered medically necessary. For the definition of Investigative, “generally accepted standards of medical practice” means standards that are based on credible scientific evidence published in peer-reviewed medical literature generally recognized by the relevant medical community, and physician specialty society recommendations, and the views of medical practitioners practicing in relevant clinical areas and any other relevant factors. In order for equipment, devices, drugs or supplies [i.e, technologies], to be considered not investigative, the technology must have final approval from the appropriate governmental bodies, and scientific evidence must permit conclusions concerning the effect of the technology on health outcomes, and the technology must improve the net health outcome, and the technology must be as beneficial as any established alternative and the improvement must be attainable outside the testing/investigational setting.
07/22/2010: Approved by Medical Policy Advisory Committee.
06/21/2011: Policy reviewed; no changes.
11/10/2011: Policy reviewed; no changes.
09/25/2012: Policy reviewed; no changes.
11/15/2013: Policy reviewed; no changes.
11/04/2014: Policy reviewed; description updated. Policy statement unchanged.
08/04/2015: Code Reference section updated for ICD-10.
11/03/2015: Policy description updated to add information regarding stage 3 colon cancer and testing. Investigational policy statement revised to include stage 3 colon cancer. It previously stated: The 12-gene expression test (Oncotype DX® colon cancer test) is consideredinvestigational, including use for predicting the likelihood of disease recurrence for patients with stage II colon cancer following surgery. Investigative definition updated in policy guidelines section.
12/31/2015: Code Reference section updated to add new 2016 CPT code 81525.
06/06/2016: Policy number A.2.04.61 added.
09/22/2016: Policy description updated regarding gene expression profiling tests. Policy statement unchanged. Policy Guidelines updated to add genetic counseling information.
08/31/2017: Policy description updated regarding gene expression profiling tests. Policy statement unchanged. Policy Guidelines updated regarding genetics nomenclature.
10/01/2018: Policy description updated regarding new data for colorectal cancer. Policy statement unchanged. Policy Guidelines updated regarding genetic counseling. Code Reference section updated to add new CPT code 0069U.
07/01/2019: Code Reference section updated to add new CPT code 0091U.
09/16/2019: Policy description updated regarding new data according to the National Cancer Institute. Policy statement unchanged. Code Reference section updated to add new CPT code 0111U, effective 10/01/2019.
09/01/2021: Policy title changed from "Multigene Expression Assay for Predicting Recurrence in Colon Cancer" to "Gene Expression Profile Testing and Circulating Tumor DNA for Predicting Recurrence in Colon Cancer." Policy description updated regarding new data for colorectal cancer and regarding tests. Policy section updated to add that circulating tumor DNA assays for determining the prognosis of stage 2 or 3 colon cancer following surgery are considered investigational. Policy Guidelines updated to remove genetic counseling information.
09/29/2021: Code Reference section updated to add new CPT code 0261U, effective 10/01/2021.
12/08/2021: Policy title changed from "Gene Expression Profile Testing and Circulating Tumor DNA for Predicting Recurrence in Colon Cancer" to "Gene Expression Profile Testing and Circulating Tumor DNA Testing for Predicting Recurrence in Colon Cancer." Policy description updated regarding gene expression profiling and ctDNA tests. Policy statements unchanged.
09/09/2022: Policy description updated regarding disparities in colorectal cancer outcomes. Removed Signatera™ ctDNA test (Natera) from list of tests as it is addressed in a separate policy. Policy statements unchanged. Policy Guidelines updated to add genetic counseling information.
09/21/2023: Policy description updated regarding new cases of colorectal cancer. Policy statements unchanged.
09/12/2024: Policy description updated regarding new data for colorectal cancer. Policy statements unchanged.
09/17/2025: Policy description updated regarding new data for colorectal cancer. Policy statements unchanged.
Blue Cross Blue Shield Association policy # 2.04.61
This may not be a comprehensive list of procedure codes applicable to this policy.
Code Number | Description |
CPT-4Note: Do not report the Oncotype DX® colon cancer test with HCPCS code S3854, Gene expression profiling panel for use in the management of breast cancer treatment (Oncotype DX® breast cancer assay). | |
0069U | Oncology (colorectal), microRNA, RT-PCR expression profiling of miR-31-3p, formalin-fixed paraffin-embedded tissue, algorithm reported as an expression score |
0091U | Oncology (colorectal) screening, cell enumeration of circulating tumor cells, utilizing whole blood, algorithm, for the presence of adenoma or cancer, reported as a positive or negative result |
0111U | Oncology (colon cancer), targeted KRAS (codons 12, 13, and 61) and NRAS (codons 12, 13, and 61) gene analysis utilizing formalin-fixed paraffin-embedded tissue |
0261U | Oncology (colorectal cancer), image analysis with artificial intelligence assessment of 4 histologic and immunohistochemical features (CD3 and CD8 within tumor-stroma border and tumor core), tissue, reported as immune response and recurrence-risk score |
81525 | Oncology (colon), mRNA, gene expression profiling by real-time RT-PCR of 12 genes (7 context and 5 housekeeping), utilizing formalin-fixed paraffin embedded tissue, algorithm reported as a recurrence score |
84999 | Unlisted chemistry procedure |
88299 | Unlisted cytogenetic study |
HCPCS | |
ICD-10 Procedure | |
ICD-10 Diagnosis |
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