Medical Policy: 02.04.28
Original Effective Date: March 2010
Reviewed: April 2015
Revised: April 2015
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policy may not apply to FEP. Benefits are determined by the Federal Employee Program.
This Medical Policy document describes the status of medical technology at the time the document
was developed. Since that time, new technology may have emerged or new medical literature may
have been published. This Medical Policy will be reviewed regularly and be updated as scientific
and medical literature becomes available.
Gene expression profiling (GEP) assays have been developed and reported for use as prognostic markers in stage II colon cancer. These assays are intended to help identify those individuals who are at high risk for recurrent disease and would be good candidates for adjuvant therapy after surgery. Several GEP assays are available thru CLIA certified laboratories. The number of gene sequences explored vary depending upon the assay used and may range from as few as 5 to as many as several hundred.
The five assays that are currently being marketed for use in the United States: ColonPRS®, Signal Genetics, New York, NY; Coloprint®, Agendia NV, Amsterdam, Netherlands; Genefx Colon®, Precision Therapeutics, Pittsburgh, PA; OncoDefender-CRC (colon and rectal cancer), Everist Genomics, Ann Arbor, MI; and Oncotype DX® Colon Cancer Test, Genomic Health, Inc., Redwood City, CA. Independent validation studies ranging in size from 33 to 1436 patients have been reported on these assays.
Colorectal cancer is classified as stage II when it has spread outside the colon and/or rectum to nearby tissue but is not detectable in the lymph nodes and has not metastasized to distant sites (also called Dukes B). The primary treatment is surgical resection of the primary cancer and colonic anastomosis.
Of patients with stage II colon cancer, 75% to 80% are cured by surgery alone. Recurrence following surgery is a major concern and is frequently the ultimate cause of death. While adjuvant chemotherapy is recommended in individuals with stage III colon cancer, its role in stage II disease is unclear. It has been estimated that in treating 100 stage II individuals with adjuvant chemotherapy, 3-4 will benefit, while others will suffer significant adverse effects. Identification of individuals who are most likely to experience a recurrence of disease would help practitioners identify those individuals who might benefit from adjuvant therapy after surgery. GEP tests are intended to be used as an aid for identifying stage II patients most likely to experience recurrence after surgery and most likely to benefit from additional treatment.
Validation of genotyping to improve treatment outcomes is a multistep process. In general, important steps in the validation process address the following:
- Analytic validity: measures technical performance, i.e., whether the test accurately and reproducibly detects the gene markers of interest.
- Clinical validity: measures the strength of the associations between the selected genetic markers and clinical status.
- Clinical utility: determines whether the use of genotyping for specific genetic markers to guide treatment decision improves patient outcomes such as survival or adverse event rate compared to standard treatment without genotyping.
Many gene expression profile (GEP) assays have been developed and reported for use as a prognostic marker in stage II colon cancer and as indicated above, five gene expression profile (GEP) tests are offered commercially in the U.S.. Information on basic elements of test performance including specimen type, sample handling, and technique used for GEP has been reported for these assays.
ColonPRS®: In 2010 Van Laar reported on a 163-gene expression test using data from 232 colon cancer patients across all stages of disease. ColonPRS® is being marketed as a research use only test and has specific warnings against clinical use.
Coloprint®: Salazar and colleagues in 2010 described the development of an 18-gene expression test (the ColoPrint® test). The test is reportedly able to stratisfy stage II colon cancers into low or high risk. This would determine if adjuvant chemotherapy is necessary. A High Risk result means that a patient with stage II colon cancer has a 20% risk of relapse within 3 years and a 22% risk of relapse within 5 years3 without adjuvant treatment. Validation studies have been published only in abstract form at this time.
Genefx Colon®: In 2011, Kennedy et al. reported on the development of a 634-probe set signature.. Cross-validation studies were used to select an optimal transcript signature for prognostic classification.The authors noted a further retrospective validation of the test in a large cohort of stage II colon cancer samples collected as part of a clinical trial is planned.
OncoDefender: The test is performed by Everist Genomics. It is a 5-gene test reportedly able to accurately predict the risk of recurrence of cancer in patients previously treated with surgical resection(i.e. removal) of a Stage I or Stage II colon cancer tumor or a Stage 1 rectal cancer tumor. However, isolated performance of the test in patients with stage II colon cancer was not reported, and several high-risk findings (bowel obstruction/perforation, and lymphovascular invasion) demonstrated higher hazard ratios than observed using the molecular signature. The study (Lenehan 2012) alluded to but did not directly address clinical utility.
Oncotype DX®: O’Connell et al. in a 2010 described the development of a 12-gene expression test (the Oncotype DX® colon cancer test).. Gene expression was quantitated from microdissected fixed paraffin-embedded primary colon cancer tissue. The test was later reduced the genes to a 7-gene prognostic signature and a separate 6-gene predictive signature. Five reference genes are also included in the assay.
No studies of a GEP for determining prognosis of patients with stage II colon cancer have been published demonstrating the effect of testing on overall reclassification of patients when compared to existing methods of risk analysis. There is no published information on the impact from use of GEP results on patient outcomes. In the absence of information showing a direct effect on outcomes or establishing a strong chain of evidence that testing would be expected to have a positive net effect on outcomes, clinical utility remains unclear.
The available evidence indicates that gene expression profile (GEP) tests for colon cancer can improve risk prediction, particularly the risk of recurrence in patients with Stage II colon cancer. However, evidence to date is insufficient to permit conclusions on how GEP classification compares with other approaches for identifying recurrence risk in stage II patients or on how GEP classification impacts patient outcomes (clinical utility). There is even less evidence to permit conclusions on how GEP classification compares with other approaches for management of other stages of colon cancer. Therefore, the use of GEP assays to predict the likelihood of disease recurrence for patients with colon cancer, is considered investigational.
To date, no gene expression test for evaluation of prognosis in stage II colon cancer has been cleared for marketing by the United States Food and Drug Administration (FDA). These tests are offered as laboratory-developed assays in clinical laboratory improvement amendment (CLIA)-licensed laboratories operated by each company and currently do not require FDA premarket review as a result of enforcement discretion.
Practice Guidelines and Position Statements
National Comprehensive Cancer Network (NCCN), Colon Cancer, Version 3.2015
Several multigene assays have been developed in hopes of providing prognostic and predictive information to aid in decisions regarding adjuvant therapy in patients with state II or III colon cancer.
- Oncotype DX colon cancer assay (Genomic Health, inc) quantifies the expression of 7 recurrence risk genes and 5 reference genes as prognostic classifier of low, intermediate or high likelihood of recurrence.
- ColoPrint (Agendia) quantifies the expression of 18 genes as a prognostic classifier of low versus high recurrence risk.
- ColDx (Almac) is a microarray based multigene assay that uses 634 probes to identify patients with stage II colon cancer at high risk of recurrence.
In summary, the information from these tests can further inform the risk of recurrence over other risk factors, but the panel questions the value added. Furthermore, there is no evidence of predictive value in terms of the potential benefit of chemotherapy to any of the available multigene assays. The panel believes that there are insufficient data to recommend the use of multigene assays to determine adjuvant therapy.
Gene expression profile (GEP) assays as a technique for managing colon cancer is considered investigational for all indications, including but not limited to its use for predicting the likelihood of disease recurrence in individuals with colon cancer following surgery.
Gene expression profile (GEP) assays, including but not limited to the following are considered investigational:
- Oncotype DX colon cancer assay
- Genefx colon
The available evidence indicates that gene expression profile tests for colon cancer can improve risk prediction, particularly regarding the risk of recurrence in patients with stage II colon cancer. However, the evidence to date is insufficient to permit conclusions on how gene expression profile (GEP) classification compares with other approaches for identifying risk in stage II patients or on how GEP classification impacts patient outcomes (clinical utility). There is even less evidence to permit conclusions on how GEP classification compares with other approaches for management of other stages of colon cancer. Therefore, use of these gene expression profile (GEP) assays, including predicting the likelihood of disease recurrence for patients with colon cancer, is considered investigational.
Procedure Codes and Billing Guidelines:
- To report provider services, use appropriate CPT* codes, Modifiers, Alpha Numeric (HCPCS level 2) codes, Revenue codes, and/or diagnosis codes.
- 81525 Oncology (colon), mRNA, gene expression profiling by real-time RT-PCR of 12 genes (7 content and 5 housekeeping), utilizing formalin-fixed paraffin-embedded tissue, algorithm reported as a recurrence score
- 84999 Unlisted chemistry procedure
- 88299 Unlisted cytogenetic study
- 81599 Unlisted multianalyt assay with algorithmic analysis
- O'Connell MJ, Lavery I, Yothers G et al. Relationship between tumor gene expression and recurrence in four independent studies of patients with stage II/III colon cancer treated with surgery alone or surgery plus adjuvant fluorouracil plus leucovorin. J Clin Oncol 2010; 28(25):3937-44.
- Gray RG, Quirke P, Handley K et al. Validation study of a quantitative multigene reverse transcriptase-polymerase chain reaction assay for assessment of recurrence risk in patients with stage II colon cancer. J Clin Oncol 2011; 29(35):4611-19.
- Lenehan PF, Boardman LA, Riegert- Johnson D et al. Generation and external validation of a tumor-derived 5-gene prognostic signature for recurrence of lymph node-negative, invasive colorectal carcinoma. Cancer. 2012 May 17. doi: 10.1002/cncr.27628. [Epub ahead of print].
- Kennedy RD, Bylesjo M, Kerr P et al. Development and independent validation of a prognostic assay for stage II colon cancer using formalin-fixed paraffin-embedded tissue. J Clin Oncol 2011; 29(35):4620-26.
- Salazar R, Roepman P, Capella G et al. Gene expression signature to improve prognosis prediction of stage II and III colorectal cancer. J Clin Oncol 2011; 29(1):17-24.
- Van Laar R. An online gene expression assay for determining adjuvant therapy eligibility in patients with stage 2 or 3 colon cancer. Br J Cancer 2010; 103(12):1852-7.
- Hong Y, Downey T, Eu KW et al. A "metastasis-prone" signature for early-stage mismatch-repair proficient sporadic colorectal cancer patients and its implications for possible therapeutics. Clin Exp Metastasis 2010;27(2):83-90.
- Kelley RK, Van Bebber SL, Phillips KA et al. Personalized medicine and oncology practice guidelines: a case study of contemporary biomarkers in colorectal cancer. J Natl Compr Canc Netw. 2011;9(1):13-25.
- Ross JS. Biomarker-based selection of therapy for colorectal cancer. Biomarkers in Medicine. 2011;5(3):319-32.
- Webber EM, Lin JS, Evelyn PW. Oncotype DX tumor gene expression profiling in stage II colon cancer. Application: prognostic, risk prediction. PLoS Curr. 2010.
- ECRI Institute. Multigene Expression Assay (Oncotype DX) for Predicting Recurrence of Colon Cancer. Plymouth Meeting (PA): ECRI Institute; 2011 Nov 16. [ECRI hotline response]. Available:http://www.ecri.org
- Maak M, Simon I et al. Independent validation of a prognostic genomic signature (ColoPrint) for patients with statge II colon cancer. Ann Surgery 2013 257(6)1053-8.
- National Comprehensive Cancer Network Clinical Practice Guidelines in Oncology. Colon Cancer V.3.2013.
- ECRI Institute. Oncotype DX multigene expression assay for predicting recurrence of colon cancer. ECRI Institute; 2013 Jul 2 [ECRI Procuct Brief]. Retrieved 7/11/13.
- National Comprehensive Cancer Network (NCCN) Colon Cancer, Version 2.2015. Also available at www.nccn.org
- ECRI Institute. Product Brief. Oncotype DX Multigene Expression Assay (Genomic Health, Inc) for Predicting Recurrence of Colon Cancer, June 2014. Also available at www.ecri.org
- Srivastava G, Renfro LA, et. al. Prospective Multicenter Study of the Impact of Oncotype DX Colon Cancer Assay Results on Treatment Recommendations in Stage II Colon Cancer Patients, Oncologist 2014 May;19(5):492-7
- UpToDate. Adjuvant Chemotherapy for Resected Stage II Colon Cancer, Hanna K. Sanoff, M.D., MPH. Topic last updated March 19, 2015. Also available at www.uptodate.com
- UpToDate. Adjuvant Therapy for Resected Stage III (node-positive) Colon Cancer. Jeffrey W. Clark, M.D., Hanna K. Sanoff, M.D., MPH. Topic last updated February 20, 2015. Also available at www.uptodate.com
- UpToDate. Overview of Gene Expression Profiling, Proteomics and MicroRNA Profiling in Clinical Oncology, Patrick C ma, M.D., MSc. Topic last updated March 18, 2015. Also available at www.uptodate.com
Date Reason Action
August 2011 Annual review Policy renewed
August 2012 Annual review Policy revised
July 2013 Annual review Policy renewed
May 2014 Annual review Policy revised
October 2014 Interim review Policy revised
April 2015 Annual review Policy revised
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