Medical Policy: 02.04.28
Original Effective Date: March 2010
Reviewed: March 2018
Revised: March 2018
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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 for use as prognostic markers in stage II or stage III colon cancer to help identify those individuals who are at high risk for recurrent disease and could be candidates for adjuvant chemotherapy.
Of patients with stage II colon cancer, 75% to 80% are cured by surgery alone, and the absolute benefit of chemotherapy for the overall patient population is small. Patients most likely to benefit from chemotherapy are difficult to identify by standard clinical and pathologic risk factors. Genomic tests are intended to facilitate identifying stage II patients most likely to experience recurrence after surgery and most likely to benefit from additional treatment.
Stage II Colorectal Cancer is divided into three subcategories: IIA, IIB and IIC. The difference between the categories lies in the extent to which the cancer has spread.
- Stage IIA: The cancer has grown into the outermost layers of the colon or rectum, but has not grown through them. It has not reached nearby organs or lymph nodes, and has not spread to distant organs.
- Stage IIB: The cancer has grown through all of the layers of the colon or rectum, but has not grown into other organs or tissues.
- Stage IIC: The cancer has grown through all of the layers of the colon or rectum, and has grown into nearby organs or tissues. The cancer has not spread to the lymph nodes or distant organs.
For patients with stage III colon cancer that have spread to nearby lymph nodes, but they have not yet spread to other parts of the body, surgery to remove the section of the colon with the cancer along with nearby lymph nodes (partial colectomy) followed by adjuvant chemotherapy is the standard treatment for this stage.
Stage III Colorectal Cancer is further divided into three separate categories: IIIA, IIIB and IIIC. The difference between the categories lies in the extent to which the cancer has spread, and how many lymph nodes have been affected.
- Stage IIIA: The cancer has grown into the submucosa. It may have also grown into the muscularis propria. The cancer has spread to 1-3 lymph nodes near the site of the primary tumor, but has not spread to distant sites.
- Stage IIIB: The cancer has grown into the outermost layer of the colon or rectum, but has not reached nearby organs. Or, it has grown through the wall of the colon or rectum and into nearby organs or tissues. The cancer has spread to 1-3 lymph nodes near the primary site, but has not spread to distant organs.
- Stage IIIC: The cancer may or may not have grown through the wall of the colon or rectum, but has spread to four or more lymph nodes near the primary site. The cancer has not metastasized to distant sites.
The clinical and pathologic features used to identify high-risk disease are not well established, and patients for whom 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, obstruction or bowel perforation at initial diagnosis, an inadequately low number of sampled lymph nodes at surgery (< 12), histologic features of aggressiveness, a high preoperative CEA level and indeterminate or positive resection margins.
In 2010 a review by Vilar and Gruber noted that microsatellite instability (MSI) and mismatch repair (MMR) deficiency in colon cancer may represent confounding factors to be considered in treatment. These factors may identify a minority (15%-20%) of the population with improved disease-free survival who may derive no benefit or may exhibit deleterious effects from adjuvant 5-flurouracil plus leucovorin based treatments. The role of MSI as a genetic marker of Lynch Syndrome is well established in the clinical setting and is now the standard of care. Both MSI detection and immunohistochemistry are highly sensitive methods for the identification of individuals with a defective MMR system, and guide clinicians towards informative, cost effective genetic testing.
Clinical utility is defined as how the results of the prognostic test will be used to change management of the patient and whether these changes in management lead to clinically important improvements in health outcomes.
A technical brief, published by the Agency for Healthcare Research and Quality in December 2012, reviewed the clinical evidence for gene expression profiling (GEP) assys for predicting outcomes, including benefit from adjuvant chemotherapy, in patients with stage II colon cancer. The 4 commercially available assays reviewed were included in the brief. No prospective studies were identified that assessed change in net health outcome with the use of a GEP assay, and no studies were identified that used a net reclassification analysis and subsequently evaluated the impact of reclassification on net health outcome. Additionally, evidence was limited on the reproducibility of test findings, indications for GEP testing in stage II patients, and whether results of GEP assays can stratify patients into groups with clinically meaningful differences in recurrence risk. No studies have been identified in subsequent literature updates that evaluated the impact of GEP testing on recurrence in patients with stage II or III colon cancer.
In the absence of direct evidence, an indirect chain of evidence could demonstrate clinical utility if all links in the chain are intact. An indirect chain of evidence for clinical utility of GEP testing involves the following series of questions:
- Does GEP testing provide prognostic information? Yes. Patients with a low recurrence score have a decreased risk of recurrence and patients with a high risk score have a higher risk of recurrence. However, the degree of difference in risk conferred by the test is not large.
- Does GEP testing provide incremental prognostic information compared to the standard clinical workup for prognosis? Uncertain. No well-done studies have compared the prognostic information from GEP testing to standard prognostic information provided by clinical and pathologic workup.
- Does the incremental prognostic information lead to classifying patients into different groups for which management differs? No. There are no well-defined treatment protocols that differ according to risk of recurrence. The intensity of surveillance and management may be impacted by results of GEP testing, but the evidence to demonstrate this is weak and not definitive.
- Do the changes in management resulting from GEP testing lead to improvements in health outcomes? No. There is no evidence that different treatment protocols for patients with different risks of recurrence improve outcomes.
The findings of this technical brief state: Published studies have not provided information related to clinical utility, the effect that using the GEP result in patient care has on net health outcome. Limited information was found for analytic validity. The current evidence does not provide the type of information needed to answer major questions about use of GEP assays in these patients.
The technical brief concluded although information is emerging about the use of GEP assays to inform the decision about use of adjuvant chemotherapy in patients with stage II colon cancer, studies to date have not provided the type of information needed to address major uncertainties.
Summary Clinical Utility
Based on review of the peer reviewed medical literature, some studies have reported management changes following GEP testing. However, these studies do not report clinical outcomes, and there is no direct evidence to determine whether GEP testing improves net health outcomes. A chain of evidence might be constructed if there was evidence that changes in the management for patients with stage II colon cancer improve health outcomes. The intensity of surveillance and management may be impacted by results of GEP testing, but the evidence to demonstrate that a change in management improve health outcomes is weak and not definitive. Therefore, the evidence does not demonstrate clinical utility.
Summary of Evidence
For individuals who have stage II or III colon cancer who receive gene expression profiling (GEP) testing, the evidence includes development and validation studies and decision-impact studies. The available evidence has shown that gene expression profile (GEP) testing for colon cancer can improve risk prediction, particularly the risk of recurrence in patients with stage II or III colon cancer. However, the degree of difference in risk conferred by the test is small. Evidence to date is insufficient to permit conclusions on whether GEP classification is sufficient to modify treatment decisions in stage II or III colon cancer. Studies showing management changes as a consequence of testing do not demonstrate whether such changes improve outcomes. The evidence is insufficient to determine the effects of the technology on net health outcomes.
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 Improvement Act (CLIA). Multigene expression assay testing for predicting recurrent colon cancer is available under the auspices of CLIA. Laboratories that offer LDTs must be licensed by CLIA for high-complexity testing. To date, the U.S. Food and Drug Administration has chosen not to require any regulatory review of these tests.
Gene expression profiling tests for colon cancer currently commercially available include:
- ColonPRS (Signal Genetics) – 163 gene expression assay for predicting risk of recurrence in individuals with colon cancer.
- ColoPrint 18 - Gene Colon Cancer Recurrence Risk Assay (Agendia) – ColoPrint is a microarray-based 18 gene expression signature for predicting the risk of distant recurrence for stage II colon cancer who have undergone surgery.
- GeneFx Colon (Helomics Therapeutics; also known as ColDx, Almac Diagnosistics) – Is a proprietary gene signature test (634 probe set signature) utilizing an individual patient’s RNA expression and a complex proprietary algorithm. GeneFx Colon is performed on a small amount of tumor tissue that categorizes patients as being at either high or low risk of having a tumor recurrence within 5 years of surgery. GeneFx Colon provides a clear result for risk recurrence that can help guide physicians regarding the use of adjuvant therapy in patients with colon cancer.
- OncoDefender-CRC (Everist Genomics) – Is a prognostic gene-based laboratory assay (5 gene test) intended to help guide treatment decisions following tumor resection in patients with pathologically confirmed stage I or II colorectal cancer diagnosis. The OncoDefender-CRC assay evaluates the expression levels of a specific panel of genes from colorectal cancer tissue samples with a proprietary computation rule. This process yields a relative measure of risk of recurrence within 3 years after surgery for stage I/II colon cancer patients.
- Oncotype DX Colon Recurrence Score (Genomic Health) – Oncotype DX Colon Cancer Assay uses an algorithm to generate a recurrence score result that is based on 12 genes: seven genes associated with recurrence and 5 genes used to normalize gene expression. This uses a technique called reverse transcriptase-polymerase chain reaction (RT-PCR) to determine the expression of a panel of 12 genes in the tumor tissue. The recurrence score result is calculated from the gene expression results, and ranges from 0-100. This GEP assay is utilized in stage II patients with adenocarcinoma or mucinous carcinoma limited to the colon. It is unknown whether the findings apply to other patients outside this criteria.
Practice Guidelines and Position Statements
National Comprehensive Cancer Network (NCCN) Colon Cancer, Version 2.2018
Principles of Risk Assessment for Stage II Disease
- Patient/physician discussion regarding the potential risks of therapy compared to potential benefits, including prognosis. This should include discussion of evidence supporting treatment, assumption of benefit from indirect evidence, morbidity associated with treatment, high risk characteristics, and patient preferences
- When determining if adjuvant therapy should be administered, the following should be taking into consideration:
- Number of lymph nodes analyzed after surgery (<12)
- Poor prognostic features (e.g. poorly differentiated histology (exclusive of those that are MSI-H); lymphatic/vascular invasion; bowel obstruction; PNI; localized perforation; close, indeterminate, or positive margins)
- Assessment of other comorbidities and anticipated life expectancy
- The benefit of adjuvant chemotherapy does improve survival by more than 5% Microsatellite instability (MSI) or Mismatch Repair (MMR) Testing
Discussion Section - Multigene Assays
Several multigene assays have been developed in hopes of providing prognostic and predictive information to aid in decisions regarding adjuvant therapy in patients with stage II or III colon cancer.
- Oncotype DX colon cancer assay quantifies the expression of 7 recurrence risk genes and 5 reference genes as prognostic classifier of low, intermediate or high likelihood of recurrence.
- ColoPrint quantifies the expression of 18 genes as a prognostic classifier of low versus high recurrence risk.
- ColDx 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
- OncoDefender - CRC Assay
- GeneFx colon (also known as ColDx)
To date, the majority of the available studies fail to provide sufficient evidence that gene expression profiling (GEP) as a technique for colorectal cancer (CRC) management lead to improved health outcomes (i.e., clinical utility). Well-designed randomized controlled trials (RCTs) are needed to determine the clinical utility of gene expression profiling as a technique for colorectal cancer (CRC) management compared with traditional clinical factors to guide medical management and improve clinical outcomes. The evidence is insufficient to determine the effects of the technology on net health outcomes.
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 (OncotypeDX colon cancer assay)
- 84999 Unlisted chemistry procedure (may be used for ColonPRS; OncoDefender CRC assay; GeneFx colon (also known as ColDx); Coloprint)
- 88299 Unlisted cytogenetic study (may be used for ColonPRS; OncoDefender CRC assay; GeneFx colon (also known as ColDx); Coloprint)
- 81599 Unlisted multianalyt assay with algorithmic analysis (may be used for ColonPRS; OncoDefender CRC assay; GeneFx colon (also known as ColDx); Coloprint)
- 81479 Unlisted molecular pathology procedure (may be used for ColonPRS; OncoDefender CRC assay; GeneFx colon (also known as ColDx); Coloprint)
- 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 Multigene Expression Assay (Oncotype DX) for Predicting Recurrence of Colon Cancer. Plymouth Meeting (PA): ECRI Institute; 2011 Nov 16. [ECRI hotline response].
- Maak M, Simon I et al. Independent validation of a prognostic genomic signature (ColoPrint) for patients with stage 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 3.2014, Discussion Mutigene Assays.
- Alan P. Venook, et al. Biological Determinants of Tumor Recurrence in Stage II Colon Cancer: Validation Study of the 12-Gene Recurrence Score in Cancer and Leukemia Group B (CALGB) 9581. Journal of Clinical Oncology, Volume 31, Number 14, May 10, 2013.
- Screening for Colorectal Cancer: U.S. Preventitive Services Task Force Recommendation Statement, Annals of Internal Medicine, Volume 149, Number 9, November 4, 2008.
- National Comprehensive Cancer Network (NCCN) Colon Cancer, Version 1.2017.
- ECRI Institute. Product Brief. Oncotype DX Multigene Expression Assay (Genomic Health, Inc) for Predicting Recurrence of Colon Cancer, June 2014.
- UpToDate Adjuvant Chemotherapy for Resected Stage II Colon Cancer, Hanna K. Sanoff, M.D., MPH. Topic last updated January 16, 2017.
- 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 1, 2017.
- 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.
- Smith JJ, Deane NG, Wu F, et al. Experimentally derived metastasis gene expression profile predicts recurrence and death in patients with colon cancer. Gastroenterology. Mar 2010;138(3):958-968. PMID 19914252
- Marisa L, de Reynies A, Duval A, et al. Gene expression classification of colon cancer into molecular subtypes: characterization, validation, and prognostic value. PLoS Med. 2013;10(5):e1001453. PMID 23700391
- Herrera M, Islam AB, Herrera A, et al. Functional heterogeneity of cancer-associated fibroblasts from human colon tumors shows specific prognostic gene expression signature. Clin Cancer Res. Nov 1 2013;19(21):5914-5926. PMID 24052018
- Zhang JX, Song W, Chen ZH, et al. Prognostic and predictive value of a microRNA signature in stage II colon cancer: a microRNA expression analysis. Lancet Oncol. Dec 2013;14(13):1295-1306. PMID 24239208
- Maak M, Simon I, Nitsche U, et al. Independent validation of a prognostic genomic signature (ColoPrint) for patients with stage II colon cancer. Ann Surg. Jun 2013;257(6):1053-1058. PMID 23295318
- Kopetz S, Tabernero J, Rosenberg R, et al. Genomic classifier ColoPrint predicts recurrence in stage II colorectal cancer patients more accurately than clinical factors. Oncologist. Feb 2015;20(2):127-133. PMID 25561511
- 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. May 17 2012;118(21):5234-5244. PMID 22605513
- Yothers G, O'Connell MJ, Lee M, et al. Validation of the 12-gene colon cancer recurrence score in NSABP C-07 as a predictor of recurrence in patients with stage II and III colon cancer treated with fluorouracil and leucovorin (FU/LV) and FU/LV plus oxaliplatin. J Clin Oncol. Dec 20 2013;31(36):4512-4519. PMID 24220557
- Reimers MS, Kuppen PJ, Lee M, et al. Validation of the 12-gene colon cancer recurrence score as a predictor of recurrence risk in stage II and III rectal cancer patients. J Natl Cancer Inst. Nov 2014;106(11). PMID 25261968
- Cartwright T, Chao C, Lee M, et al. Effect of the 12-gene colon cancer assay results on adjuvant treatment recommendations in patients with stage II colon cancer. Curr Med Res Opin. Feb 2014;30(2):321-328. PMID 24127781
- Srivastava G, Renfro LA, Behrens RJ, 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. May 2014;19(5):492-497. PMID 24710310
- Black E, Falzon L, Aronson N. Gene Expression Profiling for Predicting Outcomes in Stage II Colon Cancer Technical Brief. No. 13. (Prepared by the Blue Cross and Blue Shield Association Technology Evaluation Center Evidence-based Practice Center under Contract No. 290-2007-0058-I.) Rockville, MD: Agency for Healthcare Research and Quality. December 2012. Accessed June 12, 2015.
- Webber Elizabeth, Lin J, Whitlock E. Oncotype DX tumor gene expression profiling in stage II colon cancer. Application: Prognostic, risk prediction. Version 1 PLoS Curr 2010 September 2; 2 RRN1177.
- ECRI Genetic Test Product Brief. Oncotype DX Multigene Expression Assay (Genomic Health, Inc.) for Predicting Recurrence of Colon Cancer. August 2015.
- Reimers MS, Zeestraten EC,Kuppen PJ, et.al. Biomarkers in precision therapy in colorectal cancer. Gastroentrol Rep (Oxf) 2013 Nov:1(3):166-83
- Goel G. Evolving role of gene expression signatures as biomarkers in early-stage colon cancer. J Gastrointest Cancer. 2014 Dec:45(4):399-404. PMID 24989938
- Salazar R, Rosenberg R, Lutke Holzik M, et. al. The PARSC trial, a prospective study for the assessment of recurrence risk in stage II colon cancer (CC) patients using ColoPrint. [abstract]. J Clin Oncol. 2011;29(Suppl).
- Vilar E, Gruber SB. Microsatellite instability in colorectal cancer the stable evidence. Nat Rev Clin Oncol. Mar 2010;7(3):153-162. PMID 20142816
- Venook AP, Niedzwiecki D, Lopatin M, et. al. Biologic determinants of tumor recurrence in stage II colon cancer: validation study of the 12 gene recurrence score in cancer and leukemia group B (CALGB) 9581. J Clin Oncol. May 10 2013;31(14):1775-1781. PMID 23530100
- Breener B, Geva R, Rothney M, et. al. Impact of the 12-gene colon assay on clinical decision making for adjuvant therapy in stage II colon cancer patients. Value Health. Jan 2016;19(1):82-87. PMID 26797240
- UpToDate. Pathology and Prognostic Determinants of Colorectal Cancer. Carolyn C. Compton M.D., PhD. Topic last updated April 8, 2016.
- GeneFX Colon.
- Oncotype DX for Colon Cancer.
- Niedzwiecki D, Frankel WL, Venook AP, et. al. Association between results of a gene expression signature assay and recurrence free interval in patients with stage II colon cancer in Cancer and Leukemia Group B 9581 (Alliance). J Clin Oncol. Sep 01 2016;34(25):3047-3053. PMID 27432924
- Yamanaka T, Oki E, Yamazaki K, et. al. 12 gene recurrence score assay stratifies the recurrence risk in stage II/III colon cancer with surgery alone: The SUNRISE study. J Clin Oncol. Aug 20 2016;34(24):2906-2913. PMID 27325854
- March 2018 - Annual Review, Policy Revised
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- October 2014 - Interim review, Policy Revise
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- July 2013 - Annual Review, Policy Renewed
- August 2012 - Annual Review, Policy Revised
- August 2011 - Annual Review, Policy Renewed
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