Description
Colorectal cancer (CRC) involves the accumulation of genetic and epigenetic modifications within pathways that regulate proliferation, apoptosis, and angiogenesis resulting in carcinoma of the colon and rectum (Bardhan & Liu, 2013). Tumors originate in adenomas or flat dysplasia and evolve into different morphologic patterns with invasion and expansion (Compton, 2020).

Regulatory Status
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.

Policy:
Gene expression assays for determining the prognosis of stage II colon cancer following surgery are investigational and/or unproven and therefore considered NOT MEDICALLY NECESSARY.

Table of Terminology

Policy Guidelines
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.

There is no specific code for these laboratory tests.

Coding
If the test is a multianalyte assay with algorithmic analysis (MAAA), it would be reported with the unlisted MAAA code 81599. Otherwise, it would likely be reported using an unlisted code such as:

84999 Unlisted chemistry procedure 
88299 Unlisted cytogenetic study 

Effective Jan. 1, 2016, there will be a CPT code specific to Oncotype DX Colon Cancer Assay — 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.

Rationale
Colorectal cancer (CRC) is the second leading cause of cancer-related deaths in the United States following lung cancer (Siegel, Miller, Fuchs, & Jemal, 2022). 22% of patients with colorectal cancer will present with metastatic colorectal cancer (mCRC) at diagnosis and a significantly poorer prognosis. The five-year survival is 14% in patients with distant metastases from CRC, as compared to 71% for all CRC patients (El-Deiry et al., 2015; Wang et al., 2020).

Approximately one-quarter of the patients with colon cancer present with stage II disease (Scott Kopetz, 2008). The current National Comprehensive Cancer Network (NCCN) guidelines include adjuvant chemotherapy as a treatment option in this setting, particularly for high-risk stage II patients, as determined by clinical and pathological parameters (NCCN, 2022). Although some of the routinely used parameters for estimating recurrence risk, such as T-stage and mismatch repair (MMR) status, are well established, they may not be reliable predictors of recurrence risk in this population (Gray et al., 2011; Gunderson, Jessup, Sargent, Greene, & Stewart, 2010; Harris et al., 2008; Ribic et al., 2003; Sargent et al., 2010; Venook et al., 2013). 

Proprietary Testing
Gene expression assays have been commercially produced to predict prognosis of colon cancer. The 12-gene Oncotype DX Colon Cancer Assay (Genomic Health, Inc., Redwood City, CA) is a reverse transcriptase polymerase chain reaction-based assay that provides a Recurrence Score (RS) result (O'Connell et al., 2010). This test assesses the activity level of 12 genes (7 cancer-related genes, 5 reference genes), and this gene expression is scored from 1 – 100. This test is intended for resected stage II, MMR-P or stage III A/B colon cancer. Low risk is a score under 30, moderate risk is 31 – 40, and higher risk is ≥ 41 (Oncotype, 2020a, 2020b). 

The ColDx assay (Almac Diagnostics, Craigavon, Northern Ireland) uses microarray technology for assessing the gene expression of 634 genes to stratify patients into low and high recurrence risk groups. ColDx identified 73 high risk patients with a hazard ratio of 2.62 during cross validation. In an independent validation, the assay identified high-risk patients with a hazard ratio of 2.53 (Kennedy et al., 2011).

ColoPrint (Agendia, Amsterdam, The Netherlands) is a gene expression classifier that uses whole-genome expression data of 18 key genes to distinguish patients with low versus high risk of disease relapse. In a study using 206 fresh frozen tumor tissue samples from 188 patients with stage I through IV CRC, ColoPrint classified “60% of patients as low risk and 40% as high risk,” and was “superior to American Society of Clinical Oncology criteria in assessing the risk of cancer recurrence without prescreening for microsatellite instability” (Salazar et al., 2011). In a study of 416 stage II colon cancer patients, “ColoPrint identified 63% of patients as low risk with a 5-year ROR of 10%, whereas high-risk patients (37%) had a 5-year ROR of 21%.” Alternatively, the 2013 NCCN clinical risk factors could not distinguish low and high risk patients (S. Kopetz et al., 2015). 

Clinical Utility and Validity
Several studies have evaluated the impact of the gene expression profiling on clinical decision making in certain colon cancer subgroups. Brenner et al (Brenner et al., 2016) assessed the clinical impact of the 12-gene Colon Cancer Recurrence Score Assay in treatment of T3 mismatch repair proficient (MMR-P) stage II colon cancer. Out of 269 patients, 102 patients had their treatment changed because of the assay’s results. The authors concluded that testing significantly impacted adjuvant treatment decisions in clinical practice (Brenner et al., 2016). 

Cartwright et al. (2014) performed a web-based survey evaluating the impact of the 12-gene Colon Cancer Recurrence Score Assay in stage II colon cancer patients. 346 oncologists were surveyed about their use of the Oncotype DX assay including questions about courses of treatment before and after using the assay and the stage of cancer their patient had. The authors found that 29% of treatment recommendations were changed for patients receiving Recurrence Score testing (Cartwright et al., 2014). Srivastava et al. (2014) conducted a prospective study assessing the impact of recurrence score results on physician recommendations regarding adjuvant chemotherapy in T3 MMR-P stage II colon cancer patients. 141 patients were eligible for analysis, and the study concluded that treatment recommendation changes were made for 63 (45%) of patients (Srivastava et al., 2014). 

Chang et al. (2020) reviewed the “entire database” of the OncoType Colon Recurrence Score test to identify any age-related differences in Recurrence Score (RS) and single-gene results. 20478 Stage II and IIIA/B colon cancer patients were included. RS results were categorized into low, medium, and high risk, and single-gene results were organized by median and interquartile ranges. 72.5% of all patients and 72.6% of patients under 40 years old were found to have a low risk RS. However, there were no significant differences in either RS or single-gene results among the four age groups (< 40, 40 – 54, 55 – 64, > 65). Young-onset cancer was also not found to differ by gene expression in individual RS genes. Overall, most patients in stages II or III colon cancer were found to have low-risk disease per the OncoType assay (Chang et al., 2020).

Allar et al. (2022) evaluated how the OncoType Colon Recurrence Score influences clinical practice. The study included 105 patients with stage IIa colon cancer and investigated the association between the RS and the decision to offer adjuvant chemotherapy after resection. 52 patients underwent RS testing, seven (13%) of whom received adjuvant chemotherapy. The authors found no significant effect or clear association of RS on the odds of undergoing chemotherapy. The authors conclude that “RS was not associated with the decision to start adjuvant chemotherapy” and suggest that “the RS should not be obtained in patients with stage IIa colon cancer” (Allar, Messaris, Poylin, Schlechter, & Cataldo, 2022).

National Comprehensive Cancer Network (NCCN)
Regarding the OncoType DX colon cancer assay, the NCCN remarks that clinical validation in patients with stages II or III cancer from the QUASAR and NSABP clinical trials shows that “the recurrence scores are prognostic for recurrence, DFS [disease free survival], and OS [overall survival] in stage II and stage III colon cancer but are not predictive of benefit to adjuvant therapy”. ColoPrint, an 18-gene classifier for recurrence risk, was also found to independently predict recurrence risk and is currently being validated to predict 3-year relapse rates in patients with stage II colon cancer in a prospective trial. Similarly, ColDx, a microarray based multigene assay, was found to independently predict recurrence risk. However, despite these tests’ ability to further inform risk of recurrence, the panel questions the value added. The panel also noted that “evidence of predictive value in terms of the potential benefit of chemotherapy is lacking” and that “there are insufficient data to recommend the use of multi-gene assays, Immunoscore, or post-surgical ctDNA to estimate risk of recurrence or determine adjuvant therapy” (NCCN, 2022).

American Society for Clinical Pathology, College of American Pathologists, Association for Molecular Pathology, and American Society of Clinical Oncology Joint Guidelines
The joint guidelines state that further research is required to study the clinical validity and utility of gene expression profiling assays in colon cancer patients (Sepulveda et al., 2017).

European Society for Medical Oncology (EMSO) 
ESMO notes that “pathological staging and gene expression signatures have failed to accurately predict disease recurrence and prognosis [of CRC]” (ESMO, 2016).

Research Committee and the Guidelines Committee of the European Society of Coloproctology (ESCP)
This systematic review was performed by the committee to assess the consensus levels “in guidelines from member countries of the European Society of Coloproctology, with supporting evidence”. This review focuses on follow-up strategies for patients “after treatment with curative intent of nonmetastatic colorectal cancer” (Bastiaenen et al., 2019).

In this review, the committee concluded that “laboratory tests other than CEA [carcinoembryonic antigen] should not be part of follow-up,” although it noted that only 8 of 21 guidelines reviewed addressed this topic (Bastiaenen et al., 2019).
 

References:

1. Allar, B. G., Messaris, E., Poylin, V. Y., Schlechter, B. L., & Cataldo, T. E. (2022). Oncotype DX testing does not affect clinical practice in stage IIa colon cancer. Med Oncol, 39(5), 59. doi:10.1007/s12032-022-01660-9
2. Bardhan, K., & Liu, K. (2013). Epigenetics and colorectal cancer pathogenesis. Cancers (Basel), 5(2), 676-713. doi:10.3390/cancers5020676
3. Bastiaenen, V. P., Hovdenak Jakobsen, I., Labianca, R., Martling, A., Morton, D. G., Primrose, J. N., . . . Laurberg, S. (2019). Consensus and controversies regarding follow-up after treatment with curative intent of nonmetastatic colorectal cancer: a synopsis of guidelines used in countries represented in the European Society of Coloproctology. Colorectal Dis, 21(4), 392-416. doi:10.1111/codi.14503
4. Brenner, B., Geva, R., Rothney, M., Beny, A., Dror, Y., Steiner, M., . . . Liebermann, N. (2016). Impact of the 12-Gene Colon Cancer Assay on Clinical Decision Making for Adjuvant Therapy in Stage II Colon Cancer Patients. Value Health, 19(1), 82-87. doi:10.1016/j.jval.2015.08.013
5. Cartwright, T., Chao, C., Lee, M., Lopatin, M., Bentley, T., Broder, M., & Chang, E. (2014). Effect of the 12-gene colon cancer assay results on adjuvant treatment recommendations in patients with stage II colon cancer. Curr Med Res Opin, 30(2), 321-328. doi:10.1185/03007995.2013.855183
6. Chang, G. J., You, Y. N. Y., Russell, C. A., Tierno, M. B., Turner, M., Bennett, J. P., . . . Hochster, H. S. (2020). Young-Onset Colon Cancer and Recurrence Risk By Gene Expression. J Natl Cancer Inst. doi:10.1093/jnci/djaa019
7. Compton, C. (2020). Pathology and prognostic determinants of colorectal cancer - UpToDate. In K. Tanabe (Ed.), UpToDate. Waltham. MA.
8. El-Deiry, W. S., Vijayvergia, N., Xiu, J., Scicchitano, A., Lim, B., Yee, N. S., . . . Reddy, S. (2015). Molecular profiling of 6,892 colorectal cancer samples suggests different possible treatment options specific to metastatic sites. Cancer Biol Ther, 16(12), 1726-1737. doi:10.1080/15384047.2015.1113356
9. ESMO. (2016). ESMO Consensus Guidelines for the Management of Patients with Metastatic Colorectal Cancer. Retrieved from https://www.esmo.org/Guidelines/Gastrointestinal-Cancers/Management-of-Patients-with-Metastatic-Colorectal-Cancer
10. Gray, R. G., Quirke, P., Handley, K., Lopatin, M., Magill, L., Baehner, F. L., . . . Kerr, D. J. (2011). 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, 29(35), 4611-4619. doi:10.1200/jco.2010.32.8732
11. Gunderson, L. L., Jessup, J. M., Sargent, D. J., Greene, F. L., & Stewart, A. K. (2010). Revised TN categorization for colon cancer based on national survival outcomes data. J Clin Oncol, 28(2), 264-271. doi:10.1200/jco.2009.24.0952
12. Harris, E. I., Lewin, D. N., Wang, H. L., Lauwers, G. Y., Srivastava, A., Shyr, Y., . . . Washington, M. K. (2008). Lymphovascular invasion in colorectal cancer: an interobserver variability study. Am J Surg Pathol, 32(12), 1816-1821. doi:10.1097/PAS.0b013e3181816083
13. Kennedy, R. D., Bylesjo, M., Kerr, P., Davison, T., Black, J. M., Kay, E. W., . . . Harkin, D. P. (2011). Development and independent validation of a prognostic assay for stage II colon cancer using formalin-fixed paraffin-embedded tissue. J Clin Oncol, 29(35), 4620-4626. doi:10.1200/jco.2011.35.4498
14. Kopetz, S. (2008). Adjuvant Chemotherapy for Stage II Colon Cancer. Retrieved from https://www.cancernetwork.com/colorectal-cancer/adjuvant-chemotherapy-stage-ii-colon-cancer
15. Kopetz, S., Tabernero, J., Rosenberg, R., Jiang, Z. Q., Moreno, V., Bachleitner-Hofmann, T., . . . Salazar, R. (2015). Genomic classifier ColoPrint predicts recurrence in stage II colorectal cancer patients more accurately than clinical factors. Oncologist, 20(2), 127-133. doi:10.1634/theoncologist.2014-0325
16. NCCN. (2022, January 21). NCCN Clinical Practice Guidelines in Oncology; Colon Cancer v1.2022. Retrieved from https://www.nccn.org/professionals/physician_gls/pdf/colon.pdf
17. O'Connell, M. J., Lavery, I., Yothers, G., Paik, S., Clark-Langone, K. M., Lopatin, M., . . . Wolmark, N. (2010). 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, 28(25), 3937-3944. doi:10.1200/jco.2010.28.9538
18. Oncotype. (2020a). About the Oncotype DX Colon Recurrence Score Test. Retrieved from https://www.oncotypeiq.com/en-US/colon-cancer/healthcare-professionals/oncotype-dx-colon-recurrence-score/about-the-test
19. Oncotype. (2020b). Interpreting the Results. Retrieved from https://www.oncotypeiq.com/en-US/colon-cancer/healthcare-professionals/oncotype-dx-colon-recurrence-score/interpreting-the-results
20. Ribic, C. M., Sargent, D. J., Moore, M. J., Thibodeau, S. N., French, A. J., Goldberg, R. M., . . . Gallinger, S. (2003). Tumor microsatellite-instability status as a predictor of benefit from fluorouracil-based adjuvant chemotherapy for colon cancer. N Engl J Med, 349(3), 247-257. doi:10.1056/NEJMoa022289
21. Salazar, R., Roepman, P., Capella, G., Moreno, V., Simon, I., Dreezen, C., . . . Tollenaar, R. (2011). Gene expression signature to improve prognosis prediction of stage II and III colorectal cancer. J Clin Oncol, 29(1), 17-24. doi:10.1200/jco.2010.30.1077
22. Sargent, D. J., Marsoni, S., Monges, G., Thibodeau, S. N., Labianca, R., Hamilton, S. R., . . . Gallinger, S. (2010). Defective mismatch repair as a predictive marker for lack of efficacy of fluorouracil-based adjuvant therapy in colon cancer. J Clin Oncol, 28(20), 3219-3226. doi:10.1200/jco.2009.27.1825
23. Sepulveda, A. R., Hamilton, S. R., Allegra, C. J., Grody, W., Cushman-Vokoun, A. M., Funkhouser, W. K., . . . Nowak, J. A. (2017). Molecular Biomarkers for the Evaluation of Colorectal Cancer: Guideline From the American Society for Clinical Pathology, College of American Pathologists, Association for Molecular Pathology, and American Society of Clinical Oncology. J Mol Diagn, 19(2), 187-225. doi:10.1016/j.jmoldx.2016.11.001
24. Siegel, R. L., Miller, K. D., Fuchs, H. E., & Jemal, A. (2022). Cancer statistics, 2022. CA Cancer J Clin, 72(1), 7-33. doi:10.3322/caac.21708
25. Srivastava, G., Renfro, L. A., Behrens, R. J., Lopatin, M., Chao, C., Soori, G. S., . . . Alberts, S. R. (2014). Prospective multicenter study of the impact of oncotype DX colon cancer assay results on treatment recommendations in stage II colon cancer patients. Oncologist, 19(5), 492-497. doi:10.1634/theoncologist.2013-0401
26. Venook, A. P., Niedzwiecki, D., Lopatin, M., Ye, X., Lee, M., Friedman, P. N., . . . Bertagnolli, M. M. (2013). 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, 31(14), 1775-1781. doi:10.1200/jco.2012.45.1096
27. Wang, J., Li, S., Liu, Y., Zhang, C., Li, H., & Lai, B. (2020). Metastatic patterns and survival outcomes in patients with stage IV colon cancer: A population-based analysis. Cancer Med, 9(1), 361-373. doi:10.1002/cam4.2673

Coding Section

Procedure and diagnosis codes on Medical Policy documents are included only as a general reference tool for each policy. They may not be all-inclusive.

This medical policy was developed through consideration of peer-reviewed medical literature generally recognized by the relevant medical community, U.S. FDA approval status, nationally accepted standards of medical practice and accepted standards of medical practice in this community, Blue Cross Blue Shield Association technology assessment program (TEC) and other non-affiliated technology evaluation centers, reference to federal regulations, other plan medical policies, and accredited national guidelines.

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