Description of Procedure or Service

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 (Fearon & Vogelstein, 1990). Tumors originate in adenomas or flat dysplasia, and evolve into different morphologic patterns with invasion and expansion (Compton, 2017).

***Note: This Medical Policy is complex and technical. For questions concerning the technical language and/or specific clinical indications for its use, please consult your physician.

Policy

Multigene expression assay for predicting colon cancer recurrence is considered investigational for all applications. BCBSNC does not provide coverage for investigational services or procedures.

Benefits Application

This medical policy relates only to the services or supplies described herein. Please refer to the Member's Benefit Booklet for availability of benefits. Member's benefits may vary according to benefit design; therefore member benefit language should be reviewed before applying the terms of this medical policy.

When Multigene Expression Assay For Colon Cancer Recurrence is covered

Not applicable.

When Multigene Expression Assay For Colon Cancer Recurrence is not covered

Gene expression assays for determining the prognosis of stage II colon cancer following surgery are investigational.

Policy Guidelines

Literature Review

Colorectal cancer (CRC) is the second leading cause of cancer-related deaths in the United States following lung cancer. 20% of patients with colorectal cancer will present with metastatic colorectal cancer (mCRC) at diagnosis and a significantly poorer prognosis. The 5-year survival is 13.1% in patients with distant metastases from CRC, as compared to 64.9% for all CRC patients (El-Deiry et al., 2015).

Approximately one-quarter of the patients with colon cancer present with stage II disease (Lee, Lee, Chuang, & Lee, 2013). The current National Comprehensive Cancer Network 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, 2017). 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). These patients could therefore benefit from a tool that would further refine their risk of recurrence and facilitate individualized adjuvant treatment decisions(Brenner et al., 2016).

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). The assay has been clinically validated as a predictor of recurrence risk following surgical resection in patients with both stage II and III colon cancer(Brenner et al., 2016; Gray et al., 2011; Simon, Paik, & Hayes, 2009).

Two additional colon cancer genomic assays have become available, ColoPrint (Agendia NV, Amsterdam, The Netherlands) and ColDx assay (Almac Diagnostics, Craigavon, Northern Ireland) use microarray technology for assessing the gene expression of 18 and 634 genes, respectively, to stratify patients into low and high recurrence risk groups (Kennedy et al., 2011; Maak et al., 2013; Salazar et al., 2011). Both assays have been clinically validated using retrospective cohort studies (Brenner et al., 2016; Simon et al., 2009).

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. The authors concluded that testing significantly impacted adjuvant treatment decisions in clinical practice. Cartwright et al (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. The authors found that 29% of treatment recommendations were changed for patients receiving Recurrence Score testing, and use of the assay led to reductions in treatment intensity. Srivastava et al (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. The study concluded that treatment recommendation changes were made for 45% of patients. However, none of these studies gauged the impact of testing on patient survival or recurrence outcomes. Further research is required to study the clinical utility gene expression profiling assays in colon cancer patients (Sepulveda et al., 2017).

Applicable Federal Regulations

To date, no gene expression test for evaluation of prognosis in stage II colon cancer has been cleared for marketing by the U.S. Food and Drug Administration (FDA). These tests are offered as laboratory-developed, validated and performed by individual laboratories.

LDTs are regulated by the Centers for Medicare and Medicaid (CMS) as high-complexity tests under the Clinical Laboratory Improvement Amendments of 1988 (CLIA’88).

As an LDT, the U. S. Food and Drug Administration has not approved or cleared this test; however, FDA clearance or approval is not currently required for clinical use.

Practice Guidelines and Position Statements

National Comprehensive Cancer Network (NCCN)

Current clinical practice guidelines from NCCN state that “there are insufficient data to recommend the use of multi-gene assays to determine adjuvant therapy" in patients with stage 2 colon cancer (NCCN, 2018).

Billing/Coding/Physician Documentation Information

This policy may apply to the following codes. Inclusion of a code in this section does not guarantee that it will be reimbursed. For further information on reimbursement guidelines, please see Administrative Policies on the Blue Cross Blue Shield of North Carolina web site at www.bcbsnc.com. They are listed in the Category Search on the Medical Policy search page. 

Scientific Background and Reference Sources

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

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

Compton, C. (2017). Pathology and prognostic determinants of colorectal cancer - UpToDate. In K. Tanabe (Ed.), UpToDate. Waltham. MA.

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

Fearon, E. R., & Vogelstein, B. (1990). A genetic model for colorectal tumorigenesis. Cell, 61(5), 759- 767.

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

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

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

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

Lee, Y. C., Lee, Y. L., Chuang, J. P., & Lee, J. C. (2013). Differences in survival between colon and rectal cancer from SEER data. PLoS One, 8(11), e78709. doi:10.1371/journal.pone.0078709

Maak, M., Simon, I., Nitsche, U., Roepman, P., Snel, M., Glas, A. M., . . . Rosenberg, R. (2013).

Independent validation of a prognostic genomic signature (ColoPrint) for patients with stage II colon cancer. Ann Surg, 257(6), 1053-1058. doi:10.1097/SLA.0b013e31827c1180

NCCN. (2017). NCCN Clinical Practice Guidelines in Oncology. NCCN Clinical Practice Guidelines in Oncology.

NCCN. (2018). NCCN Clinical Practice Guidelines in Oncology; Colon Cancer v2.2018. 

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

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 fluorouracilbased adjuvant chemotherapy for colon cancer. N Engl J Med, 349(3), 247-257. doi:10.1056/NEJMoa022289

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

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

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

Simon, R. M., Paik, S., & Hayes, D. F. (2009). Use of archived specimens in evaluation of prognostic and predictive biomarkers. J Natl Cancer Inst, 101(21), 1446-1452. doi:10.1093/jnci/djp335 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

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

Policy Implementation/Update Information

1/1/2019 New policy developed. Multigene expression assay for predicting colon cancer recurrence/ prognosis of stage II colon cancer following surgery are investigational. Medical Director review 1/1/2019. Policy noticed 1/1/2019 for effective date 4/1/2019. (lpr)