Notification



Notification Issue Date:



Medical Policy Bulletin


Title:Multigene Expression Assays for Predicting Recurrence in Colon Cancer (Independence Administrators)

Policy #:06.02.32d

This policy is applicable to the Company’s commercial products only. Policies that are applicable to the Company’s Medicare Advantage products are accessible via a separate Medicare Advantage policy database.


The Company makes decisions on coverage based on Policy Bulletins, benefit plan documents, and the member’s medical history and condition. Benefits may vary based on contract, and individual member benefits must be verified. The Company determines medical necessity only if the benefit exists and no contract exclusions are applicable.

When services can be administered in various settings, the Company reserves the right to reimburse only those services that are furnished in the most appropriate and cost-effective setting that is appropriate to the member’s medical needs and condition. This decision is based on the member’s current medical condition and any required monitoring or additional services that may coincide with the delivery of this service.

This Medical Policy Bulletin 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 Bulletin will be reviewed regularly and be updated as scientific and medical literature becomes available. For more information on how Medical Policy Bulletins are developed, go to the About This Site section of this Medical Policy Web site.



Policy

Coverage is subject to the terms, conditions, and limitations of the member's contract.


This policy only applies to members for whom Independence Administrators serves as the claims administrator. For all other Independence members, refer to the policy entitled eviCore Lab Management Program.

The intent of this policy is to communicate the experimental/investigational coverage position for multigene expression assays for predicting recurrence in colon cancer.

For information on policies related to this topic, refer to the Cross References section in this policy.

Multigene expression assays for determining the prognosis of stage 2 or stage 3 colon cancer following surgery is considered experimental/investigational and, therefore, not covered because the safety and/or effectiveness of this service cannot be established by review of the available published peer-reviewed literature.
Guidelines

BENEFIT APPLICATION

Subject to the terms and conditions of the applicable benefit contract, multigene expression assays for determining the prognosis of stage 2 colon cancer are not eligible for payment under the medical benefits of the Company’s products because the service is considered experimental/investigational and, therefore, not covered.

Services that are experimental/investigational are a benefit contract exclusion for all products of the Company. Therefore, they are not eligible for reimbursement consideration.

US FOOD AND DRUG ADMINISTRATION (FDA)

Multigene expression assays for determining the prognosis of stage II colon cancer are not regulated by the FDA.

Description

Several gene expression profile (GEP) tests have been developed for use to identify those individuals with stage 2 colon cancer who are considered to be at high risk for recurrence after surgery and therefore most likely to benefit from additional treatment such as chemotherapy.

A review of several trials comparing adjuvant therapy versus surgery alone in individuals with stage 2 colon cancer showed that there was a very small benefit of chemotherapy for disease-free survival, but not for overall survival.

Colon cancer is classified as stage 2 when it has spread outside the colon and/or rectum to nearby tissue but has not spread to the lymph nodes or metastasized to distant sites. Surgical resection of the primary cancer and colonic anastomosis is the primary treatment for stage 2 colon cancer. The survival rate following surgery is 75 percent to 80 percent at 5 years. Those individuals who are most likely to benefit from chemotherapy are difficult to identify by standard clinical and pathological risk factors. The current system for determining individuals at risk depends upon a variety of factors, including tumor sub-stage 2B (T4A tumors that invade the muscularis propria and extend into pericolorectal tissues) or 2C (T4B tumors that invade or are adherent to other organs or structures); obstruction or bowel perforation at initial diagnosis; inadequately low number of sampled lymph nodes at surgery (12 or less); histological features of aggressiveness; a high preoperative carcinoembryonic antigen level; and the presence of indeterminate or positive resection margins.

Several assays are available 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.

No studies of GEP for determining prognosis of patients with stage 2 or stage 3 colon cancer have been published demonstrating the effect of testing on overall reclassification of patients when compared with existing methods of risk analysis. Cartwright et al (2014) and Srivastava et al (2014) published studies showing the effect of Oncotype DX® results on treatment recommendations made according to traditional risk classifiers in patients with stage 2 colon cancer. However, this study did not assess survival or recurrence outcomes. Currently, there is no published information on the impact of use of GEP results on patient outcomes. Absent information showing a direct effect on outcomes or establishing a strong chain of evidence that testing has a positive net effect on outcomes, the clinical utility of testing remains unclear.

A Technical Brief, published by the Agency for Healthcare Research and Quality in December 2012, reviewed the clinical evidence for GEP for predicting outcomes, including benefit from adjuvant chemotherapy, in patients with stage 2 colon cancer. The 4 assays reviewed earlier that are commercially available for clinical use were included in the brief. No prospective studies were identified that assessed change in net health outcome with use of a GEP assay, and no studies were identified that used a net reclassification analysis and subsequently evaluated the impact of the reclassification on net health outcome. Additionally, evidence was limited on the reproducibility of test findings, indications for GEP testing in stage 2 patients, and whether results of GEP assays can stratify patients into groups defined by clinically meaningful differences in recurrence risk.

Current clinical practice guidelines from the National Comprehensive Cancer Network on colon cancer state that data are insufficient “to recommend the use of multigene assays to determine adjuvant therapy” in patients with stage 2 or 3 colon cancer.

The evidence for the use of gene expression profiling (GEP) tests in patients who have stage 2 or stage 3 colon cancer includes development and validation studies. Relevant outcomes are disease-specific survival, test accuracy, test validity, and change in disease status. The available evidence indicates that GEP tests for colon cancer can improve risk prediction, particularly the risk of recurrence in patients with stage 2 or stage 3 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 2 or stage 3 patients, or on how GEP classification impacts patient outcomes (clinical utility). There is even less evidence to permit conclusions about how GEP classification compares with other approaches for management of other stages of colon cancer. The evidence is insufficient to determine the effects of the technology on health outcomes.
References


Barrier A, Boelle PY, Roser F, et al. Stage II colon cancer prognosis prediction by tumor gene expression profiling. J Clin Oncol. Oct 10 2006;24(29):4685-4691.

Barrier A, Roser F, Boelle PY, et al. Prognosis of stage II colon cancer by non-neoplastic mucosa gene expression profiling. Oncogene. Apr 19 2007;26(18):2642-2648.

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. http://www.ncbi.nlm.nih.gov/books/NBK115808/. Accessed June 13, 2016.

Blum C, Graham A, Yousefzadeh M, et al. The expression ratio of Map7/B2M is prognostic for survival in patients with stage II colon cancer. Int J Oncol. Sep 2008;33(3):579-584.

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.

Goel G. Evolving role of gene expression signatures as biomarkers in early-stage colon cancer. J Gastrointest Cancer. Dec 2014;45(4):399-404.

Eschrich S, Yang I, Bloom G, et al. Molecular staging for survival prediction of colorectal cancer patients. J Clin Oncol. May 20 2005;23(15):3526-3535.

Figueredo A, Coombes ME, Mukherjee S. Adjuvant therapy for completely resected stage II colon cancer. Cochrane Database Syst Rev. 2008(3):CD005390.

Gray RG, Quirke P, Handley K, et al. Validation study of a quantitative multigene reverse transcriptasepolymerase chain reaction assay for assessment of recurrence risk in patients with stage II colon cancer. J Clin Oncol. Dec 10 2011;29(35):4611-4619.

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.

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. Feb 2010;27(2):83-90.

Kapiteijn E, Marijnen CA, Nagtegaal ID, et al. Preoperative radiotherapy combined with total mesorectal excision for resectable rectal cancer. N Engl J Med. Aug 30 2001;345(9):638-646.

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. Dec 10 2011;29(35):4620-4626.

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.

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.

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.

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.

Mettu RK, Wan YW, Habermann JK, et al. A 12-gene genomic instability signature predicts clinical outcomes in multiple cancer types. Int J Biol Markers. Oct-Dec 2010;25(4):219-228.

National Comprehensive Cancer Network (NCCN). Clinical practice guidelines in oncology: colon cancer, version 2.2016. http://www.nccn.org/professionals/physician_gls/pdf/colon.pdf. Accessed June 13, 2016.

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. Sep 1 2010;28(25):3937-3944.

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).

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. Jan 1 2011;29(1):17-24.

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. J Clin Oncol 29: 2011 (suppl; abstr TPS167). http://meetinglibrary.asco.org/content/81592-102. Accessed June 13, 2016.

Salazar R, Tabernero J, Moreno V et al. Validation of a genomic classifier (ColoPrint) for predicting outcome in the T3-MSS subgroup of stage II colon cancer patients. J Clin Oncol 30: 2012 (suppl; abstr 3510). http://meeting.ascopubs.org/cgi/content/abstract/30/15_suppl/3510. Accessed June 13, 2016.

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.

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.

van Gijn W, Marijnen CA, Nagtegaal ID, et al. Preoperative radiotherapy combined with total mesorectal excision for resectable rectal cancer: 12-year follow-up of the multicentre, randomised controlled TME trial. Lancet Oncol. Jun 2011;12(6):575-582.

van Laar RK. An online gene expression assay for determining adjuvant therapy eligibility in patients with stage 2 or 3 colon cancer. Br J Cancer. Dec 7 2010;103(12):1852-1857.

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.

Vilar E, Gruber SB. Microsatellite instability in colorectal cancer-the stable evidence. Nat Rev Clin Oncol. Mar 2010;7(3):153-162.

Wan YW, Qian Y, Rathnagiriswaran S, et al. A breast cancer prognostic signature predicts clinical outcomes in multiple tumor types. Oncol Rep. Aug 2010;24(2):489-494.

Wang Y, Jatkoe T, Zhang Y, et al. Gene expression profiles and molecular markers to predict recurrence of Dukes' B colon cancer. J Clin Oncol. May 1 2004;22(9):1564-1571.

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.

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.





Coding

Inclusion of a code in this table does not imply reimbursement. Eligibility, benefits, limitations, exclusions, precertification/referral requirements, provider contracts, and Company policies apply.

The codes listed below are updated on a regular basis, in accordance with nationally accepted coding guidelines. Therefore, this policy applies to any and all future applicable coding changes, revisions, or updates.

In order to ensure optimal reimbursement, all health care services, devices, and pharmaceuticals should be reported using the billing codes and modifiers that most accurately represent the services rendered, unless otherwise directed by the Company.

The Coding Table lists any CPT, ICD-9, ICD-10, and HCPCS billing codes related only to the specific policy in which they appear.

CPT Procedure Code Number(s)

81525


THE FOLLOWING CODES ARE USED TO REPRESENT A GENE EXPRESSION ASSAY TEST USED TO DETERMINE THE PROGNOSIS OF STAGE 2 or 3 COLON CANCER

84999, 81479, 81599, 88299



Professional and outpatient claims with a date of service on or before September 30, 2015, must be billed using ICD-9 codes. Professional and outpatient claims with a date of service on or after October 1, 2015, must be billed using ICD-10 codes.

Facility/Institutional inpatient claims with a date of discharge on or before September 30, 2015, must be billed with ICD-9 codes. Facility/Institutional inpatient claims with a date of discharge on or after October 1, 2015, must be billed with ICD-10 codes.


ICD - 10 Procedure Code Number(s)

N/A


Professional and outpatient claims with a date of service on or before September 30, 2015, must be billed using ICD-9 codes. Professional and outpatient claims with a date of service on or after October 1, 2015, must be billed using ICD-10 codes.

Facility/Institutional inpatient claims with a date of discharge on or before September 30, 2015, must be billed with ICD-9 codes. Facility/Institutional inpatient claims with a date of discharge on or after October 1, 2015, must be billed with ICD-10 codes.


ICD -10 Diagnosis Code Number(s)

N/A


HCPCS Level II Code Number(s)

N/A


Revenue Code Number(s)

N/A

Coding and Billing Requirements


Cross References


Policy History

Revisions for 06.02.32d
11/21/2018This policy has been reissued in accordance with the Company's annual review process.


Effective 10/05/2017 this policy has been updated to the new policy template format.


Version Effective Date: 07/01/2016
Version Issued Date: 07/01/2016
Version Reissued Date: 11/26/2018

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Independence Blue Cross is an independent licensee of the Blue Cross and Blue Shield Association, serving the health insurance needs of Philadelphia and southeastern Pennsylvania.