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This medical policy (medical coverage guideline) is Copyright 2017, Blue Cross and Blue Shield of Florida (BCBSF). All Rights Reserved. You may not copy or use this document or disclose its contents without the express written permission of BCBSF. The medical codes referenced in this document may be proprietary and owned by others. BCBSF makes no claim of ownership of such codes. Our use of such codes in this document is for explanation and guidance and should not be construed as a license for their use by you. Before utilizing the codes, please be sure that to the extent required, you have secured any appropriate licenses for such use. Current Procedural Terminology (CPT) is copyright 2017 American Medical Association. All Rights Reserved. No fee schedules, basic units, relative values, or related listings are included in CPT. The AMA assumes no liability for the data contained herein. Applicable FARS/DFARS restrictions apply to government use. CPT® is a trademark of the American Medical Association. The use of specific product names is illustrative only. It is not intended to be a recommendation of one product over another, and is not intended to represent a complete listing of all products available.

05-86000-28

Original Effective Date: 02/15/09

Reviewed: 07/27/17

Revised: 08/15/17

Subject: KRAS, NRAS, and BRAF Mutation Analysis in Metastatic Colorectal Cancer

THIS MEDICAL COVERAGE GUIDELINE IS NOT AN AUTHORIZATION, CERTIFICATION, EXPLANATION OF BENEFITS, OR A GUARANTEE OF PAYMENT, NOR DOES IT SUBSTITUTE FOR OR CONSTITUTE MEDICAL ADVICE. ALL MEDICAL DECISIONS ARE SOLELY THE RESPONSIBILITY OF THE PATIENT AND PHYSICIAN. BENEFITS ARE DETERMINED BY THE GROUP CONTRACT, MEMBER BENEFIT BOOKLET, AND/OR INDIVIDUAL SUBSCRIBER CERTIFICATE IN EFFECT AT THE TIME SERVICES WERE RENDERED. THIS MEDICAL COVERAGE GUIDELINE APPLIES TO ALL LINES OF BUSINESS UNLESS OTHERWISE NOTED IN THE PROGRAM EXCEPTIONS SECTION.

           
Position Statement Billing/Coding Reimbursement Program Exceptions Definitions Related Guidelines
           
Other References Update    
           

DESCRIPTION:

Cetuximab (Erbitux®) and panitumumab (Vectibix®) are human monoclonal antibodies that target the epidermal growth factor receptor (EGFR, also known as HER-1). EGFR is expressed in many normal epithelial tissues, including the skin and hair follicle. Over expression of EGFR has been detected in many human cancers including those of the head and neck, colon and rectum. Excessive activation of EGFR is associated with advanced stages of cancer and a poor prognosis. Cetuximab and panitumumab block the EGFR receptor on both normal and cancerous cells. This binding blocks phosphorylation and activation of receptor-associated kinases, resulting in inhibition of cell growth, induction of apoptosis, and decreased survival of tumor cells that express the EGFR. Panitumumab differs from cetuximab in that it has a higher affinity for the receptor and it produces less hypersensitivity reactions.

The RAS-RAF-MAP kinase pathway is activated in the EGFR cascade. The ras proteins are Gproteins that cycle between active (RAS-GTP) and inactive (RAS-GDP) forms, in response to stimulation from a cell surface receptor such as EGFR, and act as a binary switch between the cell surface EGFR and downstream signaling pathways. The KRAS gene can harbor oncogenic mutations that result in a constitutively activated protein, independent of EGFR ligand binding, rendering antibodies to the upstream EGFR ineffective. Approximately 40% of colorectal cancer (CRC) have KRAS mutations in codons 12 and 13 in exon 2 are found in approximately 30% to 50% CRC tumors and are common in other tumor types. Another proto-oncogene that acts downstream from KRAS–NRAS harbors oncogenic mutations in codons 12, 13, or 61 that result in constitutive activation of the EGFR-mediated pathway. These mutations are less common compared with KRAS, detected in 2% to 7% of CRC specimens. It is unclear whether NRAS mutations predict poor response to anti-EGFR monoclonal antibody therapy or are prognostic of poor CRC outcome in general. A third proto-oncogene, BRAF, encodes a protein kinase and is involved in intracellular signaling and cell growth and is a principal downstream effector of KRAS. BRAF mutations occur in less than 10% to 15% of CRCs and appear to be a marker of poor prognosis. KRAS and BRAF mutations are considered to be mutually exclusive.

POSITION STATEMENT:

KRAS mutation analysis meets the definition of medical necessity to predict nonresponse prior to planned therapy with anti-EGFR monoclonal antibodies cetuximab or panitumamab in the treatment of metastatic colorectal cancer.

NRAS mutation analysis meets the definition of medical necessity to predict nonresponse prior to planned therapy with anti-EGFR monoclonal antibodies cetuximab or panitumumab in the treatment of metastatic colorectal cancer.

KRAS mutation analysis and NRAS mutation analysis is considered experimental or investigational for all other indications, as there is limited clinical evidence in peer-reviewed medical literature to permit conclusions on net health outcomes.

BRAF mutation analysis meets the definition of medical necessity to predict nonresponse prior to planned therapy with anti-EGFR monoclonal antibodies cetuximab or panitumumab in the treatment of metastatic colorectal cancer.

BILLING/CODING INFORMATION:

CPT Coding:

81210

BRAF (B-Raf proto-oncogene, serine/threonine kinase) (eg, colon cancer, melanoma), gene analysis, V600 variant(s)

81275

KRAS (Kirsten rat sarcoma viral oncogene homolog) (eg, carcinoma) gene analysis; variants in exon 2 (e.g., codons 12 and 13)

81276

KRAS (Kirsten rat sarcoma viral oncogene homolog) (eg, carcinoma) gene analysis; additional variant(s) (e.g., codon 61, codon 146)

81311

NRAS (neuroblastoma RAS viral [v-ras] oncogene homolog) (eg, colorectal carcinoma), gene analysis, variants in exon 2 (eg, codons 12 and 13) and exon 3 (eg, codon 61)

ICD-10 Diagnoses Codes That Support Medical Necessity:

C18.0 – C18.9

Malignant neoplasm of colon (code range)

C19

Malignant neoplasm of rectosigmoid junction

C20

Malignant neoplasm of rectum

C78.5

Secondary malignant neoplasm of large intestine and rectum

REIMBURSEMENT INFORMATION:

KRAS mutation analysis, NRAS mutation analysis, and BRAF mutation analysis are to be used for a one-time decision point.

PROGRAM EXCEPTIONS:

Federal Employee Program (FEP): Follow FEP guidelines.

State Account Organization (SAO): Follow SAO guidelines.

Medicare Advantage products:

The following Local Coverage Determination (LCD) was reviewed on the last guideline reviewed date: Cetuximab (Erbitux®), (L33278) located at fcso.com.

DEFINITIONS:

None applicable.

RELATED GUIDELINES:

Genetic Testing, 05-82000-28

Genetic Testing for Lynch Syndrome and Other Inherited Colon Cancer Syndromes, 05-82000-31

Tumor/Genetic Markers, 05-82000-22

OTHER:

None

REFERENCES:

  1. Allegra CJ, Rumble RB, Hamilton SR, et al. Extended RAS Gene Mutation Testing in Metastatic Colorectal Carcinoma to Predict Response to Anti-Epidermal Growth Factor Receptor Monoclonal Antibody Therapy: American Society of Clinical Oncology Provisional Clinical Opinion Update 2015. J Clin Oncol. Jan 10 2016;34(2):179-185.
  2. Amado RG, Wolf M, Peeters M, et al, Wild-Type KRAS is Required for Panitumumab Efficacy in Patients with Metastatic Colorectal Cancer, Journal of Clinical Oncology, Vol 26, No 10, 04/08.
  3. Auner V, Kriegshauser G, et al, KRAS Mutation Analysis in Ovarian Samples Using a High Sensitivity Biochip Assay, BMC Cancer April 2009.
  4. Baker JB, Dutta D, et al, Tumour Gene Expression Predicts Response to Cetuxmab in Patients with KRAS Wild-Type Metastatic Colorectal Cancer, British Journal of Cancer (2011) 104, 488-495.
  5. Blue Cross Blue Shield Association Medical Policy Reference Manual, KRAS, NRAS, and BRAF Mutation Analysis in Metastatic Colorectal Cancer , 2.04.53, 07/17.
  6. Blue Cross Blue Shield Association TEC Assessment, KRAS Mutations and Epidermal Growth Factor Receptor Inhibitor Therapy in Metastatic Colorectal Cancer, 2008.
  7. ClinicalTrials.gov, A Biomarker Trial of Tarceva in Patients with Advanced Pancreatic Cancer, sponsored by Hoffman-LaRoche, accessed 04/13/11.
  8. ClinicalTrials.gov, A Retrospective Study of Biomarkers in Non-Small Cell Lung Cancer, sponsored by National University Hospital, Singapore, accessed 04/13/11.
  9. ClinicalTrials.gov, A Study of Deforolimus in Non-Small Cell Lung Cancer Patients with KRAS Mutations, sponsored by Merck & Ariad Pharmaceuticals, accessed 01/09/09.
  10. ClinicalTrials.gov, A Study of Radiotherapy in Rectal Cancer Using Oxaliplatin, Capecitabine With or Without Cetuximab, sponsored by National University Hospital, accessed 01/09/09.
  11. ClinicalTrials.gov, FLOX + Cetuximab (Erbitux®) for Patients with Metastatic Colorectal Cancer and Wild Type K-RAS Tumor, sponsored by Odense University Hospital, accessed 12/22/08.
  12. ClinicalTrials.gov, FOCUS 3- A Study to Determine the Feasibility of Molecular Selection of Therapy Using KRAS, BRAF and Topo-1 in Patients with Metastatic or Locally Advanced Colorectal Cancer, sponsored by Medical Research Council, accessed 04/13/11.
  13. ClinicalTrials.gov, Panitumumab Combination Study with AMG 102 or AMG 479 in Wild-Type KRAS mCRC, sponsored by Amgen, accessed 12/22/08.
  14. ClinicalTrials.gov, Phase II Trial of Cetuximab/Irinotecan as a 2nd-Line Treatment to Treat Metastatic Colorectal Cancer, sponsored by Asan Medical Center, accessed 12/22/08.
  15. ClinicalTrials.gov, Randomized Phase II Study of AZD6244 MEK-Inhibitor with Erlotinib in KRAS Wild Type and KRAS Mutant Advanced Non-Small Cell Lung Cancer, sponsored by National Cancer Institute (NCI), accessed 04/13/11.
  16. ClinicalTrials.gov, Study Evaluating the Safety and Efficacy of FOLFIRI Plus Cetuximab (Erbitux) or FOLFOX Plus Cetuximab as First-Line Therapy in Subjects with KRAS Wild-Type Metastatic Colorectal Cancer (APEC-Study), sponsored by Merck KgaA, accessed 12/22/08.
  17. Etienne-Grimaldi M, Francoual M, Formento J, et al, K-ras Mutations and Treatment Outcome in Colorectal Cancer Patients Receiving Exclusive Fluoropyrimidine (FU) Therapy, American Society of Clinical Oncology 2008 Gastrointestinal Cancers Symposium.
  18. Evaluation of Genomic Applications in P, Prevention Working G. Recommendations from the EGAPP Working Group: can testing of tumor tissue for mutations in EGFR pathway downstream effector genes in patients with metastatic colorectal cancer improve health outcomes by guiding decisions regarding anti-EGFR therapy? Genet Med. Jul 2013;15(7):517-527. Accessed at egappreviews.org 05/30/16.
  19. First Coast Service Options, Inc, LCD for Cetuximab (Erbitux®), L33278, 10/01/15; accessed at fcso.com 05/26/16.
  20. Karapetis CS, Khambata-Ford S, Jonker DJ, et al, K-ras Mutations and Benefit from Cetuximab in Advanced Colorectal Cancer, The New England Journal of Medicine, Vol 359; 1757-1762, 10/08.
  21. Khambata-Ford S, Harbison CT, et al, Analysis of Potential Predictive Markers of Cetuximab Benefit in BMS099, a Phase III Study of Cetuximab and First-Line Taxane/Carboplatin in Advanced Non-Small-Cell Lung Cancer, Journal of Clinical Oncology, Vol 28, No 6, February 2010: pp. 918-927.
  22. Lievre A, Bachet JB, Boige V, et al, KRAS Mutations as an Independent Prognostic Factor in Patients with Advanced Colorectal Cancer Treated with Cetuximab, Journal of Clinical Oncology, Vol 26, No 3, 01/08.
  23. Mack PC, Holland WS, Redman M, et al, KRAS Mutation Analysis in Cetuximab-Treated Advanced Stage Non-Small-Cell Lung Cancer (NSCLC): SWOG Experience with S0342 and S0536, American Society of Clinical Oncology 2009 Annual Meeting.
  24. National Comprehensive Cancer Network (NCCN), NCCN Clinical Practice Guidelines in Oncology Colon Cancer, Version March 2017.
  25. Stoehlmacher J, Mogck U, Jakob C, et al, KRAS Mutations, EGFR Polymorphisms, and Polymorphisms of Immunoglobulin Fragment C Receptor as Predictors for Response to Cetuximab Containing Chemotherapy in Colorectal Cancer Patients; Identification of New KRAS Mutation in Codon 12, American Society of Clinical Oncology 2008 Gastrointestinal Cancers Symposium.
  26. Tabernero J, Cervantes A, Rivera F, et al, Pharmacogenomic and Pharmacoproteomic Studies of Cetuximab in Metastatic Colorectal Cancer: Biomarker Analysis of a Phase I Dose-Escalation Study, Journal of Clinical Oncology, Vol 28, No 7, March 2010: pp. 1181-1189.

COMMITTEE APPROVAL:

This Medical Coverage Guideline (MCG) was approved by the BCBSF Medical Policy & Coverage Committee on 07/27/17.

GUIDELINE UPDATE INFORMATION:

02/15/09

New Medical Coverage Guideline.

10/01/09

HCPCS Quarterly Update: added new code S3713.

12/15/09

Annual review: position statements maintained description section and references updated.

07/15/10

Annual review: position statements maintained and references updated.

06/15/11

Annual review: position statements maintained and references updated.

01/01/12

Annual HCPCS update. Added CPT code 81275.

04/01/12

Quarterly HCPCS update. Deleted code S3713.

Annual review; position statements maintained and references updated.

04/15/13

Annual review; position statements maintained, references updated; formatting changes.

04/15/14

Annual review; Medicare program exception, and references updated.

01/01/16

Annual HCPCS/CPT update; code 81276 added, code 81275 revised.

07/15/16

Revision; guideline title, description, position statement, coding, and references updated; formatting changes.

10/01/16

Revision; formatting changes.

08/15/17

Review; BRAF position statement and references updated.

Date Printed: August 21, 2017: 07:42 PM