MP-26 Genetic Testing Colon Cancer Treatment Form

Medical Policy Genetic Testing Colon Cancer Treatment Page 1

Policy Number: MP-26 Current Effective Date: 12/13/2019 Original Effective Date: 12/13/2019 Next Review/Revision Date: 12/1/2020 Plans: QUEST Integration (Medicaid) & Medicare

1. Purpose 1.1 The purpose of this policy is to define the indications for coverage of genetic testing to guide treatment of colorectal cancer. Genetic testing is available for both those with and those at risk for hereditary colon cancer. For genetic testing to assess inherited increased risk for colon cancer, see AlohaCare policy MP-09, Genetic testing for Colon Cancer Inherited Risk.
2. Policy 2.1 Colorectal cancer (CRC) is the fourth most frequently diagnosed cancer and the second leading cause of cancer-related death in the United States. For individuals diagnosed with CRC, there are many options for treatment available, which are dependent on the cancer’s clinical presentation and other factors. The current approach to treating metastatic CRC favors cytotoxic therapy using FDA-approved medications. More specifically, epidermal growth factor receptor (EGFR)-targeting agents have improved clinical outcomes in patients with CRC. Genetic mutations can affect a patient’s response to EGFR-targeting agents, thereby affecting the clinical outcome. Genetic testing can guide treatment decisions. 2.2 The KRAS (v-Ki-ras2 Kirsten Rat Sarcoma) gene encodes the K-Ras protein that regulates two pathways: Pl3K/PTEN/AKT and RAF/MEK/ERK. These pathways are targets of epidermal growth-factor receptor (EGFR) inhibitors. In patients with CRC, KRAS mutations in codons 12, 13, 61, and 146 have been associated with a lack of response to EGFR-targeted therapies; these mutations are estimated to be present in 37% to 45% of metastatic CRC patients. Certain NRAS (neuroblastoma RAS viral (v-ras) oncogene homolog) mutations also are predictive for a lack of benefit to anti-EGFR therapies, occurring in an estimated 4-5% of CRC patients. Among individuals with normal KRAS (wild-type), mutations in BRAF (B-Raf proto-oncogene, serine/threonine kinase) have been associated with a lack of response to EGFR-targeted therapies, occurring in an estimated 8-10% of CRC patients. Mutations in BRAF (V600E) are also associated with a more aggressive CRC phenotype, chemotherapy resistance, and decreased overall survival.
   The purpose of the KRAS/NRAS/BRAF mutation tests is to identify those individuals who are unlikely to respond to treatment with anti-EGFR monoclonal antibodies. 2.3 Anti-EGFR drugs such as Erbitux (cetuximab) and Vectibix (panitumumab) are typically used for metastatic CRC as first line therapy in combination with Eloxatin (oxaliplatin) and Camptosar (irinotecan) or following failure of first-line chemotherapy. The National Comprehensive Cancer Network (NCCN), American Society of Clinical Pathology (ASCP), College of American Pathologists (CAP), Association for Molecular Pathology (AMP), and the American Society of Clinical Oncology (ASCO) recommend KRAS/NRAS/BRAF mutation testing before initiating EGFR-targeted therapies for patients with EGFR-expressing metastatic CRC, and recommend that

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anti-EGFR therapy should be excluded from treatment of any patient with RAS (exon 2, 3, or 4 of KRAS or NRAS) or BRAF mutations. Changes made by the FDA to the product labels of Erbitux (cetuximab) and Vectibix (panitumumab) indicate the drugs are now not recommended for the treatment of colorectal cancer for patients with RAS mutations, or when the results of RAS mutation tests are unknown. 2.4 PIK3CA (phosphatidylinositol-4, 5-bisphosphate 3-kinase, catalytic subunit alpha) mutations have also been associated with a lack of response to EGFR targeted therapies; however, medical evidence for the role of PIK3CA mutation is limited. Microsatellite instability (MSI) has been associated with improved clinical outcomes with response to immunotherapy. While studies have been small, the FDA has extended approval of certain pharmaceuticals (e.g., Opdivo, Keytruda) to MSI-high cancer, including colorectal cancer that has progressed following treatment with a fluoropyrimidine, oxaliplatin, and irinotecan. In addition, NCCN recommends MSI testing for individuals with CRC to determine hereditability.

3. Definitions 3.1 Laboratory Developed Test (LDT): Any test developed by a laboratory without FDA approval or clearance. 3.2 Lynch Syndrome associated aka HNPCC-Related Cancer – include colorectal, endometrial, gastric, biliary tract, brain, small bowel, ureter, pancreas, ovarian, renal pelvis, and sebaceous gland adenomas and keratocanthomas. 3.3 Microsatellite Instability (MSI) – the condition of genetic hypermutability that results from impaired DNA mismatch repair (MMR) genes. MSI-H `is evidence that MMR is functioning abnormally, and is indicative of certain hereditary CRCs.
4. Procedure 4.1 Prior authorization is required. Genetic testing is covered only when test results will change the clinical management of the patient and lead to improved health outcomes. 4.2 Quest Criteria:
5. KRAS, NRAS, and BRAF mutation testing are considered medically necessary to guide the treatment of colorectal cancer when the following criteria are met: a. The patient has a diagnosis of colorectal cancer; and b. Treatment with anti-EGFR monoclonal antibodies (e.g., cetuximab and/or panitumumab) is being considered; and c. Testing will be performed on tumor tissue (metastatic or recurrent CRC tissue, or primary CRC tumor tissue); and d. The specific test is either: i. FDA-approved to determine treatment eligibility; or ii. A laboratory-developed test (LDT) with completed validation demonstrating analytical validity and clinical validity for determining treatment eligibility.
6. Microsatellite instability (MSI) and/or Immunohistochemistry for Mismatch Repair (MMR) expression are covered when the following criteria are met: a. The patient has a diagnosis of colorectal cancer; and b. Testing will be performed on tumor tissue (metastatic or recurrent CRC tissue, or primary

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CRC tumor tissue); and c. The specific test is performed in a CLIA and CAP-certified laboratory and is either:
i. FDA cleared or approved; or ii. An LDT with completed validation demonstrating analytical validity and clinical validity.

3. Multigene tests may be medically necessary when the test is an FDA-approved companion diagnostic for a potential treatment regimen. This includes the Praxis Extended RAS Panel (KRAS and NRAS mutations). 4.3 Example MSI/MMR testing Algorithm

   4.4 Medicare Criteria - Prior authorization is required.

4. Refer to Local Coverage Determination (LCD) on Genetic Testing for Lynch Syndrome (L36370). https://med.noridianmedicare.com/documents/10546/6990981/MolDX+Genetic+Testing+for+ Lynch+Syndrome+LCD/714c18f3‐0ebb‐4d18‐aaad‐f714a5801a6f
5. Limitations 5.1 Genetic testing of other genes for the treatment of CRC outside of the indications listed above is considered experimental and investigational 5.2 Requests for repeat testing must include documentation of medical necessity, including the following: recurrence of disease, change in behavior of disease, etc.

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5.3 Due to the complexity of these laboratory tests, testing must only be performed in laboratories with CLIA (Clinical Laboratory Improvement Amendments of 1988) and CAP (College of American Pathologists) certifications to adhere to U.S. federal standards and regulations on quality. 5.4 Genetic testing for the treatment of CRC performed on specimen types other than CRC tumor tissue is considered experimental and investigational. 5.5 The following tests are considered experimental and investigational due to a lack of peer-reviewed published literature documenting clinical utility for CRC treatment (not an all-inclusive list):
• COLARIS • ColonSentry test • ColoNext • Colopath-colorectal alert test • ColonSeq • ColoSeq • Colovantage test (CPT 81327) • MatePair Targeted Rearrangements (CPT 0013U) • miR-31now (CPT 0069U) • MSK-IMPACT (CPT 0048U) • OmniSeq RNA-Sequencing • Onco4D (CPT 0083U) • OncoTarget/OncoTreat (CPT 0019U) • OncotypeDx Colon • PolypDX (CPT 0002U)

6. Coding Information The following medical codes are relevant codes for diagnosis and procedures for genetic testing for colon cancer treatment and for informational purposes only. All the medical codes listed in this policy do not constitute or imply benefit coverage or provider reimbursement.

   CPT Description 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 (eg, codons 12 and 13) 81276 KRAS (Kirsten rat sarcoma viral oncogene homolog) (eg, carcinoma) gene analysis; additional variant(s) (eg, codon 61, codon 146) 81301 Microsatellite instability analysis (eg, hereditary non-polyposis colorectal cancer, Lynch syndrome) of markers for mismatch repair deficiency (eg, BAT25, BAT26), includes

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comparison of neoplastic and normal tissue, if performed 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) Medicare Only 81327 SEPT9 (Septin9) (eg, colorectal cancer) promoter methylation analysis 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 Experimental & Investigational 0002U Oncology (colorectal), quantitative assessment of three urine metabolites (ascorbic acid, succinic acid and carnitine) by liquid chromatography with tandem mass spectrometry (LC- MS/MS) using multiple reaction monitoring acquisition, algorithm reported as likelihood of adenomatous polyps 0013U Oncology (solid organ neoplasia), gene rearrangement detection by whole genome next- generation sequencing, DNA, fresh or frozen tissue or cells, report of specific gene rearrangement(s) 0019U Oncology, RNA, gene expression by whole transcriptome sequencing, formalin-fixed paraffin-embedded tissue or fresh frozen tissue, predictive algorithm reported as potential targets for therapeutic agents 0048U Oncology (solid organ neoplasia), DNA, targeted sequencing of protein-coding exons of 468 cancer-associated genes, including interrogation for somatic mutations and microsatellite instability, matched with normal specimens, utilizing formalin-fixed paraffin-embedded tumor tissue, report of clinically significant mutation(s) 0069U Oncology (colorectal), microRNA, RT-PCR expression profiling of miR-31-3p, formalin- fixed paraffin-embedded tissue, algorithm reported as an expression score 0083U Oncology, response to chemotherapy drugs using motility contrast tomography, fresh or frozen tissue, reported as likelihood of sensitivity or resistance to drugs or drug combinations

7. References/Resources 7.1 National Comprehensive Cancer Network (NCCN): NCCN Clinical Practice Guidelines in Oncology- Colon Cancer. Version 3.2019. Published: Sept 26, 2019. https://www.nccn.org/professionals/physician_gls/pdf/colon.pdf 7.2 Sepulveda AR, Hamilton SR, Allegra CJ, et al. 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. 2017 Mar;19(2):187-225. doi: 10.1016/j.jmoldx.2016.11.001. Epub 2017 Feb 6. https://ac.els-cdn.com/S1525157816302240/1-s2.0-S1525157816302240- main.pdf?tid=38fc8ca2-cf10-11e7-9034- 00000aacb362&acdnat=151130560414f9737d82246d3ecf822892252c0a6f 7.3 Bupathi M, Wu C. Biomarkers for immune therapy in colorectal cancer: mismatch-repair deficiency and others. J Gastrointest Oncol. 2016 Oct;7(5):713-720. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5056251/pdf/jgo-07-05-713.pdf

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7.4 Dietel M, Jöhrens K, Laffert MV,et al. A 2015 update on predictive molecular pathology and its role in targeted cancer therapy: a review focusing on clinical relevance. Cancer Gene Ther. 2015 Sep;22(9):417-430. doi: 10.1038/cgt.2015.39. http://www.nature.com/cgt/journal/v22/n9/pdf/cgt201539a.pdf 7.5 National Institute for Health and Clinical Excellence (NICE), Technology Appraisal (TA): Cetuximab, bevacizumab and panitumumab for the treatment of metastatic colorectal cancer after first-line chemotherapy: Cetuximab (monotherapy or combination chemotherapy), bevacizumab (in combination with non-oxaliplatin chemotherapy) and panitumumab (monotherapy) for the treatment of metastatic colorectal cancer after first-line chemotherapy. TA242. Published: January 25, 2012.
https://www.nice.org.uk/guidance/ta242/resources/cetuximab-bevacizumab-and-panitumumab-for- the-treatment-of-metastatic-colorectal-cancer-after-firstline-chemotherapy-82600427700421 7.6 Centers for Medicare and Medicaid Services (CMS). Technology Assessment of Molecular Pathology Testing for the Estimation of Prognosis for Common Cancers. AHRQ 2014
https://www.cms.gov/medicare-coverage-database/details/technology-assessments- details.aspx?TAId=94&SearchType=Advanced&CoverageSelection=Both&NCSelection=NCA% 7cCAL%7cNCD%7cMEDCAC%7cTA%7cMCD&ArticleType=BC%7cSAD%7cRTC%7cReg& PolicyType=Both&s=16&KeyWord=colon&KeyWordLookUp=Title&KeyWordSearchType=Exa ct&kq=true&bc=IAAAACAAAAAA& 7.7 United States Food and Drug Administration: List of Cleared or Approved Companion Diagnostic Devices (In Vitro and Imaging Tools) Updated 8.2.2019, accessed 10.21.2019 https://www.fda.gov/medical-devices/vitro-diagnostics/list-cleared-or-approved-companion- diagnostic-devices-vitro-and-imaging-tools

8. Review/Revision History 12/13/2019 - New policy 12/1/2020 - Retired