Clinical Policy Title: Viral oncogene mutation

Transcription

1 Clinical Policy Title: Viral oncogene mutation Clinical Policy Number: Effective Date: March 1, 2014 Initial Review Date: November 20, 2013 Most Recent Review Date: November 16, 2016 Next Review Date: November 2017 Related policies: Policy contains: KRAS, codon 12 or 13, BRAF mutation tests. EFGR copy number. Anti-EFGR monoclonal antibody agents. EFGR monoclonal antibody agents. CP# CP# CP# CP# CP# Molecular analysis for targeted therapy of non-small cell lung cancer Familial polyposis gene testing Gene expression profile testing for breast cancer Genetic testing for breast and ovarian cancer Genetic testing for prostate cancer prognosis ABOUT THIS POLICY: AmeriHealth Caritas Pennsylvania has developed clinical policies to assist with making coverage determinations. AmeriHealth Caritas Pennsylvania s clinical policies are based on guidelines from established industry sources, such as the Centers for Medicare & Medicaid Services (CMS), state regulatory agencies, the American Medical Association (AMA), medical specialty professional societies, and peer-reviewed professional literature. These clinical policies along with other sources, such as plan benefits and state and federal laws and regulatory requirements, including any state- or plan-specific definition of medically necessary, and the specific facts of the particular situation are considered by AmeriHealth Caritas Pennsylvania when making coverage determinations. In the event of conflict between this clinical policy and plan benefits and/or state or federal laws and/or regulatory requirements, the plan benefits and/or state and federal laws and/or regulatory requirements shall control. AmeriHealth Caritas Pennsylvania s clinical policies are for informational purposes only and not intended as medical advice or to direct treatment. Physicians and other health care providers are solely responsible for the treatment decisions for their patients. AmeriHealth Caritas Pennsylvania s clinical policies are reflective of evidence-based medicine at the time of review. As medical science evolves, AmeriHealth Caritas Pennsylvania will update its clinical policies as necessary. AmeriHealth Caritas Pennsylvania s clinical policies are not guarantees of payment. Coverage Policy AmeriHealth Caritas Pennsylvania considers the one-time use of Kirsten rat sarcoma (KRAS) viral oncogene mutation testing to be clinically proven and, therefore, medically necessary under the following conditions: As part of the diagnostic workup for suspected or proven metastatic colorectal carcinoma (mcrc) when anti-epidermal growth factor receptor (EGFR) is indicated as therapy. Limitations: All other uses of KRAS viral oncogene mutation testing are not medically necessary. 1

2 Alternative covered services: Fecal occult blood test (FOBT), flexible sigmoidoscopy, prothrombin time, serum glutamic-oxaloacetic transaminase (SGOT), stool DNA mutation analysis, urine proteinuria levels. Background Colorectal cancer (CRC) is cancer in the large intestine and rectum. It is one of the most common malignancies in developed countries and usually develops over a decade from benign lesions, such as polyps. Causes of CRC are multi-factorial, most likely including (in addition to polyps) family history and diet. Viral oncogenesis of CRC remains to be clearly defined. Treatment of CRC includes surgery, radiotherapy and chemotherapy. Chemotherapy includes targeted therapy against specific molecules involved in tumor growth and progression, such as EGFR or vascular endothelial growth factor (VEGF). Targeted therapies for metastatic colorectal cancer include cetuximab (EGFR), panitumumab (EGFR) and bevacizumab (VEGF), all monoclonal antibodies designed to bind to and inactivate growth factor receptors. Genetic testing, gene expression testing, or mutation testing includes a variety of laboratory tests (analysis of deoxyribonucleic acid [DNA], ribonucleic acid [RNA], genes or gene products) for the purposes of diagnosing disease, assisting in treatment decisions, predicting future disease, identifying carriers of disease or for prenatal testing. Viral oncogene mutation tests are used to select patients for EGFR or VEGF therapies. One gene of particular interest in colorectal cancer is the KRAS mutated tumor as it apparently inhibits the therapeutic response of these tumors to anti-egfr treatment. Randomized controlled trials (RCTs) and systematic reviews tabulated below demonstrate the deleterious effects on tumor response rates when the KRAS mutation is present. Searches AmeriHealth Caritas Pennsylvania searched PubMed and the databases of: UK National Health Services Centre for Reviews and Dissemination. Agency for Healthcare Research and Quality s National Guideline Clearinghouse and other evidence-based practice centers. The Centers for Medicare & Medicaid Services. Searches were conducted on October 25, 2016 using the terms viral oncogene mutation test and colorectal cancer. 2

3 Included were: Systematic reviews, which pool results from multiple studies to achieve larger sample sizes and greater precision of effect estimation than in smaller primary studies. Systematic reviews use predetermined transparent methods to minimize bias, effectively treating the review as a scientific endeavor, and are thus rated highest in evidence- grading hierarchies. Findings Guidelines based on systematic reviews. Economic analyses, such as cost-effectiveness, and benefit or utility studies (but not simple cost studies), reporting both costs and outcomes sometimes referred to as efficiency studies which also rank near the top of evidence hierarchies. The American Society of Clinical Oncology (ASCO, 2009) recommended that patients with mcrc who were candidates for anti-egfr therapy have their tumors tested for KRAS mutations because tumors with these mutations will not respond to therapy. Limiting therapy to tumors without mutations will reserve treatment for those most likely to benefit while avoiding unnecessary costs and harms to those who would not. Policy updates: In February 2016, the National Comprehensive Cancer Network (NCCN) updated their guidelines for colon cancer to recommend that KRAS and other sequence variant testing of suspected or proven sites of metastasis should be part of the pretreatment work-up for all patients diagnosed with metastatic synchronous adenocarcinoma. In addition, the NCCN Guidelines state that the EGFR inhibitors cetuximab and panitumumab are now recommended only for patients with tumors that do not have sequence variants in the KRAS gene. Hayes (2015) found that the potential patient population for viral oncogene mutation testing is all patients under consideration for treatment with anti-egfr monoclonal antibodies (cetuximab and panitumumab) for mcrc. Clinical evidence suggests that the benefit from these drugs is limited to a subgroup of up to 60 percent of CRC patients. Hayes also noted that the cost of genetic testing for KRAS sequence variants is reported to be a one-time $500 to $1000 expenditure while the treatment-duration monthly costs of cetuximab and panitumumab are $10,000 and $8,000, respectively. Westwood (2014) studied in a systematic review the various tests that are available to identify the KRAS mutations in the 17 percent of CRCs that metastasize to the liver. Five studies were included in the review: two studies provided data on the accuracy of KRAS mutation testing for predicting response to treatment in patients treated with cetuximab plus standard chemotherapy, and others provided data on the clinical effectiveness of cetuximab plus standard chemotherapy compared with that of standard chemotherapy in patients with KRAS wild-type tumors. There were no clear differences in the treatment effects reported by different studies, regardless of which KRAS mutation test was used to select 3

4 patients. There was no strong evidence that any one KRAS mutation test was more effective or costeffective than any other test. Summary of Clinical Evidence Citation NCCN (2016) Clinical practice guidelines in oncology: Colon Cancer Hayes (2015) KRAS Sequence Variant Analysis (Colorectal Cancer) Westwood (2014) KRAS mutation testing of tumours in adults with metastatic colorectal cancer: a systematic review and costeffectiveness analysis. Barni (2013) Cetuximab/irinotecanchemotherapy in KRAS wild-type pretreated metastatic colorectal cancer: a pooled analysis and review of the literature Content, Methods, Recommendations NCCN updated their guidelines for both colon and rectal cancer. Recommends KRAS sequence variant testing of either the primary colonic tumor or site of metastasis. Added that the EGFR inhibitors cetuximab and panitumumab are appropriate only for patients with tumors that do not have sequence variants in the KRAS gene. Found that the potential patient population for viral oncogene mutation testing is all patients under consideration for treatment with anti-egfr monoclonal antibodies. Clinical evidence suggests that the benefit from these drugs is applicable to a subgroup of up to 60 percent of CRC patients. Noted that the cost of genetic testing for KRAS sequence variants is far less than ongoing monthly costs of cetuximab and panitumumab (approximately $10,000 and $8,000, respectively). Systematic review of various tests to identify KRAS mutation. Five studies were included in the review: Two studies provided data on the accuracy of KRAS mutation testing for predicting response to treatment in patients treated with cetuximab plus standard chemotherapy Three studies provided data on the clinical effectiveness of cetuximab plus standard chemotherapy compared with that of standard chemotherapy in patients with KRAS wild-type tumors. There were no clear differences in the treatment effects reported by different studies, regardless of which KRAS mutation test was used to select patients. There was no strong evidence that any one KRAS mutation test was more effective or costeffective than any other test. Evaluation of cetuximan/irinotecan-chemotherapy in KRAS wild-type pretreated mcrc Studies enrolled pre-treated patients for second-line intervention or beyond; Overall response was 31.1%; survival was 12.5 months, progression-free survival was six months. Response rates and survival were similar in second-line intervention and beyond. 4

5 Citation Chen (2013) Association between KRAS codon 13 mutations and clinical response to anti-egfr treatment in patients with metastatic colorectal cancer: results from a metaanalysis Clancy (2013) KRAS mutation does not predict the efficacy of neoadjuvant chemoradiotherapy in rectal cancer: a systematic review and metaanalysis Hoyle (2013) Cetuximab, bevacizumab, and panitumumab for metastatic colorectal cancer Hoyle (2013a) Cost-effectiveness of cetuximab, cetuximab plus irinotecan, and panitumumab for third and further lines of treatment for KRAS wild-type patients with metastatic colorectal cancer. Jiang (2013) Content, Methods, Recommendations Evaluation of cetuximan/irinotecan-chemotherapy in KRAS wild-type pretreated mcrc Relevant studies (no design restrictions), July Seven studies (2,802 patients). Greater response in codon 13 mutation patients than other KRAS mutation. Evaluation KRAS mutation does not predict neo-adjuvant chemo-radiotherapy in rectal cancer Relevant published studies, no design restrictions. Eight case series (696 patients); KRAS mutations in mean 33.2±11.8%. KRAS mutations associated with decreased pathological complete response, tumor downstaging, and with increased mortality. Review of RCTs ( ) found identification of KRAS mutation does not predict neoadjuvant chemo-radiotherapy response in rectal cancer Interventions included cetuximab, bevacizumab, or panitumamab in patients with EGFxpressing KRAS wild-type mcrc that progressed after first-line therapy. Authors performed an economic model with sensitivity analyses for third- and further-line treatment. Cetuximab and panitumamab are clinically beneficial vs. supportive care but poor value for money. Evaluation of KRAS testing cost-effectiveness with regard to cetuximab; cetuximab + irinotecan; and panitumamab for third and further lines of treatment for KRAS wild-type metastatic colorectal cancer: Results over 10 years; cetuximab cost 28,860 and produced 0.6 QALYs; + irinotecan, 0.7 QALYs and 59,348; panitumamab, 0.52 and 35,213; supportive care, 0.36 QALYs, 6,256. MAB-based treatments unlikely to be cost effective but contingent on thresholds. EGFR gene copy number as a prognostic marker in colorectal cancer patients treated with cetuximab or panitumumab: a systematic review and meta-analysis Systematic review of 13 studies (1,669 patients) KRAS EGFR gene copy number as a prognostic marker in patients treated with cetuximab or panitumamab: Increased copy number associated with increased survival, independent of KRAS status. 5

6 Citation Lawrence (2013) Economic analysis of bevacizumab, cetuximab, and panitumumab with fluoropyrimidine-based chemotherapy in the first-line treatment of KRAS wild-type metastatic colorectal cancer (mcrc) Mao (2013) KRAS p.g13d mutation and codon 12 mutations are not created equal in predicting clinical outcomes of cetuximab in metastatic colorectal cancer: a systematic review and metaanalysis. Zhang (2013) Treatment related severe and fatal adverse events with cetuximab in colorectal cancer patients: a meta-analysis Behl (2012) Cost-effectiveness analysis of screening for KRAS and BRAF mutations in metastatic colorectal cancer Vale (2012) Content, Methods, Recommendations Economic analysis of bevacizumab, cetuximab and panitumamab with fluropyrmidine-based chemotherapy as first-line treatment of KRAS wild-type metastatic CRC: Probably most cost effective: bevacizumab + fluoropyrimidine-based chemotherapy Economic analysis KRASp.G13D and codon 12 mutations in predicting outcomes with cetuximab in metastatic colorectal cancer Relevant studies without design restriction, October studies (1,487 patients). KRASp.GG13D mutation patients appear to benefit more with cetuximab than those with codon 12 mutations but methods limitations argue for cautious interpretation. Severe and fatal adverse events with cetuximab: RCTs, Nine trials (8,520 patients with mcrc: severe adverse event rate higher in cetuximab than controls but no evidence of higher fatality rate. Cost effectiveness of screening for KRAS and BRAF mutations in metastatic colorectal cancer Decision analysis: screening for KRAS and BRAF in context of cetuximab treatment. Cohort of 50,000 patients simulated 10,000 times using randomly assigned attributes from RCT distributions. Screening for both mutations compared to base strategy of no anti-efg therapy: increased expected overall survival by years at cost of $22,033. Incremental cost-effectiveness ratio = $635,000/ additional year of life. Vs. anti-egf therapy without screening: adding KRAS test saved $7,500/patient; adding BRAF saved $1,013; with little reduction in survival. Mutation screening improves cost effectiveness but incremental ratio still above generally acceptable level of $100,000/QALY. Does anti-egf therapy improve outcome in advanced colorectal cancer? A systematic review and metaanalysis Cost effectiveness of screening Does anti-egf therapy improve outcomes in advanced colorectal cancer? 10 RCTs (8,782 patients). Clear benefits for KRAS wild-type patients with advanced disease. No benefit for KRAS mutation patients. 6

7 Citation Chen (2013) Incidence and risk of hypomagnesemia in advanced cancer patients treated with cetuximab: a metaanalysis. Zhou (2012) No survival benefit from adding cetuximab or panitumumab to oxali-platin-based chemotherapy in the first-line treatment of metastatic colorectal cancer in KRAS wild type patients: a metaanalysis Petrelli (2012) Risk of venous and arterial thromboembolic events associated with anti-egfr agents: a meta-analysis of randomized clinical trials NICE (2011) Content, Methods, Recommendations Systematic review of ten RCTs inclusive of 7,045 patients studied hypomagnesaemia with cetuximab: Cetuximabsignificantly increased risk of grade ¾ hypomagnesaemia RR, 8.60 (CI, ). Four RCTs (1,270 patients) evaluated survival benefit from adding cetuximab or panitumumab to oxali-platin-based chemotherapy in first-line treatment of KRAS wild-type metastatic colorectal cancer Addition of MABs did not improve survival or response rate. Phase II and III trials, no date restrictions. Anti-EGFs associated with significant risk of vascular events. The diagnosis and management of colorectal cancer Diagnosis and management of CRC is not influenced by direct reference to mutation testing or genotyping EGAPP (2009) Recommendations from the EGAPP Working Group: Can UGT1A1 genotyping reduce morbidity and mortality in patients with metastatic colorectal cancer treated with irinotecan? Posed question Can UGT1A1 genotyping reduce morbidity and mortality in patients with metastatic colorectal cancer treated with irinotecan? Found insufficient evidence to draw conclusion. 7

8 Citation NICE (2009) Cetuximab for the firstline treatment of metastatic colorectal cancer ASCO (2009) Content, Methods, Recommendations RCT studied cetuximab as first-line treatment for KRAS wild-type metastatic colorectal cancer Effectiveness of cetuximab + folinic acid (FOL) + fluorouracil (F) and irinotecan (IRI) was superior to FOLFIRI alone. Recommendations: Cetuximab + FOLFOX (5-flurouricil, folinic acid and oxaliplatin) is recommended as first-line treatment for mcrc only when: The primary colorectal tumor has been resected or is potentially operable. Metastases are confined to the liver and unresectable. Manufacturer rebates 16% of cetuximab cost per patient. Testing for KRAS gene mutations in patients with metastatic colorectal carcinoma to predict response to anti-epidermal growth factor receptor monoclonal antibody therapy Recommended that patients with mcrc who were candidates for anti-egfr therapy have their tumors tested for KRAS mutations Tumors with these mutations will not respond to therapy. Limiting therapy to tumors without mutations will reserve treatment for those most likely to benefit while avoiding unnecessary costs and harms to those who would not. Glossary Cetuximab (Erbitux ) and Panitumumab (Vectibix ) Monoclonal antibody EGFR inhibitors used for the treatment of mcrc and approved in 2009 by the U.S. Food and Drug Administration (FDA) for the treatment of KRAS wild-type colon cancer, since they have little or no effect in tumors demonstrating the KRAS mutation. Erbitux (cetuximab) A recombinant, human/mouse chimeric monoclonal antibody that binds specifically to the human EGFR. EGFR is a transmembrane glycoprotein that is constitutively expressed in many normal epithelial tissues, including the skin and hair follicles. Over-expression of EGFR is detected in many human cancers, including those of colorectal and head and neck origin. Interaction of EGFR with normal ligands leads to phosphorylation and activation of a series of intracellular tyrosine kinases, which in turn regulate transcription of molecules involved with cellular growth and survival, motility, proliferation, and transformation. Epidermal growth factor (EGF) A protein that stimulates cell growth, proliferation, and differentiation, EGF was discovered in 1986 by Cohen and Levi-Montalcini, who were awarded the Nobel Prize in Physiology and Medicine. EGF acts by binding with cell surface receptors to initiate a cascade of events leading to the expression of RAS genes involved in malignant transformation. Anti-EGFR inhibitors generate significant tumor response in up to 30 percent of CRC patients, but 8

9 70 percent will not benefit from treatment and recently developed tests aim to identify those patients most likely to respond. FOLFIRI A chemotherapy combination that includes the drugs FOL Folinic acid (also called leucovorin, calcium folinate or FA) F Fluorouracil (also called 5FU) IRI Irinotecan (Campto ) FOLFOX A chemotherapy combination that includes the drugs FOL Folinic acid (also called leucovorin, calcium folinate or FA) F Fluorouracil (also called 5FU) OX Oxaliplatin (Eloxatin ) Irinotecan A topoisomerase inhibitor chemotherapeutic agent frequently used for CRC and incorporated in the FOLFIRI regimen (5-fluorouricil, leucovorin and irinotecan). KRAS wild-type Used to indicate the approximately 60 percent 70 percent of CRCs without a KRAS mutation. Monoclonal antibodies (MABs) Antibodies are products of the immune system directed against infectious agents (microbes) or other cells recognized by the host as foreign. Monoclonal indicates identical chemical structures because the antibodies are produced by a clone of cells all originating in the same parent cell. MABs are produced in the laboratory or commercially by hybridoma technology, which fuses human cancer cells with spleen cells from a mouse immunized with the antigen against which the MAB will be directed. The fused cells are then cultured and handled with specialized laboratory techniques to produce the quantity of MABs needed. MAB applications include diagnostic tests and therapeutic agents for immune-mediated diseases (rheumatoid arthritis, ulcerative colitis, transplant rejection) and cancer. RAS genes Viral oncogenes that contribute to cancer development when mammalian cells are infected and provide targets for pharmaco-genetic tests to guide treatment selection in colorectal cancer. This group of genes, named for the laboratory settings in which they were first characterized, includes Kirsten rat sarcoma (KRAS), Harvey rat sarcoma (HRAS) and neuroblastoma rat sarcoma (NRAS). Pharmacogenetics A term describing the relationships between variations in the human genome (differences in DNA sequences, copy number or transcription perturbances) and individual variations in response to drug therapy; (i.e., the genetic determinants of drug behavior). References Professional society guidelines/other: 9

10 Allegra CJ, Jessup JM, Somerfield MR, et al. American Society of Clinical Oncology (ASCO) provisional clinical opinion: testing for KRAS gene mutations in patients with metastatic colorectal carcinoma to predict response to anti-epidermal growth factor receptor monoclonal antibody therapy. J Clin Oncol. 2009;27(12): Hayes, Inc. Hayes Medical Technology Report. KRAS Sequence Variant Analysis (Colorectal Cancer). Lansdale, Pa. Hayes Inc.; May, National Comprehensive Cancer Network (NCCN). Clinical practice guidelines in oncology: colon cancer. V NCCN website: Last accessed October 25, National Institute for Health and Clinical Excellence (NICE). The diagnosis and management of colorectal cancer. London (UK): National Institute for Health and Clinical Excellence (NICE); (Clinical guideline; no. 131). National Institute for Health and Clinical Excellence (NICE). Cetuximab for the first-line treatment of metastatic colorectal cancer. London (UK): National Institute for Health and Clinical Excellence (NICE); (Technology Appraisal Guidance; no.176). Peer-reviewed references: Behl AS, Goddard KAB, Flottemesch TJ, et al. Cost-effectiveness analysis of screening for KRAS and BRAF mutations in metastatic colorectal cancer. Journal of the National Cancer institute. 2012;104(23): Barni S, Ghilardi M, Borgonovo K, Cabiddu M, Zaniboni A, Petrelli F. Cetuximab/irinotecanchemotherapy in KRAS wild-type pretreated metastatic colorectal cancer: a pooled analysis and review of the literature. Reviews on Recent Clinical Trials. 2013: epub. Blons H, Rouleau E, Charrier N, et al, on behalf of the MOKAECM collaborative group. Performance and cost efficiency of KRAS mutation testing for metastatic colorectal cancer in routine diagnosis: The MOKAECM Study, a nationwide experience. PLOSone.2013;8(7):e Chang GJ, Kaiser AM, Mills S, Rafferty JF, Buie WD. Practice parameter for the management of colon cancer. Diseases of the Colon and Rectum. 2012;55(8): Chen J, Ye Y, Sun H, Shi G. Association between KRAS codon 13 mutations and clinical response to anti- EGFR treatment in patients with metastatic colorectal cancer: results from a meta-analysis. Cancer Chemotherapy and Pharmacology. 2013;71(1):

11 Chen P, Wang L, Li H, Liu B, Zou Z. Incidence and risk of hypomagnesemia in advanced cancer patients treated with cetuximab: a meta-analysis. Oncology Letters. 2013;5 (6): Clancy C, Burke JP, Coffey JC. KRAS mutation does not predict the efficacy of neo-adjuvant chemoradiotherapy in rectal cancer: a systematic review and meta-analysis. Surgical Oncology. 2013;22(2): Evaluation of Genomic Applications in Practice and Prevention (EGAPP) Working Group. Recommendations from the EGAPP Working Group: Can UGT1A1 genotyping reduce morbidity and mortality in patients with metastatic colorectal cancer treated with irinotecan? Genetics in Medicine. 2009;11(1): Hoyle M, Crathorne L, Peters J, et al. Cetuximab, bevacizumab, and panitumumab for metastatic colorectal cancer. Health Technology Assessment.2013;17(14). Hoyle M, Peters J, Crathorne L, et al. Cost-effectiveness of cetuximab, cetuximab plus irinotecan, and panitumumab for third and further lines of treatment for KRAS wild-type patients with metastatic colorectal cancer. Value in Health. 2013a; 16(2): Jiang Z, Li C, Li F, Wang X. EGFR gene copy number as a prognostic marker in colorectal cancer patients treated with cetuximab or panitumumab: a systematic review and meta-analysis. PLOSone.2013;8(2). Lawrence D, Maschio M, Leahy KJ, Yunger S, Easaw JC, Weinstein MC. Economic analysis of bevacizumab, cetuximab, and panitumumab with fluoropyrimidine-based chemotherapy in the firstline treatment of KRAS wild-type metastatic colorectal cancer (mcrc). Journal of Medical Economics. 2013; Oct 25. [Epub ahead of print]. Lindeman NI, Cagle PT, Beasley MB, et al. Molecular testing guideline for selection of lung cancer patients for EGFR and ALK tyrosine kinase inhibitors: guideline from the College of American Pathologists, International Association for the Study of Lung Cancer, and Association for Molecular Pathology. Archives of Pathology and Laboratory Medicine. 2013; 137(6): Loupakis F, Cremolini C, Salvatore L, et al. Clinical impact of anti-epidermal growth factor receptor monoclonal antibodies in first-line treatment of metastatic colorectal cancer: meta-analytical estimation and implications for therapeutic strategies. Cancer. 2012;118(6): Mao C, Huang Y-F, Yang Z-Y, Zheng D-Y, Chen J-Z, Tang J-L. KRAS p.g13d mutation and codon 12 mutations are not created equal in predicting clinical outcomes of cetuximab in metastatic colorectal cancer: a systematic review and meta-analysis. Cancer. 2013; 119(4):

12 Petrelli F, Cabiddu M, Borgonovo K, Barni S. Risk of venous and arterial thromboembolic events associated with anti-egfr agents: a meta-analysis of randomized clinical trials. Annals of Oncology. 2012; 23(7): Siddiqui AD, Piperdi B. KRAS mutation in colon cancer: a marker of resistance to EGFR-1 therapy. Annals of Surgical Oncology. 2010;17(4): Tan C, Du X. KRAS mutation testing in metastatic colorectal cancer. World Journal of Gastroenterology. 2012;18(37): Vale CL, Tierney JF, Fisher D, et al. Does anti-egf therapy improve outcome in advanced colorectal cancer? A systematic review and meta-analysis. Cancer Treatment Reviews. 2012;38(6): Westwood M, van Asselt T, Ramaekers B, et al. KRAS mutation testing of tumours in adults with metastatic colorectal cancer: a systematic review and cost-effectiveness analysis. Health Technol Assess. 2014;18(62): Zhang DI, Ye J, Xu T, Xiong B. Treatment related severe and fatal adverse events with cetuximab in colorectal cancer patients: a meta-analysis. Journal of Chemotherapy. 2013;25(3): Zhou S-W, Huang Y-Y, Wei Y, Jiang Z-M, Zhang Y-D, Yang Q, Xie D-R. No survival benefit from adding cetuximab or panitumumab to oxali-platin-based chemotherapy in the first-line treatment of metastatic colorectal cancer in KRAS wild type patients: a meta-analysis. PLOSone. 2012;7(11):e Clinical Trials: Searched clinicaltrials.gov on October 25, 2016 using terms KRAS mutation testing Open Studies. 19 studies found, 2 relevant. University Health Network, Toronto. A Trial of Trametinib and Panitumumab in RAS/RAF Wild Type Advanced Colorectal Cancer. ClinicalTrials.gov Web site. Published March 23, Updated June 21, Accessed October 25, Institut de Cancérologie de Lorraine. Detection of KRAS, NRAS et BRAF Mutations in Plasma Circulating DNA From Patients With Metastatic Colorectal Cancer (ColoBEAM). ClinicalTrials.gov Web site. Published March 3, Updated July 18, Accessed October 25, CMS National Coverage Determination (NCDs): 12

13 No NCDs identified as of the writing of this policy. Local Coverage Determinations (LCDs): No NCDs identified as of the writing of this policy. Commonly submitted codes Below are the most commonly submitted codes for the service(s)/item(s) subject to this policy. This is not an exhaustive list of codes. Providers are expected to consult the appropriate coding manuals and bill accordingly. CPT Code Description Comment EGRF(epidermal growth factor receptor) gene analysis, common variants KRAS gene analysis, variants in codons 12 and 13. ICD-10 Code Description Comment C18.0 Malignant neoplasm of cecum C18.2 Malignant neoplasm of ascending colon C18.3 Malignant neoplasm of hepatic flexure C18.4 Malignant neoplasm of transverse colon C18.5 Malignant neoplasm of splenic flexure C18.6 Malignant neoplasm of descending colon C18.8 Malignant neoplasm of overlapping sites of colon C18.9 Malignant neoplasm of colon, unspecified C19 Malignant neoplasm of rectosigmoid junction HCPCS Level II N/A Description Comment 13