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Clinical Policy Title: Viral oncogene mutation

Clinical Policy Number: CCP.1068

Effective Date: March 1, 2014

Initial Review Date: November 20, 2013

Most Recent Review Date: November 6, 2018

Next Review Date: November 2019

RELATED POLICIES:

CCP.1218 Molecular analysis for targeted therapy for lung cancer

CCP.1099 Afirma™ gene expression classifier for indeterminate thyroid nodules

CCP.1050 Familial polyposis gene testing

CCP.1045 Gene expression profile testing for breast cancer

CCP.1012 Genetic testing for breast and ovarian cancer

CCP.1121 Genetic testing for prostate cancer prognosis

CCP.1097 COLARIS® testing for Lynch syndrome

ABOUT THIS POLICY: AmeriHealth Caritas has developed clinical policies to assist with making coverage determinations. AmeriHealth Caritas’ 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 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’ 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’ clinical policies are reflective of evidence-based medicine at the time of review. As medical science evolves, AmeriHealth Caritas will update its clinical policies as necessary. AmeriHealth Caritas’ clinical policies are not guarantees of payment.

Coverage Policy

AmeriHealth Caritas considers the one-time use of Kirsten rat sarcoma (also known as KRAS) viral

oncogene mutation testing to be clinically proven and, therefore, medically necessary under the

following conditions (Barni, 2013; Chen, 2013; Clancy, 2013; Hoyle, 2013; Tosi, 2017; Westwood,

2014):

As part of the diagnostic workup for suspected or proven metastatic colorectal carcinoma

when anti-epidermal growth factor receptor (also known as EGFR) is indicated as therapy

Policy contains:

Kirsten rat sarcoma, codon 12 or 13, BRAF mutation tests.

Epidermal growth factor receptor copy number.

Anti-epidermal growth factor receptor

monoclonal antibody agents.

Epidermal growth factor receptor

monoclonal antibody agents.

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(Hoyle, 2013, Jiang, 2013, Vale, 2012).

Limitations:

All other uses of Kirsten rat sarcoma viral oncogene mutation testing are not medically necessary.

Alternative covered services:

Fecal occult blood test, flexible sigmoidoscopy, prothrombin time, serum glutamic-oxaloacetic

transaminase, stool deoxyribonucleic acid mutation analysis, urine proteinuria levels.

Background

Colorectal cancer 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 colorectal cancer are multi-factorial, most likely including (in addition to polyps)

increasing age and family history (National Cancer Institute, 2018). Colorectal cancer diagnoses occur

more frequently among African Americans than among other racial/ethnic groups. A previous

diagnosis of ovarian cancer or inflammatory bowel disease is associated with increased risk.

Actionable lifestyle factors including tobacco and alcohol use, diet, body weight, and exercise are also

associated with higher risk (American Cancer Society, 2018). Viral oncogenesis of colorectal cancer

remains to be clearly defined.

Treatment of colorectal cancer includes surgery, radiotherapy and chemotherapy. Chemotherapy

includes targeted therapy against specific molecules involved in tumor growth and progression, such

as epidermal growth factor receptor or vascular endothelial growth factor. Targeted therapies for

metastatic colorectal cancer include cetuximab (epidermal growth factor receptor), panitumumab

(epidermal growth factor receptor) and bevacizumab (vascular endothelial growth factor), 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, ribonucleic acid, 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 epidermal growth factor receptor or

vascular endothelial growth factor therapies. One gene of particular interest in colorectal cancer is

the Kirsten rat sarcoma mutated tumor as it apparently inhibits the therapeutic response of these

tumors to anti-epidermal growth factor receptor treatment. Randomized controlled trials and

systematic reviews tabulated below demonstrate the deleterious effects on tumor response rates

when the Kirsten rat sarcoma mutation is present.

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Searches

AmeriHealth Caritas searched PubMed and the databases of:

UK National Health Services Centre for Reviews and Dissemination.

Agency for Healthcare Research and Quality and other evidence-based practice centers.

The Centers for Medicare & Medicaid Services.

Searches were conducted on September 26, 2018 using the terms “viral oncogene mutation test” and

“colorectal cancer.”

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.

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.

Findings

The American Society of Clinical Oncology (2009) recommended that patients with metastatic

colorectal carcinoma who were candidates for anti-epidermal growth factor receptor therapy

have their tumors tested for Kirsten rat sarcoma 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.

The updated National Comprehensive Cancer Network guidelines for colon cancer recommend that

Kirsten rat sarcoma 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 (2016). In addition, the guidelines state that the epidermal growth factor receptor

inhibitors cetuximab and panitumumab are now recommended only for patients with tumors that do

not have sequence variants in the Kirsten rat sarcoma gene.

Westwood’s (2014) systematic review studied the various tests that are available to identify the Kirsten

rat sarcoma mutations in the 17 percent of colorectal cancers that metastasize to the liver. Five studies

were included in the review: two studies provided data on the accuracy of Kirsten rat sarcoma mutation

testing for predicting response to treatment in patients treated with cetuximab plus standard

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chemotherapy, and others provided data on the clinical effectiveness of cetuximab plus standard

chemotherapy compared with that of standard chemotherapy in patients with Kirsten rat sarcoma wild-

type tumors. There were no clear differences in the treatment effects reported by different studies,

regardless of which Kirsten rat sarcoma mutation test was used to select patients. There was no strong

evidence that any one Kirsten rat sarcoma mutation test was more effective or cost-effective than any

other test.

Policy updates:

A systematic review (Tosi, 2017) studied the predictive capability of mutations in patients with

colorectal cancer liver metastases who undergo complete liver resection. Meta-analysis revealed that

Kirsten rat sarcoma viral oncogene homolog mutation was negatively associated with overall survival.

(hazard ratio [HR], 1.674; 95% confidence interval [CI], 1.341-2.089; P < 0.001) and relapse-free survival

(HR, 1.529; 95% CI, 1.287-1.817; P < 0.001). Meta-analysis of overall survival in b-viral oncogene

homolog B1 mutation also demonstrated a negative association with overall survival (HR, 3.055; 95% CI,

1.794-5.204; P < 0.001). The authors concluded that the data support integration of mutational status

into a combined predictive score for prospective assessment of outcome after resection of colorectal

cancer liver metastases in clinical studies.

In 2018, two guideline/other publications were added to the reference list. Policy ID changed from

05.01.01 to CCP.1068.

Summary of Clinical Evidence

Citation Content

Tosi (2017) Effect of KRAS and BRAF Mutations on Survival of Metastatic Colorectal Cancer After Liver Resection: A Systematic Review and Meta-Analysis

Key points:

A systematic review studied the predictive capability of mutations in patients with colorectal cancer liver metastases who undergo complete liver resection.

Meta-analysis revealed that Kirsten rat sarcoma viral oncogene homolog mutation was negatively associated with overall survival. (hazard ratio [HR], 1.674; 95% confidence interval [CI], 1.341-2.089; P < 0.001) and relapse-free survival (HR, 1.529; 95% CI, 1.287-1.817; P < 0.001).

Meta-analysis of overall survival in b-viral oncogene homolog B1 mutation also demonstrated a negative association with overall survival (HR, 3.055; 95% CI, 1.794-5.204; P < 0.001).

The authors concluded that the data support integration of mutational status into a combined predictive score for prospective assessment of outcome after resection of colorectal cancer liver metastases in clinical studies.

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Citation Content

National Comprehensive Cancer Network (2016) Clinical practice guidelines in oncology: Colon Cancer

Key points:

National Comprehensive Cancer Network updated their guidelines for both colon and rectal cancer.

Recommends Kirsten rat sarcoma sequence variant testing of either the primary colonic tumor or site of metastasis.

Added that the epidermal growth factor receptor inhibitors cetuximab and panitumumab are appropriate only for patients with tumors that do not have sequence variants in the Kirsten rat sarcoma gene.

Westwood (2014) KRAS mutation testing of tumours in adults with metastatic colorectal cancer: a systematic review and cost-effectiveness analysis.

Key points:

Systematic review of various tests to identify Kirsten rat sarcoma mutation. Five studies were included in the review:

- Two studies provided data on the accuracy of Kirsten rat sarcoma 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 Kirsten rat sarcoma wild-type tumors.

There were no clear differences in the treatment effects reported by different studies, regardless of which Kirsten rat sarcoma mutation test was used to select patients.

There was no strong evidence that any one Kirsten rat sarcoma mutation test was more effective or cost-effective than any other test.

Barni (2013) Cetuximab/irinotecan-chemotherapy in KRAS wild-type pretreated metastatic colorectal cancer: a pooled analysis and review of the literature

Key points:

Evaluation of cetuximan/irinotecan-chemotherapy in Kirsten rat sarcoma wild-type pretreated metastatic colorectal carcinoma

Studies enrolled pre-treated patients for second-line intervention or beyond; 2007 – 12 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.

Chen (2013) Association between KRAS codon 13 mutations and clinical response to anti-EGFR treatment in patients with metastatic colorectal cancer: results from a meta-analysis

Key points:

Evaluation of cetuximan/irinotecan-chemotherapy in Kirsten rat sarcoma wild-type pretreated metastatic colorectal cancer

Relevant studies (no design restrictions), — July 2012. Seven studies (2,802 patients). Greater response in codon 13 mutation patients than other Kirsten rat sarcoma mutation.

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Citation Content

Clancy (2013) KRAS mutation does not predict the efficacy of neo-adjuvant chemo- radiotherapy in rectal cancer: a systematic review and meta-analysis

Key points:

Evaluation Kirsten rat sarcoma mutation does not predict neo-adjuvant chemo-radiotherapy in rectal cancer

Relevant published studies, no design restrictions. Eight case series (696 patients); Kirsten rat sarcoma mutations in mean 33.2±11.8%. Kirsten rat sarcoma mutations associated with decreased pathological complete response,

tumor down-staging, and with increased mortality.

Hoyle (2013) Cetuximab, bevacizumab, and panitumumab for metastatic colorectal cancer

Key points:

Review of randomized controlled trials (2005-10) found identification of Kirsten rat sarcoma mutation does not predict neo-adjuvant chemo-radiotherapy response in rectal cancer

Interventions included cetuximab, bevacizumab, or panitumamab in patients with EGF-expressing Kirsten rat sarcoma wild-type metastatic colorectal cancer 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.

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.

Key points:

Evaluation of Kirsten rat sarcoma testing cost-effectiveness with regard to cetuximab; cetuximab + irinotecan; and panitumamab for third and further lines of treatment for Kirsten rat sarcoma 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.

Monoclonal antibody-based treatments unlikely to be cost effective but contingent on thresholds.

Jiang (2013) EGFR gene copy number as a prognostic marker in colorectal cancer patients treated with cetuximab or panitumumab: a systematic review and meta-analysis

Key points:

Systematic review of 13 studies (1,669 patients) Kirsten rat sarcoma epidermal growth factor receptor gene copy number as a prognostic marker in patients treated with cetuximab or panitumamab:

Increased copy number associated with increased survival, independent of Kirsten rat sarcoma status.

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Citation Content

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)

Key points:

Economic analysis of bevacizumab, cetuximab and panitumamab with fluropyrmidine-based chemotherapy as first-line treatment of Kirsten rat sarcoma wild-type metastatic colorectal cancer:

Probably most cost effective: bevacizumab + fluoropyrimidine-based chemotherapy

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 meta-analysis.

Key points:

Economic analysis Kirsten rat sarcomap.G13D and codon 12 mutations in predicting outcomes with cetuximab in metastatic colorectal cancer

Relevant studies without design restriction, — October 2011. 10 studies (1,487 patients). Kirsten rat sarcomap.GG13D mutation patients appear to benefit more with cetuximab than

those with codon 12 mutations but methods limitations argue for cautious interpretation.

Zhang (2013) Treatment related severe and fatal adverse events with cetuximab in colorectal cancer patients: a meta-analysis

Key points:

Severe and fatal adverse events with cetuximab: Randomized controlled trials, 2000 – 2012. Nine trials (8,520 patients with metastatic colorectal carcinoma: severe adverse event rate

higher in cetuximab than controls but no evidence of higher fatality rate.

Behl (2012) Cost-effectiveness analysis of screening for KRAS and BRAF mutations in metastatic colorectal cancer

Key points:

Cost effectiveness of screening for Kirsten rat sarcoma and BRAF mutations in metastatic colorectal cancer

Decision analysis: screening for Kirsten rat sarcoma and BRAF in context of cetuximab treatment.

Cohort of 50,000 patients simulated 10,000 times using randomly assigned attributes from randomized controlled study distributions.

Screening for both mutations compared to base strategy of no anti-EFG therapy: increased expected overall survival by 0.034 years at cost of $22,033.

Incremental cost-effectiveness ratio = $635,000/ additional year of life. Vs. anti-EGF therapy without screening: adding Kirsten rat sarcoma 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.

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Citation Content

Vale (2012) Does anti-EGF therapy improve outcome in advanced colorectal cancer? A systematic review and meta-analysis

Key points:

Cost effectiveness of screening does anti-EGF therapy improve outcomes in advanced colorectal cancer?

10 randomized controlled trials (8,782 patients). Clear benefits for Kirsten rat sarcoma wild-type patients with advanced disease. No benefit for Kirsten rat sarcoma mutation patients.

Chen (2013) Incidence and risk of hypomagnesemia in advanced cancer patients treated with cetuximab: a meta-analysis.

Key points:

Systematic review of ten randomized controlled trials inclusive of 7,045 patients studied hypomagnesaemia with cetuximab:

Cetuximabsignificantly increased risk of grade ¾ hypomagnesaemia RR, 8.60 (CI, 5.08 – 14.54).

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 meta-analysis

Key points:

Four randomized controlled trials (1,270 patients) evaluated survival benefit from adding cetuximab or panitumumab to oxali-platin-based chemotherapy in first-line treatment of Kirsten rat sarcoma wild-type metastatic colorectal cancer

Addition of monoclonal antibodies did not improve survival or response rate.

Petrelli (2012) Risk of venous and arterial thromboembolic events associated with anti-EGFR agents: a meta-analysis of randomized clinical trials

Key points:

Phase II and III trials, no date restrictions. Anti-EGFs associated with significant risk of vascular events.

NICE (2011) The diagnosis and management of colorectal cancer

Key points:

Diagnosis and management of colorectal cancer 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?

Key points:

Posed question “Can UGT1A1 genotyping reduce morbidity and mortality in patients with metastatic colorectal cancer treated with irinotecan?”

Found insufficient evidence to draw conclusion.

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Citation Content

National Institute for Health and Care Excellence (2009) Cetuximab for the first-line treatment of metastatic colorectal cancer

Key points:

Trial studied cetuximab as first-line treatment for Kirsten rat sarcoma 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 metastatic colorectal cancer 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.

American Society of Clinical Oncology (2009) Testing for KRAS gene mutations in patients with metastatic colorectal carcinoma to predict response to anti-epidermal growth factor receptor monoclonal antibody therapy

Key points:

Recommended that patients with metastatic colorectal carcinoma who were candidates for anti-epidermal growth factor receptor therapy have their tumors tested for Kirsten rat sarcoma 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.

References

Professional society guidelines/others:

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):2091-2096. Doi: 10.1200/JCO.2009.21.9170.

National Cancer Institute. Colorectal cancer prevention (PDQ®)-Health professional version. National

Institutes of Health. https://www.cancer.gov/types/colorectal/hp/colorectal-prevention-pdq. March 1,

2018. Accessed September 26, 2018.

National Comprehensive Cancer Network (NCCN). NCCN clinical practice guidelines in oncology (NCCN

Guidelines®). Colon cancer. NCCN evidence blocksTM. V3.NCCN website:

https://www.nccn.org/professionals/physician_gls/pdf/colon_blocks.pdf. September 18, 2018. Last

accessed September 26, 2018.

National Institute for Health and Clinical Excellence (NICE). The diagnosis and management of colorectal

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cancer. Clinical guideline; no. 131. National Institute for Health and Clinical Excellence (NICE).

https://www.nice.org.uk/guidance/cg131. 2011. Updated December, 2014. Accessed September 26,

2018.

National Institute for Health and Clinical Excellence (NICE). Cetuximab and panitumumab for previously

untreatedmetastatic colorectal cancer. London (UK): National Institute for Health and Clinical Excellence

(NICE); 2009. Technology Appraisal Guidance TA439. https://www.nice.org.uk/guidance/ta439. 2009.

Accessed September 26, 2018.

Simon S. Six ways to lower your risk for colorectal cancer. American Cancer Society.

https://www.cancer.org/latest-news/six-ways-to-lower-your-risk-for-colon-cancer.html. May 30, 2018.

Accessed September 26, 2018.

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. J Natl Cancer Inst. 2012;104(23):1785-1795. Doi:

10.1093/jnci/djs433.

Barni S, Ghilardi M, Borgonovo K, Cabiddu M, Zaniboni A, Petrelli F. Cetuximab/irinotecan-chemotherapy

in KRAS wild-type pretreated metastatic colorectal cancer: a pooled analysis and review of the literature.

Rev Recent Clin Trials. 2013: epub. Doi: 10.2174/15748871113089990042.

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. PLOS One.2013;8(7):e68945. Doi:

10.1371/journal.pone.0068945.

Chang GJ, Kaiser AM, Mills S, Rafferty JF, Buie WD. Practice parameter for the management of colon

cancer. Dis Colon Rectum. 2012;55(8):831-843. Doi: 10.1097/DCR.0b013e3182567e13.

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

Chemother Pharmacol. 2013;71(1):265-272. Doi: 10.1007/s00280-012-2005-9.

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. Oncol Lett. 2013;5 (6):1915-1920. Doi: 10.3892/ol.2013.1301.

Clancy C, Burke JP, Coffey JC. KRAS mutation does not predict the efficacy of neo-adjuvant chemo-

radiotherapy in rectal cancer: a systematic review and meta-analysis. Surg Onc. 2013;22(2):105 –111.

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Doi: 10.1016/j.suronc.2013.02.001.

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? Genet Med.

2009;11(1):15 – 20. Doi: 10.1097/GIM.0b013e31818efd9d.

Hoyle M, Crathorne L, Peters J, et al. The clinical effectiveness and cost-effectiveness of cetuximab

(mono- or combination chemotherapy), bevacizumab (combination with non-oxaliplatin chemotherapy)

and panitumumab (monotherapy) for the treatment of metastatic colorectal cancer after first-line

chemotherapy (review of technology appraisal No.150 and part review of technology appraisal No. 118):

a systematic review and economic model. Health Technol Assess. 2013;17(14):1-237.

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 Health. 2013a; 16(2):288-296. Doi: 10.1016/j.jval.2012.11.001.

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. PLOS One.2013;8(2).

Doi: 10.1371/journal.pone.0056205.

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 first-line treatment of

KRAS wild-type metastatic colorectal cancer (mCRC). J Med Econ. 2013; Oct 25. Doi:

10.3111/13696998.2013.852097.

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. Arch

Pathol Lab Med. 2013; 137(6):828-860.

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):1523-1532. Doi: 10.1002/cncr.26460.

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):714-721. Doi: 10.1002/cncr.27804.

Petrelli F, Cabiddu M, Borgonovo K, Barni S. Risk of venous and arterial thromboembolic events

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associated with anti-EGFR agents: a meta-analysis of randomized clinical trials. Ann Oncol. 2012;

23(7):1672-1679. Doi: 10.1093/annonc/mdr592.

Siddiqui AD, Piperdi B. KRAS mutation in colon cancer: a marker of resistance to EGFR-1 therapy. Ann

Surg Oncol. 2010;17(4):1168-1176. Doi: 10.1245/s10434-009-0811-z.

Tan C, Du X. KRAS mutation testing in metastatic colorectal cancer. World J Gastroenterol.

2012;18(37):5171-5180. Doi: 10.3748/wjg.v18.i37.5171.

Tosi F, Magni E, Amatu A, et al. Effect of KRAS and BRAF mutations on survival of metastatic colorectal

cancer after liver resection: a systematic review and meta-analysis. Clin Colorectal Cancer. 2017. pii:

S1533-0028(17)30031-2. Doi: 10.1016/j.clcc.2017.01.004.

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 Treat Rev. 2012;38(6):618 – 25. Doi:

10.1016/j.ctrv.2011.11.002.

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):1-132. Doi: 10.3310/hta18620.

Zhang DI, Ye J, Xu T, Xiong B. Treatment related severe and fatal adverse events with cetuximab in

colorectal cancer patients: a meta-analysis. J Chemother. 2013;25(3):170-175. Doi:

10.1179/1973947813Y.0000000070.

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. PLOS One. 2012;7(11):e50925. Doi:

10.1371/journal.pone.0050925.

Centers for Medicaid & Medicare Services National Coverage Determinations:

No National Coverage Determinations identified as of the writing of this policy.

Local Coverage Determinations :

L33434 K-ras Testing Required before Epidermal Growth Factor Receptor antibody use in colorectal

cancer.

Commonly submitted codes

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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

81235 EGRF(epidermal growth factor receptor) gene analysis, common variants

81275 Kirsten rat sarcoma 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

Description

Comment

N/A