Medical Policy: 02.04.52 

Original Effective Date: July 2015 

Reviewed: June 2021 

Revised: June 2021 

 

Notice:

This policy contains information which is clinical in nature. The policy is not medical advice. The information in this policy is used by Wellmark to make determinations whether medical treatment is covered under the terms of a Wellmark member's health benefit plan. Physicians and other health care providers are responsible for medical advice and treatment. If you have specific health care needs, you should consult an appropriate health care professional. If you would like to request an accessible version of this document, please contact customer service at 800-524-9242.

 

Benefit Application:

Benefit determinations are based on the applicable contract language in effect at the time the services were rendered. Exclusions, limitations or exceptions may apply. Benefits may vary based on contract, and individual member benefits must be verified. Wellmark determines medical necessity only if the benefit exists and no contract exclusions are applicable. This medical policy may not apply to FEP. Benefits are determined by the Federal Employee Program.

 

This Medical Policy 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 will be reviewed regularly and be updated as scientific and medical literature becomes available.

 

Description:

Topographic genotyping is referred to as integrated molecular pathology, is a type of quantitative genetic mutational analysis. Interspace Diagnostics has created two topographic tests, PancraGEN and BarreGEN which combines genetic testing with pathology services, such as sample preparation, genetic testing and interpretation of the results by a pathologist. These tests are proposed as adjunctive tools when a definitive pathologic diagnosis or prognosis is inconclusive.  

 

The PathFinderTG is a patented topographic genotyping test platform that combines anatomic pathology with quantitative genetic mutational analysis. Interpace Diagnostics acquired RedPath Integrated Pathology and has since cultivated and developed the PancraGEN and BarreGEN molecular pathology panels on the PathFinderTG platform.

 

PancraGEN

PancraGEN is a proprietary integrated molecular pathology test that assesses the cumulative DNA mutations in key oncogenes and tumor suppressor genes associated with pancreatic cancer. PancraGEN can help assess risk of malignancy in patients with pancreatic cysts and enhance diagnostic tools such as EUS imaging, CEA, cytology and other risk factors by providing more information for use in management decisions for surveillance versus surgical intervention.

Specimen type utilized is aspirated pancreatic cyst fluid and PancraGEN identifies the following:

 

  • Oncogene Mutations
    • KRAS and GNAS; and
  • The following tumor suppressor gene mutations:

 

VHL, OGG1 3p
PTEN, MXI1 10q
TP53 17p
SMAD4, DCC 18q
CDKN2A 9p
RNF43, NME1 17q
PSEN2, TFF1 21q
CMM1, LMYC 1p
MCC, APC 5q
NF2 22q

 

The PancraGEN molecular panel using PathFinderTG also provides risk stratification of patient’s pancreaticobiliary sample by integrating clinical features and the following test components:

  • Oncogene point mutations (KRAS and GNAS)
  • Tumor suppressor gene mutations (loss of heterozygosity through fragment analysis)

 

The PacraGEN report categorizes patients into four group according to their risk (benign, statistically indolent, statistically higher- risk or aggressive) and provides either the probability of benign disease over 3 years or the probability of high-grade dysplasia/carcinoma.

 

Low Risk Supports Surveillance

  • Benign: 97% probability of benign disease over the next 3 years. Patient lacks significant molecular alterations.
  • Statistically Indolent (SI): 97% probability of benign disease over the next 3 years. Patient has significant molecular alteration but lacks concerning clinical features.

 

High-Risk Supports Intervention

  • Statistically Higher Risk (SHR): 65% probability of HDG/carcinoma. Patient has significant molecular alteration accompanied by concerning clinical features.
  • Aggressive: 91% probability of HGD/carcinoma. Patients has multiple significant DNA abnormalities.

 

BarreGEN

BarreGEN (esophageal cancer risk classifier) is a molecular based assay that helps resolve the risk of progression of Barrett’s Esophagus (BE) to esophageal cancer.

 

Barrett’s esophagus (BE) is a precancerous condition typically caused by gastroesophageal reflux disease (GERD) and is a major risk for esophageal cancer. Other risks for Barrett’s esophagus (BE) include age, male sex, white race, obesity, tobacco use, and family history of GERD, BE or esophageal cancer. While individuals with BE are at higher risk of esophageal cancer, progression to cancer is uncommon. Roughly, only 0.5% people with BE develop cancer each year. While uncommon there is a potential for the progression of cellular changes that can lead to esophageal cancer. BarreGEN is utilized to help identify Barrett’s esophagus (BE) patients at higher risk of esophageal cancer.

 

Triaging patients according to their risk of future progression to esophageal cancer would help to limit unnecessary repeat endoscopies in patients with low risk and justify more aggressive management in patients with higher risk, perhaps even supporting early means of cancer prevention such as ablation. However, differentiating the presence and stage of dysplasia remains a challenge for pathologists, resulting in high inter-observer variability in diagnosing the level of dysplasia and the associated risk of esophageal cancer.

 

BarreGEN is a molecular based assay conducted using tissue biopsy sample that quantifies the mutational load (ML) in esophageal specimens obtained from patients with BE. ML provides a measure of cumulative genomic instability (DNA damage). In looking at key genomic loci 1p (CMM1, L-myc), 3p (VHL, HoGG1), 5q (MCC, APC), 9p (CDKN2A), 10q (PTEN, MXI1), 17p (TP53), 17q (RNF43, NME1), 18q (SMAD4, DCC), 21q (TFF1, PSEN2) and 22q (NF2) in patients with BE and assessing DNA damage in tumor suppressor genes associated with progression to HGD and esophageal cancer, the risk of more advanced disease can be determined. The use of BarreGEN purports this testing assists the physicians understanding if dysplasia is present or if there is a risk for developing dysplasia or cancer in the future, which assists in treatment management decisions for cancer preventative treatments such as ablation or provide justification for when such treatments may not be necessary.

 

Currently, there is insufficient evidence in the published, peer-reviewed, scientific literature to demonstrate that topographic genotyping using PancraGEN or BarreGEN is an effective method to aid in the diagnosis or management of individuals with pancreatic cysts or Barrett’s esophagus (BE) when other testing methods, such as endoscopic ultrasound and microscopic analysis and staining, fail or are inconclusive. There is a lack of peer-reviewed evidence demonstrating that the use of topographic genotyping in the diagnosis and management of individuals with pancreatic cysts or Barrett’s esophagus (BE) results in improved clinical outcomes. The evidence is insufficient to determine the effects of this technology on net health outcomes.

 

Practice Guidelines and Position Statements

National Comprehensive Cancer Network (NCCN)

Genetic/Familial High-Risk Assessment: Breast, Ovarian and Pancreatic Version 2.2021

This current NCCN guideline does not include any information regarding the use of topographic genotyping (PancraGEN).

 

Esophageal and Esophagogastric Junction Cancers Version 2.2021 

This current NCCN guideline does not include any information regarding the use of topographic genotyping (BarreGEN).

 

The American Gastroenterological Association

The American Gastroenterological Association guidelines have no recommendations for the use of topographic genotyping for evaluating pancreatic cysts.

 

The American Society of Gastrointestinal Endoscopy

The American Society of Gastrointestinal Endoscopy guideline (2016) states Molecular analysis (which requires only 200 mL of fluid) may be most useful in small cysts with nondiagnostic cytology, equivocal cyst fluid CEA results, or when insufficient fluid is present for CEA testing. However, additional research is needed to determine the precise role molecular analysis of cyst fluid will play in evaluating pancreatic cystic lesions.

 

American College of Gastroenterology

The College (2018) published guidelines on the diagnosis and management of pancreatic cysts. The guidelines stated that the evidence for the use of molecular biomarkers for identifying high-grade dysplasia or pancreatic cancer is insufficient to recommend their routine use. However, molecular markers may help identify intraductal papillary mucinous neoplasms and mucinous cystic neoplasms in cases with an unclear diagnosis and if results are likely to change the management (conditional recommendation; very low quality evidence).

Regulatory Status

Topographic genotyping are laboratory-developed tests under the Clinical Laboratory Improvement Amendments (CLIA) and do not require approval by the U.S. Food and Drug Administration for clinical use.

 

Prior Approval:

Not applicable

 

Policy:

See Related Medical Policy

02.01.23 Treatment of GERD and Barrett’s Esophagus 

 

Topographic genotyping using the PathfinderTG system is considered investigational for all indications including, but not limited to the following, because the evidence is insufficient to determine the effects of this technology on net health outcomes:

  • PancraGEN
  • BarreGEN

 

Procedure Codes and Billing Guidelines:

To report provider services, use appropriate CPT* codes, Alpha Numeric (HCPCS level 2) codes, Revenue codes, and/or diagnosis codes.

  • 84999 Unlisted chemistry procedure
  • 89240 Unlisted miscellaneous pathology test
  • 81599 Unlisted multianalyte assay with algorithmic analysis
  • 81479 Unlisted molecular pathology procedure

 

Selected References:

  • Nikiforova MN, et al. Molecular diagnostics of gliomas. Arch Pathol Lab Med 2011 Jul;135(7):558-68.
  • Sawhney MS, et al. Comparison of carcinoembryonic antigen and molecular analysis in pancreatic cyst fluid. Gastrointest Endosc 2009;69:1106-10.
  • Shen J, et al. Molecular analysis of pancreatic cyst fluid. Cancer Cytopathol 2009;117:217-227.
  • Sreenarasimhaiah J, et al. A comparative analysis of pancreas cyst fluid CEA and histology with DNA mutational analysis in the detection of mucin producing or malignant cysts. JOP 2009;10(2):163-8.
  • Trikalinos TA, et al. A systematic review of loss-of-heterozygosity based topographic genotyping with PathfinderTG®. AHRQ Technology Assessment Program (Project ID GEND0308). 2010 Mar 1
  • Tse DT, et al. Microdissection genotyping analysis of the effect of intraarterial cytoreductive chemotherapy in the treatment of lacrimal gland adenoid cystic carcinoma. Am J Ophthalmol 2006 Jan;141(1):54-61.
  • National Comprehensive Cancer Network. NCCN clinical practice guidelines in oncology: pancreatic adenocarcinoma, version 1.2020.
  • RedPath Integrated Pathology Overview & copy;2013.
  • Centers for Medicare and Medicaid Services, CMS Manual System and other CMS publications and services
  • Oh HC, Kim MH, Hwang CY, et al. Cystic lesions of the pancreas: challenging issues in clinical practice. Am J Gastroenterol. 2008;103(1):229-239.
  • Khalid A, Brugge W. ACG practice guidelines for the diagnosis and management of neoplastic pancreatic cysts. Am J Gastroenterol. 2007;102(10):2339-2349.
  • National Comprehensive Cancer Network. NCCN clinical practice guidelines in oncology: central nervous system cancers, version 2.2021.
  • Loren D, Kowalski T, Siddiqui A, et al. Influence of integrated molecular pathology test results on real-world management decisions for patients with pancreatic cysts: analysis of data from a national registry cohort. Diagnostic Pathology. 2016;11:5.
  • Muthusamy, V. Chandrasekhara, V. Acosta, R. et. al The role of endoscopy in the diagnosis and treatment of cystic pancreatic neoplasms, ASGE Standards of practice committee,  Gastrointest Endosc 2016;84:1-9 
  • Singhi AD, Zeh HJ, Brand RE, et al. American Gastroenterological Association guidelines are inaccurate in detecting pancreatic cysts with advanced neoplasia: a clinicopathologic study of 225 patients with supporting molecular data. Gastrointest Endosc. 2016; 83(6):1107-1111.
  • National Comprehensive Cancer Network (NCCN). NCCN clinical practice guidelines in oncology: esophageal and esophagogastric junction cancers. Version 2.2020.
  • Kowalski T, Siddiqui A, Loren D, et al. Management of patients with pancreatic cysts: analysis of possible false negative cases of malignancy. J Clin Gastroenterol. Sep 2016;50(8):649-657. PMID 27332745
  • Tamura K, Ohtsuka T, Date K, et al. Distinction of invasive carcinoma derived from intraductal papillary mucinous neoplasms from concomitant ductal adenocarcinoma of the pancreas using molecular biomarkers. Pancreas. Jul 2016;45(6):826-835. PMID 26646266
  • National Comprehensive Cancer Network (NCCN). NCCN clinical practice guidelines in oncology: hepatobiliary cancers. Version 3.2020
  • Kushnir VM, Mullady DK, Das K, et al. The diagnostic yield of malignancy comparing cytology, fish, and molecular analysis of cell free cytology brush supernatant in patients with biliary strictures undergoing endoscopic retrograde cholangiography (ERC): a prospective study. J Clin Gastroenterol. Aug 13 2018. PMID 30106834
  • Gonda TA, Viterbo D, Gausman V, et al. Mutation profile and fluorescence in situ hybridization analyses increase detection of malignancies in biliary strictures. Clin Gastroenterol Hepatol. Jun 2017;15(6):913-919 e911. PMID 28017843
  • ACG Clinical Guideline: Diagnosis and Management of Pancreatic Cysts. American Journal of Gastroenterology. 113(4):464–479, APR 2018 DOI: 10.1038/ajg.2018.14. 
  • Tanaka, M., Fernandez-Del Castillo, C., Kamisawa, T., Jang, J. Y., Levy, P., Ohtsuka, T., . . . Wolfgang, C. L. (2017). Revisions of international consensus Fukuoka guidelines for the management of IPMN of the pancreas. Pancreatology, 17(5), 738-753
  • National Comprehensive Cancer Network (NCCN) Genetic/Familial High-Risk Assessment: Breast, Ovarian and Pancreatic Version 2.2021.

 

Policy History:

  • June 2021 - Annual Review, Policy Revised
  • June 2020 - Annual Review, Policy Revised
  • June 2019 - Annual Review, Policy Revised
  • June 2018 - Annual Review, Policy Revised
  • June 2017 - Annual Review, Policy Revised
  • June 2016 - Annual Review, Policy Revised
  • July 2015 - New Policy

Wellmark medical policies address the complex issue of technology assessment of new and emerging treatments, devices, drugs, etc.   They are developed to assist in administering plan benefits and constitute neither offers of coverage nor medical advice. Wellmark medical policies contain only a partial, general description of plan or program benefits and do not constitute a contract. Wellmark does not provide health care services and, therefore, cannot guarantee any results or outcomes. Participating providers are independent contractors in private practice and are neither employees nor agents of Wellmark or its affiliates. Treating providers are solely responsible for medical advice and treatment of members. Our medical policies may be updated and therefore are subject to change without notice.

 

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