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What is the TissueCypher® Barrett’s Esophagus Assay?

 

The first diagnostic test of its kind that predicts the risk of developing high grade dysplasia or esophageal cancer in patients with Barrett’s Esophagus, and is an aid to pathologist interpretation of standard pinch biopsies from upper GI endoscopy procedures.

 

This clinical assay is the first test to combine quantitative analysis of multiple protein-based biomarkers with tissue structure information to predict risk of progression to high grade dysplasia (HGD) and esophageal adenocarcinoma (EAC) in patients with Barrett’s Esophagus. The test is intended for patients with diagnoses at the early end of the Barrett’s spectrum (non-dysplastic (ND), indefinite for dysplasia (IND) or low grade dysplasia (LGD)).

 

TissueCypher Delivers Real Predictive Power9,10,11

 

Tissue Cypher is the only assay of its kind to provide deep tissue interrogation of standard pinch biopsies from upper GI Endoscopy procedures, and deliver individualized risk prediction. It objectively quantifies multiple molecular, cellular and morphologic changes that can’t be assessed by standard histology, and assists pathologist interpretation of risk.

 

The test automatically integrates this quantitative data into an individualized risk score to help you and your patient make decisions on surveillance and treatment.

 

Delivers a simple risk score that indicates the likelihood that a patient will progress to high grade dysplasia or EAC

 

Quantifies key expression features of 9 unique biomarkers including immune system biomarkers, and tissue morphology

 

Background on Barrett’s Esophagus and Esophageal Cancer

 

  • Esophageal cancer is one of the fastest growing cancers (by incidence) in the world. The incidence of this once rare cancer has increased by more than 500% since the 1970s1. Esophageal cancer remains highly lethal, with a 5-year survival rate of 18%2. This dramatic increase in esophageal cancer incidence closely tracks with increases in obesity and chronic gastrointestinal reflux (GERD) in western countries, and these are major risk factors for the development of esophageal cancer.
  • Chronic reflux in the esophagus causes changes to the molecular and cellular features of the esophagus, which often results in a condition called Barrett’s Esophagus. Barrett’s is a serious complication of GERD, and a risk factor for the development of esophageal cancer. Today, gastroenterologists cannot adequately determine which patients with Barrett’s Esophagus will progress to esophageal cancer. As a result, patients with Barrett’s must undergo regular surveillance endoscopies to check the status of the condition. New diagnostic and prognostic tests are needed to provide actionable information to physicians and patients managing Barrett’s Esophagus.
  • Histopathology Alone Can’t Predict Whether BE Will Progress to EAC.1-4,15
  • Until now, there has been no adequate way to determine the risk level of patients with Barrett’s Esophagus. There is no single biomarker that can sufficiently diagnose the grade of dysplasia or predict malignant progression since multiple pathways play a role in disease progression. As a result, many high-risk patients do not receive the intervention they need,11 while low-risk patients have undergone unnecessary surveillance endoscopies and experienced needless anxiety about developing EAC.7

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Clinical Validation Studies

 

Cernostics has completed two multi-institutional independent clinical validation studies on the TissueCypher™ Barrett’s Esophagus Assay. The first study demonstrated that the assay can predict future risk of development of HGD or EAC (n=366 patients).9 The second study demonstrated that the assay can detect a field effect associated with existing HGD and EAC that has been missed by standard endoscopy with random sampling (n=175).10 The clinical evidence indicates:

 

  • TissueCypher™ identifies a high-risk subset of patients at 9.4x increased risk of progression to HGD or EAC within 5 years, and has stronger prognostic power than current clinical variables, including the pathologic diagnosis.9
  • The assay detects multiple molecular and cellular changes, including stromal changes, that are associated with neoplastic transformation.9
  • TissueCypher™ Assay identifies a subset of patients who have very low risk of progression within 5 years.9

 

In addition, further evidence from these studies indicates that the test identifies patients with Barrett’s Esophagus that have existing/prevalent HGD/EAC that has not been detected by standard surveillance protocols.10

 

  • The detection of existing HGD/EAC can be confounded by the random nature of endoscopic sampling, which may miss dysplastic areas, and also by inter-observer variation, particularly in a background of chronic inflammation and reactive atypia that are common in BE.14,15,16
  • TissueCypher™ Assay identifies a subset of patients who have low pathologic diagnoses of non-dysplastic (ND), indefinite for dysplasia (IND) or low grade dysplasia (LGD), but have HGD or EAC elsewhere in their esophagus that was missed by random endoscopic sampling.10
  • TissueCypher™ detection of multiple molecular and cellular abnormalities in the expanded neoplastic field may overcome the limitations of random sampling and subjective diagnoses, and has the potential to enable earlier detection of HGD and EAC in BE.10

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How it Works

 

  • TissueCypher® is an aid to pathologist interpretation of standard pinch biopsies from upper GI endoscopy procedures. TissueCypher® testing objectively quantifies multiple molecular, cellular and morphologic changes that cannot be assessed by standard histology.9,10,11

 

TissueCypherHowItWorks

 

TissueCypher Workflow and Processing

 

 

TissueCypherWorkflow

 

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Answer the Important Questions with Confidence

 

  • Which patients are at high risk for progression to HGD or EAC?
    • In an independent clinical validation study, TissueCypher® identified patients at 9.4x increased risk of progression to HGD or EAC within 5 years.9
    • It has stronger prognostic power than current clinical variables, including the pathologic diagnosis.9
    • It detects multiple molecular and cellular changes associated with neoplastic transformation.9
  • Which patients are at very low risk of progression?
    • TissueCypher® identifies patients who have a very low risk of progression within 5 years.9
    • Gives you and your patient additional information to help optimize surveillance frequency.
    • Increase confidence that surveillance and treatment decisions are tailored to each individual patient.
  • Which patients may already have HGD or EAC and don’t know it yet?10
    • Recent clinical data indicates that the deeper tissue interrogation of TissueCypher® may detect a field effect associated with prevalent HGD and EAC. This provides additional information to help you detect existing HGD and EAC that might have been missed by standard endoscopic surveillance.10
    • TissueCypher® provides additional information that may help overcome the limitations of random sampling and subjective diagnoses, potentially enabling earlier detection of HGD and EAC.10

 

TissueCypher Technology

 

Clinical Report

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Tissue Sample Requirements & Patient Inclusion Criteria

 

  • The TissueCypher Barrett’s Esophagus Assay is a multiplexed immunolabeling test that evaluates unstained tissue sections, and is compatible with standard formalin fixed, paraffin-embedded (FFPE) biopsy tissue specimens.
  • The assay requires nine (9) glass slides with serial sections taken at five (5) micron thickness from formalin-fixed, paraffin-embedded tissue blocks:
    • that have not been treated with Bouin’s reagent or methylene blue;
    • that are labeled with the patient unique identifier and the serial section number;
    • one of which is stained with hematoxylin and eosin according to ordering institution’s standard protocol;
    • the remaining eight of which are unstained;
    • that are freshly-prepared and shipped to Cernostics less than 48 hours after sectioning; and
    • all of which are shipped in cork-lined slide boxes (with a paper towel in between the slides and slide box lid, with the slide box secured with tape) for next day delivery
  • If multiple biopsies are taken from the patient, nine (9) serial sections from each biopsy location should be provided.
  • The use of eosin or other tissue penetrating stains during tissue processing is not compatible with TissueCypher.

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Billing Policy

 

  • Patient Billing Information
    • Insured Patients
      Insurance providers require Cernostics to bill patients for any applicable deductible, co‐insurance and co‐payment amounts. These amounts are determined by the patient’s insurer, not by Cernostics, and are reported to the patient by his or her insurer on an explanation of benefits (“EOB”) or similar statement.When Cernostics is not contracted with an insurance plan, we will typically bill patients for the amount designated by their plan as the patient’s responsibility, including any balance remaining on the bill if the insurer pays less than the “reasonable,” “usual and customary,” or “allowable” charge (collectively the “Allowable Charge”) for the services provided. The Allowable Charge will be determined by your insurer on the EOB. If the full Allowable Charge is paid to Cernostics by the insurer, patients will not be billed by Cernostics.
    • Uninsured Patients
      If patient is not insured Cernostics may be able to offer an uninsured rate. Please contact Cernostics directly at (412) 828-0900, for rates based on the services.
  • Payment Options and Financial Support Program
    Cernostics understands that paying for care may in some situations be burdensome for patients and result in some patients avoiding certain necessary services because they are concerned about the expense. We are committed to delivering the best patient care possible, we have established programs to ensure affordable access to our testing solutions:

    • Patient Financial Support Program
      Patients with special financial needs may be eligible for additional support to help defray some of Cernostics testing costs. Cernostics encourages patients who may not be able to pay fully for Cernostics services to contact us for an assessment of eligibility for financial support in accordance with federal guidelines.
    • Payment Plan
      Cernostics may enter into a payment plan for outstanding balances. Patient eligibility for a payment plan shall be determined on a case-by-case basis.
  • Insurance Payments Made Directly to Patients
    Please be aware that some insurers may send the insurance payment for Cernostics services directly to patients, placing the sole burden on the patient to handle payments to Cernostics. Patients that receive a check for services provided by Cernostics are responsible for forwarding this payment to Cernostics. Please write on the back of the check “Pay to Cernostics Inc.”, include a signature and mail to Cernostics at the address below:

    Cernostics, Inc., 116 Research Drive, Bethlehem, PA 18016

    All patients are encouraged to call Cernostics directly at (412) 828-0900, if they have questions or concerns about their patient statement.

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How to Order TissueCypher

 

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Resources/FAQs

 

TissueCypher™ Barrett’s Esophagus Assay Frequently Asked Questions for Physicians

What is the TissueCypher™ Barrett's Esophagus Assay?9,10,11
The TissueCypher™ Barrett's Esophagus Assay is the first test to combine protein expression with tissue structure information to predict risk of progression to high grade dysplasia (HGD) and esophageal adenocarcinoma (EAC) in patients with Barrett's Esophagus. The test is intended for patients with diagnoses at the early end of the Barrett's spectrum (non-dysplastic (ND), indefinite for dysplasia (IND) or low grade dysplasia (LGD)) where there is an opportunity to: i) identify high-risk patients and to intervene early with treatments such as RFA and EMR to prevent progression in the future, and ii) identify low-risk patients in whom surveillance intervals can be extended to minimize unnecessary use of care.
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How do I order the TissueCypher™ Barrett's Esophagus Assay?
The TissueCypher™ Barrett's Esophagus Assay is offered as a clinical lab service exclusively by Cernostics, a clinical laboratory located in Pittsburgh, PA (CLIA #39D2110302).  To order the test the physician office completes a Cernostics Test Requisition Form, and emails this to the company for processing.  The requisition form can be found at www.cernostics.com.
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How does this test work?9,10,11
The test evaluates multiple epithelial and stromal processes in Barrett's biopsies to produce an individualized risk score for progression to high grade dysplasia (HGD) or esophageal adenocarcinoma (EAC). The test employs multiplexed fluorescence labeling of 9 tissue system biomarkers, including epithelial biomarkers and biomarkers of immune cell subsets and stromal processes and also morphology, in anatomic pathology specimens. The labeled slides are scanned by whole slide digital imaging and analyzed by image analysis software to objectively quantify biomarkers in the context of tissue morphology. This is coupled to a multivariable classifier to integrate the biomarker and morphology data into a risk score that is correlated with risk of malignant progression within 5 years in Barrett's esophagus patients. The risk score will provide the physician and patient with a clear indication of the likelihood that the patient will progress to esophageal cancer.
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What is the clinical evidence that supports clinical use of the TissueCypher™ Barrett's Esophagus Assay?9,10,11
Cernostics has completed two multi-institutional independent clinical validation studies on the TissueCypher™ Barrett's Esophagus Assay. The first study demonstrated that the assay can predict future risk of development of HGD or EAC (n=366 patients). The second study demonstrated that the assay can detect a field effect associated with existing HGD and EAC that has been missed by standard endoscopy with random sampling (N=175).  The clinical evidence indicates:
  • TissueCypher™ identifies a high-risk subset of patients at 9.4x increased risk of progression to HGD or EAC within 5 years, and has stronger prognostic power than current clinical variables, including the pathologic diagnosis. 9
  • The assay detects multiple molecular and cellular changes, including stromal changes, that are associated with neoplastic transformation. 9
  • TissueCypher™ Assay identifies a subset of patients who have very low risk of progression within 5 years. 9
  • Does the TissueCypher™ Barrett's Esophagus Assay identify patients with Barrett's Esophagus that may have existing/prevalent HGD/EAC that has not been detected by standard surveillance protocols? 10
  • The detection of existing HGD/EAC can be confounded by the random nature of endoscopic sampling, which may miss dysplastic areas, and also by inter-observer variation, particularly in a background of chronic inflammation and reactive atypia that are common in BE. 10
  • TissueCypher™ Assay identifies a subset of patients who have low pathologic diagnoses of non-dysplastic (ND), indefinite for dysplasia (IND) or low grade dysplasia (LGD), but have HGD or EAC elsewhere in their esophagus that was missed by random endoscopic sampling. 10
  • TissueCypher™ detection of multiple molecular and cellular abnormalities in the expanded neoplastic field may overcome the limitations of random sampling and subjective diagnoses, and has the potential to enable earlier detection of HGD and EAC in BE. 10
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How does the TissueCypher Barrett's Esophagus Assay compare to standard histopathology?
The TissueCypher™ technology is quantitative and objective, which represents a significant improvement over standard histopathology, which is qualitative and subjective. The deep tissue interrogation provided by TissueCypher™ enables detection of multiple pathways associated with carcinogenesis, and multiple molecular and cellular changes that precede definitive morphologic changes. These changes include stromal changes such as infiltrating immune cells and angiogenesis, which play important roles in tumor development, but are not assessed by other technologies and tests in the Barrett's space.
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What kind of specimen is needed?
The assay requires preparing nine (9) glass slides with serial tissue sections taken at five (5) micron thickness from formalin-fixed, paraffin-embedded tissue blocks.  These sections cannot have been treated with Bouin's reagent or methylene blue.  The first section must be stained with hematoxylin and eosin according to a standard protocol; and the remaining eight serial sections will be unstained.  All will be shipped in a cork-lined slide box for next day delivery.
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How many biopsies can be evaluated from each patient?
Cernostics will evaluate sections from a minimum of one biopsy level from every patient, and can evaluate as many biopsy levels as are obtained during an upper GI endoscopy procedure.  Tissue sections should be provided from the biopsy level with the highest grade histopathological diagnosis at a minimum.  Cernostics will test every submitted biopsy level.  When multiple biopsy levels are submitted Cernostics will provide an individual score for each biopsy level. The patient's overall risk score will be based on the highest scoring biopsy level
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What is turnaround time for obtaining the test results?
We will return a test result to the ordering physician within fourteen business days of receiving the tissue specimens, and a complete test requisition order form.
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What information do I need to provide on the test requisition form?
The Requisition shall include the patient's name, date of birth, gender, medical record number, Specimen collection date, ordering physician's first and last name, treating physician's first and last name, initial pathology diagnosis confirming Barrett's Esophagus and stage (non-dysplastic, indefinite for dysplasia or low grade dysplasia), unique number or code assigned to the Specimen that is the subject of the Requisition.
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How do I interpret the result of the test?9,10,11
The assay provides physicians and patients with an individualized risk score from 0-10 and risk class (low, intermediate, high) to guide decision-making on surveillance frequency and therapies. The risk score is correlated with a probability of progression that is specified on the assay report. The report also includes an explanation of high risk abnormalities detected by the assay, where applicable. The information provided will be adjunctive to the ordering physicians' normal workup for patients with Barrett's esophagus. The 3-tier classifier identifies patients at very low risk of progressing to HGD/EAC within 5 years. This finding indicates that the frequency of endoscopic surveillance in this patient group can potentially be extended to 5 years. The classifier also identifies patients at very high risk of progression. Current clinical guidelines recommend endoscopic ablative therapy for confirmed HGD and there is growing evidence to support ablative therapy for confirmed LGD . The patients identified as high-risk by the classifier include patients with LGD, IND and ND confirmed by an expert GI pathologist. The independent validation of this risk prediction approach provides support to extend ablative therapy to BE patients with IND and ND by objectively identifying tissue changes indicative of future progression.
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Does insurance cover this test?
Cernostics bills according to Common Procedural Terminology (CPT) Codes approved by the American Medical Association.  These codes are paid by all payers in the United States, including the Center for Medicaid and Medicare Services, and private insurance carriers.  Specific insurance coverage will depend on the patient's individual plan.  Insurance providers require Cernostics to bill patients for any applicable deductible, co-insurance and co-payment amounts.  These amounts are determined by health insurance providers, not by Cernostics, and are reported to your patient by the insurance carrier on an explanation of benefits ("EOB") or similar statement.
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How much money will my patient be charged for this test?
Patient charges will depend on the patient's specific insurance plan and coverage.  For example, some diagnostic tests may be subject to deductible amounts, co-payments, or co-insurance.
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References

 

  1. Pohl H and Welch HG. J Natl Cancer Inst 2005; 95:142-146; Brown et al., J Natl Cancer Inst. 2008;100:1184–1187.
  2. Cancer Facts & Figures 2014 American Cancer Society 2014
  3. Reid, B. J., Haggitt, R. C., Rubin, C. E., Roth, G., Surawicz, C. M., Van Belle, G., et al. Observer variation in the diagnosis of dysplasia in Barrett's esophagus. Hum Pathol, 19: 166-78, 1988.
  4. Montgomery, E., Bronner, M. P., Goldblum, J. R., Greenson, J. K., Haber, M. M., Hart, J., et al. Reproducibility of the diagnosis of dysplasia in Barrett esophagus: a reaffirmation. Hum Pathol, 32: 368-78, 2001.
  5. Odze, R. D. Diagnosis and grading of dysplasia in Barrett's oesophagus. J Clin Pathol, 59: 1029-38, 2006.
  6. Goldblum, J. R. Controversies in the diagnosis of Barrett esophagus and Barrett-related dysplasia: one pathologist's perspective. Arch Pathol Lab Med, 134: 1479-84, 2010.
  7. Sangle, NA, et al. Overdiagnosis of High-grade Dysplasia in Barrett's Esophagus: A Multicenter, International Study, Mod Path, 28, 758-765, 2015
  8. Visrodia, K, et al. Magnitude of Missed Esophageal Adenocarcinoma After Barrett's Esophagus Diagnosis: A Systemic Review and Meta-analysis. Gastroenterology, 150: 599-607, 2016
  9. Critchley-Thorne, RJ, et al. Development of a Tissue Systems Pathology Test That Predicts Progression of Barrett's Esophagus. Cancer Epidemiol Biomarkers Prev. 2016 OnlineFirst.
  10. Critchley-Thorne, RJ, et al. A Tissue Systems Pathology Test Detects Molecular and Cellular Abnormalities Associated with Prevalent High Grade Dysplasia and Esophageal Cancer in Barrett's Esophagus Patients. Manuscript submitted for review.
  11. Prichard, JW, et al. TissueCypher: A Systems Biology Approach to Anatomic Pathology. J Pathol Inform, 2015, 6:1, p48
  12. Data from health economics modeling study of 20,000 hypothetical BE patients conducted with Geisinger Health System. Submitted and accepted for presentation at the International Society for Pharmacoeconomic & Outcomes Research Meeting, Washington DC, May 2016
  13. Shaheen NJ, Weinberg DS, Denberg TD, Chou R, Qaseem A, Shekelle P. Upper endoscopy for gastroesophageal reflux disease: best practice advice from the clinical guidelines committee of the American College of Physicians. Ann Intern Med;157(11):808-16.
  14. Abrams JA, Kapel RC, Lindberg GM, et al. Adherence to biopsy guidelines for Barrett's esophagus surveillance in the community setting in the United States. Clin Gastroenterol Hepatol 2009;7:736-42; quiz 710.
  15. Kerkhof M, van Dekken H, Steyerberg EW, et al. Grading of dysplasia in Barrett's oesophagus: substantial interobserver variation between general and gastrointestinal pathologists. Histopathology 2007;50:920-7.
  16. SchöLvinck D, Van Der Meulen K, Bergman JJ, et al. Detection of Lesions in Dysplastic Barrett's Esophagus: Are Expert Endoscopists Doing a Better Job Than Community Endoscopists? Gastrointestinal Endoscopy 2015;81:AB139.
  17. Phoa, KN, et.al., Radiofrequency Ablation vs. Endoscopic Surveillance for Patients with Barrett's Esophagus and Low Grade Dysplasia, JAMA 2014, 311 (12), 1209-1217.

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