Coverage Policy Manual
Policy #: 2008022
Category: Laboratory
Initiated: August 2008
Last Review: April 2022
  Genetic Test: Microarray-Based Gene Expression Testing for Cancers of Unknown Primary

Description:
Cancers of unknown primary (CUP) represent 3% to 4% of all cancers diagnosed in the United States. These cancers are heterogeneous and many accompanied by poor prognoses. A detailed history and physical combined with imaging and tissue pathology can identify some, but not all, primary sources of secondary tumor. It is suggested that identifying a likely primary source with gene expression profiling to direct treatment may improve health outcomes.
 
Background
 
Cancers of Unknown Primary
Cancers of unknown primary (CUP), or occult primary malignancies, are tumors that have metastasized from an unknown primary source; they make up approximately 3% of all cancer cases in the United States.
 
Most cancers of unknown primary are adenocarcinomas or undifferentiated tumors; less commonly, they may be squamous carcinomas, melanoma, soft tissue sarcoma, or neuroendocrine tumors. Osteo- and chondrosarcomas rarely produce cancers of unknown primary. The most common primary sites of cancers of unknown primary are lung and pancreas, followed by colon and stomach, then breast, ovary, prostate, and solid-organ carcinomas of the kidney, thyroid, and liver. Conventional methods used to aid in the identification of the origin of a CUP include a thorough history and physical examination; computed tomography (CT) scans of the chest, abdomen, and pelvis; routine laboratory studies; and targeted evaluation of specific signs and symptoms (Oien, 2008).
 
Cancers of unknown primary can be classified into 4 categories. Adenocarcinomas compose approximately 70% of cancers of unknown primary. Neuroendocrine tumors compose approximately 1%, squamous cell carcinomas 5% and poorly differentiated cancer 20% to 25% of cancers of unknown primary.
 
Biopsy of a CUP with detailed pathology evaluation may include immunohistochemical (IHC) analysis of the tumor. IHC identifies different antigens present on different types of tumors and can usually distinguish an epithelial tumor (i.e., carcinoma) from a melanoma or sarcoma. Detailed cytokeratin panels often allow further classification of a carcinoma; however, tumors of different origins may show overlapping cytokeratin expression. The results of IHC may provide a narrow differential of possible sources of a tumor’s origin, but not necessarily a definitive answer.
 
Treatment is based on the histologic type and clinical features. About 20% of patients with cancer of unknown primary have features that guide treatment. However, about 80% of patients with cancer of unknown primary have a poor prognosis with a survival of 3–6 months despite a variety of chemotherapeutic combinations. Multiple sites of involvement are observed in about 50% of patients, commonly in the lungs, liver, bones and lymph nodes. The premise of tissue of origin testing in cancers of unknown primary is that identifying a likely primary tumor site will inform treatment selection leading to improved survival and other outcomes.
 
Gene Expression Profiling Tests for Cancers of Unknown Primary
Selected gene expression profiling tests are described below:
 
    • The Tissue of Origin test (formerly known as PathWork and Response DX: Tissue of Origin), manufactured by Cancer Genetics, is an Oligonucleotide microarray that assesses 2000 genes and 15 tumor types.
    • The CancerTYPE ID, manufactured by Biotheranostics, is a RT-qPCR test that assesses 92 genes and 54 tumor types.
 
 
Regulatory Status
In 2008, the Pathwork® Tissue of Origin Test (Response Genetics; now Cancer Genetics, Cancer Genetics merged with StemoniX in 2020) was cleared for marketing with limitations* by the U.S Food and Drug Administration (FDA) through the 510(k) process (FDA product code: OIW), with subsequent clearances for expanded applications in 2010 and minor modifications in 2012. The FDA determined that the test was substantially equivalent to existing tests for use in measuring the degree of similarity between the RNA expression pattern in a patient's fresh-frozen tumor and the RNA expression patterns in a database of tumor samples (poorly differentiated, undifferentiated, and metastatic cases) that were diagnosed according to current clinical and pathologic practice.
 
*Limitations to the clearance were as follows:
 
    • The Pathwork® Tissue of Origin Test is not intended to establish the origin of tumors that cannot be diagnosed according to current clinical and pathologic practice, (e.g., carcinoma of unknown primary).
    • It is not intended to subclassify or modify the classification of tumors that can be diagnosed by current clinical and pathologic practice, nor to predict disease course, or survival or treatment efficacy, nor to distinguish primary from metastatic tumor.
    • Tumor types not in the Pathwork® Tissue of Origin Test database may have RNA expression patterns that are similar to RNA expression patterns in tumor types in the database, leading to indeterminate results or misclassifications.
 
Clinical laboratories may develop and validate tests in-house and market them as a laboratory service; laboratory-developed tests must meet the general regulatory standards of the Clinical Laboratory Improvement Amendments (CLIA). CancerTYPE ID® (Biotheranostics, San Diego, CA) is available under the auspices of the CLIA. Laboratories that offer laboratory-developed tests must be licensed by the CLIA for high-complexity testing. To date, the FDA has chosen not to require any regulatory review of this test.
 
Coding
Effective 3/2015, CPT published a specific CPT code for this service:
 
81540: Oncology (tumor of unknown origin), mRNA, gene expression profiling by real-time RT-PCR of 92 genes (87 content and 5 housekeeping) to classify tumor into main cancer type and subtype, utilizing formalin-fixed paraffin-embedded tissue, algorithm reported as a probability of a predicted main cancer type and subtype

Policy/
Coverage:
Effective April 2022
 
Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria
 
Genetic testing to determine the tissue type of a tumor (i.e., Tissue of Origin, Cancer TYPE ID) does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness.
 
For members with contracts without primary coverage criteria, the use of any gene assay to determine the tissue type of a tumor (i.e., Tissue of Origin, Cancer TYPE ID) is considered investigational. Investigational services are specific contract exclusions in most member benefit certificates of coverage.
 
Effective prior to April 2022
 
Genetic testing with the Pathwork Tissue of Origin or any similar gene assay, for use in determining the tissue type of a tumor, does not meet Primary Coverage Criteria that there be scientific evidence of effectiveness.
 
For individual contracts without Primary Coverage Criteria  the use of the Pathwork Tissue of Origin or any similar gene assay, for use in determining the tissue type of a tumor, is considered investigational and is not covered.  Investigational services are an exclusion in the member benefit certificate.

Rationale:
In a clinical validation study presented in abstract form (Monzon, 2007) involving 487 metastatic, poorly differentiated and undifferentiated tumors that had been identified as one of the 15 tumor types on the panel, the Pathwork test demonstrated 89% positive agreement and 99% negative agreement with the diagnosis reached by standard methods.
 
In a concordance study (Dumur, 2008), there was 94% agreement across 4 labs using the test on 60 metastatic, poorly differentiated and undifferentiated specimens.
 
However, there are no peer-reviewed clinical studies demonstrating any impact of Pathwork testing on clinical outcomes.
 
The FDA 510(k) approval document for the Pathwork® Tissue of Origin Test contains the following information:
The Pathwork® Tissue of Origin Test is intended to measure the degree of similarity between the RNA expression pattern in a patient’s fresh-frozen tumor and the RNA expression patterns in a database of tumor samples (poorly differentiated, undifferentiated and metastatic cases) that were diagnosed according to then current clinical and pathological practice. The database contains examples of RNA expression patterns for fifteen common malignant tumor types: bladder, breast, colorectal, gastric, hepatocellular, kidney, non-small cell lung, ovarian, pancreatic, prostate, and thyroid carcinomas, melanoma, testicular germ cell tumor, non-Hodgkins lymphoma (not otherwise specified), and soft tissue sarcoma (not otherwise specified). The Pathwork® Tissue of Origin Test result is intended for use in the context of the patient’s clinical history and other diagnostic tests evaluated by a qualified clinician.  
 
The Pathwork® Tissue of Origin Test is not intended to establish the origin of tumors (e.g. carcinoma of unknown primary) that cannot be diagnosed according to current clinical and pathological practice. It is not intended to subclassify or modify the classification of tumors that can be diagnosed by current clinical and pathological practice, nor to predict disease course or survival or treatment efficacy, nor to distinguish primary from metastatic tumor. Tumor types not in the Pathwork® Tissue of Origin Test database may have RNA expression patterns that are similar to patterns in the database.  Therefore, results cannot be used to distinguish tumor types in the database from tumor types not in the database.
 
2010 Update
A literature search was conducted through September 2010.  There were no new studies identified that would prompt a change in the coverage statement.  
 
Analytic Validity
Since this policy was written in December 2008, there have been no additional studies providing information on the analytic validity of the Pathwork® test.
 
Clinical Validity
Since 2008 when this policy was created, 1 large (547 samples) blinded validation study has been published. Monzon and colleagues conducted a multicenter validation study of the Pathwork® test (Monzon, 2008).  The specimens included poorly differentiated, undifferentiated, and metastatic tumors. A total of 351 frozen specimens and electronic files of microarray data on 271 specimens were obtained, with 547 meeting all inclusion criteria. A similarity score was given to the specimens, which was then compared to the original pathology report that accompanied the specimen. Overall, the Pathwork® performance comparing the profiles of the 547 specimens to the panel of 15 known tumor types showed an overall agreement of 87.8% with the reference diagnosis. Sensitivity and specificity were 87.8% and 99.4%, respectively, with the original pathology report acting as the reference standard. The authors acknowledged that since there was no independent confirmation of the original pathology, using the pathology reports as the reference standard could introduce errors into the study results. Rates of nonagreement were 7.1% and 5.1% for those called indeterminate (95% CI; 3.4–7.3%). Agreement differed by site: 94.1% for breast, 72% for both gastric and pancreatic. Performance differences between tissue sites were statistically different. Rates of agreement between test result and reference diagnosis differed by site: 88%, 84.4%, 92.3%, and 89.7% for Clinical Genomics facility, Cogenics, Mayo Clinic, and the International Genomics Consortium, respectively, but these differences were not statistically significant.
 
Clinical Utility
Monzon et al evaluated the clinical utility of the test in a retrospective study of tumor specimens from 21 patients diagnosed with cancer of unknown primary (CUP) (Monzon, 2010). Microarray scanning was performed on the 21 tumor specimens. Pathwork Diagnostics analyzed the data files and generated a report for each specimen.   The test scores were sent to a blinded study site pathologist who made a final call of positive or indeterminate using predetermined cutoff points.  The results were then compared to the clinicopathologic information for each specimen.  Positive results were found in 16 (76%) of 21 study specimens. The test was indeterminate in five cases (24%).  The study was limited by the small size and lack of gold standard for comparison.  The authors state, “Further studies evaluating the impact of gene expression-based test results on therapy choice and treatment outcome for CUP patients are warranted”.  Without knowledge of how this would affect clinical practice and health outcomes for patients diagnosed through the use of this test, the policy statement remains unchanged.
 
National Comprehensive Cancer Network Guidelines
National Comprehensive Cancer Network guidelines for the workup of an occult primary malignancy address the use of molecular methods in the classification of tumors. They conclude that gene expression profiling seems promising but that prospective clinical trials are needed to confirm if this approach can be used to choose treatment options that would improve patients’ prognosis.  This is in agreement with the current policy statement.
 
2012 Update                         
A literature review was conducted through December 2011.  There was no new information identified that would prompt a change in the coverage statement.  Two additional tests were identified (CuPrint and miReview) that identify site of origin for cancers of unknown primary.  There is a lack of scientific evidence concerning the clinical utility of these two tests.
 
2013 Update
The RTI-International-University of North Carolina at Chapel Hill conducted a technology assessment for the Agency for Health Care Research and Quality (AHRQ) (Meleth, 2013). The technology assessment reported results of a review of the literature on commercially available genetic tests used to assess tissue origin in testing cancers with unknown origin. Three genomic tests were evaluated (CancerTypeID, miRview, and PathworkDx) for analytical and clinical validity as well as clinical utility. It should be noted that most of the studies included in the assessment were funded completely or in part by the manufacturers of the tests. The assessment concluded there is insufficient evidence to assess the clinical utility of these tests. Future research is needed to evaluate the effect of these tests on treatment decisions and patient outcomes. The authors stress that future studies should be conducted by “research groups that have no evident conflict of interest (AHRQ, 2013). These conclusions further support our coverage statement.
 
A search of the clinicaltrials.gov website identified the following ongoing clinical trial:
NCT01540058- Trial Comparing a Strategy Based on Molecular Analysis to the Empiric Strategy in Patients With CUP. Phase 3 trial. Estimated study completion date is October 2016. (TOO Pathwork Test). Study sponsored by Institut Gustave Roussy and the National Cancer Institute, France.
 
2014 Update
A literature search was conducted using the MEDLINE database through August 2014. There was no new literature identified that would prompt a change in the coverage statement.
 
2016 Update
A literature search was conducted using the MEDLINE database through March 2016. There was no new literature identified that would prompt a change in the coverage statement.
 
2018 Update
Annual policy review completed with a literature search using the MEDLINE database through March 2018. No new literature was identified that would prompt a change in the coverage statement.
      
2019 Update
A literature search was conducted through March 2019.  There was no new information identified that would prompt a change in the coverage statement.  
 
2020 Update
A literature search was conducted through March 2020.  There was no new information identified that would prompt a change in the coverage statement.  
 
2021 Update
Annual policy review completed with a literature search using the MEDLINE database through March 2021. No new literature was identified that would prompt a change in the coverage statement.
 
2022 Update
Annual policy review completed with a literature search using the MEDLINE database through March 2022. No new literature was identified that would prompt a change in the coverage statement.

CPT/HCPCS:
81479Unlisted molecular pathology procedure
81504Oncology (tissue of origin), microarray gene expression profiling of > 2000 genes, utilizing formalin fixed paraffin embedded tissue, algorithm reported as tissue similarity scores
81540Oncology (tumor of unknown origin), mRNA, gene expression profiling by real time RT PCR of 92 genes (87 content and 5 housekeeping) to classify tumor into main cancer type and subtype, utilizing formalin fixed paraffin embedded tissue, algorithm reported as a probability of a predicted main cancer type and subtype

References: Bloom G, Yang IV, Boulware D et al.(2004) Multi-platform, multi-site, microarray-based human tumor classification. Am J Pathol 2004; 164(1):9-16.

Bridgewater J, van Laar R, Floore A et al.(2008) Gene expression profiling may improve diagnosis in patients with carcinoma of unknown primary. Br J Cancer 2008; 98(8):1425-30.

Dumur CI et al.(2008) Interlaboratory performance of a microarray-based gene expression test to determine tissue of origin in poorly differentiated and undifferentiated cancers. J Mol Diagn, 2008;10:67-77.

Horlings HM, van Laar RK, Kerst JM et al.(2008) Gene expression profiling to identify the histogenetic origin of metastatic adenocarcinomas of unknown primary. J Clin Oncol 2008; 26(27):4435-41.

http://www.fda.gov/cdrh/reviews/K080896.pdf; accessed 9/4/08.

Ma XJ, Patel R, Wang X et al.(2006) Molecular classification of human cancers using a 92-gene real-time quantitative polymerase chain reaction assay. Arch Pathol Lab Med 2006; 130(4):465-73.

Monzon FA, Lyons-Weiler M, Buturovic LJ et al.(2009) Multicenter validation of a 1,550-gene expression profile for identification of tumor tissue origin. J Clin Oncol 2009; 27(15):2503-08.

Monzon FA, Lyons-Weiler M, Buturovic LJ, et al.(2007) Validation of a gene expression-based tissue of origin test applied to poorly differentiated and undifferentiated cancers. Assoc Molecular Pathol Annual Meeting, 2007; Abstract #ST02.

Monzon FA, Medeiros F, Lyons-Weiler M et al.(2010) Identification of tissue of origin in carcinoma of unknown primary with a mircroarray-based gene expression test. Diagnostic Pathology 2010;5(3).

Nass D., Rosenwald s., Meiri e., et al.(2008) MiR-92b and miR-9/9*are specifically expressed in brain primary tumors and can be used to differentiate primary from metastatic brain tumors. Brain Pathol. Published online July 8 2008.

National Cancer Institute.(2011) U.S. National Institutes of Health. Physician data query (PDQ). Carcinoma of unknown primary (PDQ®): treatment [2011 Update]. 2011. Available online at: http://www.cancer.gov/cancertopics/pdq/treatment/unknownprimary/healthprofessional. Last accessed October 2011.

National Comprehensive Cancer Network.(2010) Clinical Practice Guidelines in Oncology. Occult Primary. Version 1.2010. Available online at http://www.nccn.org/professionals/physician_gls/PDF/occult.pdf . Last accessed November 2009.

Oien KA, Evans TR.(2008) Raising the profile of cancer of unknown primary. J Clin Oncol 2008; 26(27):4373-5.

Raman G., Wallace B., Patel K., et al.(2011) Update on horizon scans of genetic tests currently available for clinical use in cancers. AHRQ Technology Assessment Program. April 15, 2011.

Ramaswamy S, Tamayo P, Rifkin R et al.(2001) Multiclass cancer diagnosis using tumor gene expression signatures. Proc Natl Acad Sci USA 2001; 98(26):15149-54.

Rosenfeld N., Aharonov R., Meiri E., et al.(2008) MicroRNAs accurately identify cancer tissue origin. Nat Biotechnol. 2008 Apr;26(4):462-9.

Su AI, Welsh JB, Sapinoso LM et al.(2001) Molecular classification of human carcinomas by use of gene expression signatures. Cancer Res 2001; 61(20):7388-93.

Talantov D, Baden J, Jatkoe T et al.(2006) A quantitative reverse transcriptase-polymerase chain reaction assay to identify metastatic carcinoma tissue of origin. J Mol Diagn 2006; 8(3):320-9.

Technology assessment on genetic testing or molecular pathology testing of cancers with unknown primary site to determine origin. AHRQ Technology Assessment Report. Project ID: CANU5011. Technology Assessments. February 20, 2013. Agency for Healthcare Research and Quality (AHRQ), Rockville, MD. http://www.ahrq.gov/research/findings/ta/index.html.

Tothill RW, Kowalczyk A, Rischin D et al.(2005) An expression-based site of origin diagnostic method designed for clinical application to cancer of unknown origin. Cancer Res 2005; 65(10):4031-40.


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