Molecular Genomic Profiling for Cancers of Unknown Primary

POLICY NUMBER

A.2.04.54

DESCRIPTION

Cancers of unknown primary represent 3% to 4% of cancers diagnosed in the United States. These cancers are heterogeneous and many accompanied by poor prognoses. A detailed history and physicalcombined with imaging and tissue pathology can identify some, but not all, primary sources of secondary tumors. It is suggested that identifying the likely primary source with gene expressionprofilingto direct treatment may improve health outcomes.

Cancers of Unknown Primary

Cancers of unknown primary, or occult primary malignancies, are tumors that have metastasized from an unknown primary source; they make up about 3% of all cancers 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 cancer of unknown primary include a thorough history and physical examination, computed tomography scans of the chest, abdomen, and pelvis; routine laboratory studies and targeted evaluation of specific signs and symptoms.

Diagnosis and Classification

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 cancer of unknown primary with detailed pathology evaluation may include immunohistochemical analysis of the tumor. Immunohistochemical analysis identifies different antigens present in different types of tumors and can usually distinguish an epithelial tumor (i.e., carcinoma) from melanoma or sarcoma. Detailed cytokeratin panels often allow further classification of carcinoma; however, tumors of different origins may show overlapping cytokeratin expression. The results of immunohistochemical analysis may provide a narrow differential of possible sources of a tumor’s origin, but not necessarily a definitive answer.

Treatment Selection and Health Outcomes

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 to 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.

Molecular Genomic Profiling

Recent advances in molecular genomic profiling techniques, gene expression profiling (GEP) and comprehensive genomic profiling (CGP), have the potential to offer new therapy options to individuals with cancer of unknown primary (CUP). GEP is the measurement of gene expression levels within a cell at a given timepoint, to create a global picture of cellular function, and has been used to identify the tissue of origin in individuals with CUP. The basis of these tests rest on the assumption that metastatic tumors will have similar genomic markers or a profile as the primary tumor and can help guide treatment management. Assays used in GEP utilize messenger RNA (mRNA)-, DNA-, or microRNA (miRNA)-based platforms, which analyze anywhere between 10 and 2000 genes simultaneously and can distinguish between 6 and 50 different cancer types. CGP refers to high throughput sequencing of the genome or select regions to determine the nucleotide sequence within DNA or RNA. More specifically, CGP refers to next-generation sequencing (NGS) approaches that utilize a single assay to sequence thousands of genes for genomic alterations that are associated with FDA-approved therapies. Assays used in CGP are NGS based platforms that are capable of sequencing millions of base pairs and can detect single-nucleotide polymorphisms, relocations, fusions, and copy number variants with impeccable precision.

Tests Reviewed in This Policy

Selected gene expression profiling tests are described in the table below.

Gene Expression Profiling Tests for Cancers of Unknown Primary

RT-qPCR: real-time quantitative polymerase chain reaction.ªFormerly PathWork and ResponseDX: Tissue of Origin

In 2008, the PathWork® Tissue of Origin Test™ (Response Genetics was acquired by Cancer Genetics, Cancer Genetics merged with StemoniX in 2020 and was renamed Vyant Bio, Inc. in 2021) was cleared for marketing with limitations* by the U.S Food and Drug Administration (FDA) through the 510(k) process, 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 histopathologic 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., a cancer 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 or to predict disease course, or survival or treatment efficacy, or to distinguish primary from metastatic tumor.

• Tumor types not in the PathWork® Tissue of Origin Test database may have RNA expression patterns 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 (LDTs) 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 LDTs must be licensed by the CLIA for high-complexity testing. To date, the U.S. Food and Drug Administration has chosen not to require any regulatory review of this test.

POLICY

Gene expression and/or comprehensive genomic profiling is considered investigational to evaluate the site of origin of a tumor of unknown primary, to distinguish a primary from a metastatic tumor, or to guide treatment selection.

POLICY EXCEPTIONS

Federal Employee Program (FEP) may dictate that all FDA-approved devices, drugs or biologics may not be considered investigational and thus these devices may be assessed only on the basis of their medical necessity.

POLICY GUIDELINES

The coverage guidelines outlined in the Medical Policy Manual should not be used in lieu of the Member's specific benefit plan language.

Investigative is defined as the use of any treatment procedure, facility, equipment, drug, device, or supply not yet recognized as a generally accepted standard of good medical practice for the treatment of the condition being treated and; therefore, is not considered medically necessary. For the definition of Investigative, “generally accepted standards of medical practice” means standards that are based on credible scientific evidence published in peer-reviewed medical literature generally recognized by the relevant medical community, and physician specialty society recommendations, and the views of medical practitioners practicing in relevant clinical areas and any other relevant factors. In order for equipment, devices, drugs or supplies [i.e, technologies], to be considered not investigative, the technology must have final approval from the appropriate governmental bodies, and scientific evidence must permit conclusions concerning the effect of the technology on health outcomes, and the technology must improve the net health outcome, and the technology must be as beneficial as any established alternative and the improvement must be attainable outside the testing/investigational setting. 

POLICY HISTORY

3/2/2009: Policy added.

04/22/2010: Policy description and statement unchanged. FEP verbiage added to the Policy Exceptions section.

12/28/2010: Policy description and statement updated regarding the Pathwork® Tissue of Origin test and test kit-FFPE. The new test for FFPE specimens added as investigational.

01/17/2012: Policy reviewed; no changes.

01/14/2013: Added the following new 2013 CPT code to the Code Reference section: 81479.

02/20/2013: Policy description revised to add information regarding other tests commercially available besides Pathwork. The policy statement was changed to be generalizable to gene expression profiling and not specific to the Pathwork test.

02/26/2014: Policy reviewed; no changes to policy statement. Removed deleted molecular diagnostic procedure codes from the Code Reference section. Added the following new 2014 CPT code(s) to the Code Reference section: 81504.

12/31/2014: Added the following new 2015 CPT code to the Code Reference section: 81519.

01/08/2015: Policy title changed from "Microarray-based Gene Expression Testing for Cancers of Unknown Primary" to "Gene Expression-Based Assays for Cancers of Unknown Primary." Policy description updated regarding devices. Policy statement unchanged.

04/27/2015: Removed CPT code 81519 from the Code Reference section.

07/20/2015: Code Reference section updated for ICD-10.

12/31/2015: Investigative definition updated in policy guidelines. Code Reference section updated to add new 2016 CPT code 81540.

01/04/2016: Policy description updated. Policy statement unchanged.

06/06/2016: Policy number A.2.04.54 added.

03/27/2017: Policy description updated regarding tissue of origin testing. Policy statement unchanged. Policy guidelines updated regarding standard terminology for variant classification; added genetic counseling information.

04/04/2018: Policy description updated regarding the Pathwork® Tissue of Origin Test™. Policy statement unchanged. Policy Guidelines updated regarding genetic counseling.

04/04/2019: Policy description updated regarding gene expression profiling tests. Policy statement unchanged.

04/15/2020: Policy description updated regarding the prognosis of patients with cancer of unknown primary. Policy statement unchanged.

05/26/2021: Policy description updated regarding diagnosis and classification of cancers of unknown primary, treatment selection and health outcomes, and gene expression profiling tests. Policy statement unchanged. Policy Guidelines updated to remove genetics nomenclature and genetic counseling information.

05/12/2022: Policy description updated regarding gene expression profiling tests for cancers of unknown primary. Policy statement unchanged.

04/14/2023: Policy description updated regarding treatment selections and outcomes and gene expression profiling tests. Policy statement unchanged.

04/18/2024: Policy description updated regarding tests. Policy statement unchanged.

07/18/2025: Policy title changed from "Gene Expression-Based Assays for Cancers of Unknown Primary" to "Molecular Genomic Profiling for Cancers of Unknown Primary." Policy description updated regarding molecular genomic profiling. Policy statement updated to add comprehensive genomic profiling as investigational to evaluate the site of origin of a tumor of unknown primary, to distinguish a primary from a metastatic tumor, or to guide treatment selection.

SOURCE(S)

Blue Cross and Blue Shield Association policy #2.04.54

CODE REFERENCE

This may not be a comprehensive list of procedure codes applicable to this policy.

Investigational Codes

CPT copyright American Medical Association. All rights reserved. CPT is a registered trademark of the American Medical Association.