Proteogenomic Testing for Patients with Cancer Form

500 EXCHANGE STREET, PROVIDENCE, RI 02903-2699 MEDICAL COVERAGE POLICY | 1 (401) 274-4848 WWW.BCBSRI.COM EFFECTIVE DATE: 01|01|2024 POLICY LAST REVIEWED: 08|20|2025 OVERVIEW Proteogenomics refers to the integration of genomic information with proteomic and transcriptomic information to provide a more complete picture of genome function. The current focus of proteogenomics is primarily on the diagnostic, prognostic, and predictive potential of proteogenomics in various cancers. One commercial proteogenomic test is available, the GPS CancerTM test. MEDICAL CRITERIA Medicare Advantage Plans and Commercial Products Not applicable PRIOR AUTHORIZATION
Medicare Advantage Plans and Commercial Products There is no specific CPT code for this service and an Unlisted CPT code should be used (See Coding Section for details). All Unlisted genetic testing CPT codes require prior authorization to determine what service is being rendered and if the service is covered or not medically necessary. See the Related Policies section.
Prior authorization is required for Medicare Advantage Plans and recommended for Commercial Products and is obtained via the online tool for participating providers. See the Related Policies section. POLICY STATEMENT Medicare Advantage Plans Proteogenomic testing of patients with cancer (including, but not limited to the GPS Cancer test) is not covered for all indications as the evidence is insufficient to determine that the technology results in an improvement in the net health outcome. Commercial Products Proteogenomic testing of patients with cancer (including, but not limited to the GPS Cancer test) is considered not medically necessary for all indications as the evidence is insufficient to determine that the technology results in an improvement in the net health outcome. Some genetic testing services are not covered and a contract exclusion for any self-funded group that has excluded the expanded coverage of biomarker testing related to the state mandate, R.I.G.L. §27-19- 81 described in the Biomarker Testing Mandate policy. For these groups, a list of which genetic testing services are covered with prior authorization, are not medically necessary or are not covered because they are a contract exclusion can be found in the Coding section of the Genetic Testing Services or Proprietary Laboratory Analyses policies. Please refer to the appropriate Benefit Booklet to determine whether the member’s plan has customized benefit coverage. Please refer to the list of Related Policies for more information. Note: Laboratories are not allowed to obtain clinical authorization or participate in the authorization process on behalf of the ordering physician. Only the ordering physician shall be involved in the authorization, appeal or other administrative processes related to prior authorization/medical necessity.
In no circumstance shall a laboratory or a physician/provider use a representative of a laboratory or anyone with a relationship to a laboratory and/or a third party to obtain authorization on behalf of the ordering physician, to facilitate any portion of the authorization process or any subsequent appeal of a claim where the Medical Coverage Policy | Proteogenomic Testing for Patients with Cancer

500 EXCHANGE STREET, PROVIDENCE, RI 02903-2699 MEDICAL COVERAGE POLICY | 2 (401) 274-4848 WWW.BCBSRI.COM

authorization process was not followed and/or a denial for clinical appropriateness was issued, including any element of the preparation of necessary documentation of clinical appropriateness. If a laboratory or a third party is found to be supporting any portion of the authorization process, BCBSRI will deem the action a violation of this policy and severe action will be taken up to and including termination from the BCBSRI provider network. If a laboratory provides a laboratory service that has not been authorized, the service will be denied as the financial liability of the participating laboratory and may not be billed to the member.

COVERAGE Benefits may vary between groups and contracts. Please refer to the appropriate Benefit Booklet, Evidence of Coverage or Subscriber Agreement for applicable not medically necessary/not covered benefits/coverage.

BACKGROUND Proteogenomics The term proteome refers to the entire complement of proteins produced by an organism or cellular system, and proteomics refers to the large-scale comprehensive study of a specific proteome. Similarly, the term transcriptome refers to the entire complement of transcription products (messenger RNAs), and transcriptomics refers to the study of a specific transcriptome. Proteogenomics refers to the integration of genomic information with proteomic and transcriptomic information to provide a more complete picture of the function of the genome.

A system’s proteome is related to its genome and genomic alterations. However, while the genome is relatively static over time, the proteome is more dynamic and may vary over time and/or in response to selected stressors. Proteins undergo a number of modifications as part of normal physiologic processes. Following protein translation, modifications occur by splicing events, alternative folding mechanisms, and incorporation into larger complexes and signaling networks. These modifications are linked to protein function and result in functional differences that occur by location and over time.

Some of the main potential applications of proteogenomics in medicine include: • Identifying biomarkers for diagnostic, prognostic, and predictive purposes • Detecting cancer by proteomic profiles or “signatures” • Quantitating levels of proteins and monitoring levels over time for: o Cancer activity o Early identification of resistance to targeted tumor therapy • Correlating protein profiles with disease states.

Proteogenomics is an extremely complex field due to the intricacies of protein architecture and function, the many potential proteomic targets that can be measured, and the numerous testing methods used. Types of targets currently being investigated, and the testing methods used and under development next are discussed briefly herein.

Proteomic Targets A proteomic target can be any altered protein that results from a genetic variant. Protein alterations can result from germline and somatic genetic variants. Altered protein products include mutated proteins, fusion proteins, alternative splice variants, noncoding messenger RNAs, and posttranslational modifications.

Mutated Protein (Sequence Alterations) A mutated protein has an altered amino acid sequence that arises from a genetic variant. A single amino acid may be replaced in a protein or multiple amino acids in the sequence may be affected. Mutated proteins can arise from germline or somatic genetic variants. Somatic variants can be differentiated from germline variants by comparison with normal and diseased tissue.

Fusion Proteins Fusion proteins are the product of one or more genes that fuse together. Most fusion genes discovered have been oncogenic, and fusion genes have been shown to have clinical relevance in a variety of cancers.

500 EXCHANGE STREET, PROVIDENCE, RI 02903-2699 MEDICAL COVERAGE POLICY | 3 (401) 274-4848 WWW.BCBSRI.COM

Alternative Splice Events Posttranslational enzymatic splicing of proteins results in numerous protein isoforms. Alternative splicing events can lead to abnormal protein isoforms with altered function. Some alternative splicing events have been associated with tumor-specific variants.

Noncoding RNAs Noncoding portions of the genome serve as the template for noncoding RNA (ncRNA), which plays various roles in the regulation of gene expression. There are 2 classes of ncRNA: shorter ncRNAs, which include microRNAs and related transcript products, and longer ncRNAs, which are thought to be involved in cancer progression.

Posttranslational Modifications Posttranslational Modifications of histone proteins occur in normal cells and are genetically regulated. Histone proteins are found in the nuclei and play a role in gene regulation by structuring the DNA into nucleosomes. A nucleosome is composed of a histone protein core surrounded by DNA. Nucleosomes are assembled into chromatin fibers composed of multiple nucleosomes assembled in a specific pattern. PTMs of histone proteins include a variety of mechanisms, including methylation, acetylation, phosphorylation, glycosylation, and related modifications.

Proteogenomic Testing Methods Proteogenomic testing involves isolating, separating, and characterizing proteins from biologic samples, followed by correlation with genomic and transcriptomic data. Isolation of proteins is accomplished by trypsin digestion and solubilization. The soluble mix of protein isolates is then separated into individual proteins. This is generally done in multiple stages using high-performance liquid chromatography ion- exchange chromatography, 2-dimensional gel electrophoresis, and related methods. Once individual proteins are obtained, they may be characterized using various methods and parameters, some of which we describe below. There is literature addressing the analytic validity of these testing techniques.

Immunohistochemistry and Fluorescence in situ Hybridization Immunohistochemistry (IHC) and fluorescence in situ hybridization are standard techniques for isolating and characterizing proteins. IHC identifies proteins by using specific antibodies that bind to the protein. Therefore, this technique can only be used for known proteins and protein variants because it relies on the availability of a specific antibody. This technique also can only test a relatively small number of samples at once.

There are a number of reasons why IHC and fluorescence in situ hybridization are not well-suited for large- scale proteomic research. They are semiquantitative techniques and involve subjective interpretation. They are considered low-throughput assays that are time-consuming and expensive and require a relatively large tissue sample. Some advances in IHC and fluorescence in situ hybridization have addressed these limitations, including tissue microarray and reverse phase protein array. • Tissue microarrays can be constructed that enable simultaneous analysis of up to 1000 tissue samples. • Reverse phase protein array, a variation on tissue microarrays, allows for a large number of proteins to be quantitated simultaneously.

Mass Spectrometry Mass spectrometry (MS) separates molecules by their mass to charge ratio and has been used as a research tool for studying proteins for many years. The development of technology that led to the application of MS to biologic samples has advanced the field of proteogenomics rapidly. However, the application of MS to clinical medicine is in its formative stages. There are currently several types of mass spectrometers and a lack of standardization in the testing methods. Additionally, MS equipment is expensive and currently largely restricted to tertiary research centers.

500 EXCHANGE STREET, PROVIDENCE, RI 02903-2699 MEDICAL COVERAGE POLICY | 4 (401) 274-4848 WWW.BCBSRI.COM

The potential utility of MS lies in its ability to provide a wide range of proteomic information efficiently, including: • Identification of altered proteins; • Delineation of protein or peptide profiles for a given tissue sample; • Amino acid sequencing of proteins or peptides; • Quantitation of protein levels; • 3-dimensional protein structure and architecture; and • Identification of posttranslational modifications.

Mass Spectrometry Sampling Applications “Top-down” MS refers to identification and characterization of all proteins in a sample without prior knowledge of which proteins are present. This method provides a profile of all proteins in a system, including documentation of posttranslational modifications and other protein isoforms. This method, therefore, provides a protein “profile” or “map” of a specific system. Following initial analysis, intact proteins can be isolated and further analyzed to determine amino acid sequences and related information.

“Bottom-up” MS refers to the identification of known proteins in a sample. This method identifies peptide fragments that indicate the presence of a specific protein. This method depends on having peptide fragments that can reliably identify a specific protein. This method depends on having peptide fragments that can reliably identify a specific protein. Selective reaction monitoring MS is a bottom-up modification of MS that allows for direct quantification and specific identification of low-abundance proteins without the need for specific antibodies. This method requires the selection of a peptide fragment or “signature” that is used to target the specific protein. Multiplex assays have also been developed to quantitate the epidermal growth factor receptor, human epidermal growth factor receptors 2 and 3, and insulin-like growth factor-1 receptor.

Bioinformatics Due to the complexity of proteomic information, the multiple tests used, and the need to integrate this information with other genomic data, a bioinformatics approach is necessary to interpret proteogenomic data. Software programs integrate and assist in the interpretation of the vast amounts of data generated by proteogenomics research. One software platform that integrates genomic and proteomic information is PARADIGM, which is used by The Cancer Genome Atlas (TCGA) project for data analysis. Other software tools currently available include: • The Genome Peptide Finder matches the amino acid sequence of peptides predicted de novo with the genome sequence. • The Proteogenomic Mapping Tool is an academic software for mapping peptides to the genome. • Peppy is an automated search tool that generates proteogenomic data from translated databases and integrates this information for analysis. • VESPA is a software tool that integrates data from various platforms and provides a visual display of integrated data.

GPS Cancer Test The GPS CancerTM test is a commercially available proteogenomic test intended for patients with cancer. The test includes whole-genome sequencing, whole transcriptome (RNA) sequencing, and quantitative proteomics by MS. The test is intended to inform personalized treatment decisions for cancer, and treatment options are provided when available, although treatment recommendations are not. Treatment options may include U.S. (United States) Food and Drug Administration (FDA)-approved targeted drugs with potential for clinical benefit, active clinical trials of drugs with potential for clinical benefit, and/or available drugs to which cancer may be resistant.

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 Act (CLIA). The GPS Cancer™ test (NantHealth) is available under the auspices of CLIA.

500 EXCHANGE STREET, PROVIDENCE, RI 02903-2699 MEDICAL COVERAGE POLICY | 5 (401) 274-4848 WWW.BCBSRI.COM

Laboratories that offer laboratory-developed tests must be licensed by CLIA for high-complexity testing. To date, the FDA has chosen not to require any regulatory review of this test.

For individuals who have cancer and indications for genetic testing who receive proteogenomic testing (eg, GPS Cancer test), the evidence includes cross-sectional studies that correlate results with standard testing and that report comprehensive molecular characterization of various cancers, and cohort studies that use proteogenomic markers to predict outcomes and that follow quantitative levels over time. Relevant outcomes are overall survival, disease-specific survival, test accuracy and validity, and treatment-related mortality and morbidity. There is no published evidence on the clinical validity or utility of the GPS Cancer test. For proteogenomic testing in general, the research is at an early stage. Very few studies have used proteogenomic tumor markers for diagnosis or prognosis, and at least 1 study has reported following quantitative protein levels for surveillance purposes. Further research is needed to standardize and validate proteogenomic testing methods. Once standardized and validated testing methods are available, the clinical validity and utility of proteogenomic testing can be adequately evaluated. The evidence is insufficient to determine that the technology results in an improvement in the net health outcome.

CODING Medicare Advantage Plans and Commercial Products There is no specific CPT code for the GPS Cancer test. It would likely be reported with the unlisted molecular pathology procedure code 81479.

RELATED POLICIES Biomarker Testing Mandate
Genetic Testing Services
Unlisted Procedures

PUBLISHED Provider Update, October 2025 Provider Update, September 2024 Provider Update, September/November 2023 Provider Update, October 2022 Provider Update, October 2021

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500 EXCHANGE STREET, PROVIDENCE, RI 02903-2699 MEDICAL COVERAGE POLICY | 6 (401) 274-4848 WWW.BCBSRI.COM

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    This medical policy is made available to you for informational purposes only. It is not a guarantee of payment or a substitute for your medical judgment in the treatment of your patients. Benefits and eligibility are determined by the member's subscriber agreement or member certificate and/or the employer agreement, and those documents will supersede the provisions of this medical policy. For information on member-specific benefits, call the provider call center. If you provide services to a member which are determined to not be medically necessary (or in some cases medically necessary services which are non-covered benefits), you may not charge the member for the services unless you have informed the member and they have agreed in writing in advance to continue with the treatment at their own expense. Please refer to your participation agreement(s) for the applicable provisions. This policy is current at the time of publication; however, medical practices, technology, and knowledge are constantly changing. BCBSRI reserves the right to review and revise this policy for any reason and at any time, with or without notice. Blue Cross & Blue Shield of Rhode Island is an independent licensee of the Blue Cross and Blue Shield Association. CLICK THE ENVELOPE ICON BELOW TO SUBMIT COMMENTS