Medical Policy

This document addresses proteogenomic testing for the evaluation of malignancies in persons who have been diagnosed with cancer.

Proteogenomic tests include, but may not be limited to:

• DarwinOncoTarget^™ (Darwin Health, New York, NY)
• Genomic Proteomic Spectrometry, or GPS Cancer^™ test (NantHealth, Culver City, CA)

Investigational and Not Medically Necessary:

Proteogenomic testing is considered investigational and not medically necessary for all indications.

Proteogenomics refers to the complex integration of genomic, proteomic, and transcriptomic data to provide a more comprehensive picture of the function of the genome. Proteogenomic testing differs from proteomic testing in that proteomic testing is typically limited to the measurement of protein products alone without the inclusion of genomic and transcriptomic information.

Research on the use of proteogenomic testing for individuals with oncologic conditions is in the early stages of development (Paull, 2021). Examples of proteogenomic tests in the United States include the GPS Cancer test and the DarwinOncoTarget test. At the time of this review, no peer-reviewed published studies on the clinical validity or utility of these tests, and no guidelines or recommendations by professional medical societies or governmental organizations were identified.

Several studies have been published on whole exome and tumor-normal sequencing, which may be applicable to one component of the GPS cancer test (Beltran, 2015; Jones, 2015; Mandelker, 2017; Teer, 2017). These studies have described the ability of whole exome and tumor-normal sequencing to identify individuals within a population with inheritable genetic mutations with potential clinical ramifications, including the identification of mutations for which specific pharmacological therapies are available, in a rare percentage of the time. However, the methods used are not the same as the GPS test and these studies do not provide any data related to clinical or health-related outcomes that may result from the use of whole exome and tumor-normal sequencing, let alone the GPS test. These remain outstanding questions that need to be addressed in properly designed and conducted trials.

Conclusion

There is insufficient information to draw conclusions regarding the clinical validity or utility of commercial proteogenomic tests in the diagnosis, prognosis, or management of individuals with oncologic conditions. Additional research is needed to determine if these tests result in improved health outcomes and which population of individuals with oncologic conditions might benefit.

Cancer is a significant health problem in the United States (US), and according to the American Cancer Society (2021) cancer is the second most common cause of death in the US. Prognosis and therapeutic approach are determined using tumor location, stage, grade, and the individual’s underlying physical condition.

Genomic study examines all of the genes of an organism, proteomic study addresses all of the proteins expressed by those genes. Proteogenomics combines proteomic and genomic data. In this approach, customized protein sequence databases employ genomic and transcriptomic information to help identify novel peptides not found in reference protein sequence databases. The proteomic data provides protein-level evidence of gene expression and helps to refine gene models. Due in large part to the emergence of next generation sequencing technologies such as RNA sequencing and improvements in the depths and throughput of mass spectrometry-based proteomics, the pace of proteogenomics research has greatly accelerated (Nesvizhskii, 2014).

Proteogenomics may someday provide a detailed analysis of the molecular components and underlying mechanisms associated with the development of various cancers. This work is driven in part by the hypothesis that a better understanding of both proteomics and genomics will improve diagnosis and treatment decisions in individuals with oncologic conditions. Potential clinical applications of proteogenomics include, but are not limited to:

• Detecting diagnostic, prognostic, and predictive biomarkers;
• Identifying cancer by proteomic signatures (also referred to as proteomic profiles);
• Quantitatively measuring and monitoring protein levels over time to identify cancer activity and early resistance to targeted tumor therapy;
• Linking protein profiles with specific disease states.

According to information on the NantHealth website, the GPS Cancer test integrates quantitative targeted proteomics detected by mass spectrometry with whole transcriptome and whole genome sequencing, of both cancer tissue and normal tissue. The GPS Cancer test is marketed as a tool to diagnose molecular alterations in an individual’s cancer, and to identify personalized therapeutic regimens.

DarwinOncoTarget is described as a diagnostic platform that “detects and assesses the full repertoire of aberrantly active and pharmacologically actionable proteins” in a tumor sample that is independent of the DNA mutational state. A report is generated that identifies the proteins and target drugs/investigational compounds that may be used.

Genome: The total genetic composition of an organism.

Genomic data: Information derived from the sequencing of DNA or RNA fragments.

Proteome: The complete set of proteins expressed by a genome.

Proteomic data: Data related to the functioning of protein; generally obtained using a combination of liquid chromatography and tandem mass spectrometry.

Proteomics: The comprehensive and integrative study of proteins and their biological functions.

Transcriptome: The sum total of all the messenger RNA molecules expressed from the genes in a specified cell population or organism. May also be defined as the array of mRNA transcripts expressed in a particular cell or tissue type.

Whole transcriptome (RNA) sequencing: A next-generation sequencing technique used to identify and measure RNA in a biological sample at a given moment in time. Also known as RNA sequencing and whole transcriptome shotgun sequencing.

The following codes for treatments and procedures applicable to this document are included below for informational purposes. Inclusion or exclusion of a procedure, diagnosis or device code(s) does not constitute or imply member coverage or provider reimbursement policy. Please refer to the member’s contract benefits in effect at the time of service to determine coverage or non-coverage of these services as it applies to an individual member.

When services are Investigational and Not Medically Necessary:
When the code describes a procedure indicated in the Position Statement section as investigational and not medically necessary.

Peer Reviewed Publications:

1. Ansong C, Purvine SO, Adkins JN, et al. Proteogenomics: needs and roles to be filled by proteomics in genome annotation. Brief Funct Genomic Proteomic. 2008; 7(1):50-62.
2. Armengaud J. A perfect genome annotation is within reach with the proteomics and genomics alliance. Curr Opin Microbiol. 2009; 12(3):292-300.
3. Huang PJ, Lee CC, Tan BC, et al. CMPD: cancer mutant proteome database. Nucleic Acids Res. 2015; 43(Database issue):D849-855.
4. Keshava Prasad TS, Goel R, Kandasamy K, et al. Human Protein Reference Database--2009 update. Nucleic Acids Res. 2009; 37(Database issue):D767-772.
5. Nesvizhskii AI. Proteogenomics: concepts, applications and computational strategies. Nat Methods. 2014; 11(11):1114-1125.
6. Paull EO, Aytes A, Jones SJ et al.A modular master regulator landscape controls cancer transcriptional identity. Cell. 2021; 184(2):334-351.
7. Renuse S, Chaerkady R, Pandey A. Proteogenomics. Proteomics. 2011; 11(4):620-630.
8. Rivers RC, Kinsinger C, Boja ES, et al. Linking cancer genome to proteome: NCI's investment into proteogenomics. Proteomics. 2014; 14(23-24):2633-2636.
9. Subbannayya Y, Pinto SM, Gowda H, et al. Proteogenomics for understanding oncology: recent advances and future prospects. Expert Rev Proteomics. 2016; 13(3):297-308.

1. American Cancer Society. Facts and Figures. Available at: https://www.cancer.org/latest-news/facts-and-figures-2021.html. Accessed on October 6, 2022.
2. Office of Cancer Clinical Proteomics Research, National Cancer Institute. Proteomics and Proteogenomics. Available at: https://proteomics.cancer.gov/. Accessed on October 6, 2022.

DarwinOncoTarget
GPS Cancer Test
Proteogenomic Test

The use of specific product names is illustrative only. It is not intended to be a recommendation of one product over another, and is not intended to represent a complete listing of all products available.

Applicable to Commercial HMO members in California: When a medical policy states a procedure or treatment is investigational, PMGs should not approve or deny the request. Instead, please fax the request to Anthem Blue Cross Grievance and Appeals at fax # 818-234-2767 or 818-234-3824. For questions, call G&A at 1-800-365-0609 and ask to speak with the Investigational Review Nurse.

Federal and State law, as well as contract language, including definitions and specific contract provisions/exclusions, take precedence over Medical Policy and must be considered first in determining eligibility for coverage. The member’s contract benefits in effect on the date that services are rendered must be used. Medical Policy, which addresses medical efficacy, should be considered before utilizing medical opinion in adjudication. Medical technology is constantly evolving, and we reserve the right to review and update Medical Policy periodically.

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