Germline and Somatic Biomarker Testing (Including Liquid Biopsy) for Targeted Treatment in Prostate Cancer (BRCA1/2, Homologous Recombination Repair Gene Alterations, NTRK Gene Fusion)

POLICY NUMBER

A.2.04.155

DESCRIPTION

Biomarker-targeted therapy has shown a clear survival benefit in individuals with metastatic prostate cancer. Typically, the evaluation of biomarker status requires tissue biopsy. Circulating tumor DNA (ctDNA) (also known as liquid biopsy) is proposed as a non-invasive alternative.

Targeted Treatment in Metastatic Castrate Resistant Prostate Cancer

DNA damage happens daily, and most are repaired to allow normal cell functioning. Double strand breaks (DSB) in the DNA are particularly damaging. Repair of DSB utilizes the homologous recombination repair (HRR) pathway. Many types of cancer, however, are unable to repair DNA damage. This leads to the accumulation of genetic errors, such as loss of DNA, rearrangements in the DNA, and loss of entire genes. The consequence of these errors is genomic instability. The loss of the HRR and associated genomic instability is called homologous recombination deficiency (HRD). HRD is associated with several types of cancer including prostate cancer, where estimates as high as 30% of metastatic castrate-resistant prostate cancer (mCRPC) tumors have genetic changes that result in the loss of DNA repair capacity.

Friends of Cancer Research convened a consortium addressing the lack of consistency in the way HRD is defined and measurement methods. They proposed the following definition: “HRD is a phenotype that is characterized by the inability of a cell to effectively repair DNA double-strand breaks using the HRR pathway.” Additionally, they encourage the use of “HRD” and “HRP” to reflect homologous recombination deficiency and homologous recombination proficiency. While the consortium did not explicitly define how to measure homologous recombination repair status, they acknowledge that it might involve gene variant testing as well as genomic instability measurement and call for transparency and standardization.

Specific to prostate cancer, the National Comprehensive Cancer Network (NCCN) prostate cancer guideline gives examples of HRR genes (BRCA1, BRCA2, ATM, BARD1, BRIP1, CDK12, CHEK1, CHEK2, FANCL, PALB2, RAD51B, RAD51C, RAD51D, and RAD54L). Germline and somatic alterations in these genes may be predictive of the clinical benefit of PARP inhibitors in mCRPC. Olaparib (Lynparza) and rucaparib (Rubraca) were the first PARP inhibitors to receive FDA approval for the treatment of mCRPC. In 2023, niraparib in combination with abiraterone acetate (marketed as Akeega) and talazoparib (Talzenna) were also approved for use in mCRPC (see the table below).

Circulating Tumor DNA (Liquid Biopsy)

Normal and tumor cells release small fragments of DNA into the blood, which is referred to as cell-free DNA. Cell-free DNA from nonmalignant cells is released by apoptosis. Most cell-free tumor DNA is derived from apoptotic and/or necrotic tumor cells, either from the primary tumor, metastases, or circulating tumor cells. Unlike apoptosis, necrosis is considered a pathologic process and generates larger DNA fragments due to incomplete and random digestion of genomic DNA. The length or integrity of the circulating DNA can potentially distinguish between apoptotic and necrotic origin. Circulating tumor DNA (ctDNA) can be used for genomic characterization of the tumor.

Neurotrophic Receptor Tyrosine Kinase (NTRK) Gene Fusion Testing

The presence of NTRK gene fusion can be detected by multiple methods including next-generation sequencing, reverse transcription-polymerase chain reaction, fluorescence in situ hybridization and immunohistochemistry. Next-generation sequencing provides the most comprehensive view of a large number of genes and may identify NTRK gene fusions as well as other actionable alterations, with minimal tissue needed. The fluorescence in situ hybridization using break-apart probes can detect gene rearrangements in DNA that may generate a fusion transcript. The immunohistochemistry techniques have generally been used in the research setting. Reverse transcription-polymerase chain reaction is designed to identify only known translocation partners and breakpoints and cannot identify novel breakpoints or novel fusion partners.

The table below summarizes the targeted treatments approved by the FDA for individuals with prostate cancer, along with the approved companion diagnostic tests. The information in the table below was current as of August 21, 2023. An up-to-date list of FDA cleared or approved companion diagnostics is available at https://www.fda.gov/medical-devices/in-vitro-diagnostics/list-cleared-or-approved-companion-diagnostic-devices-in-vitro-and-imaging-tools .

Targeted Treatments for Metastatic Prostate Cancer and FDA Approved Companion Diagnostic Tests

ªIndications not specific to prostate cancer.NCCN: National Comprehensive Cancer Network.Sources: Food and Drug Administration (2023); Drugs@FDA  (2023)

Laboratory-Developed Tests

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

Related medical policies –

• Germline Genetic Testing for Hereditary Breast/Ovarian Cancer Syndrome and Other High-Risk Cancers (BRCA1, BRCA2, PALB2)

• Genetic Testing for Lynch Syndrome and Other Inherited Colon Cancer Syndromes

• Genetic Testing for Li-Fraumeni Syndrome

• Gene Expression Profiling and Protein Biomarkers for Prostate Cancer Management

• Comprehensive Genomic Profiling for Selecting Targeted Cancer Therapies

• Circulating Tumor DNA and Circulating Tumor Cells for Cancer Management (Liquid Biopsy)

• Germline and Somatic Biomarker Testing (Including Liquid Biopsy) for Targeted Treatment and Immunotherapy in Breast Cancer

• Somatic Biomarker Testing for Immune Checkpoint Inhibitor Therapy (BRAF, MSI/MMR, PD-L1, TMB)

• Genetic and Protein Biomarkers for the Diagnosis and Cancer Risk Assessment of Prostate Cancer

• Somatic Biomarker Testing (Including Liquid Biopsy) for Targeted Treatment and Immunotherapy in Non-Small-Cell Lung Cancer (EGFR, ALK, BRAF, ROS1, RET, MET, KRAS, HER2, PD-L1, TMB)

• Somatic Biomarker Testing (Including Liquid Biopsy) for Targeted Treatment in Metastatic Colorectal Cancer (KRAS, NRAS, BRAF, and HER2)

• Somatic Genetic Testing to Select Individuals with Melanoma or Glioma for Targeted Therapy (BRAF)

• Genetic Testing for PTEN Hamartoma Tumor Syndrome

• Genetic Cancer Susceptibility Panels Using Next Generation Sequencing

POLICY

Germline BRCA1/2 variant analysis for individuals with metastatic castrate-resistant prostate cancer (mCRPC) to select treatment with FDA-approved targeted therapies may be considered medically necessary.

All other uses of germline BRCA1/2 variant analysis to guide prostate cancer targeted therapy are considered investigational.

Somatic testing using tissue biopsy for homologous recombination repair (HRR) gene alterations (BRCA1, BRCA2, ATM, BARD1, BRIP1, CDK12, CHEK1, CHEK2, FANCL, PALB2, RAD51B, RAD51C, RAD51D, and RAD54L) to select treatment for mCRPC with FDA-approved targeted therapies may be considered medically necessary.

All other uses of somatic testing using tissue biopsy for HRR gene alterations to guide prostate cancer targeted therapy are considered investigational.

Somatic testing using circulating tumor DNA testing (liquid biopsy) for BRCA1, BRCA2, and ATM alterations to select treatment for mCRPC with FDA-approved targeted therapies may be considered medically necessary.

All other uses of somatic testing using circulating tumor DNA testing (liquid biopsy) to guide prostate cancer targeted therapy are considered investigational.

Simultaneous testing using liquid and tumor biopsies (outside of paired or concurrent somatic-germline testing) to guide treatment in individuals with prostate cancer is considered investigational (see Policy Guidelines).

Testing of NTRK gene fusions in individuals with mCRPC to select treatment with FDA-approved targeted therapies may be considered medically necessary.

POLICY EXCEPTIONS

None

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.

Testing for individual genes (not gene panels) associated with FDA-approved therapeutics for therapies with National Comprehensive Cancer Network (NCCN) recommendations of 2A or higher are not subject to extensive policy review. Note that while the FDA approval of companion diagnostic tests for genes might include tests that are conducted as panels, the FDA approval is for specific genes (such as driver mutations) and not for all of the genes on the test panel.

For expanded panel testing, see the Comprehensive Genomic Profiling for Selecting Targeted Cancer Therapies medical policy.

For somatic biomarker testing related to use of immune checkpoint inhibitor therapy (BRAF, microsatellite instability/mismatch repair [MSI/MMR], PD-L1, tumor mutational burden [TMB]), see the Somatic Biomarker Testing for Immune Checkpoint Inhibitor Therapy (BRAF, MSI/MMR, PD-L1, TMB) medical policy.

Note that TMB is often included in panel tests and might not have separate coding.

For guidance on testing criteria between policy updates, refer to the FDA's List of Cleared or Approved Companion Diagnostic Devices (In Vitro and Imaging Tools) ( https://www.fda.gov/medical-devices/in-vitro-diagnostics/list-cleared-or-approved-companion-diagnostic-devices-in-vitro-and-imaging-tools ) for an updated list of FDA-approved tumor markers and consult the most current version of NCCN management algorithms.

Repeat Genomic Testing

There may be utility in repeated testing of gene variants for determining targeted therapy or immunotherapy in individuals with prostate cancer, as tumor molecular profiles may change with subsequent treatments and re-evaluation may be considered at time of cancer progression for treatment decision-making (See NCCN PROS-B 3 of 3). The American Society of Clinical Oncology (ASCO) currently suggests repeat genomic testing for individuals on targeted therapy with suspected acquired resistance, especially if choice of next-line therapy would be guided. The ASCO guidance is not tumor specific, and it cautions to consider clinical utility.

Paired Somatic-Germline Testing

Testing for genetic changes in tumor tissue assesses somatic changes. Some somatic testing involves a paired blood analysis in order to distinguish whether findings in tumor tissue are acquired somatic changes or germline changes. Some laboratories offer paired tumor sequencing and germline sequencing which is done at the same time and in the same laboratory. The goal of this paired testing is to identify truly somatic changes to guide treatment. However, paired testing can also identify potential germline changes that might indicate an inherited cancer syndrome. These results would need to be confirmed through germline testing if personal and family cancer history is consistent with an inherited cancer syndrome (see policies related to inherited cancer syndromes, Germline Genetic Testing for Hereditary Breast/Ovarian Cancer Syndrome and Other High-Risk Cancers (BRCA1, BRCA2, PALB2) , Genetic Testing for Lynch Syndrome and Other Inherited Colon Cancer Syndromes , Genetic Testing for PTEN Hamartoma Tumor Syndrome , Genetic Testing for Li-Fraumeni Syndrome ).

Paired genetic testing is different than concurrent somatic-germline testing. In concurrent testing, the germline results are not used to filter the somatic results. Rather, the laboratories perform large, separate panels of germline and somatic variants. The goal is to identify options for genome-informed treatment and to identify hereditary cancer risk. For concurrent panel testing, see the Genetic Cancer Susceptibility Panels Using Next Generation Sequencing medical policy for germline panel, and see the Comprehensive Genomic Profiling for Selecting Targeted Cancer Therapies medical policy for somatic panel.

Concurrent Somatic Liquid-based and Tissue-based Genomic Testing

Liquid biopsy testing uses blood samples and assesses cancer DNA and non-cancer DNA in the same blood sample. The goal is to identify options for genome-informed treatment. Some providers will order a liquid biopsy test and a tissue biopsy test at the same time, not for filtering or for comparison as in the paired genetic testing section above, but to hasten time to treatment. If the intent of concurrent testing is to follow an individual over time for resistance mutations/response to therapy, then consideration could be given to doing liquid biopsy at diagnosis with the tissue biopsy to make sure that whatever mutations are going to be followed longitudinally can be detected by the liquid biopsy. For example, monitoring of BRCA mutation evolution (reversion mutations) in individuals with prostate cancer during poly adenosine diphosphate-ribose polymerase (PARP) inhibitor therapy may be achieved with serial circulating tumor DNA (ctDNA) sampling, and allow for earlier detection of resistance and selection of alternative therapies to reduce the risk of resistance. This testing strategy has not been fully studied, and is not yet discussed in the NCCN guidelines for prostate cancer.

Genetic Counseling

Genetic counseling is primarily aimed at individuals who are at risk for inherited disorders, and experts recommend formal genetic counseling in most cases when genetic testing for an inherited condition is considered. The interpretation of the results of genetic tests and the understanding of risk factors can be very difficult and complex. Therefore, genetic counseling will assist individuals in understanding the possible benefits and harms of genetic testing, including the possible impact of the information on the individual's family. Genetic counseling may alter the utilization of genetic testing substantially and may reduce inappropriate testing. Genetic counseling should be performed by an individual with experience and expertise in genetic medicine and genetic testing methods.

Medically Necessary is defined as those services, treatments, procedures, equipment, drugs, devices, items or supplies furnished by a covered Provider that are required to identify or treat a Member's illness, injury or Mental Health Disorders, and which Company determines are covered under this Benefit Plan based on the criteria as follows in A through D:

A. consistent with the symptoms or diagnosis and treatment of the Member's condition, illness, or injury; and

B. appropriate with regard to standards of good medical practice; and

C. not solely for the convenience of the Member, his or her Provider; and

D. the most appropriate supply or level of care which can safely be provided to Member. When applied to the care of an Inpatient, it further means that services for the Member's medical symptoms or conditions require that the services cannot be safely provided to the Member as an Outpatient.

For the definition of medical necessity, “standards of good 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. BCBSMS makes no payment for services, treatments, procedures, equipment, drugs, devices, items or supplies which are not documented to be Medically Necessary. The fact that a Physician or other Provider has prescribed, ordered, recommended, or approved a service or supply does not in itself, make it Medically Necessary.

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

08/01/2023: New policy added. Approved by the Medical Policy Advisory Committee.

04/01/2024: Policy title changed from "Germline and Somatic Biomarker Testing (Including Liquid Biopsy) for Targeted Treatment and Immunotherapy in Prostate Cancer (BRCA1/2, Homologous Recombination Repair Gene Alterations, Microsatellite Instability/Mismatch Repair, Tumor Mutational Burden)" to "Germline and Somatic Biomarker Testing (Including Liquid Biopsy) for Targeted Treatment in Prostate Cancer (BRCA1/2, Homologous Recombination Repair Gene Alterations)." Policy description updated regarding targeted treatments in metastatic prostate cancer and FDA approved companion diagnostic tests. Removed information and policy statements regarding mismatch repair deficiency/microsatellite instability and tumor mutational burden as these are addressed in a separate policy. Policy statements updated for clarity and to add that somatic testing using circulating tumor DNA testing (liquid biopsy) for BRCA1, BRCA2, and ATM alterations to select treatment for mCRPC with FDA-approved targeted therapies may be considered medically necessary. Policy Guidelines updated regarding somatic biomarker testing related to use of immune checkpoint inhibitor therapy. Removed information regarding genetics nomenclature. Code Reference section updated to add CPT codes 81163, 81164, 81165, 81166, 81167, 81212, 81215, 81216, 81217, 81307, and 81308 as medically necessary. Added CPT code 81432 as investigational. Removed CPT code 81301.

12/31/2024: Code Reference section updated to revise description for CPT code 81432 effective 01/01/2025.

02/03/2025: Policy title updated to include NTRK gene fusion. Policy description updated regarding neurotrophic receptor tyrosine kinase gene fusion testing and immunotherapy for solid tumors. Added policy statement that testing of NTRK gene fusions in individuals with mCRPC to select treatment with FDA-approved targeted therapies may be considered medically necessary. Code Reference section updated to add CPT codes 81191, 81192, 81193, and 81194.

SOURCE(S)

Blue Cross Blue Shield Association policy # 2.04.155

CODE REFERENCE

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

The code(s) listed below are ONLY medically necessary if the procedure is performed according to the "Policy" section of this document.

Medically Necessary Codes

Investigational Codes

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