Germline and Somatic Biomarker Testing (Including Liquid Biopsy) for Targeted Treatment in Ovarian Cancer (BRCA1, BRCA2, Homologous Recombination Deficiency, NTRK)

POLICY NUMBER

A.2.04.156

DESCRIPTION

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

Biomarker Testing and Targeted Treatment in Ovarian 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 ovarian cancer. Poly adenosine diphosphate-ribose polymerase (PARP) inhibitors are used to target tumor cells with alterations in the HRR genes BRCA1 and BRCA2. Currently, 3 PARP inhibitors are FDA-approved for use in ovarian cancer (see the table below).

In ovarian cancer targeted therapies, HRD-positive status is generally defined by either a deleterious or suspected deleterious BRCA mutation, and/or genomic instability. Myriad MyChoice® is an FDA-approved companion diagnostic for the assessment of tumor genomic instability score (GIS) and the detection and classification of variants in the BRCA1 and BRCA2 genes, for the selection of patients who are eligible for targeted treatment. A patient’s Myriad HRD status is determined by detecting single nucleotide variants (SNVs), variants in homopolymer stretches, insertions and deletions (indels), and large rearrangements (LRs) in the BRCA1 and BRCA2 genes, and determining a genomic instability score (GIS) using DNA obtained from ovarian tumor tissue. A positive Myriad HRD Status result is due to either the presence of a pathogenic variant in BRCA1 and/or BRCA2 and/or a GIS above a defined threshold. Approximately 41% to 50% of epithelial ovarian cancers are estimated to exhibit HRD. Germline alterations in BRCA1 and BRCA2 genes have been identified in up to 17% of individuals diagnosed with epithelial ovarian cancer, and somatic mutations are found in an additional 7%.

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 can be used for genomic characterization of the tumor.

The table below summarizes the targeted treatments approved by the FDA for individuals with ovarian cancer, along with the approved companion diagnostic tests. The information in the table below was current as of August 1, 2024. 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 .

Voluntarily Withdrawn Indications for Maintenance Therapy

In 2022, the manufacturers of all 3 PARP inhibitors used to treat ovarian cancer voluntarily withdrew indications for third-line or greater treatment in ovarian cancer. The withdrawals were based on updated survival results from the ARIEL4 (NCT02855944), SOLO3 (NCT02282020), and QUADRA (NCT02354586) trials. The withdrawals did not affect other indications in ovarian cancer.

Targeted Treatments for Ovarian Cancer and NTRK fusions with FDA-Approved Companion Diagnostic Tests

Sources: Food and Drug Administration (2023); Drugs@FDA

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

• Comprehensive Genomic Profiling for Selecting Targeted Cancer Therapies

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

• Molecular Testing for Germline Variants Associated with Ovarian Cancer (BRIP1, RAD51C, RAD51D, NBN)

• 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)

• 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 may be considered medically necessary for individuals with advanced epithelial ovarian, fallopian tube, or primary peritoneal cancer to select treatment with FDA-approved targeted therapies.

Somatic BRCA1/2 variant analysis using tumor tissue may be considered medically necessary for individuals with advanced epithelial ovarian, fallopian tube, or primary peritoneal cancer to select treatment with FDA-approved targeted therapies.

All other uses of germline and somatic BRCA1/2 variant analysis to guide targeted therapy for ovarian, fallopian tube, or primary peritoneal cancer are considered investigational.

Homologous recombination deficiency (HRD) analysis of tumor tissue may be considered medically necessary for individuals with advanced epithelial ovarian, fallopian tube, or primary peritoneal cancer to select treatment with FDA-approved targeted therapies.

All other uses of HRD testing of tumor tissue to guide targeted therapy for ovarian, fallopian tube, or primary peritoneal cancer are considered investigational.

BRCA1/2 variant analysis using circulating tumor DNA (liquid biopsy) may be considered medically necessary for individuals with advanced epithelial ovarian, fallopian tube, or primary peritoneal cancer to select treatment with FDA-approved targeted therapies when tissue-based analysis is not clinically feasible.

All other uses of circulating tumor DNA testing (liquid biopsy) to guide targeted therapy in individuals with ovarian, fallopian tube, or primary peritoneal cancer are considered investigational.

NTRK1, NTRK2, and NTRK3 gene fusion analysis of tumor tissue may be considered medically necessary for individuals with advanced epithelial ovarian, fallopian tube, or primary peritoneal cancer to select treatment with FDA-approved targeted therapies.

All other uses of NTRK1, NTRK2, and NTRK3 gene fusion analysis of tumor tissue to guide targeted therapy for ovarian, fallopian tube, or primary peritoneal cancer are considered investigational.

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

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 National Comprehensive Cancer Network (NCCN) management algorithms.

This policy does not address germline testing for inherited risk of developing cancer.

Repeat Genomic Testing

There may be utility in repeated testing of gene variants for determining targeted therapy or immunotherapy in individuals with ovarian cancer, as a resistance mechanism to platinum-based chemotherapies and poly adenosine diphosphate-ribose polymerase (PARP) inhibitors in BRCA-mutant cancers is the acquisition of BRCA reversion mutations that restore protein function. ASCO currently suggests repeat genomic testing for patients 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 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 a patient 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 BRCA mutation evolution (reversion mutations) in individuals with ovarian cancer during PARP inhibitor therapy may be achieved with serial 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 ovarian cancer.

Genetic Counseling

Genetic counseling is primarily aimed at patients 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.

04/04/2024: Policy title changed from "Germline and Somatic Biomarker Testing (Including Liquid Biopsy) for Targeted Treatment and Immunotherapy in Ovarian Cancer (BRCA1, BRCA2, Homologous Recombination Deficiency, Tumor Mutational Burden, Microsatellite Instability/Mismatch Repair)" to "Germline and Somatic Biomarker Testing (Including Liquid Biopsy) for Targeted Treatment in Ovarian Cancer (BRCA1, BRCA2, Homologous Recombination Deficiency)." Policy description revised to remove information regarding microsatellite instability/mismatch repair and tumor mutational burden as it is addressed in a separate policy. Added information regarding biomarker testing and targeted treatment in ovarian cancer, voluntarily withdrawn indications for maintenance therapy, and targeted treatments for ovarian cancer and FDA-approved companion diagnostic tests. Updated related medical policies. Medically necessary statement regarding germline and somatic BRCA1/2 variant analysis separated into two policy statements. Added medically necessary statement regarding BRCA1/2 variant analysis using circulating tumor DNA (liquid biopsy). Revised investigational statement regarding all other uses of circulating tumor DNA testing. Policy Guidelines updated to remove genetics nomenclature update. Added link to a related policy and added information regarding tumor mutational burden. Code Reference section updated to add CPT codes 81163, 81164, 81165, 81166, 81167, 81212, 81215, 81216, 81217, 0129U, and 81432.

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. Policy description updated regarding targeted treatments for ovarian cancer and NTRK fusions with FDA-approved companion diagnostic tests. Added statement that NTRK1, NTRK2, and NTRK3 gene fusion analysis of tumor tissue may be considered medically necessary for individuals with advanced epithelial ovarian, fallopian tube, or primary peritoneal cancer to select treatment with FDA-approved targeted therapies. All other uses of NTRK1, NTRK2, and NTRK3 gene fusion analysis of tumor tissue to guide targeted therapy for ovarian, fallopian tube, or primary peritoneal cancer are considered investigational. Code Reference section updated to add CPT codes 81191, 81192, 81193, and 81194.

SOURCE(S)

Blue Cross Blue Shield Association policy # 2.04.156

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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