Germline and Somatic Biomarker Testing (Including Liquid Biopsy) for Targeted Treatment in Breast Cancer (BRCA1, BRCA2, PIK3CA, Ki-67, RET, BRAF, ESR1, NTRK)

POLICY NUMBER

A.2.04.151

DESCRIPTION

Multiple biomarkers are being evaluated to predict response to targeted treatments for patients with advanced or high-risk breast cancer. These include tissue-based testing as well as circulating tumor DNA and circulating tumor cell testing (known as liquid biopsy).

The objective of this policy is to examine whether biomarker testing for BRCA variants, PIK3CA, ESR1, Ki-67, RET, BRAF, circulating tumor DNA, or circulating tumor cells improves the net health outcome in patients with breast cancer who are considering targeted therapy.

BRCA Variant Testing

The prevalence of BRCA variants is approximately 0.2% to 0.3% in the general population. The prevalence may be much higher for particular ethnic groups with characterized founder mutations (eg, 2.5% [1/40] in the Ashkenazi Jewish population). Family history of breast and ovarian cancer is an important risk factor for the BRCA variant; additionally, age and ethnicity could be independent risk factors.

Several genetic syndromes with an autosomal dominant pattern of inheritance that features breast cancer have been identified. Of these, hereditary breast and ovarian cancer (HBOC) and some cases of hereditary site-specific breast cancer have in common causative variants in BRCA (breast cancer susceptibility) genes. Families suspected of having HBOC syndrome are characterized by an increased susceptibility to breast cancer occurring at a young age, bilateral breast cancer, male breast cancer, ovarian cancer at any age, as well as cancer of the fallopian tube and primary peritoneal cancer. Other cancers, such as prostate cancer, pancreatic cancer, gastrointestinal cancers, melanoma, and laryngeal cancer, occur more frequently in HBOC families. Hereditary site-specific breast cancer families are characterized by early-onset breast cancer with or without male cases, but without ovarian cancer. This policy refers collectively to both as hereditary breast and/or ovarian cancer.

Germline variants in the BRCA1 and BRCA2 genes are responsible for the cancer susceptibility in most HBOC families, especially if ovarian cancer or male breast cancer are features. However, in site-specific cancer, BRCA variants are responsible only for a proportion of affected families. BRCA gene variants are inherited in an autosomal dominant fashion through maternal or paternal lineage. It is possible to test for abnormalities in BRCA1 and BRCA2 genes to identify the specific variant in cancer cases and to identify family members at increased cancer risk. Family members without existing cancer who are found to have BRCA variants can consider preventive interventions for reducing risk and mortality.

Young age of onset of breast cancer, even in the absence of family history, is a risk factor for BRCA1 variants. Winchester estimated that hereditary breast cancers account for 36% to 85% of patients diagnosed before age 30. In several studies, BRCA variants were independently predicted by early age at onset, being present in 6% to 10% of breast cancer cases diagnosed at ages younger than various premenopausal age cutoffs (age range, 35-50 years). In cancer-prone families, the mean age of breast cancer diagnosis among women carrying BRCA1 or BRCA2 variants is in the 40s. In the Ashkenazi Jewish population, it was reported that 13% of 248 cases with no known family history and diagnosed before 50 years of age had BRCA variants. In a similar study, 31% of Ashkenazi Jewish women, unselected for family history, diagnosed with breast cancer at younger than 42 years of age had BRCA variants. Other studies have indicated that early age of breast cancer diagnosis is a significant predictor of BRCA variants in the absence of family history in this population.

In patients with “triple-negative” breast cancer (ie, negative for expression of estrogen, progesterone, and overexpression of human epidermal growth factor receptor 2 [HER2] receptors), there is an increased prevalence of BRCA variants. Pathophysiologic research has suggested that the physiologic pathway for the development of triple-negative breast cancer is similar to that for BRCA-associated breast cancer. Young and colleagues studied 54 women with high-grade, triple-negative breast cancer with no family history of breast or ovarian cancer, representing a group that previously was not recommended for BRCA testing. Six BRCA variants (5 BRCA1, 1 BRCA2) were found, for a variant rate of 11%. Finally, in a study of 77 patients with triple-negative breast cancer, it was reported that 15 patients (19.5%) had BRCA variants (12 in BRCA1, 3 in BRCA2).

PIK3CA Testing

Alterations in the protein coding gene PIK3CA (Phosphatidylinositol-4,5-Bisphosphate 3-Kinase Catalytic Subunit Alpha) occur in approximately 40% of patients with HR-positive, HER2-negative breast cancer.

Ki-67

Ki-67 is a nuclear protein used to detect and quantify the rate of tumor cell proliferation and has been investigated as a prognostic biomarker for breast cancer.

Rearranged During Transfection

The REarranged during Transfection (RET) proto-oncogene encodes a receptor tyrosine kinase growth factor. Translocations that result in fusion genes with several partners have been reported, and occur in about 5-10% of thyroid cancer cases (primarily papillary thyroid carcinoma) and 1%-2% of non-small-cell lung cancer cases. RET fusions in breast cancer, occur in less than 1% of cases.

BRAF

RAF proteins are serine/threonine kinases that are downstream of RAS in the RAS-RAF-ERK-MAPK pathway. The most common mutation locus is found in codon 600 of exon 15 (V600E) of the BRAF gene, causing constitutive hyperactivation, proliferation, differentiation, survival, and oncogenic transformation. BRAF mutations occur in approximately 1% of breast cancer cases.

ESR1

Mutations in ESR1, which occur in approximately 10-20% of patients with metastatic estrogen receptor-positive breast cancer, confer resistance to endocrine therapy via constitutive activation of estrogen receptor-mediated growth activity.

Circulating Tumor DNA

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 CTCs. 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.

Circulating Tumor Cells

Intact circulating tumor cells (CTCs) are released from a primary tumor and/or a metastatic site into the bloodstream. The half-life of a CTC in the bloodstream is short (1-2 hours), and CTCs are cleared through extravasation into secondary organs. Most assays detect CTCs through the use of surface epithelial markers such as EpCAM and cytokeratins. The primary reason for detecting CTCs is prognostic, through quantification of circulating levels.

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.

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. Laboratories that offer laboratory-developed tests must be licensed by the Clinical Laboratory Improvement Amendments for high-complexity testing. To date, the U.S. Food and Drug Administration has chosen not to require any regulatory review of these tests.

The table below summarizes available targeted treatments with FDA approval for breast cancer (including immunotherapy) and the FDA cleared or approved companion diagnostic tests associated with each. The information in the table below was current as of October 16, 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 .

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

^aThe FDA-approved indication for adjuvant therapy with abemaciclib was expanded in March 2023 and no longer requires Ki-67 testing. NCCN's recommendation for adjuvant abemaciclib use was similarly updated to no longer stipulate Ki-67 testing.^bCovered in Policy A.2.04.157.dMMR: mismatch repair deficient; ER: estrogen receptor; FDA: U.S. Food & Drug Administration; HER2: human epidermal growth factor receptor 2; HR: hormone receptor; MSI-H: microsatellite instability-high; N/A: not applicable; NCCN: National Comprehensive Cancer Network; NTRK: neurotrophic-tropomyosin receptor kinase; PD-1: programmed death receptor-1; PD-L1: programmed death-ligand 1; PIK3CA: phosphatidylinositol 3-kinase catalytic alpha polypeptide; SERD: selective estrogen receptor degrader; TNBC: triple-negative breast cancer

In August 2021, Genentech voluntarily withdrew accelerated approval of atezolizumab (Tecentriq) for use in patients with PD-L1 positive, triple-negative breast cancer following FDA assessment of confirmatory trial results.

Related medical policies - 

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

• Comprehensive Genomic Profiling for Selecting Targeted Cancer Therapies

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

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

• Assays of Genetic Expression in Tumor Tissue as a Technique to Determine Prognosis in Patients with Breast Cancer

POLICY

BRCA1 and BRCA2 Testing

Genetic testing for BRCA1 or BRCA2 germline variants may be considered medically necessary to predict treatment response to PARP inhibitors (eg, olaparib [Lynparza] and talazoparib [Talzenna]) for human epidermal receptor 2 (HER2)-negative metastatic and early stage, high-risk breast cancer (see Policy Guidelines).

Genetic testing of BRCA1 or BRCA2 germline or somatic variants in individuals with breast cancer for guiding therapy is considered investigational in all other situations.

PIK3CA Testing

PIK3CA testing may be considered medically necessary to predict treatment response to alpelisib (Piqray) in individuals with hormone receptor-positive, HER2-negative advanced or metastatic breast cancer who have progressed on or after an endocrine-based regimen (see Policy Guidelines).

• When tumor tissue is available, use of tissue for testing is preferred but is not required (see Circulating Tumor DNA Testing below).

PIK3CA testing of tissue in individuals with breast cancer is considered investigational in all other situations.

Ki-67 testing

Ki-67 testing to predict treatment response to abemaciclib (Verzenio) in individuals with breast cancer is considered investigational.

RET Testing

RET testing to predict treatment response to selpercatinib (Retevmo) in individuals with breast cancer is considered investigational.

BRAF Testing

BRAF testing to predict treatment response to dabrafenib (Tafinlar) plus trametinib (Mekinist) in individuals with breast cancer is considered investigational.

Circulating Tumor DNA Testing (Liquid Biopsy)

PIK3CA testing using FoundationOne Liquid CDx may be considered medically necessary to predict treatment response to alpelisib (Piqray) in individuals with hormone receptor-positive, HER2 negative advanced or metastatic breast cancer who have progressed on or after an endocrine-based regimen (see Policy Guidelines).

• When tumor tissue is available, use of tissue for testing is preferred but is not required.

ESR1 testing using Guardant360 CDx may be considered medically necessary to predict treatment response to elacestrant (Orserdu) in individuals with estrogen receptor-positive, HER2-negative advanced or metastatic breast cancer with disease progression following at least 1 line of endocrine therapy (see Policy Guidelines).

Circulating tumor DNA testing in individuals with breast cancer is considered investigational in all other situations.

Circulating Tumor Cell Testing

Analysis of circulating tumor cells to select treatment in individuals with breast cancer is considered investigational.

NTRK Gene Fusion Testing

NTRK gene fusion testing may be considered medically necessary for individuals with recurrent unresectable (local or regional) or stage IV breast cancer to select individuals for treatment with FDA-approved therapies.

NTRK gene fusion testing in individuals with breast cancer is considered investigational in all other situations.

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.

See U.S. Food and Drug Administration labels, clinical trials, and NCCN guidelines for specific population descriptions. Descriptions varied slightly across sources.

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

This policy does not address HER2 testing. Agents targeted against HER2 with approved companion diagnostic tests include monoclonal antibodies (margetuximab, pertuzumab, trastuzumab) and antibody-drug conjugates (ado-trastuzumab emtansine, fam-trastuzumab deruxtecan), which are not true targeted therapies.

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

Testing for individual genes (not gene panels) associated with FDA-approved therapeutics (i.e., as companion diagnostic tests) for therapies with National Comprehensive Cancer Network (NCCN) recommendations of 2A or higher are not subject to extensive evidence 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 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.

Breast Cancer Risk Groups

In the OlympiA trial, patients with HER2-negative early-stage breast cancer (Clinical Stage I-III) and germline BRCA1/2 mutations treated with (neo)adjuvant chemotherapy were considered at high risk of recurrent disease when the following eligibility criteria were met for treatment with olaparib:

• Patients with triple-negative breast cancer who were treated with adjuvant chemotherapy were required to have axillary node-positive disease or an invasive primary tumor measuring at least 2 cm on pathological analysis. Patients treated with neoadjuvant chemotherapy were required to have not achieved pathological complete response.

• Patients treated with adjuvant chemotherapy for hormone receptor (HR)-positive, HER2-negative breast cancer were required to have at least 4 pathologically confirmed positive lymph nodes. Those treated with neoadjuvant chemotherapy were required to have not achieved a pathological complete response with a clinical stage, pathologic stage, estrogen receptor status, and tumor grade (CPS+EG) score of 3 or higher (Table 1). This scoring system estimates relapse probability on the basis of clinical and pathological stage (CPS) and estrogen-receptor status and histologic grade (EG). Scores range from 0 to 6, with higher scores reflecting a worse prognosis.

Table 1. CPS+EG Score^a,b

AJCC: American Joint Committee on Cancer; CPS+EG: clinical stage, pathologic stage, ER status, and tumor grade; ER: estrogen receptor.^aAdapted from Tung et al (2021; PMID 34343058).^bAdd points for clinical stage, pathologic stage, ER status, and nuclear grade to yield a sum between 0 and 6.

Paired Genetic Testing

Testing for genetic changes in tumor tissue assesses somatic changes. However, most somatic testing involves a paired blood analysis in order to distinguish whether findings in tumor tissue are acquired somatic changes or inherited germline changes. As such, simultaneous sequencing of tumor and normal tissue can recognize potential secondary germline changes that may identify risk for other cancers as well as identify risk for relatives. Thus, some laboratories offer concurrent full germline and somatic testing or paired tumor sequencing and germline sequencing, through large panels of germline and somatic variants. For paired panel testing involving germline components, see the Genetic Cancer Susceptibility Panels Using Next Generation Sequencing medical policy. For paired panel testing involving somatic components, see the Comprehensive Genomic Profiling for Selecting Targeted Cancer Therapies medical policy.

Genetics Nomenclature Update

The Human Genome Variation Society nomenclature is used to report information on variants found in DNA and serves as an international standard in DNA diagnostics. It is being implemented for genetic testing medical evidence review updates starting in 2017 (see Table 2). The Society's nomenclature is recommended by the Human Variome Project, the HUman Genome Organization, and by the Human Genome Variation Society itself.

The American College of Medical Genetics and Genomics and the Association for Molecular Pathology standards and guidelines for interpretation of sequence variants represent expert opinion from both organizations, in addition to the College of American Pathologists. These recommendations primarily apply to genetic tests used in clinical laboratories, including genotyping, single genes, panels, exomes, and genomes. Table 3 shows the recommended standard terminology- "pathogenic," "likely pathogenic," "uncertain significance," "likely benign," and "benign"- to describe variants identified that cause Mendelian disorders.

Table 2. Nomenclature to Report on Variants Found in DNA

 Table 3. ACMG-AMP Standards and Guidelines for Variant Classification

ACMG-AMP: American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

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:

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

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

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

4. 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

09/01/2021: New policy added. Approved by Medical Policy Advisory Committee.

12/21/2022: Code Reference section updated to revise the description on CPT codes 81445 and 81455, effective 01/01/2023.

01/16/2023: Policy title changed from "Biomarker Testing (Including Liquid Biopsy) for Targeted Treatment and Immunotherapy in Breast Cancer" to "Germline and Somatic Biomarker Testing (Including Liquid Biopsy) for Targeted Treatment and Immunotherapy in Breast Cancer." Policy description updated regarding BRCA variant testing, Ki-67, and targeted treatments for metastatic breast cancer and FDA approved companion diagnostic tests. Added policy statements for BRCA1 and BRCA2 testing and Ki-67 testing. Updated investigational statements for PD-L1 and MSI-H/dMMR testing. Removed medically necessary statement for PD-L1 testing regarding Tecentriq. Policy Guidelines updated regarding breast cancer risk groups, paired genetic testing, genetics nomenclature update, and genetic counseling. Code Reference section updated to add CPT code 0242U as investigational.

03/13/2023: Policy description updated regarding the RET proto-oncogene, BRAF gene, and targeted treatments for metastatic breast cancer and FDA approved companion diagnostic tests. Added investigational statements for RET and BRAF testing. Policy Guidelines updated regarding testing for individual genes.

09/25/2023: Code Reference section updated to add new CPT code 0404U, effective 10/01/2023.

12/21/2023: Code Reference section updated to revise the code descriptions for CPT codes 81445 and 81455, effective 01/01/2024.

04/01/2024: Policy title changed from "Germline and Somatic Biomarker Testing (Including Liquid Biopsy) for Targeted Treatment and Immunotherapy in Breast Cancer" to "Germline and Somatic Biomarker Testing (Including Liquid Biopsy) for Targeted Treatment in Breast Cancer (BRCA1, BRCA2, PIK3CA, Ki-67, RET, BRAF, ESR1)." Policy description updated to remove information regarding Programmed Cell Death Ligand, Mismatch Repair Deficiency/Microsatellite Instability, and Tumor Mutational Burden as these are addressed in a separate medical policy. Added information regarding mutations in ESR1 and targeted treatments for metastatic cancer. Policy section updated to remove statements regarding PD-L1 Testing, MSI-H/dMMR Testing, and Tumor Mutational Burden Testing. Added medically necessary statement regarding ESR1 testing. Policy Guidelines updated to state that this policy does not address HER2 testing. Code Reference section updated to add CPT codes 81162, 81163, 81164, 81165, 81166, 81167, 81212, 81215, 81216, 81217, and 81402. Removed CPT code 81301.

10/01/2024: Code Reference section updated to add new CPT code 0491U.

02/07/2025: Policy title updated to include NTRK. Policy description updated regarding NTRK gene fusion testing and targeted treatments for metastatic breast cancer. Policy statement revised to state that NTRK gene fusion testing may be considered medically necessary for individuals with recurrent unresectable (local or regional) or stage IV breast cancer to select individuals for treatment with FDA-approved therapies.

10/01/2025: Code Reference section updated to add new ICD-10 diagnosis codes C50.A0, C50.A1, and C50.A2.

SOURCE(S)

Blue Cross Blue Shield Association policy # 2.04.151

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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