LCD L38566: MolDX: Phenotypic Biomarker Detection in Circulating Tumor Cells

This is a limited coverage policy for assays that detect biomarkers from circulating tumor cells (CTCs).

Criteria for Coverage

Cancers with established biomarker testing, as recommended by society or national guidelines

Assays that detect biomarkers from CTCs are covered when ALL of the following are met:

• The patient has been diagnosed with cancer

• The specific cancer type has an associated biomarker

• The associated biomarker has already established clinical utility (CU) in the peer-reviewed published literature for the intended cancer type and for the specific indication in the intended patient population

• The biomarker’s CU may include any of the following: it can be used to diagnose, risk-stratify, predict, or monitor response to therapy, as recommended by national or society guidelines (i.e., American Society of Clinical Oncology (ASCO), National Comprehensive Cancer Network (NCCN))

• At least 1 of the following criteria are met AND there is clear documentation of at least 1 of these in the medical record:

• The patient’s cancer has not previously been tested for the specific biomarker, OR

• The patient has newly metastatic cancer, and a metastatic lesion has not been tested for the specific biomarker, OR

• The patient demonstrates signs of clinical, radiological or pathologic disease progression, OR

• There is concern for resistance to treatment based on specific and well-established clinical indications

• Testing for the biomarker can be performed using CTCs

• The CTC-based biomarker test successfully completes a comprehensive Technical Assessment (TA) by Molecular Diagnostic Services Program (MolDX ® ) that will ensure that Analytical Validity (AV) (including an analytical and clinical validation), Clinical Validity (CV), and CU criteria are met to establish the test as Reasonable and Necessary.

• The clinical validation has demonstrated performance that is equivalent or superior to tissue-based testing or another already-accepted test for the same biomarker for the same intended use.

• CV (for new analytes) must be established through studies published in the peer-reviewed literature for the intended use of the test in the intended population.

• Tissue-based testing for the specific biomarker is infeasible (e.g., quantity not sufficient or invasive biopsy is medically contraindicated) OR will not provide sufficient information for subsequent medical management (e.g., in cases where human epidermal growth factor receptor 2 (HER2) overexpression is negative in a tissue biopsy but may be positive in the CTCs, due to tumor heterogeneity). There is clear documentation of at least 1 of these reasons for testing in the medical record.

• For a given patient encounter, only 1 test for assessing the biomarker may be performed UNLESS a second test, meeting all the criteria established herein, is reasonable and necessary as an adjunct to the first test.

• Duplicate testing of the same biomarker ( from the same sample type and for the same clinical indication ) using different methodologies is not covered. For example, testing for androgen receptor splice variant 7 (AR-V7) from CTCs by messenger RNA (mRNA) as well as immunohistochemistry (IHC)-based methodologies, for the same clinical indication, will not be covered.

Testing for biomarkers in cancer is often a routine part of medical care. 1 Biomarker testing can be performed from tissue samples, or from samples obtained using less-invasive means such as the liquid biopsy. In the liquid biopsy approach, testing is performed on cancer-derived components (including CTCs) found in peripheral blood or other body fluids. 2 Specifically, the testing of CTCs in liquid biopsy specimens involves cell capture, enrichment, and downstream molecular characterization, with the goal of impacting disease management in cancer. 3 Current technological approaches for identifying biomarkers from CTCs include distinguishing the comparatively rare tumor cells from among the large number of normal cells by image processing and/or direct capture techniques, along with staining for the biomarker of interest. 4-7

CTCs can be used to detect biomarkers important for prognosis, identifying treatment, and monitoring response to treatments in cancer. Biomarker detection from CTCs may therefore serve as a potential alternative to biomarker detection from biopsy specimens for certain cancers, including breast and prostate. 4-7

Breast Cancer

In 1998 the Food and Drug Administration (FDA) approved the drug Herceptin ® (trastuzumab) for the treatment of HER2 over-expressing breast cancer. Testing for HER2 has become 1 of the most important sources of information in making management decisions regarding systemic therapy in breast cancer. The NCCN guidelines on breast cancer recommend that all patients who have new primary or newly metastatic breast cancers be tested for HER2 using a methodology outlined in the ASCO/College of American Pathologists (CAP) guideline. 8,9 Traditionally, testing for HER2 was performed using tissue. Testing from tissue, however, can be associated with complications. For example, breast malignancies may metastasize to the brain, 10 and analyses of complications following brain biopsies have shown a wide array of complications ranging from neurologic complications to general surgical complications. 11,12