LCD L38972: MolDX: Lab-Developed Tests for Inherited Cancer Syndromes in Patients with Cancer

This policy describes and clarifies coverage for Lab-Developed Tests (LDTs), Federal Drug Administration (FDA)-cleared, and FDA-approved clinical laboratory tests in hereditary cancer tests including Next Generation Sequencing (NGS) tests as allowable under the National Coverage Determination (NCD) 90.2, under section D describing Medicare Administrative Contractor (MAC) discretion for coverage. This policy’s scope is specific for hereditary germline testing, and is exclusive of polygenic risk scores, solid tumor, hematologic malignancies, circulating tumor deoxyribonucleic acid ( DNA) testing (ctDNA), and other acquired cancer-related tests.

Criteria for Coverage

All the following must be present for coverage eligibility:

• The patient must have

• Any cancer diagnosis

• AND a clinical indication for germline (inherited) testing for hereditary cancer

• AND a risk factor for germline (inherited) cancer

• AND has not been previously tested with the same germline genetic content.

• The test has satisfactorily completed a Technical Assessment (TA) by Molecular Diagnostic Services Program (MolDX ® ) for the stated indications of the test.

• The test performed includes at least the minimum genetic content (genes or genetic variants) with definitive or well-established guidelines-based evidence required for clinical decision making for its intended use that can be reasonably detected by the test.

• Because these genes and variants will change as the literature and drug indications evolve, they are listed separately in associated documents, such as the MolDX® TA forms.

• A single gene or variant may be tested if it is the only gene or variant considered to be reasonable and necessary for a cancer type.

• If a previous test was performed with a similar/duplicative intended use, a subsequent test is only reasonable and necessary if the non-duplicative genetic content of the second test is reasonable and necessary.

• If the test is an NGS test, it must abide by all conditions listed in the NCD 90.2.

Situations in which a test should not be used or coverage is denied:

The test in question will be non-covered if:

• It is an NGS test does not fulfill all the criteria set forth in the NCD 90.2

• A previous test was performed for the same genetic content

• It is a panel or single gene test used to identify a known familial variant(s) that could be identified with a test targeted to that specific variant(s)

• It is a panel or single gene test used to confirm a variant(s) detected by somatic tumor testing that can be confirmed by a test targeted to that specific variant(s)

• A satisfactory TA is not completed

• For tests that are currently covered but a TA submission has not been made, providers must submit complete TA materials by the original effective date of the policy or coverage will be denied.

An estimated 5-10% of cancers have a heritable component, and there are a growing number of hereditary cancer syndromes. 1-5 Identifying pathogenic variants in genes associated with hereditary cancer syndromes can uncover genomic mechanisms that have predictive, diagnostic, and prognostic utility to patients and are used to better their management. 6-8 Pathogenic variants in germline genes have been associated with an increased lifetime risk of hereditary breast and ovarian (HBOC), colorectal (CRC), as well as other cancers, such as endometrial, pancreatic, prostate, and melanoma. Traditionally, testing of genes associated with hereditary cancers was performed based on specific gene-disease relationships and an individual’s personal or family history, often in a single-gene reflex fashion. However, the growing number of genes known to be associated with hereditary cancer syndromes and the overlap between clinical presentations has challenged this paradigm.

The application of NGS technology has facilitated multi-gene panel testing for definitive genes associated with many hereditary cancer syndromes. NGS has been shown to be more efficient than single-gene sequential testing, and is becoming a routine component of the diagnostic process. 1,9-11 For example, BRCA1 and BRCA2 (BRCA1/2) have historically been the most frequently tested genes in HBOC. Yet, it is now estimated that more than half of the individuals with hereditary breast cancer carry pathogenic variants in genes other than BRCA1/2. 10,12-14 Breast cancer is also a component of several other hereditary cancer syndromes, such as Li-Fraumeni syndrome, Cowden syndrome, hereditary diffuse gastric cancer and Peutz-Jeghers syndrome. 15-19 Studies estimate that approximately 30% of all CRC cases are an inherited form of disease 20-22 and nearly 5% are associated with highly penetrant hereditary clinical presentations. Lynch syndrome (LS), previously known as hereditary non-polyposis colorectal cancer (HNPCC), is the most common hereditary CRC syndrome accounting for 2-3% of all CRC. It is caused by germline pathogenic variants in 5 mismatch repair genes, MHL1 , MSH2, MSH6, EPCAM and PMS2. Traditionally, a testing cascade of microsatellite instability (MSI) analysis and/or immunohistochemistry was performed followed by testing of individual single genes. However, NGS allows for a majority of the genes to be tested simultaneously, reducing the time to diagnosis and reducing costs. 11,23 The National Comprehensive Cancer Network (NCCN) guidelines have also expanded to incorporate testing of multiple genes into medical management recommendations. 5,24-26 The established Centers for Medicare and Medicaid Services (CMS) NCD 90.2 confirms testing using NGS to be both reasonable and necessary in Medicare beneficiaries.

Clinical Indications and Risk Factors

Although inherited cancer syndromes each have their own clinical criteria for testing, there are some findings that are associated more frequently with hereditary cancers when compared to those that are acquired including: diagnosis at an earlier age than what is typically seen for that cancer type, 2 or more affected close blood relatives (first-, second-, and third-degree relatives) on the same side of the family with the same type of cancer, and multiple affected generations within 1 family. Additional findings include multiple cancer types occurring in the same individual, cancers that develop bilaterally, and presence of congenital conditions known to be associated with a particular cancer syndrome. 3,27