This policy describes and clarifies coverage for Lab-Developed Tests (LDTs),
Food and Drug Administration (FDA)-cleared, and FDA-approved clinical
laboratory tests utilizing Next-Generation Sequencing (NGS) in cancer 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 solid tumor testing, and is exclusive of
hematologic malignancies, circulating tumor DNA testing (ctDNA), and other
cancer-related uses of NGS, such as germline testing in/for patients with
cancer.

NGS testing in solid tumors is becoming a routine component of the diagnostic
process1; the results can uncover the genomic mechanisms of cancer that have
predictive, diagnostic, and prognostic utility to the patient and are used to
better their management.2 Understanding the mechanisms of disease and
targeting treatment based on those aberrant processes (i.e., targeted
therapies for biomarkers) has improved patient outcomes in many tumor types
and is the basis of Precision Medicine.3 Capturing mutations and other
relevant genetic/genomic information is standard of care for determining
clinical care for many tumor types, including the most common, such as
melanoma, lung, colorectal, and breast carcinoma.4-7 NGS adds the ability to
capture abundant genomic data both efficiently, and relatively cheaply, and
its use is showing to improve patient outcomes although studies in this regard
are ongoing.8 The established Centers for Medicare & Medicaid Services (CMS)
National Coverage policy NCD 90.2 confirms these tests to be both reasonable
and necessary in Medicare beneficiaries.

**Professional Society Clinical Practice Guidelines**  
Guidelines for validating clinical NGS tests for use in cancer have been
published in a joint effort by the Association for Molecular Pathology and the
College of American Pathologists.9 Guidelines for employing bioinformatics
pipelines for NGS testing have also been published by these groups10, as well
as guidelines for interpreting somatic variants in these panels (these same
groups in collaboration with the American Society of Clinical Oncology).11

Guidelines from several societies currently suggest or prefer the use of NGS
over other methods for lung cancer12,13 and colorectal cancer.14,15

Additionally, societal guidelines recommend genetic testing for other tumor
types that can be identified by NGS, such as melanoma, thyroid, brain, and
ovarian cancers, among others.7,16-20

**Test Description**  
NGS is not a specific test, but a sequencing methodology utilized to capture
genomic information. Unlike Sanger sequencing (the prior standard technology)
that typically provides sequence information for a single deoxyribonucleic
acid (DNA) strand/molecule, NGS allows for massively parallel sequencing of
millions of DNA molecules concurrently.21,22 This allows for capturing many
relevant genomic targets simultaneously, usually by utilizing capture
technologies such as polymerase chain reaction (PCR) amplification or hybrid
capture. As such, NGS tests for use in cancer are often comprised of gene
panels whose content is either relevant to a specific tumor type or condition,
or a larger panel of genes that can be used for multiple tumor types.

NGS tests can vary significantly for many reasons. While NGS defines a broad
methodology for massively parallel sequencing, different technologies that
have different strengths, weaknesses, and technical limitations or liabilities
are available.23 The most common sequencing platforms in clinical use today
are from Illumina and Thermo Fisher. While both sequence by synthesis similar
to Sanger sequencing, these platforms utilize different chemistries, signal
amplification, and detection methods. Gene panels can include only the
portions of genes that contain the most critical clinically relevant
information, or be comprehensive, containing entire exonic gene regions
(coding regions), introns (non-coding regions), and even sequence ribonucleic
acid (RNA) for detecting gene fusions. Downstream from the pre-analytic
processes mentioned above, the bioinformatics used to process and assess the
resultant sequencing reads and identifies variants/mutations which can yield
different results based on the software used and what types of variants the
test is attempting to detect. These software tools must take the resultant
sequencing file (generally starting with the FASTQ format), align all possible
sequences with a reference genome (BAM/SAM), and identify variants from the
reference (typically a VCF file).10 Once such variants are identified, they
must be assessed for validity and subsequently for their clinical relevance.
The types of genomic information reported can vary, as tests can uncover a
myriad of genomic alterations such as single nucleotide variants (SNVs),
Insertions/Deletions (INDELs), Copy Number Alterations (CNAs; these can be
simply amplifications at a single locus or chromosomal gains and losses), and
gene fusions/translocations. The resultant information can also be used to
calculate additional relevant information, such as Tumor Mutation Burden
(TMB), or the presence of microsatellite instability (MSI). All of these
variant classes have demonstrated clinical utility.

As such, NGS testing in cancer comprises a large heterogeneous group of assays
that are substantially different from each other. Additionally, NGS testing is
highly complex and requires expertise from handling the specimen, to running
complex equipment, to understanding the required bioinformatics, to
interpreting the findings and creating an actionable medical report.

Two types of tests are considered for coverage, "Hot-spot" tests and
comprehensive genomic profile tests. The definition of these terms, in
addition to appropriate coding information is located in the Coverage Articles
associated with this Local Coverage Determination (LCD). These tests can
detect any combination of the previously described variant types, but in
general, Hot-spot tests are limited to SNVs and small INDELs, whereas CGPs can
detect those variants in addition to CNAs, larger INDELs, gene
fusions/translocations, and can be used to calculate MSI status and TMB.

**Analytical Validity and Clinical Utility**  
Because of the number of variables described above, additional work must be
performed to assess if any given test is both reasonable and necessary for
Medicare beneficiaries and to ensure that Medicare claims are properly
understood and executed. Molecular Diagnostic Services Program (MolDX) has
instituted a process for completing a Technical Assessment (TA) that ensures
that tests are appropriate for their indications and are properly validated
according to published guidelines described above (when applicable).
Specifically, in order to understand if a test is both reasonable and
necessary, it must be delineated if a test has the properly validated
technology, variant types, gene and variant coverage, and bioinformatics
capability to deliver a clinically useful result for the Medicare beneficiary,
given their diagnosis.

Labs seeking coverage for LDTs, FDA-cleared, or FDA-approved tests that are
not nationally covered utilizing NGS in cancer must submit documentation to
allow MolDX to complete a TA. Forms to complete the process are available on
the MolDX website. Tests that are currently covered by Palmetto GBA are not
exempt from this process. Tests that are currently covered and have not
undergone a TA by MolDX will be non-covered unless complete documents to
perform a TA are submitted in a timely manner described below.

**Criteria for Coverage**

All the following must be present for coverage eligibility:

  * As per NCD 90.2, this test is reasonable and necessary when: 
    * the patient has either: 
      * Recurrent cancer
      * Relapsed cancer
      * Refractory cancer
      * Metastatic cancer
      * Advanced cancer (stages III or IV)
    * AND has not been previously tested by the same test for the same genetic content
    * AND is seeking further treatment
  * The test has satisfactorily completed a TA by MolDX for the stated indications of the test
  * The assay performed includes at _least_ the minimum genes and genomic positions required for the identification of clinically relevant FDA-approved therapies with a companion diagnostic biomarker as well as other biomarkers known to be necessary 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.

**Situations in which Test should not be used or coverage is denied:**  
The test in question will be non-covered if:

  * It does not fulfill all the criteria set forth in the NCD 90.2 as stated above
  * Another CGP test was performed on the same tumor specimen (specimen obtained on the same date of service)
  * A TA is not completed satisfactorily by MolDX for new tests
  * For tests that are currently covered but a TA submission has not been made, providers must submit completed TA materials by February 10th, 2020, or coverage will be denied

**Level of Evidence**  
Quality: Strong/variable depending on biomarker and specific test  
Strength: Strong/variable depending on biomarker and specific test  
Weight: Strong/variable depending on biomarker and specific test

Given the abundant literature on genetic and genomic testing in cancer
diagnosis and care, this contractor feels strongly that NGS methodology for
testing is appropriate for use in Medicare beneficiaries. However, given the
variability for what information tests can provide, additional information
must be submitted by providers to ensure the contractor A) understands what
test is being performed; B) Why it is being performed; C) If the test is both
necessary and reasonable for cancer care for its intended use.