Response to Comments: Genetic Testing for Oncology

Please note that multiple comments were received regarding the Contractor’s compliance with various regulations. Comments 1-7 address these comments, but the lead in paragraph below will not be repeated in each comment.

Multiple comments were received regarding the Contractor’s compliance with various regulations, including:

• Protecting Access to Medicare Act of 2014 (42 U.S.C. § 1395m-1(g)(1)(A))
• 21st Century Cures Act (Pub. L. 114-255, Sec. 4009; 42 U.S.C. § 1395y(l)(5)(D); SSA 1862(l)(5))
• Definition of an LCD (42 U.S.C. § 1395ff(f)(2)(B); SSA 1869(f)(2)(B))
• CMS IOM Publication 100-08, Medicare Program Integrity Manual, Chapter 13 Local Coverage Determination.

The proposed LCD does not meet the definition of an LCD “a determination by a fiscal intermediary or a carrier under part A or part B, as applicable, respecting whether or not a particular item or service is covered on an intermediary–or carrier–wide basis under such parts, in accordance with section 1862(a)(1)(A).”

Thank you for your comments.

The proposed LCD does meet the definition of an LCD as it addresses the particular service DNA and RNA testing in the practice of oncology in the Medicare population. To follow the precedent established by CMS, National Coverage Determinations (NCDs) do not routinely address each individual company’s item or service but rather address the overall item or service. Examples include NCD 90.2 Next Generation Sequencing (NGS) and NCD 190.3 Cytogenetic Studies.

In addition, category I CPT codes are not typically specific to an individual company’s item or service. While we are aware that the Proprietary Laboratory Analyses (PLA) codes are company specific, sequencing of DNA and RNA is not unique to one company even if subsequent analytics such as algorithms can be company specific.

The Summary of Evidence contains a narrative that describes the scientific evidence supporting the selection of the three knowledge bases chosen to determine whether the item or service meets the SSA 1862(a)(1)(A) reasonable and necessary criteria. In addition, the Analysis of Evidence has been revised to address how the potential knowledge bases were evaluated against the Good Practice Guidelines found in the Clinical Practice Guidelines: Directions for a New Program written by the Institute of Medicine in 1990. Also, the final LCD contains a narrative that describes the scientific evidence used to make coverage determinations for specific DNA and RNA tests brought to our attention during the comment period. These tests were not covered through any of the three selected knowledge bases and the majority were reviewed individually based on the comments from the stakeholders.

It is not clear how CPT codes were chosen for coverage or non-coverage and how particular diagnosis codes were chosen for inclusion, given that the LCD contains no discussion of covered clinical indications for any particular test. Also, the requirement of dual diagnosis codes for commonly performed services will create undue burden on providers and would be incorrect coding per the ICD-10-CM instructions.

For both CPT and ICD-10 codes, all categorization (groups 1-81) within the final LCA was determined through a review of the three knowledge bases and/or a review of peer reviewed literature for the specific tests. CPT codes were placed in the non-coverage category when the specific test or DNA/RNA analysis was not found in one of the three knowledge bases or was not adequately supported for clinical validity and/or clinical utility in peer reviewed literature.

To address the concern that dual diagnosis coding is an undue burden to providers, the Contractor asserts that histologic, cytologic, and/or flow cytometric evidence of cancer or a suspicion of cancer is an important precursor to molecular testing. In NCD 90.2 for Next Generation Sequencing (NGS), CMS requires that the beneficiary have recurrent, relapsed, refractory, metastatic, or advanced stage III or IV cancer for somatic cancers and a cancer diagnosis for germline cancer. However, we recognize dual diagnosis coding would not always be correct coding. Therefore, it was decided that for most of the listed CPT codes, this would not be an appropriate requirement. For some testing described by CPT codes, dual diagnosis ICD-10-CM coding is still appropriate.

The Contractor proposes to “outsource” determinations of reasonableness and medical necessity of a test to unaccountable “knowledge bases,” based on their inclusion or exclusion of the test.

The contractor followed the precedent outlined in the CMS IOM Publication 100-02, Chapter 15, Section 50.4.5 - Off-Label Use of Drugs and Biologicals in an Anti-Cancer Chemotherapeutic Regimen. CMS uses the American Hospital Formulary Service-Drug Information (AHFS-DI), National Comprehensive Cancer Network (NCCN) Drugs and Biologics Compendium, Micromedex DrugDex, Clinical Pharmacology, and Lexi-Drugs to determine medically reasonable and necessary off label use. In addition, NCCN was recognized by CMS in 2016 and renewed in 2021 as a qualified Provider Led Entity (PLE) for the Medicare Appropriate Use Criteria (AUC) Program for the development of AUC and the establishment of policy and decision-making for diagnostic imaging in patients with cancer. 

The Contractor did not explain how often each of the selected “knowledge bases” updates or changes their guidelines, whether or how often they would review the “knowledge bases” to search for guideline changes, and whether they would follow the requirements set forth in the Medicare Program Integrity Manual, Chapter 13, Section 13.2 for providing the public with advance notice of non-coverage of a test.

The three knowledge bases we are referencing, Memorial Sloan Kettering Cancer Center Oncology Knowledge Base (OncoKB), National Institute of Health funded Clinical Genome Resource (ClinGen), and NCCN, are updated as follows: OncoKB updates their data and website approximately monthly, and states they aim to update Food and Drug Administration (FDA) approved content as soon as possible. The ClinGen website updates occur quarterly, and approved gene-disease validity classifications are re-curated on a set schedule, depending on the strength of the classification (definitive, strong, moderate, limited, etc.). National Comprehensive Cancer Network Guidelines are reviewed and updated at least annually, and interim Guidelines Panel meetings are held throughout the year to evaluate new evidence and regulatory approvals of drugs or biologics. Guidelines may not be changed if a change is not warranted based on the reviewed evidence. It should be noted that all three knowledge bases allow test developers to request inclusion, based on evidence review. As the knowledge bases are updated, the LCA will also be updated in compliance with the Medicare regulatory requirements. If a current knowledge base no longer meets LCD inclusion criteria, the Contractor will follow the IOM LCD process for updating an LCD. As a reminder, the LCD has been revised to include an option to submit an LCD reconsideration request for a determination whether a specific DNA/RNA test meets CMS IOM Publication 100-08, Chapter 13, Section 13.5.4 reasonable and necessary criteria.

The LCD reconsideration process would be eliminated by the proposed LCD.

The LCD has been revised to include an option to submit an LCD reconsideration request for a determination whether other knowledge bases or a specific DNA/RNA test meets CMS IOM Publication 100-08, Chapter 13, Section 13.5.4 reasonable and necessary criteria.

The LCD would limit beneficiary access to care and change current coverage to noncoverage.

The purpose of the LCD is not to limit beneficiary access to care but to ensure that Medicare is paying for services/tests that are deemed medically reasonable and necessary as supported by evidence.

It is important to assess genetic testing in the context of oncology with a rigorous, evidence-based approach to facilitate the appropriate testing for all eligible Medicare beneficiaries.

The majority of the CPT codes non-covered in the Genetic Testing for Oncology article are not found in the current, active LCDs (e.g., Biomarkers for Oncology) addressing this topic. These CPT codes are only located in the coding guideline Billing and Coding: Molecular Pathology and Genetic Testing A58917 (JH/JL) A58918 (JN) which includes the statement “This instruction focuses on coding and billing for molecular pathology diagnostics and genetic testing. Nothing stated in this instruction implies or infers coverage.” (emphasis added)

Payment for services granted on a claim-to-claim basis and not addressed by any currently active LCDs does not guarantee coverage of these services in the future.

The Contractor did not follow the requirements for consultation prior to releasing the proposed LCD.

CMS IOM Publication 100-08, Chapter 13, Section 13.2.3 Clinical Guidelines, Consensus Documents & Consultation states: “Prior to drafting and during the development of an LCD, if available the MACs shall supplement their research (see section 13.5.3) with clinical guidelines, consensus documents or consultation by experts (recognized authorities in the field), medical associations or other health care professionals for an advisory opinion, when applicable.” (emphasis added)

MACs are given discretion (“if available”, “when applicable”) in deciding when supplementary material, if any, is required for development of an LCD. Moreover, which type of supplementary material utilized (“clinical guidelines, consensus documents or consultation by experts, medical associations or other health care professionals”) is also at the MACs’ discretion.

The Contractor supplemented their research through guidelines such as Clinical Practice Guidelines: Directions for a New Program from the Institute of Medicine and clinical practice guidelines published by the NCCN. As referenced in the LCD, Poonacha and Go state that clinical practice guidelines published by NCCN are “the most comprehensive and widely used standard in clinical practice in the world.”

Multiple comments were received regarding the Contractor limiting coverage to three multiple-evidence based third-party knowledge bases, OncoKB, ClinGen, and NCCN. Please note that comments 8 through 15 all address this concern, but the lead in paragraph will not be repeated in each comment.

It is not appropriate to cede evidence curation and analysis to third-party guideline compendia in the context of a Medicare coverage determination.

Thank you for your comments.

The Contractor followed the precedent outlined in the CMS IOM Publication 100-02, Chapter 15, Section 50.4.5 - Off-Label Use of Drugs and Biologicals in an Anti-Cancer Chemotherapeutic Regimen. CMS uses the AHFS-DI, NCCN Drugs and Biologics Compendium, Micromedex DrugDex, Clinical Pharmacology, and Lexi-Drugs to determine medically reasonable and necessary off label use. In addition, NCCN was recognized by CMS in 2016 and renewed in 2021 as a qualified PLE for the AUC Program for the development of AUC and the establishment of policy and decision-making for diagnostic imaging in patients with cancer.

The LCD does not explain why the three particular “knowledge bases” were chosen, why others were not chosen, and why other types of evidence-based resources, such as professional society recommendations, were not chosen. There is no discussion as to how the attributes in the Institute of Medicine (US) Committee to Advise the Public Health Service on Clinical Practice Guidelines, which were recommended in a report published in 1990, are relevant to coverage of genetic tests and how the selected knowledge bases meet the recommended attributes.  

As identified in the Institute of Medicine’s seminal work Clinical Practice Guidelines: Directions for a New Program, there are eight recommended attributes for clinical practice guidelines. These include validity, reliability/reproducibility, clinical applicability, clinical flexibility, clarity, development via a multidisciplinary process, scheduled review, and documentation. These attributes were referenced in the selection of knowledge bases for genetic testing.

The “Summary of Evidence” section within the LCD contains a comprehensive narrative that describes the evidence supporting the selection of the three knowledge bases chosen to determine whether the item or service meets the SSA 1862(a)(1)(A) reasonable and necessary criteria. In addition, the “Analysis of Evidence” section within the LCD has been revised to further delineate how all potential knowledge bases were evaluated against the Good Practice Guidelines.

To provide contrast with knowledge bases that were selected for use in the LCD, here are a few knowledgebases that were considered but not selected, with key points leading to this decision:

Human Gene Mutation Database (HGMD^®) (www.hgmd.cf.ac.uk)

• Requires paid subscription to access

COSMIC (cancer.sanger.ac.uk; accessed March 21, 2023)

• Lack of transparency regarding both curators and their COIs
• Vague criteria for review of publications and evidence in regards to genetic mutations
• Licensing requirements (through QIAGEN) for commercial access to Actionability Data

Online Mendelian Inheritance in Man^® (OMIM)

• Lack of transparency regarding both curators and their COIs
• Vague criteria for review of publications and evidence in regards to genetic mutations

The LCD did not explain how often each of the selected knowledge bases updates or changes their guidelines, whether or how often the Contractor would review these and other knowledge bases to determine if they continue to meet IOM guidelines and to search for guideline changes, whether the contractor would provide the public with advance notice of non-coverage of a test, and what will happen if a knowledge base no longer meets the guidelines.

Please refer to Comment and Response #4.

None of the selected knowledge bases are designed to assess clinical utility and analytical validity. Further, none of these knowledge bases are designed to be test technology validators.

Per the CMS website, CMS regulates all laboratory testing (except research) performed on humans in the U.S. through the Clinical Laboratory Improvement Amendments (CLIA) in order to ensure accurate and reliable test results. All clinical laboratories must be properly CLIA certified to receive Medicare payments.

The analytical validation under CLIA includes an analysis of accuracy, precision, analytical sensitivity, analytical specificity, reportable range, reference interval, and any other performance characteristics required for the test system in the laboratory that intends to use it.

The FDA regulates manufacturers and devices under the Federal Food, Drug, and Cosmetic Act (FFDCA) to ensure that devices are reasonably safe and effective. The FDA defines laboratory tests as devices. The FDA’s review of analytical validity is done prior to the marketing of the test system. Per the FDA, a Laboratory Developed Test (LDT) is an in vitro diagnostic test that is manufactured by and used within a single laboratory (i.e., a laboratory with a single CLIA certificate). Laboratory Developed Tests are subject to regulatory oversight by the FDA and are considered “devices”.

For an LDT developed without receiving FDA clearance or approval, CLIA prohibits the release of any test results prior to the laboratory establishing certain performance characteristics relating to analytical validity for the use of that test system in the laboratory’s own environment [see 42 CFR 493.1253(b)(2)]. Clinical Laboratory Improvement Amendments limits the analytical validation to the specific conditions, staff, equipment, and patient population of the particular laboratory. The laboratory-specific analytical validation is not meaningful outside of the laboratory that did the analysis. In addition, the laboratory’s analytical validation of LDTs is reviewed during CLIA’s routine biennial survey.

The FDA’s premarket clearance and approval processes also assesses clinical validity, which is the accuracy with which the test identifies, measures, or predicts the presence or absence of a clinical condition or predisposition in a patient, as part of the review that is focused on the safety and effectiveness of the test system.

Each of the knowledge bases chosen (ClinGen, NCCN, and OncoKB) have an evidence-based process for reviewing biomarkers/assays and providing a level of evidence or recommendation for their use. This process includes evaluation of the biomarker/assay’s clinical validity and clinical utility. If a biomarker/assay is included in one of the three knowledge bases and meets the criteria as described in the LCD, it will be considered that the requirements for clinical validity and clinical utility have been met.

Clinical utility is addressed by all three knowledge bases as demonstrating actionability in clinical decision making.

• For OncoKB, actionability in clinical decision making is met when Level 1, 2, or R1 (therapeutic), Level Dx1 or Dx2 (diagnostic), or Level Px1 or Px2 (prognostic) are met.
• For ClinGen, actionability in clinical decision making is met when the disease severity meets Level 1, 2, or 3, AND the likelihood of disease meets Level 3A or 3B, AND the effectiveness of the intervention meets Level 2A, 2B, 3A, or 3B, AND the nature of intervention meets Level 2 or 3 AND the validity of the gene-disease relationship meets moderate, strong, or definitive.
• For NCCN, actionability in clinical decision making is met when Category 1 or 2A are met.

It takes years for innovative tests to be included in consensus-based clinical practice guidelines, despite sufficient evidence of analytical and clinical validity and clinical utility for indications relevant to Medicare beneficiaries. Certain types of oncology biomarker tests, such as multi-analyte assays with algorithmic analysis (MAAAs), tumor mutational burden (TMB) tests, minimal residual disease (MRD) tests, or comprehensive genomic profiling (CGP), are not included in all three knowledge bases. Multi-analyte assays with algorithmic analysis, TMB tests, MRD tests, and CGP are dependent on inclusion in the NCCN guidelines. Requiring inclusion in one of the three “knowledge bases” would create a barrier to access to critical diagnostics for Medicare beneficiaries.

We understand that two of the three knowledge bases selected do not include MAAAs, TMB tests, MRD tests, or CGP. Each of the knowledge bases selected has a different lens with which to view genetic tests for oncology. For instance, OncoKB focuses on somatic variants. Due to concerns expressed regarding the requirement for use of one of the three multiple-evidence based third-party knowledge bases, the LCD has been revised to include an option to submit an LCD reconsideration request for a determination whether the test meets CMS IOM Publication 100-08, Chapter 13, Section 13.5.4 reasonable and necessary criteria. 

There is no open meeting for any of the three knowledge bases listed for interested parties to transparently discuss the evidence supporting a coverage or non-coverage decision or to understand the evidence reviewed by the knowledge bases’ committee members. These knowledge bases and guideline committees have the ability to be as rigid and unchanging or as fluid and everchanging in their recommendations as they deem appropriate, creating an inaccessible and unstable system for determining if a test is covered.

All three of these knowledge bases allow test developers to request inclusion, based on an evidence review. Each has their own process for submitting evidence for evaluation and inclusion, and we would encourage test developers to follow those processes if they are interested in having their proprietary laboratory analyses included. We encourage you to visit their individual websites for more information about this process.

Due to concerns expressed regarding the requirement for use of one of the three multiple-evidence based third-party knowledge bases, as noted above, the LCD has been revised to include an option to submit an LCD reconsideration request for a determination whether the test meets CMS IOM Publication 100-08, Chapter 13, Section 13.5.4 reasonable and necessary criteria.

The NCCN decentralizes decision-making to individual disease-state based committees that vary in their structure and composition which may not reflect input from certain specialties or subsets of healthcare providers. The NCCN guideline committees represent only 45% of National Cancer Institute centers and are not bound to or well versed in the criteria established by Medicare to determine reasonableness and necessity. They do not have any requirement to provide evidence review on specific tests. The NCCN does not use a formal objective process to evaluate evidence. Rather, recommendations are included by consensus-based approach, making comparisons between NCCN committee members’ criteria for assigning level of evidence to the criteria set up by Medicare impossible. Also, concerns were expressed with regard to NCCN Category 2B recommendations being non-covered, which will result in non-coverage of numerous tests that are currently allowable under existing policies.

NCCN, is only one of the databases in the LCD that providers may use. It was selected as a knowledge base because it is evidence-based, widely available, created and/or facilitated by an organization with a focus on oncology, and met criteria including development via a multidisciplinary process, scheduled review, and documentation. In addition, NCCN was selected based on their use of multiple experts in this rapidly evolving field, rigorous standards, and acceptance by CMS. While NCCN does use panel consensus to determine guidelines inclusion and/or classification of evidence categories, it should be noted that this follows a thorough review of the evidence. We found no NCCN Category 2B tests in the compendium that were genes with positive coverage statements in any other JN active LCDs. As a reminder, providers have the option to submit an LCD reconsideration request for a determination whether a test meets CMS IOM Publication 100-08, Chapter 13, Section 13.5.4 reasonable and necessary criteria.

Inclusion in NCCN guideline documents does not always have a corresponding entry in the NCCN Biomarker Compendium.

With regard to the NCCN Guidelines not always relating to inclusion in the Biomarkers Compendium, we recognize this is a challenge. For the purposes of coverage related to this LCD, inclusion in the guidelines or inclusion in the Biomarkers Compendium are interchangeable (either is acceptable with Category 1 or 2A classification). Furthermore, if a test is included in Guidelines but not the Biomarkers Compendium, NCCN has historically been appreciative to receive this information from the provider community. Please remember that NCCN Guidelines are only one mechanism in the LCD for determining coverage and providers have the option to submit an LCD reconsideration request for a determination whether a test meets CMS IOM Publication 100-08, Chapter 13, Section 13.5.4 reasonable and necessary criteria.

A comment was received agreeing with NCCN’s comments during the Open Meeting.

NCCN supports the Contractor’s use of evidence-based and continuously updated clinical guidelines to ensure patients with cancer have access to appropriate testing. As noted within the Proposed LCD, NCCN Guidelines are developed by multidisciplinary expert panels from NCCN Member Institutions in an evidence-based process integrated with expert consensus. The NCCN Guidelines are updated at least annually, but quite often are updated more frequently, with 215 total version updates across all guidelines in 2021.

The NCCN Guidelines are considered the standard for clinical care and policy in oncology in the United States. Our Guidelines are also available through a multitude of health information technology vendors, used by payers representing more than 85% of covered lives in the United States, and form the basis for insurance coverage policy and quality evaluation. NCCN was recognized by CMS in 2016 and renewed in 2021 as a qualified PLE for the AUC Program for the development of AUC and the establishment of policy and decision-making for diagnostic imaging in patients with cancer.

The NCCN imposes strict policies to shield the guidelines development processes from external influences. The "firewall" surrounding the NCCN Guidelines processes includes: financial support policies; panel participation and communication policies; guidelines disclosure policies; and policies regarding relationships to NCCN's other business development activities. The guidelines development is supported exclusively by the Member Institutions' dues and does not accept any form of industry or other external financial support for the guidelines development program.

External parties are invited to submit requests for specific issues or topics to be discussed and considered by the NCCN Guidelines Panel. Examples of such parties include patient advocates, clinicians, industry, and/or payers. Guidelines panels will consider published scientific data for drugs, biologics, diagnostics, procedures, or devices used for cancer prevention, detection, treatment, or supportive care within the NCCN Guidelines. Submissions are accepted throughout the year and are triaged to be addressed on an interim basis or during the annual review process. Submission Requests are requested to be two to four pages in length and include contact information, Guidelines Panel name, specific changes recommended, whether the submitted use is FDA approved or not for that indication, rationale for the recommended changes, and citation of relevant literature supporting the recommended changes.

As part of the NCCN practices to ensure transparency, any discussion and/or changes to recommendations in the Submission Request are listed in the transparency document along with the actions taken by the Guidelines Panel. Additionally, the original Submission Request materials are posted to the NCCN website concurrently with the transparency document. Additional information can be found on the NCCN Submission Request website located at
https://www.nccn.org /guidelines/submissions-request-to-the-guidelines-panels.

The NCCN Biomarkers Compendium^® is intended to be a resource for payers, providers, and health care entities navigating the rapidly changing evidence-base for medically necessary biomarker testing in oncology. The NCCN Biomarkers Compendium® contains information derived directly from the NCCN Guidelines to support decision-making around the use of biomarker testing in patients with cancer. The NCCN Biomarkers Compendium is updated continuously in conjunction with the NCCN guidelines to stay evergreen. The goal of the NCCN Biomarkers Compendium is to provide essential details for testing methodologies which have been approved by NCCN Guideline Panels and are recommended within the NCCN Guidelines. Included in the Biomarkers Compendium are testing methodologies that measure changes in genes or gene products and used for the purposes of diagnosis, screening, monitoring, surveillance, prediction, and prognostication. Numerous independent studies have found adherence to NCCN Guidelines improves care delivery and outcomes for patients with cancer.

 Thank you for your comments.

Multiple comments were received requesting clarification regarding several of the Contractor’s existing LCDs. Commenters requested to know which LCDs/LCAs would be retired when the Genetic Testing for Oncology LCD is finalized. Also, commenters requested information regarding non-genetic tests currently covered in some of the LCDs and whether a new policy assuring coverage would be written. Commenters also requested information regarding the coding guidance article A58918).

Thank you for your comments. As discussed during the June Open Meeting, the following LCDs/LCAs will be retired following finalization of the proposed LCD:

• L36499/A57449 BRCA1 and BRCA2 Genetic Testing,
• L34912/A57450 Genetic Testing for Lynch Syndrome, and
• L34519/A57451 Molecular Pathology Procedures.

Following the process for retiring LCDs/LCAs, the LCDs/LCAs will be retired on the date the new LCD becomes effective. Additionally, the following LCA will be reviewed for overlapping or duplicative instructions:

• A58918 Molecular Pathology and Genetic Testing

Once the LCDs and LCAs are retired, non-genetic tests currently covered in some of the LCDs will be considered for payment based on Medicare medically reasonable and necessary threshold for coverage. A service that is not addressed in a CMS NCD, an LCD, a billing and coding article, or a CMS manual instruction is subject to medically reasonable and necessary threshold. Services billed to the Medicare program should be clearly supported in the medical record documentation in case a claim falls under pre-payment or post-payment review. Providers are responsible for selecting the most appropriate code for their services, and they are required to bill to specificity. For any denied claim, providers have appeals rights.

The coding article A58918 Molecular Pathology and Genetic Testing provides billing and coding guidance for molecular pathology services, genomic sequencing procedures other multianalyte assays, multianalyte assays with algorithmic analyses, applicable PLA codes, and Tier 1 and Tier 2 molecular pathology procedures. The article focuses on coding and billing for molecular pathology diagnostics and genetic testing. Nothing stated in the articles implies or infers coverage.

Multiple comments were received requesting clarification regarding how NCDs would interact with the LCD Genetic Testing for Oncology. The commenters requested the LCD to address LDTs, especially those incorporating next-generation sequencing panels.

Thank you for your comments. The LCD has been updated to include information regarding LDTs and the NCD 90.2. Detailed information regarding the NCDs 90.2, 190.3, and 210.3 are provided below.

NCD 90.2 Next Generation Sequencing (NGS)

The NCD is only applicable to diagnostic lab tests using NGS for somatic (acquired) and germline (inherited) cancers.

In the January 27, 2020, decision memo (CAG-00450R) released by the CMS Coverage Analysis Group (CAG), “This NCD only considered NGS for DNA sequencing to detect genomic mutations.”

Per NCD 90.2, MACs may determine coverage of diagnostic lab tests using NGS for RNA sequencing and/or in conjunction with protein analysis.

In addition, the January 27, 2020, decision memo states, “this NCD reconsideration permits coverage decisions regarding coverage of NGS for hematologic malignancies to be made by the MACs.” (emphasis added) The CAG cited difficulties differentiating between somatic (acquired) versus germline (inherited) origins of mutations and difficulties clearly staging these malignancies. This memo indicates that the requirements listed under somatic (acquired) and germline (inherited) categories only apply to non-hematologic malignancies.

First, the FDA status of an NGS test determines whether a test is evaluated under the NCD or under MAC discretion.

For an NGS test to be covered under the NCD:

• For somatic (acquired) cancer, the NGS test must have FDA approval or clearance as a companion in vitro diagnostic AND have an FDA-approved or -cleared indication for use in that patient’s cancer.
• For germline (inherited) cancer, the NGS test must have FDA approval or clearance.
• For both somatic and germline cancer, the results must be provided to the treating physician for management of the patient using a report template to specify treatment options.

CAG defined treating physician in the March 16, 2018, decision memo (CAG-00450N) as follows: “the treating physician is engaged in decision making with the patient as to whether to order a diagnostic laboratory test using NGS to identify targeted treatment options or enroll in a cancer clinical trial. We believe that results from this test must be used by the treating physician in the management of the patient.”

Second, coverage is permitted only when the patient and their cancer meet very specific criteria as detailed in the NCD. This patient criteria is applied to somatic (acquired) and germline (inherited) cancers that are under both NCD coverage and MAC discretion.

For an NGS test to be covered under the NCD or MAC discretion for somatic (acquired) cancer:

• The patient must have:

1. either recurrent, relapsed, refractory, metastatic, or advanced stage III or IV cancer; AND
2. not been previously tested with the same test using NGS for the same cancer genetic content, AND
3. decided to seek further cancer treatment (e.g., therapeutic chemotherapy)

For an NGS test to be covered under the NCD for germline (inherited) cancer:

• The patient must have:

1. ovarian or breast cancer; AND,
2. a clinical indication for germline (inherited) testing for hereditary breast or ovarian cancer; AND,
3. a risk factor for germline (inherited) breast or ovarian cancer; AND
4. not been previously tested with the same germline test using NGS for the same germline genetic content.

For an NGS test to be covered under the MAC discretion for germline (inherited) cancer:

• The patient must have:

1. any cancer diagnosis; AND,
2. a clinical indication for germline (inherited) testing of hereditary cancers; AND,
3. a risk factor for germline (inherited) cancer; AND,
4. not been previously tested with the same germline test using NGS for the same germline genetic content.

CAG defined “clinical indication” and “risk factor” for germline (inherited) cancer in the January 27, 2020, decision memo. A clinical indication is a sign, symptom, laboratory test result, or medical condition, or a combination of these indications, that leads to the recommendation of a treatment, laboratory test, or procedure for a disease or condition. A risk factor is a variable associated with an increased risk of a disease, such as age, gender, or family history of disease.

According to Medicare regulations (CMS IOM Publication 100-08, Chapter 13, Section 13.2.4), NCD requirements take precedent over LCDs. As a result, for NGS testing, all requirements in NCD 90.2 must be met before coverage can be considered through this LCD. For all DNA-only NGS testing of non-hematologic malignancies where MACs determine coverage, the NCD and LCD criteria must both be met for coverage.

At this time, CMS has coverage with editing in place for CPT codes 0022U Oncomine^™ Dx, 0037U FoundationOne CDx^™, 0111U Praxis^™ Extended RAS Panel, 0172U myChoice^® CDx, 0239U FoundationOne^® Liquid CDx, and 0242U Guardant360^® CDx.

Other types of tests (e.g., Southern blot hybridization, Polymerase chain reaction, Sequencing In situ hybridization, Northern blot hybridization, Immunohistochemistry, Western blot hybridization, Sanger sequencing, Fluorescence in situ hybridization) are outside the scope of the NCD and are subject to the LCD indications and limitations.

NCD 190.3 Cytogenetics Studies

The term cytogenetic studies is used to describe the microscopic examination of the physical appearance of human chromosomes.

Medicare covers these tests when they are reasonable and necessary for the diagnosis or treatment of the following conditions:

• Genetic disorders (e.g., mongolism) in a fetus;
• Failure of sexual development;
• Chronic myelogenous leukemia;
• Acute leukemias lymphoid (FAB L1-L3), myeloid (FAB M0-M7), and unclassified; or
• Myelodysplasia

At this time, CMS has coverage with editing in place for CPT codes 88230 through 88291. According to Medicare regulations, NCD requirements take precedent over LCDs.

NCD 210.3 Colorectal Cancer Screening Tests

1.  The Cologuard™ – Multi-target Stool DNA (sDNA) Test

Effective for dates of service on or after October 9, 2014, The Cologuard test is covered once every three years for Medicare beneficiaries that meet all of the following criteria:

• Age 50 to 85 years, AND,
• Asymptomatic (no signs or symptoms of colorectal disease including but not limited to lower gastrointestinal pain, blood in stool, positive guaiac fecal occult blood test (gFOBT) or fecal immunochemical test (iFOBT)), AND,
• At average risk of developing colorectal cancer (no personal history of adenomatous polyps, colorectal cancer, or inflammatory bowel disease, including Crohn’s Disease and ulcerative colitis; no family history of colorectal cancers or adenomatous polyps, familial adenomatous polyposis, or hereditary nonpolyposis colorectal cancer).

At this time, CMS has coverage with editing in place for CPT code 81528.

2.  Blood-based Biomarker Tests

Blood-based DNA testing detects molecular markers of altered DNA that are contained in the cells shed into the blood by colorectal cancer and pre-malignant colorectal epithelial neoplasia.

At this time, CMS has no tests identified as meeting NCD coverage criteria.

MACs do not have authority to determine coverage for screening tests.

Multiple comments were received from beneficiaries and their family members regarding bladder cancer testing. Tests included in many of the comments were FoundationOne, Cxbladder Detect, and Cxbladder Monitor.

Thank you for your comments.

PubMed and Google Scholar were searched for peer-reviewed, evidence-based literature bases which provided information regarding analytic and clinical validity and clinical utility for the Cxbladder tests. Key words used to search in combination included: Cxbladder, Cxbladder detect, Cxbladder triage, Cxbladder monitor, molecular testing, urine test, bladder cancer, urine biomarker(s), mRNA, uRNA, gene expression profile test, GEP test, 5 gene expression assay, prognostic, and TERT and FGFR3 mutations. Please refer to the LCD “Summary of Evidence” and “Analysis of Evidence” for the complete review. In summary, these tests do not have sufficient evidence to warrant coverage in Medicare patients.

It is important to assess genetic testing in the context of oncology with a rigorous, evidence-based approach to facilitate the appropriate testing for all eligible Medicare beneficiaries.

Regarding FoundationOne, coverage is provided through NCD 90.2 Next Generation Sequencing (NGS) for the FoundationOne CDx and FoundationOne Liquid CDx tests, which are billed with CPT codes 0037U and 0239U and therefore, the LCD does not alter NCD coverage for these tests. The billing and coding article states, “For coverage information regarding CPT codes 0022U, 0037U, 0111U, 0172U, 0239U, and 0242U, please refer to NCD 90.2 Next Generation Sequencing (NGS).”

Multiple comments were received expressing concerns regarding Covered Indication #1/Limitation #3; “The provider has either established a diagnosis of cancer or found significant evidence to create suspicion for cancer in their patient via a clinical evaluation and abnormal results (cancer or suspicious for cancer) from histologic and/or cytologic examination. “

Commenters indicated that hematolymphoid neoplasms and their precursors are not explicitly covered since the terms “histologic and/or cytologic examination” may not apply. Other diagnostic testing methods, such as flow cytometry, cytogenetics, including karyotyping and fluorescence in situ hybridization, and antigen receptor gene rearrangement assays for B- and T-lymphoid cells are well-established as routinely used tests for the diagnostic evaluation of hematologic and lymphoid malignancies in addition to radiological imaging, which is commonly used to establish the diagnosis of cancer. Additionally, the organ-specific RADS system is an additional method for addressing criteria for establishing reasonable suspicion for cancer.

Additional concerns included patients may not be candidates for a tissue biopsy due to high risk of complications. The commenters indicated that evidence from clinical evaluation and other testing may be sufficient to form a suspicion of cancer. Predictive biomarker testing may still be recommended and, likely, performed through cell-free, circulating tumor deoxyribonucleic acid (ctDNA) testing from a liquid biopsy. Commenters were also concerned that this requirement would eliminate coverage for MRD testing.

We appreciate the suggestions that Covered Indication #1 may be too restrictive. It is not the intention of the Contractor to create undue burden on providers for commonly performed services.

At this time, it is our understanding, that genetic testing should not be a first-line diagnostic workup, and that prior to commencing genetic testing for a Medicare beneficiary, a provider should either establish a diagnosis of cancer or have a substantiated suspicion of cancer.

Establishing a diagnosis of cancer requires at baseline pathologic evidence via histology or cytology. Note that histology includes microscopic examination of tissue sections and cytology includes microscopic evaluation of fluids such as pleural effusions, blood, and bone marrow [e.g., smears] or tissue such as core biopsies [e.g., touch prep].

Regarding concerns for patients who may not be candidates for a tissue biopsy due to high risk of complications, we did identify in the NCCN guidelines some cancers where cell-free, circulating tumor deoxyribonucleic acid was recommended as an alternative if a tissue biopsy could not be obtained.

Also, for the purposes of this LCD, a substantiated suspicion of cancer requires direct, physical sampling of a lesion, such as a needle aspiration or excision of tissue, followed by microscopic evaluation (histology or cytology). For hematologic lesions, we recognize that flow cytometry is often performed concurrently with histology and/or cytology. Given this accepted diagnostic practice, the LCD will be adjusted to include flow cytometry as sufficient for establishing a substantiated suspicion of cancer.

While radiologic testing can identify lesions that are suspicious for cancer, confirmation requires a physical sampling and microscopic examination of the lesion. Indirect laboratory testing (e.g., serum tumor markers such as Prostate Specific Antigen [PSA]), even when used with other indirect diagnostic tests such as radiology can still prove misleading without direct microscopic examination of lesional cells/tissue.

While cytogenetics, fluorescent in situ hybridization, and antigen receptor gene rearrangement assays of B- and T-lymphoid cells can all be used in the evaluation of cancer, these are not first-line tests; instead, these three tests are performed in addition to histologic or cytologic evaluations. Each of these tests require lesional tissue or cells, which when obtained, already receive histologic and/or cytologic evaluation. Moreover, to our knowledge, not one of these three tests would be sufficient alone to diagnose cancer; instead, these tests provide supportive evidence in the context of a prior histologic or cytologic result. As a result, requiring histologic or cytologic evaluation before molecular testing makes sense for these three tests.

The requirement for histologic, cytologic, and/or flow cytometric evidence of cancer or a suspicion of cancer additionally addresses the pernicious issue of ordering genetic testing without full knowledge of the patient’s cancer history, which includes ordering broad genetic testing for cancers only described by an organ system. For example, the term “colon cancer” is non-specific and includes multiple subsets of cancers with a variety of manifestations. If a provider does not, at minimum, have a pathology report on the histology of the “colon cancer,” it cannot be expected that molecular testing, even hereditary cancer testing, would be tailored to the patient’s specific needs.

In the case of molecular testing ordered as a set of tests evaluating a concern for cancer (e.g., bone marrow biopsy submitted for morphologic, flow cytometric, and molecular evaluation all at once), tests should be performed reflexively to prevent unnecessary testing. If there is no histologic, cytologic, or flow cytometric evidence diagnosing or creating a suspicion for cancer, subsequent molecular testing would not be covered under this LCD policy.

Oncologic genetic testing is considered screening if it is performed before the ordering provider either establishes a diagnosis of cancer or a substantiated suspicion of cancer through histologic, cytologic, and/or flow cytometric testing. This limitation follows the regulation that screening tests in asymptomatic patients are generally non-covered by Medicare except under very specific circumstances, as discussed in CMS IOM Publication 100-02, Medicare Benefit Policy Manual, Chapter 15, Section 280 Preventive and Screening Services.

This also means that MRD testing, which by definition requires a previous diagnosis of cancer and would thus have an associated pathology report, should not be mistaken as pre-diagnostic screening. As of the writing of this response, please note that not all MRD tests meet coverage criteria, so please closely review the LCD coverage requirements.

Multiple comments were received expressing concerns regarding Limitation #1; “A genetic test where either analytical validity, clinical validity, or clinical utility has not been established.” Commenters were concerned about how analytical validity is expected to be assessed for LDTs and the potential to unintentionally restrict coverage due to lack of clarity in the requirements. 

Thank you for your comments. Per the CMS website, the CMS regulates all laboratory testing (except research) performed on humans in the U.S. through the CLIA in order to ensure accurate and reliable test results. All clinical laboratories must be properly CLIA certified to receive Medicare payments.

The analytical validation under CLIA includes an analysis of accuracy, precision, analytical sensitivity, analytical specificity, reportable range, reference interval, and any other performance characteristics required for the test system in the laboratory that intends to use it.

The FDA regulates manufacturers and devices under the FFDCA to ensure that devices are reasonably safe and effective. The FDA defines laboratory tests as devices. The FDA’s review of analytical validity is done prior to the marketing of the test system. Per the FDA, a LDT is an in vitro diagnostic test that is manufactured by and used within a single laboratory (i.e., a laboratory with a single CLIA certificate). LDTs are subject to regulatory oversight by the FDA and are considered “devices”.

For an LDT developed without receiving FDA clearance or approval, CLIA prohibits the release of any test results prior to the laboratory establishing certain performance characteristics relating to analytical validity for the use of that test system in the laboratory’s own environment [see 42 CFR 493.1253(b)(2)]. The CLIA limits the analytical validation to the specific conditions, staff, equipment and patient population of the particular laboratory. The laboratory-specific analytical validation is not meaningful outside of the laboratory that did the analysis. In addition, the laboratory’s analytical validation of LDTs is reviewed during CLIA’s routine biennial survey.

The FDA’s premarket clearance and approval processes also assesses clinical validity, which is the accuracy with which the test identifies, measures, or predicts the presence or absence of a clinical condition or predisposition in a patient, as part of the review that is focused on the safety and effectiveness of the test system.

Each of the knowledge bases chosen (ClinGen, NCCN, and OncoKB) have an evidence-based process for reviewing biomarkers/assays and providing a level of evidence or recommendation for their use. This process includes evaluation of the biomarker/assay’s clinical validity and clinical utility. If a biomarker/assay is included in one of the three knowledge bases and meets the criteria as described in the LCD, it will be considered that the requirements for clinical validity and clinical utility have been met.

A comment was received expressing concerns regarding Limitation #4; “Genetic testing of asymptomatic patients for the purposes of screening the patient or their relatives.” A commenter stated asymptomatic testing may be necessary for some patients in need of genetic testing to determine whether they need enhanced surveillance and reproductive counseling. 

Thank you for your comment. This limitation follows the regulation that screening tests in asymptomatic patients are generally non-covered by Medicare except under very specific circumstances, as discussed in CMS IOM Publication 100-02, Medicare Benefit Policy Manual, Chapter 15, Section 280 Preventive and Screening Services. 

Multiple comments were received expressing concerns regarding Limitation #5: “Repetitions of the same genetic test on the same genetic material.” Several comments were received regarding tests for MRD being denied by this limitation.

Thank you for your comments. The intended purpose of this limitation is to prevent inappropriately billing Medicare twice for the same exact test on the same exact specimen. Medicare does not cover repetition of testing for reasons such as revalidations, quality control, or failure of a first test attempt. However, the limitation language is written in order to permit repeat testing that monitors a condition, such as MRD. In the case of testing that monitors a condition, each specimen is distinct by virtue of representing unique time points in the patient’s clinical course. Moreover, the limitation language of this LCD also permits the same genetic material to be used for two medically reasonable and necessary tests if the tests cover distinct genetic content.

Multiple comments were received expressing concerns regarding the limitation “Genetic tests for hereditary cancer syndromes, which are considered germline testing, may only be performed once per beneficiary’s lifecycle.” Commenters were concerned a clinical laboratory would not be able to determine if a germline genetic test had previously been performed when it receives an order from a physician or non-physician practitioner (NPP). Other commenters ask that some allowance be made for incidental repeat testing or for specific situations where technological changes require revisiting the same genomic regions with different approaches or targets. Also, a commenter was concerned mosaic hereditary cancer syndromes can require several tests to establish the diagnosis and can have the same implications for the patient as non-mosaic hereditary cancer syndromes.

Thank you for your comments. Any laboratory test that investigates the same germline genetic content, for the same genetic information, that has already been tested in the same Medicare beneficiary is not medically reasonable and necessary as it is duplicative. By definition, the germline sequence of an individual does not change over time. Therefore, repeat testing of the same germline content for the same genetic information does not provide new clinical information. In the uncommon circumstances where repeat germline testing is required, such as concern for mosaicism or significant new discoveries regarding germline content (e.g., new variants), individual consideration through the appeal process is available.

The Code of Federal Regulations (CFR) Title 42, Section 410.32(d)(2)(iii) states “The entity submitting the claim may request additional diagnostic and other medical information to document that the services it bills are reasonable and necessary. If the entity requests additional documentation, it must request material relevant to the medical necessity of the specific test(s), taking into consideration current rules and regulations on patient confidentiality.”

A comment was received in support for the provider qualifications requirement. Other comments were received expressing concerns regarding the provider qualifications requirement. Commenters noted that the ordering provider and treating provider may be part of the patient care team but are not necessarily the same provider. 

Thank you for your comments. We recognize that in cancer treatment and many other specialties, interprofessional collaboration and a team-approach to patient management are considered to be the gold standard. However, per the CFR 42 Section 410.32, diagnostic laboratory tests, and other diagnostic tests must be ordered by the physician who is treating the beneficiary, that is, the physician who furnishes a consultation or treats a beneficiary for a specific medical problem and who uses the results in the management of the beneficiary's specific medical problem. Tests not ordered by the physician who is treating the beneficiary are not medically reasonable and necessary. Non-physician practitioners that are enrolled in the program, who are operating within the scope of their authority under State law and within the scope of their Medicare statutory benefit, are also considered for this purpose, as treating and managing a beneficiary’s specific medical problem. Furthermore, currently, certified genetic counselors are not recognized healthcare providers in the Medicare program, but they may be a part of a patient’s healthcare team working collaboratively with other providers.

Also, as stated in the response #18, CMS defined a treating physician as the physician who is engaged in decision making with the patient. The results from the test must be used by the treating physician in the management of the patient.

Multiple comments were received regarding CPT codes that were not included in the LCA. Commenters were concerned regarding coverage for CPT codes 81445, 81450, and 81455. 

Thank you for your comments. Due to some CPT codes not being included in the LCA, a note was added to the LCA and the comment period was extended for transparency regarding the LCA changes. The CPT codes 81445, 81450, and 81455 have limited coverage based on the NCD 90.2 and LCD coverage criteria.

The scope of the Genetic Testing for Oncology LCD is for all DNA and RNA testing in the practice of oncology in the Medicare population. The coverage criteria in this LCD applies to all technologies used in the performance of DNA and RNA testing in the practice of oncology except for those instances where CMS has coverage criteria in an NCD. Please refer to comment and response #18 for more details regarding NCDs 90.2, 190.3, and 210.3. The LCA has instructions for billing a targeted genomic sequence analysis panel.

Per the Medicare National Correct Coding Initiative (NCCI) Policy Manual Chapter 10, “CPT codes 81445, 81450, and 81455 describe targeted genomic sequence, DNA analysis or combined DNA and RNA analysis. CPT code 81445 applies to solid organ neoplasm type (5-50 genes) and CPT code 81450 applies to hematolymphoid neoplasm type (5-50 genes), while CPT code 81455 applies to the number of genes analyzed for either a solid or hematolymphoid neoplasm (51 or greater genes). Providers/suppliers may not report CPT code 81455 with either CPT codes 81445 or 81450. CPT codes 81449, 81451, and 81456 describe targeted genomic sequence RNA analysis using a separate method.”

“All genomic sequencing procedures and molecular multianalyte assays (e.g., CPT codes 81410-81471), many multianalyte assays with algorithmic analyses (e.g., CPT codes 81490-81599, 0004M-XXXXM), and many PLA (e.g., CPT codes 0001U-XXXXU) are DNA or RNA analytic methods that simultaneously assay multiple genes or genetic regions. A provider/supplier shall not additionally separately report testing for the same gene or genetic region by a different methodology (e.g., CPT codes 81105-81408, 81479, 88364-88377). CMS payment policy does not allow separate payment for multiple methods to test for the same analyte.”

“A Tier 1 or Tier 2 molecular pathology procedure CPT code should not, in general, be reported with a genomic sequencing procedure, molecular multianalyte assay, multianalyte assay with algorithmic analysis, or PLA CPT code where the CPT code descriptor includes testing for the analyte described by the Tier 1 or Tier 2 molecular pathology code. Procedures reported together must be both medically reasonable and necessary (e.g., sequencing of procedures) and ordered by the physician who is treating the beneficiary and using the results in the management of the beneficiary's specific medical problem.”

“If one laboratory procedure evaluates multiple genes using a next generation sequencing procedure, the laboratory shall report only one unit of service of one genomic sequencing procedure, molecular multianalyte assay, multianalyte assay with algorithmic analysis, or PLA CPT code. If no CPT code accurately describes the procedure performed, the laboratory may report CPT code 81479 (Unlisted molecular pathology procedure) with one unit of service or may report multiple individual CPT codes describing the component test results when medically reasonable and necessary. Procedures reported together must be both medically reasonable and necessary (e.g., sequencing of procedures) and ordered by the physician who is treating the beneficiary and using the results in the management of the beneficiary's specific medical problem.”

For tests that are genomic sequencing procedures that simultaneously assay multiple genes or genetic regions, coverage would be dependent on the genetic content examined and whether the content is covered for the patient’s specific medical condition by the LCD.

• A targeted genomic sequence analysis panel that tests 5 to 50 genes and contains genes that meets LCD coverage criteria for the management of the patient’s specific medical condition to improve the patient’s outcome may be billed with CPT codes 81445, 81449, 81450, or 81451.
• A targeted genomic sequence analysis panel that tests for 51 or greater genes and contains genes that meets LCD coverage criteria for the management of the patient’s specific medical condition to improve the patient’s outcome may be billed with the CPT codes 81455 or 81456.
• A targeted genomic sequence analysis panel that tests five or greater genes and contains NO genetic content covered by the LCD criteria is billed with CPT codes 81445, 81449, 81450, 81451, 81455, or 81456 and the appropriate modifier to indicate a non-covered service.

It would not be expected that providers would perform, for an oncologic condition, a genomic sequencing procedure (e.g., next generation sequencing) that simultaneously assays multiple genes or genetic regions which would not be accurately described by CPT codes 81445, 81449, 81450, 81451, 81455 or 81456. Frequent utilization of CPT code 81479 and/or multiple individual CPT codes describing the component test results will be subject to review.

A comment was received from a provider in UPMC’s Division of Molecular & Genomic Pathology, with regard to the ThyroSeq^® Cancer Risk Classifier (CRC) test, PLA code 0287U, which is currently listed in Group 3 of the draft LCA. The commenter believed that 0287U was inappropriately placed in this group, because Group 3 contains codes used for indeterminate thyroid nodules, and 0287U does not meet this criterion. The ThyroSeq CRC test is intended for use in malignant thyroid neoplasms, and the highest specificity ICD-10-CM code used to describe this service would be C73 (malignant neoplasm of thyroid gland). Therefore, the commenter identified 0287U would be more appropriately placed in Group 4, because the Group 4 ICD-10-CM code group contains C73. Two articles were submitted with the comment:

The commenter also noted that the ThyroSeq Genomic Classifier (GC) test, PLA code 0026U was appropriately listed in Group 3 as it is used for indeterminate thyroid nodules. Two follow-up comments were received after revisions to the draft LCA were made on July 28th, reiterating the same concerns.

Thank you for your comments. Two published full-text references were submitted with the comment, in addition to one unpublished manuscript. As you have identified, Group 3 of the draft LCA was intended to contain codes used for indeterminate thyroid nodules, while Group 4 contained codes used for malignant thyroid neoplasms.

Regarding the ThyroSeq CRC test, PubMed and Google Scholar were searched for peer-reviewed, evidence-based literature bases which provided information regarding analytic and clinical validity and clinical utility for the ThyroSeq Cancer Risk Classifier test. Key words used to search in combination included: ThyroSeq, ThyroSeq Cancer Risk Classifier, ThyroSeq CRC, molecular testing, thyroid nodule(s), thyroid cancer, Bethesda VI, Bethesda VI nodules, FNA(s), fine needle aspiration biopsy, formalin fixed paraffin-embedded (FFPE), prognostic, and TERT TP53 AKT1 PIK3CA mutations.

Please refer to the LCD “Summary of Evidence” and “Analysis of Evidence” for the complete review. In summary, this test does not have sufficient evidence to warrant coverage in Medicare patients.

It is important to assess genetic testing in the context of oncology with a rigorous, evidence-based approach to facilitate the appropriate testing for all eligible Medicare beneficiaries.

In addition, the LCD was revised to include an option to submit an LCD reconsideration request for a determination whether the test meets CMS IOM Publication 100-08, Chapter 13, Section 13.5.4 reasonable and necessary criteria.

Thank you for validating that the ThyroSeq GC test, PLA code 0026U, was appropriately listed in the indeterminate thyroid nodules group (Group 75 in the final LCA).

A comment was received from Dr. Mark Pilley, contractor medical director for SafeGuard Services LLC, stating the proposed LCD/LCA provides “important guidance and strategic listing of resources available for use when performing medical review.”

Thank you for your comments. The Contractor appreciates your feedback.

Comments were submitted by First Ascent Biomedical stating general support for the LCD and providing information regarding the role of “Functional Testing” to augment initial genetic test results. The commenters then invited the Contractor to provide "thoughts and/or discussion" regarding the information and literature provided with their comment.

Thank you for your comments. Five pieces of full-text literature were submitted describing the clinical utility of Functional Precision Medicine as it pertains to Acute Myeloid Leukemia (three articles), Recurrent/Relapsed Childhood Rhabdomyosarcoma (one article), and Ovarian Cancer (one article). As you stated, some providers choose to use functional testing as an additional step in the genetic testing process. If the functional test chosen is included in one of the three knowledge bases listed in the LCD (ClinGen, NCCN, or OncoKB) and meets coverage criteria as described in the LCD, the functional test will be considered medically reasonable and necessary, and therefore, covered. In addition, the LCD was revised to include an option to submit an LCD reconsideration request for a determination whether the test meets CMS IOM Publication 100-08, Chapter 13, Section 13.5.4 reasonable and necessary criteria. If the functional test chosen is not listed in one of the knowledge bases and/or does not meet coverage criteria as described in the LCD, the test will not be covered. After review of the information provided, no changes have been made to the language in the LCD.

Multiple comments were received regarding the differences in genetic testing, biomarker testing, and genomic testing as well as requesting definitions for a variety of biomarker tests that utilize genetic analysis including, CGP, NGS, Comprehensive Biomarker testing, Multi-Analyte Panels, Biomarker panels, Multi-gene panels, Circulating tumor DNA, and testing for MRD. Comments were also received regarding germline versus somatic alterations and concerns that the proposed LCD does not follow CMS’ definition of clinical utility.

In addition, comments were received regarding NCCN guidelines versus compendium terminology.

Thank you for your comments. The LCD has been updated to clarify existing definitions and include additional definitions.

The scope of the Genetic Testing for Oncology LCD is for all DNA and RNA testing in the practice of oncology in the Medicare population. The coverage criteria in this LCD applies to all technologies used in testing of DNA and RNA in the practice of oncology except for those instances where CMS has coverage criteria in an NCD. Please refer to comment and response #18 for more details regarding NCDs 90.2, 190.3, and 210.3. The LCA also has instructions for billing a targeted genomic sequence analysis panel.

The NCCN Biomarkers Compendium is updated continuously in conjunction with the NCCN Guidelines to stay current. The goal of the Biomarkers Compendium is to provide essential details for testing methodologies which have been approved by NCCN Guideline Panels and are recommended within the Guidelines. Included in the Biomarkers Compendium are testing methodologies that measure changes in genes or gene products and used for the purposes of diagnosis, screening, monitoring, surveillance, prediction, and prognostication. The information within the Biomarkers Compendium is extracted directly from Guideline algorithms, principles pages, and footnotes, and all entries are reviewed and approved by the Guideline Panel pathologist or other panel member with expertise in the area. Information within the Biomarkers Compendium focuses on the biology or abnormality being measured rather than on commercially available tests or test kits, with methodologic information provided only if included in the parent Clinical Practice Guideline. For the purposes of coverage related to this LCD, guidelines inclusion or inclusion in the Biomarkers Compendium are interchangeable (either is acceptable with Category 1 or 2A classification). Furthermore, if a test is included in Guidelines but not the Biomarkers Compendium, NCCN has historically been appreciative to receive this information from the provider community.

Comments were received stating the Contractor should not limit the size of gene panels because the market has progressed beyond small panels and patients who had several hundred gene panels have found that their tumor contains a mutation that is used to develop a drug long after the original tumor genome was sequenced. Also, the commenters stated the LCD was insufficient to allow stakeholders, beneficiaries, and the public to understand coverage for specific tests. It was recommended a maintained and up-to-date internet searchable list of tests be created by the Contractor. 

Thank you for your comments. The LCA has been updated to clarify appropriate coding for specific tests.

Per the Medicare National Correct Coding Initiative (NCCI) Policy Manual Chapter 10, “CPT codes 81445, 81450, and 81455 describe targeted genomic sequence, DNA analysis or combined DNA and RNA analysis. CPT code 81445 applies to solid organ neoplasm type (5-50 genes) and 81450 applies to hematolymphoid neoplasm type (5-50 genes), while CPT code 81455 applies to the number of genes analyzed for either a solid or hematolymphoid neoplasm (51 or greater genes). Providers/suppliers may not report CPT code 81455 with either CPT codes 81445 or 81450. CPT codes 81449, 81451, and 81456 describe targeted genomic sequence RNA analysis using a separate method.”

“All genomic sequencing procedures and molecular multianalyte assays (e.g., CPT codes 81410-81471), many multianalyte assays with algorithmic analyses (e.g., CPT codes 81490-81599, 0004M-XXXXM), and many PLA (e.g., CPT codes 0001U-XXXXU) are DNA or RNA analytic methods that simultaneously assay multiple genes or genetic regions. A provider/supplier shall not additionally separately report testing for the same gene or genetic region by a different methodology (e.g., CPT codes 81105-81408, 81479, 88364-88377). CMS payment policy does not allow separate payment for multiple methods to test for the same analyte.”

“A Tier 1 or Tier 2 molecular pathology procedure CPT code should not, in general, be reported with a genomic sequencing procedure, molecular multianalyte assay, multianalyte assay with algorithmic analysis, or proprietary laboratory analysis CPT code where the CPT code descriptor includes testing for the analyte described by the Tier 1 or Tier 2 molecular pathology code. Procedures reported together must be both medically reasonable and necessary (e.g., sequencing of procedures) and ordered by the physician who is treating the beneficiary and using the results in the management of the beneficiary's specific medical problem.”

“If one laboratory procedure evaluates multiple genes using a next generation sequencing procedure, the laboratory shall report only one unit of service of one genomic sequencing procedure, molecular multianalyte assay, multianalyte assay with algorithmic analysis, or proprietary laboratory analysis CPT code. If no CPT code accurately describes the procedure performed, the laboratory may report CPT code 81479 (Unlisted molecular pathology procedure) with one unit of service or may report multiple individual CPT codes describing the component test results when medically reasonable and necessary.”

For tests that are genomic sequencing procedures that simultaneously assay multiple genes or genetic regions, coverage would be dependent on the genetic content examined and whether the content is covered for the patient’s specific medical condition by the LCD.

• A targeted genomic sequence analysis panel that tests 5 to 50 genes and contains genes that meets LCD coverage criteria for the management of the patient’s specific medical condition to improve the patient’s outcome may be billed with CPT codes 81445, 81449, 81450, or 81451.
• A targeted genomic sequence analysis panel that tests for 51 or greater genes and contains genes that meets LCD coverage criteria for the management of the patient’s specific medical condition to improve the patient’s outcome may be billed with the CPT codes 81455 or 81456.
• A targeted genomic sequence analysis panel that tests five or greater genes and contains NO genetic content covered by the LCD criteria is billed with CPT codes 81445, 81449, 81450, 81451, 81455, or 81456 and the appropriate modifier to indicate a non-covered service.

It would not be expected that providers would perform, for an oncologic condition, a genomic sequencing procedure (e.g., next generation sequencing) that simultaneously assays multiple genes or genetic regions which would not be accurately described by CPT codes 81445, 81449, 81450, 81451, 81455 or 81456. Frequent utilization of CPT code 81479 and/or multiple individual CPT codes describing the component test results will be subject to review.

The NCD 90.2 is only applicable to DNA sequencing diagnostic laboratory tests using NGS for non-hematologic, somatic (acquired) and germline (inherited) cancers.

• For non-hematologic DNA sequencing NGS tests that meet CMS FDA approval or clearance in NCD 90.2 section B.1.b. or section B.2.b., follow NCD requirements in section B.1.a. or section B.2.a.
• For non-hematologic DNA sequencing NGS tests that do not meet CMS NCD 90.2 section B requirements that are performed in CLIA-certified laboratories, refer to NCD 90.2 section D AND the LCD for coverage criteria.
• For NGS tests with combined DNA and RNA analysis of somatic and germline cancers, RNA analysis of somatic and germline cancers, and NGS tests for hematologic cancers, refer to the LCD for coverage criteria.

Please refer to comment and response #18 for more details regarding NCD 90.2.

The Contractor will not be providing a database containing coverage determinations by test or company name. For updates on covered services, refer to the quarterly CPT/HCPCS code updates in the billing and coding article. American Medical Association (AMA) CPT/HCPCS codes provide the official nationwide description of services among physicians, patients and third parties.

Multiple comments were submitted on behalf of Clinical Genomics, Inc., the developer of Colvera^®, a circulating tumor DNA test for recurrence monitoring in patients previously diagnosed with colorectal cancer. The comments were seeking clarification on coverage of the Colvera test, CPT code 0229U, and clarified that Colvera is not a screening test. The commenter stated the current JH/JL Biomarkers for Oncology article, A52986, includes a provision for the Colvera test "to detect residual disease following surgery or treatment for primary or recurrent colorectal cancer, and to surveil for recurrence of a previously treated colorectal cancer," which was added after a September 30, 2021, article revision. The comments requested the proposed LCD allow coverage of Colvera, CPT code 0229U for the same indications in colon cancer.

A follow-up comment was received after the update to the proposed LCD/LCA on July 28, 2022. The commenter noted opposition to the removal of Colvera from reference under NCD 210.3 Colorectal Cancer Screening Tests and adding it to Group 6 – Noncovered.

Thank you for your comments. No full-text references were submitted with the comments. We agree the Colvera test is not a screening test for colorectal cancer. As noted, the Colvera test, CPT code 0229U, was included in the JH/JL Biomarkers for Oncology article, A52986. NCCN, ClinGen, and OncoKB were searched for Colvera, and as of the date of the search, Colvera was not included in any of the knowledge bases. Therefore, CPT code 0229U was removed from the NCD coding guidance note and added to the noncovered codes group. If Colvera is added to NCCN, ClinGen, or OncoKB knowledge bases or a reconsideration is received with full-text references and it is determined that Colvera meets coverage criteria as described in the LCD, the billing and coding article will be updated accordingly.

PubMed and Google Scholar were searched for peer-reviewed, evidence-based literature which provided information regarding analytic and clinical validity and clinical utility for the COLVERA test. Key words used to search in combination included: COLVERA, Colvera, blood test, molecular testing, colorectal cancer (CRC), CEA test, ctDNA, colorectal adenocarcinoma, real-time PCR test, DNA methylation, CRC surveillance and BACT and IKZF1.

Please refer to the LCD “Summary of Evidence” and “Analysis of Evidence” for the complete review. In summary, this test does not have sufficient evidence to warrant coverage in Medicare patients.

It is important to assess genetic testing in the context of oncology with a rigorous, evidence-based approach to facilitate the appropriate testing for all eligible Medicare beneficiaries.

Of note, the LCD was revised to include an option to submit an LCD reconsideration request for a determination whether the test meets CMS IOM Publication 100-08, Chapter 13, Section 13.5.4 reasonable and necessary criteria.

Multiple comments and full text articles were received regarding Castle Biosciences, Incorporated’s four GEP tests (DecisionDx- Melanoma, DecisionDx- SCC, MyPath Melanoma, and DecisionDx DiffDx-Melanoma). The commenters stated the proposed LCD’s new coverage framework restricts or eliminates the coverage of tests which were previously reviewed on an individual basis. MAC review of evidence was requested along with an alternative pathway for coverage outside of knowledge base inclusion. 

Thank you for your comments.

At this time, The Contractor does not have an LCD with a positive coverage statement for any of the Castle Biosciences, Inc. tests which include the DecisionDx-SCC (40-GEP) (CPT code 0315U), MyPath Melanoma (23-GEP) (CPT code 0090U), DecisionDx DiffDx-Melanoma (35-GEP) (CPT code 0314U), DecisionDx-Melanoma (31-GEP) (CPT code 81529), and DecisionDx-Uveal Melanoma (CPT code 81552). These CPT codes are only located in A58918  Billing and Coding: Molecular Pathology and Genetic Testing which includes the statement “This instruction focuses on coding and billing for molecular pathology diagnostics and genetic testing. Nothing stated in this instruction implies or infers coverage.”

Payment for services on an individual basis prior to the development of an LCD to address coverage for a service does not guarantee coverage in the future.

CMS IOM Publication 100-08, Chapter 13, Section 13.2.3 states “Acceptance by individual health care providers, or even a limited group of health care providers, does not indicate general acceptance of the item or service by the medical community.”

The NCCN Guidelines were reviewed and the tests MyPath Melanoma (23-GEP) (CPT code 0090U), DecisionDx DiffDx-Melanoma (35-GEP) (CPT code 0314U), and DecisionDx-Uveal Melanoma (CPT code 81552) were found to meet LCD coverage criteria.

Regarding DecisionDx-Melanoma (31-GEP) (CPT code 81529), PubMed and Google Scholar were searched for peer-reviewed, evidence-based literature which provided information regarding analytic and clinical validity and clinical utility for the DecisionDx-Melanoma test. Key words used to search in combination included: DecisionDx, DecisionDx-Melanoma, Castle Biosciences, molecular testing, melanoma, skin cancer, sentinel lymph node biopsy, SLNB, GEP test, gene expression profile, stage I melanoma, stage II melanoma, stage III melanoma, 31-gene profile test, 28-gene profile test, cutaneous melanoma, and formalin-fixed paraffin embedded (FFPE) tissue.

Regarding DecisionDx-SCC (40-GEP) (CPT code 0315U), PubMed and Google Scholar were searched for peer-reviewed, evidence-based literature which provided information regarding analytic and clinical validity and clinical utility for the DecisionDx-SCC test. Key words used to search in combination included: DecisionDx, DecisionDx-SCC, Castle Biosciences, molecular testing, melanoma, skin cancer, prognostic test, SCC, cutaneous squamous cell carcinoma, cSCC, GEP test, gene expression profile, metastasis, 40-gene profile test, and formalin-fixed paraffin embedded (FFPE) tissue.

Please refer to the LCD “Summary of Evidence” and “Analysis of Evidence” for the complete review. In summary, these tests do not have sufficient evidence to warrant coverage in Medicare patients.

It is important to assess genetic testing in the context of oncology with a rigorous, evidence-based approach to facilitate the appropriate testing for all eligible Medicare beneficiaries.

Of note, the LCD was revised to include an option to submit an LCD reconsideration request for a determination whether the test meets CMS IOM Publication 100-08, Chapter 13, Section 13.5.4 reasonable and necessary criteria.

Several comments were received regarding concerns about non-coverage for Pacific Edge Diagnostics’ assays Cxbladder Detect and Cxbladder Monitor, CPT codes 0012M and 0013M.

The commenters stated the new LCD eliminates the coverage of tests which are currently paid for by Medicare. The commenters also noted that this appears to discriminate against new, innovative tests because it takes years for tests to be listed in the knowledge bases in spite of clinical evidence, and this delay may impair access of Medicare beneficiaries to receive these tests. The commenters noted that these assays assist providers with determining the need for further investigation in patients with hematuria at high risk for bladder cancer, while potentially reducing evaluation needs in those at low risk for bladder cancer.

Thank you for your comments.

The purpose of the LCD is not to limit beneficiary access to care but to ensure that Medicare is paying for services/tests that are deemed medically reasonable and necessary as supported by evidence.

At this time, the Contractor does not have an LCD with a positive coverage statement for any of the Pacific Edge Diagnostics tests which include the Cxbladder Detect (CPT code 0012M) and Cxbladder Monitor (CPT code 0013M). These CPT codes are only located in the article Billing and Coding: Molecular Pathology and Genetic Testing A58918 which includes the statement “This instruction focuses on coding and billing for molecular pathology diagnostics and genetic testing. Nothing stated in this instruction implies or infers coverage.”

In addition, the JH/JL LCD L35396 Biomarkers for Oncology revision 24 on October 4, 2018, states “LCD revised and published on 10/04/2018 to update the policy in response to inquiry and reconsideration requests; all literature reviewed and added to policy. Non-coverage reaffirmed for CPT codes 0012M and 0013M for Cxbladder.” No additional revisions were made to this LCD providing coverage for Cxbladder.

Payment for services on an individual basis prior to the development of an LCD to address coverage for a service does not guarantee coverage in the future.

CMS IOM Publication 100-08, Chapter 13, Section 13.2.3 states “Acceptance by individual health care providers, or even a limited group of health care providers, does not indicate general acceptance of the item or service by the medical community.”

PubMed and Google Scholar were searched for peer-reviewed, evidence-based literature bases which provided information regarding analytic and clinical validity and clinical utility for the Cxbladder test. Key words used to search in combination included: Cxbladder, Cxbladder detect, Cxbladder triage, Cxbladder monitor, molecular testing, urine test, bladder cancer, urine biomarker(s), mRNA, uRNA, gene expression profile test, GEP test, 5 gene expression assay, prognostic, and TERT and FGFR3 mutations. Outside of publications from Pacific Edge Diagnostics or studies with funding from that company, only a few peer-reviewed papers have been published addressing the performance of Cxbladder tests.

Please refer to the LCD “Summary of Evidence” and “Analysis of Evidence” for the complete review. In summary, these tests do not have sufficient evidence to warrant coverage in Medicare patients.

It is important to assess genetic testing in the context of oncology with a rigorous, evidence-based approach to facilitate the appropriate testing for all eligible Medicare beneficiaries.

Due to concerns expressed regarding the requirement for use of one of the three multiple-evidence based third-party knowledge bases, the LCD has been revised to include an option to submit an LCD reconsideration request for a determination whether the test meets CMS IOM Publication 100-08, Chapter 13, Section 13.5.4 reasonable and necessary criteria.

Comments were received on behalf of Interpace Biosciences, Inc., with concerns about plans to retire the JH/JL LCD L34864 Loss-of-Heterozygosity Based Topographic Genotyping with PathfinderTG. PancraGEN (formerly PathFinder TG) is currently covered under L34864, effective for dates of service on and after 10/01/2015. If L34864 is retired, coverage for PancraGEN will be removed without an evidentiary basis.

Additionally, supplemental comments were received on behalf of Interpace Biosciences, Inc. The supplemental comments included a full-text clinical validation study for the next generation ThyraMIR v2, which was actively in use as of August 29, 2022. It was noted that ThyraMIR v2 will provide statistically significant improvements in diagnostic accuracy at the same payment rate. Concerns about other elements of the proposed LCD were reinforced.

Thank you for your comments. We appreciate the information regarding ThyraMIR v2.

NCCN, ClinGen, and OncoKB were searched for PancraGEN, and as of the date of the search, PancraGEN was not included in any of the knowledge bases.

PubMed and Google Scholar were searched for peer-reviewed, evidence-based literature that provided information regarding the analytic and clinical validity and clinical utility for the PancraGEN test. Key words used to search in combination included: PancraGEN, PathfinderTG, molecular testing, topographic genotyping, pancreatic cyst(s), pancreatic cyst fluid, solid pancreatic lesions, and KRAS and/or GNAS mutations.

Please refer to the LCD “Summary of Evidence” and “Analysis of Evidence” for the complete review. In summary, this test does not have sufficient evidence to warrant coverage in Medicare patients.

It is important to assess genetic testing in the context of oncology with a rigorous, evidence-based approach to facilitate the appropriate testing for all eligible Medicare beneficiaries.

Of note, the LCD was revised to include an option to submit an LCD reconsideration request for a determination whether the test meets CMS IOM Publication 100-08, Chapter 13, Section 13.5.4 reasonable and necessary criteria.

A comment was received requesting the LCD include a specific category for Next Generation Sequencing (NGS) for hematologic and lymphoid malignancies since NCD 90.2 only addresses NGS for solid tumors.

Thank you for your comment. The scope of the Genetic Testing for Oncology LCD is for all DNA and RNA testing in the practice of oncology in the Medicare population. The NCD for NGS testing, as you have stated, is limited to solid tumors. The coverage criteria in this LCD applies to all technologies used in the performance of DNA and RNA testing in the practice of oncology except for those instances where CMS has coverage criteria in an NCD. Please refer to comment and response #18 for more details regarding NCDs 90.2, 190.3, and 210.3. The LCA has instructions for billing a targeted genomic sequence analysis panel.

A comment was received from MD Anderson Cancer Center regarding suggested improvements to the LCD and LCA. A clarification example is needed of when to bill panel codes versus individual genes. A matrix is needed for cross-referencing levels of evidence among the three compendia. Additional widely used compendia with well-established evidence-based recommendations like WHO classification should be allowed.

Thank you for your comments. The LCA has been updated with a clarification example and tables have been added to the LCD to assist in determining coverage for a genetic test.

While it is agreed that the WHO classifications are excellent guidelines for oncology, these guidelines require purchase of the material in addition to limitations such as not having accompanying scoring metrics, limits in conflict of interest information, and absence of an accompanying searchable knowledge base. It is anticipated that WHO classifications are taken into consideration for other knowledge bases (e.g., see NCCN Guideline for Neuroendocrine and Adrenal Tumors, Reference #28).

Due to concerns expressed regarding the requirement for use of one of the three multiple-evidence based third-party knowledge bases, the LCD has been revised to include a fourth option to submit an LCD reconsideration request for a determination whether a specific compendium meets CMS IOM Publication 100-08, Chapter 13, Section 13.5.4 reasonable and necessary criteria.