LCD L39367: Genetic Testing in Oncology: Specific Tests

Compliance with the provisions in this LCD may be monitored and addressed through post payment data analysis and subsequent medical review audits.

History/Background and/or General Information

With advancement in science and technology comes the ability to incorporate genetic testing for oncology biomarkers into clinical care, with the goal of improved patient outcomes. The scope of this LCD encompasses the MAC’s review of 10 tests that are utilized in the practice of oncology in the Medicare population.

As defined by the Food and Drug Administration (FDA) and National Institutes of Health (NIH) Biomarker Working Group, a biomarker is “A defined characteristic that is measured as an indicator of normal biological processes, pathogenic processes, or biological responses to an exposure or intervention, including therapeutic interventions,” and may include molecular, histologic, radiographic, or physiologic characteristics. 1 (p.46)

Cancer is a disease caused by changes or alterations to a person’s genome. Some genetic changes or alterations can be inherited (also known as germline mutations). About 5-10% of all cancer diagnoses result from germline mutations, and over 50 hereditary cancer syndromes are known. Other cancer-causing (oncogenic) genetic changes or alterations result from acquired genetic damage (also known as somatic mutations). Somatic mutations can arise in numerous scenarios, including exposure to chemicals that alter DNA (carcinogens) or ultraviolet (UV) radiation from the sun. 2

Biomarker testing is a part of precision medicine (also known as personalized laboratory medicine). Precision medicine is a tailored approach to medical care and treatment. Because each patient has a unique combination of genetic heritage and somatic changes, and therefore, a unique pattern of biomarkers, precision medicine for oncology involves the use of biomarker testing to pinpoint the disease management needs of individual patients and avoid the use of treatments which are unlikely to be successful. 3 Much of this testing involves direct evaluation of the genetics of the malignancy through various testing methodologies. These methodologies can include high level genetic evaluations such as karyotyping (analysis of chromosomes) to more detailed evaluations such as identifying specific pathogenic point variations (analysis of specific nucleotide changes).

Additionally, testing may be used to check for a single biomarker or multiple biomarkers at the same time via a multigene test or panel. 2 As a result, the growing compendium of products described as biomarkers requires careful evaluation to determine what testing configurations are reasonable and necessary under Medicare.

Biomarkers for oncology can be generally classified into 4 functional types 4 :

• Diagnostic biomarkers detect or confirm the presence of a disease or condition.

• Prognostic biomarkers provide information about the likely course of a disease process and potential patient outcomes if left untreated.

• Predictive biomarkers forecast a patient’s response and/or benefit to a specific treatment.

• Therapeutic biomarkers identify potential targets for a medical intervention. (e.g., targeted drug therapy)

In certain circumstances, genetic testing for oncology biomarkers in patients with the corresponding appropriate medical condition could have the potential to assist patient management in the Medicare population. However, given the complexity and rapidly expanding knowledge in this topic area, we must vigilantly avoid testing that generates confusion and that does not improve patient outcomes. In order for services to be considered reasonable and necessary, they must impact the management of the patient and lead to improved patient outcomes. Specialized clinical expertise in oncology in addition to advanced knowledge in both genetic variation and effect on gene function is required to facilitate optimal outcomes for patients.

Definitions

Analytical validation is a process intended to determine if a test, tool, or instrument has acceptable technical performance (sensitivity, specificity, accuracy, precision, etc.). Analytical validation is an assessment of the test’s technical performance (the test measures what it was designed to measure), not its usefulness or clinical significance. 1,5 Analytical validity includes the ability of the test to accurately and reliably detect the mutation and/or variant. 5

Biomarkers A biological molecule found in blood, other body fluids, or tissues that is a sign of a normal or abnormal process, or of a condition or disease. A biomarker may be used to see how well the body responds to a treatment for a disease or condition. Also called molecular marker and signature molecule. 6

Cancer Screening An attempt to detect cancer early by routine examination of apparently healthy people. 7

Cancer Surveillance is closely watching a patient’s condition but not treating it unless there are changes in test results. Surveillance is also used to find early signs that a disease has come back. During surveillance, certain exams and tests are done on a regular schedule. 8

Cell-free DNA (cfDNA) is a laboratory method that involves analyzing free (i.e., no longer within the cell) DNA contained within a biological sample, most often to look for genomic variants associated with a hereditary or genetic disorder. For example, prenatal cfDNA testing is a non-invasive method used during pregnancy that examines the fetal DNA that is naturally present in the maternal bloodstream. Cell-free DNA testing is also used for the detection and characterization of some cancers and to monitor cancer therapy. 9

Clinical Indication for Germline testing 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 hereditary disease or condition. 10

Circulating tumor DNA (ctDNA) are small pieces of DNA that are released into a person’s blood by tumor cells as they die. A sample of blood can be used to look for and measure the amount of ctDNA and identify specific mutations (changes) in the DNA. Circulating tumor DNA is being used as a biomarker to help diagnose some types of cancer, to help plan treatment, or to find out how well treatment is working or if cancer has come back. 11

Clinical validity is defined as the ability of a test to classify a patient’s specific circumstance into a diagnostic, prognostic, or predictive functional category. It should be noted that clinical validity is not a fixed value. Clinical validity includes the ability of the test to accurately and reliably detect the disease of interest in the defined population. 5,12

Clinical utility is defined as the ability of a test to provide information related to the patient’s care and management, and thus, its ability to inform treatment decisions. CMS is most focused on assessing clinical utility in the context of whether or not a test is used to guide patient management and whether or not use of the test results leads to treatment that improves health outcomes. 5,12

Comprehensive Genomic Profiling (CGP) is, at this time, a term with many potential interpretations depending on which entity uses the term and in what context the term is used. Because of this, the term Comprehensive Genomic Profiling will not be utilized within this LCD . It is recognized that knowledge bases like NCCN sometimes use the term CGP, but it must be recognized that the term’s precise definition depends on the unique context in which it is utilized. Because of this, the way CGP is defined in one guideline will not necessarily translate to other guidelines.

FDA-cleared or approved test system means a test system was cleared or approved by the FDA through the premarket notification (510(k)) or premarket approval (PMA) process for in-vitro diagnostic use. (See CFR, Title 42, Volume 2, Chapter IV, Part 493.2 Laboratory Requirements: Definitions)

Genetic Testing , for the purposes of this LCD, describes any and all assays evaluating DNA and/or RNA without regard for a test’s purpose, methodology, or output. Examples of “genetic testing” include DNA sequencing of genes and surrounding non-coding regions, quantification of RNA expression, identification of epigenetic changes to the DNA, and evaluation of overall changes in chromosome structure. Moreover, this term encompasses all testing that includes genetic evaluation without regard to other included test components such as simultaneous protein testing and algorithmic analyses (e.g., multianalyte assays with algorithmic analyses [MAAAs]). Widely accepted terminology used in oncology such as “biomarker testing,” “genetic testing for an inherited mutation,” and “genetic testing for inherited cancer risk” are included under the umbrella term “genetic testing” for the purposes of this LCD, recognizing that molecular oncology is a highly complex and rapidly evolving field and thus, more inclusive terminology is required.

Genomic Testing , for the purposes of this LCD, will not be used as a defining term . Depending on the context, genomic testing can describe testing that includes both genes and non-coding sequences; however, given how this term is not always used precisely, we chose to avoid using this term to define policy in this LCD.

Genomic Sequencing Procedures (GSPs) are DNA and/or RNA sequence analysis methods that simultaneously assay multiple genes or genetic regions relevant to a clinical situation. They may target specific combinations of genes or genetic material or assay the exome or genome. 13

Germline The sequence of cells in the line of direct descent from zygote to gametes, as opposed to somatic cells (all other body cells). Mutations in germline cells are transmitted to offspring; mutations in somatic cells are not transmitted to offspring. 14

Kit means all components of a test that are packaged together. (See CFR, Title 42, Volume 2, Chapter IV, Part 493.2 Laboratory Requirements: Definitions)

Laboratory Developed Tests (LDT) defined by the FDA as an in vitro diagnostic test that is manufactured by and used within a single laboratory. 15

Liquid biopsy is a test performed on blood to either look for cancer cells circulating in the blood or for DNA from tumor cells that are in the blood. 16

Minimal residual disease (MRD) is a term used to describe a very small number of cancer cells that remain in the body during or after treatment. Minimal residual disease can be found only by highly sensitive laboratory methods. Also called measurable residual disease. 17

Multianalyte Assays with Algorithmic Analyses (MAAAs) are procedures that utilize multiple results derived from panels of analyses of various types, including molecular pathology assays, fluorescent in situ hybridization assays, and non-nucleic acid-based assays. Algorithmic analysis using the results of the assays as well as other patient information is performed and typically reported as a numeric score(s) or as a probability. 18

Neoplasm An abnormal mass of tissue that forms when cells grow and divide more than they should or do not die when they should. Neoplasms may be benign (not cancer) or malignant (cancer). 19

Next Generation Sequencing (NGS) is a high-throughput method used to sequence a part or the whole of an individual’s genome. This technique utilizes DNA sequencing technologies that are capable of processing multiple DNA sequences in parallel. Also called massively parallel sequencing. Note that NGS is also utilized to analyze RNA, however, the RNA is typically converted to complementary DNA (cDNA) before analysis. 20

Reflex testing means confirmatory or additional laboratory testing that is automatically requested by a laboratory under its standard operating procedures for patient specimens when the laboratory's findings indicate test results that are abnormal, are outside a predetermined range, or meet other pre-established criteria for additional testing. (See CFR, Title 42, Volume 2, Chapter IV, Part 493.2 Laboratory Requirements: Definitions)

Risk Factor for Germline testing is a variable associated with an increased risk of a disease, such as age, sex, or family history of disease. 10

Somatic, a term synonymous with acquired, refers to genetic code alterations that develop after birth (e.g., occurring in neoplastic cells) 21

A Substantiated Suspicion of Cancer requires direct, physical sampling of a lesion, such as a needle aspiration or excision of tissue, followed by microscopic (histologic or cytologic) or flow cytometric evaluation of the sample. For the purposes of this LCD, radiologic suspicion of cancer is not considered “substantiated.” (Except where otherwise specified in the Covered Indications as reasonable and necessary.)

Treating physician is 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 then 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 reasonable and necessary. Nonphysician 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. (see CFR, Title 42, Volume 2, Chapter IV, Part 410.32(a))

Tumor mutation burden (TMB) is the total number of mutations (changes) found in the DNA of cancer cells. 22

Covered Indications

For services to be considered reasonable and necessary, the below is required :

The provider has either established a diagnosis of cancer or found significant evidence to create suspicion for cancer in their patient. (See SSA 1862(a)(1)(A)) Both a clinical evaluation AND abnormal results from histologic, cytologic and/or flow cytometric examination are required to establish a diagnosis of cancer or suspicion of cancer. If then, as a next step in the clinical management of the patient, genetic testing would directly impact the management of the patient’s specific condition, the testing would be indicated. (see CFR, Title 42, Volume 2, Chapter IV, Part 410.32(a))

UroVysion has been determined to demonstrate actionability in clinical decision-making as described below:

• UroVysion: This FDA-approved adjunctive test is intended for use in conjunction with and not in lieu of current standard diagnostic procedures to aid in the initial diagnosis of bladder carcinoma in patients with persistent hematuria and subsequent monitoring for tumor recurrence in patients previously diagnosed with bladder cancer following administration of Bacillus Calmette-Guerin (BCG). 23 Therefore, UroVysion is reasonable and necessary when at least one of the following conditions is met:

• To clarify indeterminate or nondiagnostic cytology results in patients with persistent gross or microscopic hematuria suspected of having urothelial cancer following a complete history and physical, cystoscopy, and imaging of the urinary tract in alignment with published, peer-reviewed specialty society guidelines. 24,25,26 OR

• Surveillance in patients already diagnosed with non-muscle invasive bladder cancer (NIMBC) under evaluation for the response to intravesical BCG in alignment with published, peer-reviewed specialty society guidelines 26

Limitations

The following are considered not reasonable and necessary:

• Genetic testing in patients who do not have either an established diagnosis of cancer or substantiated suspicion of cancer as determined by a clinical evaluation and abnormal results (cancer or suspicious for cancer) from histologic, cytologic, and/or flow cytometric examination. (Except where otherwise specified in the Covered Indications as reasonable and necessary) (See SSA Section 1862(a)(1)(A))

• Genetic testing of asymptomatic patients for the purposes of screening the patient or their relatives. (See SSA Section 1862(a)(1)(A))

• Repetitions of the same genetic test on the same genetic material. (i.e., revalidations, quality control, or failure of a first test attempt)(see Medicare NCCI Policy Manual, Chapter 10, Section A Introduction)

• DecisionDx-SCC*

• Cxbladder Detect*

• Enhanced Cxbladder Detect*

• Cxbladder Monitor*

• Cxbladder Triage*

• Colvera*

• PancreaSeq Genomic Classifier*

• PancraGEN*

• ThyroSeq CRC*

*Please see below Summary and Analysis of Evidence sections for citations.

Provider Qualifications

The following provider qualification requirements must be met for the service to be considered reasonable and necessary. The ordering provider of a genetic test for a patient with an established diagnosis of cancer or substantiated suspicion of cancer must:

• Be the treating clinician who is responsible for the management of the patient’s cancer; and,

• Understand how the test result will impact the patient’s condition; and,

• Have presented this information to the patient eliciting patient understanding.

(See Code of Federal Regulations, Title 42, Volume 2, Chapter IV, Part 410.32(a)).

Notice: Services performed for any given diagnosis must meet all of the indications and limitations stated in this LCD, the general requirements for medical necessity as stated in CMS payment policy manuals, any and all existing CMS national coverage determinations, and all Medicare payment rules.

Introduction

Please refer to the “History/Background and/or General Information” section for general information on testing of RNA and DNA as it applies to oncology.

This evidence review focuses on genetic testing used to guide oncologic treatment and whether the evidence behind this testing is adequate to draw conclusions about improved health outcomes for the Medicare population. In general, health outcomes of interest include patient mortality, morbidity, quality of life, and function.

For use in the Medicare population, tests themselves must demonstrate analytic validity, clinical validity, and clinical utility. Tests should enhance clinical decision-making, directly informing clinical management and improving patient outcomes.