Compliance with the provisions in this policy may be monitored and addressed
through post payment data analysis and subsequent medical review audits.  
  
 **History/Background and/or General Information**  
  
The emergence of personalized laboratory medicine has been characterized by a
multitude of testing options which can more precisely pinpoint management
needs of individual patients. As a result, the growing compendium of products
described as biomarkers requires careful evaluation by both clinicians and
laboratorians as to what testing configurations are reasonable and necessary
under the Medicare Act. There are a plethora of burgeoning tools, including
both gene-based (genomic) and protein-based (proteomic) assay formats, in
tandem with more conventional (longstanding) flow cytometric, cytogenetic,
etc. biomarkers. Classified somewhat differently, there are highly-diverse
approaches ranging from single mutation biomarkers to multiple biomarker
platforms, the latter of which often depend upon sophisticated biomathematical
interpretative algorithms.  
  
The term "biomarker" refers to a broad subcategory of medical signs (i.e.,
objective indications of medical state observed from outside the patient)
which can be measured accurately and reproducibly. Medical signs stand in
contrast to medical symptoms, which are limited to indications of health or
illness perceived by the patient. In 1998, the National Institute of Health
(NIH) defined a biomarker as: "a characteristic that is objectively measured
and evaluated as an indicator of normal biologic processes pathogenic
processes, or pharmacologic response to a therapeutic intervention."  
  
This current LCD focuses upon selected testing in oncology, with some emphasis
upon applying the revised 2016 CPT molecular coding format. The LCD primarily
applies to molecular biomarker testing but does involve some other types of
related biomarker testing, such as proteomics.  
  
There are separate Local Coverage Determinations (LCDs) that address other
biomarkers, which include a multitude of assays which are not specifically
discussed below. (Please refer to the Novitas website at [www.novitas-
solutions.com](https://www.novitas-
solutions.com/webcenter/portal/NovitasSolutions) for a complete listing of
LCDs.)  
  
Local Medicare coverage of such biomarkers must be predicated upon four
fundamental principles:

  1. First, the biomarkers must have proven clinical validity/utility (CVU). 
  2. Second, to support the medical necessity of the service, there must be acceptance/uptake of specific testing into patient management. **It is essential that physicians be familiar enough with all specific biomarkers, which they order, such that all test results may become clinically actionable.**
  3. Providers managing oncological conditions must demonstrate that the use of biomarkers will be used to assist in the management/treatment of the beneficiary.
  4. Peer-reviewed full manuscript evidence is required to support combination panels for multiple biomarkers, particularly regarding their alleged composite clinical validity/utility. For example; such potential billing for multiple, diverse biomarkers (e.g., diagnostic/monitoring/prognostic/predictive) can only achieve medical necessity when it is clearly evident how each requested biomarker can be individually contributory.

It is useful to categorize oncology biomarkers into functional clusters which
reflect both (1) The predominant intent of testing (with the caveat that
individual assays may cross over into more than one category) and (2) the
relative evidentiary expectations:

  1. Oncology Biomarkers Used for Diagnosis/Classification/Monitoring/Surveillance: These types of assays are supportable by case-control sensitivity/specificity studies, with appropriate designs in place to minimize the extent of bias and confounding.
  2. Oncology Biomarkers Used for Prognosis/Prediction: Oncology biomarkers used for prognosis/prediction (i.e., a predictive biomarker is associated with response [benefit] or lack of response to a particular therapy, relative to other available therapy, whereas a prognostic biomarker provides information on the likely outcome of the disease in an untreated individual).

There is a complex and diverse set of study methods which can drive the robust
formulation of evidence for such esoteric testing, which are well-summarized
by Deverka et al. at the Center for Medical Technology Policy, but there are
currently NO standardized thresholds or benchmarks for evaluating the
CVU/medical necessity of emerging biomarkers. However, the following sources
(although not exhaustive and complete) may help support CVU when requesting
reconsideration for coverage of biomarkers that are not included in this LCD:

  1. FDA labeling documentation.
  2. National Comprehensive Cancer Network (NCCN) Biomarkers Compendium recommendations, particularly where Category 1 evidence is noted.
  3. Findings from well-established, independent technology assessments (e.g., Evaluation of Genomic Applications in Practice and Prevention [EGAPP], Agency for Healthcare Research and Quality [AHRQ], Blue Cross and Blue Shield Association Technology Evaluation Center [BCBSA TEC] and the Cochrane Collaboration).
  4. Other independent, objective evaluations or systematic literature reviews, which can substantively contribute to the evidence base, including, but not restricted to, emerging National Institutes of Health (National Cancer Institute) guidelines for the accrual of genomics/proteomics clinical validity/utility evidence. Although there is not a prescriptive format for such systematic reviews, the documentation (submitted to Novitas) for reconsideration purposes should include the following three elements: 
    * Some type of recurring/periodic Committee structure, which is comprised of at least qualified biomathematicians/methodologists, molecular pathology laboratory specialists and relevant clinicians (e.g., oncologists).
    * Evidence of active sharing of the critical evaluations in a manner that enables sufficiently broad input into this process, and a feasibly wide acceptance of this process by representative molecular pathology stakeholders. There is no preference between such a Committee being based at a single site, or even rotating among several sites.
    * Transparency of the biomarker evaluations via minutes (or a summary of minutes).

  
**Covered Indications**  
  
 **MOLECULAR TESTS**  
  
Covered clinical types of application(s) are identified below as diagnostic
(DX), prognostic (PROG) or predictive (PRED).

1.  Colorectal Cancer

  *     * KRAS (12/13) - PRED of resistance to an anti-EGFR agent
    * KRAS codon 61 - PRED of resistance to an anti-EGFR agent
    * KRAS codon 146 - PRED of resistance to an anti-EGFR agent
    * NRAS - PRED of resistance to an anti-EGFR agent
    * BRAF - PRED of resistance to an anti-EGFR agent + DX (sporadic vs. Lynch syndrome)
    * PIK3CA - PRED of resistance to an anti-EGFR agent + PROG for local recurrence
    * MSI by PCR - PRED of 5-FU resistance + DX
    * MLH1 promoter hypermethylation - PRED of 5-FU resistance + DX
    * mRNA (oncotype-Colon) - PRED for the recurrence risk for patients with Stage II colon cancer
    * Hereditary colon cancer disorders
    * Sept9

ColonSeq

This testing provides information to the patient and provider regarding
potential treatment options and implications for RAS and BRAF mutations.

Please refer to DA52986-Billing and Coding: Biomarkers for Oncology regarding
coding and billing information.

2.  Non-Small Cell Lung Cancer (NSCLC)

    * EGFR- PRED of anti-EGFR response
    * KRAS (12/13) - PRED of anti-EGFR resistance
    * KRAS codon 61 - PRED of anti-EGFR resistance
    * KRAS codon 146 - PRED of anti-EGFR resistance
    * BRAF - PROG + PRED for anti-RAF inhibitor  
  
ThermoFisher Oncomine DX Target Test for Non-Small Cell Lung Cancer (NSCLC) is
a 23 gene panel including a 3 gene target test (companion test) approved by
the FDA in June 2017 for NSCLC from tissue specimens.  It can simultaneously
identify the three gene variants that are a key to targeted therapy selection:
BRAF and ROS1, and EGFR.  The targeted therapies are dabrafenib (Tafinlar) in
combination with trametinib (Mekinist), crizotinib (Xalkori), and gefitinib
(Iressa), respectively.  These three drugs are approved therapies for NSCLC
patients with the above gene variants. Oncomine DX Target Test is the only FDA
approved companion test that detects ROS1 fusions and that detects BRAF V600E,
but it does not detect ALK fusions. Coverage is limited as specified in NCD
90.2, Next Generation Sequencing (NGS) for Patients with Advanced Cancer.
Please refer to the NCD at [https://www.cms.gov/medicare-coverage-
database/details/ncd-
details.aspx?NCDId=372&ncdver=1&bc=AAAAQAAAAAAA](https://www.cms.gov/medicare-
coverage-database/details/ncd-details.aspx?NCDId=372&ncdver=1&bc=AAAAQAAAAAAA)
for full coverage details.

LungSeq

Testing for genetic alteration in these genes can determine targeted therapy
options that have the potential to decrease tumor burden, decrease symptoms,
increase survival, and dramatically improve the quality of life for patients
with specific genetic alterations.

Please refer to A52986, Billing and Coding: Biomarkers for Oncology regarding
coding and billing information.

3.  Melanoma

    * BRAF - PRED of response to Vemurafenib
    * KIT - PRED of response to Imatinib (TKI)
    * NRAS - PROG + PRED for anti-MEK inhibitor
  *    
4.  Uveal Melanoma
    * GNAQ - PROG
    * GNA11 - PROG 

5.  Brain

    * BRAF - PRED
    * EGFR - PRED
    * MGMT - PRED
    * IDH1 - DX + PROG
    * IDH2 - DX + PROG
    * PIK3CA - PRED
    * PTEN - PRED
    * CIMP - PRED
    * TERT - DX

6.  Thyroid

    * BRAF - DX + PRED
    * KRAS - PRED for Selumetinib
    * HRAS - PRED for Selumetinib
    * NRAS - PRED for Selumetinib
    * PIK3CA - PRED
    * RET - DX
    * PAX8/PPARG- DX

ThyraMIR Thyroid miRNA classifier (aPCR based microRNA gene expression
classifier) (PRED) evaluates the expression levels of 10miRNA genes within an
FNA biopsy: miR-29b-1-5p, miR-31-5p, miR-138-1-3p, miR-139-5p, miR-146b-5p,
miR-155, miR-204-5p, miR-222-3p, miR-375, and miR-551b-3p.  
  
Oncology Thyroid, provides gene expression analysis of 142 genes utilizing
fine needle aspirate, algorithm reported as a categorical result (Afirma -
PRED).  
  
ThyraMIR is used as a companion test to ThyGeNEXT when ThyGeNEXT results are
inconclusive.

      * ThyraMIR, ThyGeNEXT and Afirma services will be considered reasonable and necessary for patients with any of the following conditions:  
  

        * An indeterminate pathology on fine needle aspiration
        * Patients with one or more thyroid nodules with a history or characteristics suggesting malignancy such as:  

          * Nodule growth over time
          * Family history of thyroid cancer
          * Hoarseness, difficulty swallowing or breathing
          * History of exposure to ionizing radiation
          * Hard nodule compared with rest of gland consistency
          * Presence of cervical adenopathy
      * RosettaGX Reveal thyroid MicroRNA test, an assay used for the classification of indeterminate thyroid nodules, will be considered reasonable and necessary when the conditions outlined above for ThyraMIR, ThyGeNEXT and Afirma are met.
      * ThyroSeq is a test utilized to better define the need for thyroid surgery and the type of such surgery. ThyroSeq will be considered reasonable and necessary when the conditions outlined above for ThyraMir, ThyGeNEXT and Afirma are met.

7.  Ovary/Fallopian Tube/Peritoneum

      * AKT1 - PRED for PI3K/AKT/mTOR inhibitors
      * BRAF - DX + PROG
      * KRAS - DX + PROG
      * MLH1 promoter hypermethylation - DX
      * MSI by PCR - DX
      * PIK3CA - PRED for PI3K/AKT/mTOR inhibitors
      * PTEN - PRED for PI3K/AKT/mTOR inhibitors
      * TP53 - DX + PROG

8.  Uterus

      * AKT1 - PRED for PI3K/AKT/mTOR inhibitors
      * BRAF - PRED
      * KRAS - PRED
      * MLH1 promoter hypermethylation - DX
      * MSI by PCR - DX
      * PIK3CA - PRED for PI3K/AKT/mTOR inhibitors
      * PTEN - PRED for PI3K/AKT/mTOR inhibitors + DX + PROG
      * TP53 - DX + PROG

9.  Urinary Tract

      * FGFR3 - PROG
      * MSI by PCR - DX
      * MLH1 promoter hypermethylation - DX

10.  Prostate

      * The PROGENSA PCA3 Assay (PRED) is an FDA-approved, automated molecular test (assay) that helps physicians determine the need for repeat prostate biopsies in men who have had a previous negative biopsy.
      * PTEN - PROG and THER
      * RB1 - DX and PROG
      * TP53 - PROG

11.  Gastrointestinal Stomal Tumor

      * KIT - PRED for Sumatinib + DX
      * PDGFRA - PRED for Sumatinib + DX

12.  Cancer of Unknown Primary (CUP)

Molecular testing, using the Rosetta Cancer Origin TestTM (PROG), is considered
reasonable and necessary in the pathologic diagnoses of CUP when a
conventional surgical pathology/imaging work-up is unable to identify a
primary neoplastic site. Other applications of this technology are considered
not reasonable and necessary and are considered investigational in the use of
diagnosis of specific tumor types such as NSCLC and renal cancers.

TUO CTID (Cancer Type ID) (DX) is considered reasonable and necessary in the
pathologic diagnoses of CUP when a conventional surgical pathology/imaging
work-up is unable to identify a primary neoplastic site. Other applications of
this technology are considered not reasonable and necessary and are considered
investigational in the use of diagnosis of specific tumor types such as NSCLC
and renal cancers.

13.  Leukemias and Lymphomas

      * Acute lymphoid leukemia (ALL)  

        * JAK1
        * JAK2
        * BCR/ABL1 - DX
        * ABL1 (kinase domain) - PROG
        * IGH - DX
        * TCRB - DX
        * TCRG - DX
        * TP53 - PROG
        * MLL/AF4 - DX
        * E2A/PBX1 - DX
        * ETV6/RUNX1 - DX
        * KRAS
        * NRAS
        * NOTCH1
        * FBXW7
      * Acute myeloid leukemia (AML, and including acute promyelocytic leukemia): All PROG, except where noted below.  

        * TP53
        * PML/RARA - DX
        * RUNX1/RUNX1T1 - DX
        * CBFB/MYH11 - DX
        * FLT3 ITD
        * FLT3 D835
        * NPM1
        * KRAS
        * NRAS
        * KIT
        * CEBPA
        * IDH1
        * IDH2
        * DNMT3A
        * JAK2 (p.V617F)
        * JAK2 (exon 12)
        * MPL
        * DEK/CAN - DX
        * ASXL1
        * EZH2
        * TET2
        * PML/RARalpha
        * U2AF1
        * SRSF2
        * ZRSR2
      * Hairy cell leukemia   

        * BRAF
        * IGH somatic hypermutation - PROG
        * IGH - DX
      * Aplastic anemia   

        * TCRB - DX
        * TCRG - DX
      * Burkitt's lymphoma   

        * IGH - DX
        * TP53 - PROG
      * Myeloproliferative diseases (MPD - essential thrombocytosis [ET], myelofibrosis & polycythemia vera [PV])   

        * KIT
        * TP53
        * BCR/ABL1 - DX
        * JAK2 (p.V617F) - DX
        * JAK2 (exon 12) - DX
        * MPL - DX
        * CALR - DX
        * CSF3R - DX
        * ASXL1 - PROG
        * TET2 - PROG
        * EZH2 - PROG
        * Calr (exon 9)
      * Chronic myeloid leukemia (CML) and chronic myelomonocytic leukemia (CMML)  

        * ABL1 T3151 - CML only
        * KRAS - PROG
        * NRAS - PROG
        * BCR/ABL1 - DX
        * ABL1 (kinase domain) - PRED for Imatinib
        * FLT3 ITD - PROG
        * FLT3 D835 - PROG
        * KIT - PROG
        * JAK2 (p.V617F) - PROG
        * JAK2 (exon 12) - PROG
      * Chronic lymphoid leukemia (CLL)  

        * IGH - DX
        * IGH somatic hypermutation - PROG
        * TP53 - PROG
        * IGH direct probe method
        * BTK
        * PLCG2
        * BIRC3
        * BTK
        * NOTCH1
        * SF3B1
      * Follicular lymphoma 
        * IGH/BCL2 - DX
      * Hypereosinophilia Syndrome (HES)  

        * KIT (including p.D816V) - PROG + DX
        * FIP1L1/PDGFRA Fusion - DX
      * Mantle cell lymphoma  

        * CCND1/IGH - DX
      * Mastocytosis  

        * KIT (including p.D816V) - PROG + DX
        * FIP1L1/PDGFRA Fusion - DX
        * TCRG - DX
      * T-cell prolymphocytic leukemia  

        * JAK1
        * JAK3
        * TCRB - DX
        * TCRG - DX
      * T-cell large granular lymphocytic leukemia(TLGLL) 
        * STAT3
        * STAT5B
      * Myelodysplastic syndrome (MDS): All below biomarkers are PROG.  

        * FLT3 ITD
        * FLT3 D835
        * NPM1
        * KRAS
        * NRAS
        * KIT
        * CEBPA
        * IDH1
        * IDH2
        * DNMT3A
        * JAK2 (p.V617F)
        * JAK2 (exon 12)
        * MPL
        * ASXL1
        * EZH2
        * TET2
      * Cytogenomic microarray analysis, or alternatively, a single nucleotide polymorphism (SNP) array for the same testing, is covered for the identification of various mutations. These tests are used in the diagnosis/prognosis of various hematological malignancies.  
  

      * Waldenstrom's Lymphoplasmacytic Lymphoma 
        * MYD88

14.  Myeloma Gene Expression Profile (MyPRS) (PROG) isolates plasma cells from myeloma patients, extracts DNA, which is then subjected to MicroArray testing and application of validated software programs to identifying patterns of genetic abnormalities. Seventy highly predictive genes have been identified and correlated to myeloma early relapse. MyPRS gives a predictive risk signature as high-risk or low-risk at this time. A high risk score predicts a less than 20% three-year complete remission where as a low-risk predicts a five-year complete remission of greater than 60%. The predictive value for the stratification of therapeutic interventions allows these patients to be treated in a more personalized manner based on their own genetic profile.  
  
This test is considered reasonable and necessary only after the initial
diagnosis of multiple myeloma has been made and will be available to be used
in the stratification of therapeutic interventions. It would be inappropriate
to use this test as a diagnostic tool or as a monitoring device of ongoing
therapy. Other testing is available for this function.  
  
The coverage is set to include only two clinical settings:

    * Once after initial diagnosis is made. In the event MyPRS was not tested at diagnosis of myeloma and there is ongoing initial therapy with persistent disease, MyPRS can be done still as an initial test.  
  
OR  
  

    * If relapse has occurred and a change in the therapeutic modalities is contemplated.

Please refer to the limitations section of this policy for frequency
limitations.

15.  Hereditary neuroendocrine tumor disorders - Must include 6 genes with genomic sequence analysis NEX GEN including:

  *     * MAX
    * SDHB
    * SDHC
    * SDHD
    * TMEM127
    * VHL

Please refer to the limitations section of this policy for frequency
limitations.

16.  Hereditary neuroendocrine tumor disorders; duplication/deletion analysis panel - must include analysis for:

  *     * SDHB
    * SDHC
    * SDHD
    * VHL

17. Neuroendocrine Tumors

  *     * MGMT - PROG
    * PTEN - PROG and THER
    * RB1 - DX and PROG
    * TP53 - DX and PROG
    * TSC2 - PROG

18.  Prosigna breast cancer gene signature assay (PROG)

  
**Background**  
  
Women with early breast cancer and up to 3 locally positive lymph nodes whose
tumor is estrogen-receptor positive will usually receive anti-hormonal therapy
such as tamoxifen or aromatase inhibitors. U.S. (NCCN) and international (St.
Gallen) guidelines predicate the decision for adjuvant chemotherapy on the
size and grade of the breast cancer and other factors including genomic assays
that provide additional information on risk of recurrence (Hernandez-Ava et
al., 2013). According to a 2014 review, "Prognostic factors provide an
indication of whether a patient needs subsequent therapy." (Paoletti & Hayes,
2014). Similarly, another 2014 review article states, "Efforts should be
focused on reducing chemotherapy in patients unlikely to benefit." (Rampurwala
et al., 2014).  
  
The PAM50 breast cancer gene signature test was developed in the late 1990s
and initial studies showed a strong correlation with breast cancer recurrence
and with complete pathologic response to neoadjuvant chemotherapy (Parker et
al., 2009). While test results are reported on a scale of 1-100 as a Risk of
Recurrence (ROR) score, the underlying algorithm is also able to classify
cases into the luminal A and B, Her2neu, and triple-negative subtype
classifications.  
  
The Nanostring nCounter nucleic acid analysis system replicates the PAM50
algorithm, as an FDA cleared kit, the Prosigna Breast Cancer Gene Signature
Assay (FDA, 2013). The Prosigna package insert was most recently updated in
January, 2015 (FDA, 2015) reflecting additional studies (Sestak et al., 2014).
Notably, the Prosigna platform and the original PAM50 platform have a 0.997
correlation (Dowsett et al., 2013).  
  
For the FDA, the Prosigna test was validated in a large population of post-
menopausal, estrogen-receptor positive women based on 1,017 cases of the
TransATAC study (Dowsett et al., 2013). The study showed a strong correlation
with long-term breast cancer recurrence and added substantial additional
prognostic information over a clinical treatment score based on standard
clinical variables. This study was replicated in an independent population,
also on the Prosigna test, using 1,620 samples from the ABCSG8 trial (Gnant,
2014). A separate analysis of these trials validated prediction of distant
recurrence in years 5-10 after initial diagnosis (Sestak et al., 2014) and has
been incorporated in the FDA labeling (FDA, 2015). The Prosigna test is issued
as separate reports, consistent with FDA review and labeling, for node-
negative and node-positive (1-3 node) populations. Analytic performance,
precision, reproducibility, and analysis of the clinical validations are
provided in the FDA labeling
(https://www.accessdata.fda.gov/cdrh_docs/reviews/K130010.pdf).  
  
Clinical utility of this breast cancer gene signature has also been assessed.
The study of Martin et al. (2015) showed a 20% decision impact on decisions
for or against adjuvant chemotherapy in an all-comers population of 200 new
cases of incident breast cancer, when Prosigna test information became
available after all other clinical information had been considered. The net
rates of selecting adjuvant chemotherapy for low, intermediate, and high risk
cases was similar to that observed in a meta-analysis of Oncotype DX decision
data (Carlson & Roth, 2013). Additional support for the use of these test
results in treatment decisions comes from Parker et al. (2009), in which there
was a strong association with neoadjuvant chemotherapy response. Low-scoring
cases have a very low chance of complete pathological response to neoadjuvant
chemotherapy, while high-scoring cases approach a 50% chance of complete
pathological response. The same findings have been observed for other breast
cancer gene signatures based on prognostic algorithms (Chang et al., 2008).

The Prosigna test is reasonable and necessary when performed according to the
FDA label (https://www.accessdata.fda.gov/cdrh_docs/reviews/K130010.pdf).

19.  Desmoid Fibromatosi

  *     * CTNNB1 - DX and PROG

20. Hepatic Adenoma

  *     * CTNNB1 - DX and PROG

21.  Bladder

  *     * CDKN2A - PROG
    * FGFR1 - PROG
    * FGFR3 - PROG
    * MTOR - PROG
    * PIK3CA - DX and PROG
    * PTEN - PROG
    * RB1 - PROG
    * TP53 - PROG

  
**_NON-MOLECULAR ASSAYS_**

  1. The VeriStrat assay is a mass spectrophotometric, serum-based predictive proteomics assay for NSCLC patients, where "first line" EGFR mutation testing is either wild-type or not able to be tested (e.g., if tissue might not be available). This test is a driver of therapy, most notably EGFR inhibitors such as erlotinib, and it has been validated by randomized controlled studies (Carbone et al. and Stinchecomb et al.) and physician uptake data (Akerley et al.) to support this particular coverage niche.   
  

  2. This LCD does not address ALK and ROS1 FISH assays, which are indicated as predictive biomarkers for Crizotinib therapy, since they are currently covered assays. However, it is expected that non-molecular testing for these two biomarkers should provide adequate predictive information.  
  

  3. FISH tests for bladder cancer are complex tests based on precision reagents, controls, and mathematical algorithms, all of which must be validated in clinical trials in order to support cutoff points for critical patient care decisions. Therefore, in each local physician's office or laboratory, this category of testing is not easily replicated by miscellaneous research use or ASR reagents. Novitas will consider the coverage of FISH test kits based on peer-reviewed literature and approved manufacturer claims.   
  

  4. Although multiple bladder cancer FISH tests may be covered according to the above general criteria, UroVysionTM Bladder Cancer Kit (UroVysionTM Kit) will be considered medically reasonable and necessary only when performed according to the FDA label (https://www.accessdata.fda.gov/cdrh_docs/pdf3/P030052b.pdf) as follows:   
  
The UroVysion Bladder Cancer Kit (UroVysionTM Kit) is designed to detect
aneuploidy for chromosomes 3, 7, 17, and loss of the 9p2l locus via
fluorescence in situ hybridization (FISH) in urine specimens from persons with
hematuria suspected of having bladder cancer. Results from the UroVysion Kit
are intended for use, in conjunction with and not in lieu of current standard
diagnostic procedures, as an aid for initial diagnosis of bladder carcinoma in
patients with hematuria and subsequent monitoring for tumor recurrence in
patients previously diagnosed with bladder cancer.  
  

  5.  The OVA1TM proteomic assay (PROG) will be considered reasonable and necessary when performed according to the FDA label (https://www.accessdata.fda.gov/cdrh_docs/pdf15/K150588.pdf).  
  

  6. The Risk of Ovarian Malignancy Algorithm (ROMATM) is a qualitative serum test (PROG) that combines the results of HE4 EIA, ARCHITECT CA 125 II TM and menopausal status into a numerical score. ROMATM is intended (per FDA clearance) to aid in assessing whether a premenopausal or postmenopausal woman who presents with an ovarian adnexal mass is at high or low likelihood of finding malignancy at surgery. ROMATM will be considered reasonable and necessary for women who meet the FDA labeling criteria (https://www.accessdata.fda.gov/cdrh_docs/pdf10/K103358.pdf).   
  

**_Limitations_**  
  
 **Note:** Please refer to the indications for any restrictions specific to
the various assays. Please see NCD 90.2 for coverage details related to Next
Generation Sequencing (NGS) for Patients with Advanced Cancer.

    1. Most genomic testing should be a once in a lifetime test. Documentation in the medical record should clearly support the need for repeat testing to include the following: recurrence of disease, change in behavior of disease, etc.  
  

    2. The following tests will all be covered once per lifetime per beneficiary: 
      * Brain Molecular Biomarkers
      * Hereditary neuroendocrine tumor disorders
      * Hereditary neuroendocrine tumor disorders; duplication/deletion analysis
      * ThyraMIR, Afirma, ThyGeNEXT, RosettaGX Reveal and ThyroSeq tests 
        * Should the unlikely situation of a second, unrelated thyroid nodule with indetermindate pathology occur, coverage may be considered upon appeal with supporting documentation
      * TUO CTID (Caner TYPE ID)  
  

    3. While some biomarkers have utility for testing once per lifetime, there are some tumor specific scenarios where repeat testing would be needed for assessment of response to therapy or to identify basis of disease progression. In cases with metastatic or recurrent tumors, repeat testing may be useful in determining further clinical management. Also, biomarkers such as BCR-ABL1 fusion, PML-RARA fusion are useful in monitoring response to therapy and predict a response up to four times per annum.

**Notice:** Services performed for any given diagnosis must meet all of the
indications and limitations stated in this policy, 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.

Please refer to the "History/Background and/or General Information" section
for general information on biomarkers.  
  
Multiple sources of literature were submitted for consideration. The
literature consisted of various investigational, observational, and
experimental studies, as well as some letters to the editor in support of the
leukemia biomarkers expansion, and ThyGeNEXT panel. The literature was
reviewed; the following is a summary of the evidence submitted:  
  
Numerous articles were submitted in support of the Leukemia biomarker
expansion request. Taking into consideration the independent, objective
evaluation and systematic literature review, which substantively contributed
to the evidence base of the requested leukemia biomarkers and subsequently
approved by the Molecular Testing Evaluation Committee (MTEC), all the
requested biomarkers are considered reasonable and necessary for the listed
disease states below:

  * Acute Lymphoblastic Leukemia 
    * JAK1
    * JAK2
    * KRAS
    * NRAS
    * NOTCH1
    * FBXW7
  * Acute Myeloid Leukemia 
    * TP53
    * U2AF1
    * SRSF2
    * ZRSR2
  * Chronic Lymphocytic Leukemia 
    * BIRC3
    * BTK
    * PLCG2
    * NOTCH1
    * SF3B1
  * Chronic Myeloid Leukemia 
    * ABL1 T315I
  * Hairy Cell Leukemia 
    * BRAF
  * Myeloproliferative Diseases 
    * KIT
    * TP53
  * Prolymphocytic Leukemia 
    * JAK1
    * JAK3
  * T-cell Large Granular Lymphocytic Leukemia 
    * STAT3
    * STAT5B

  
Consistent with the literature review, NCCN rating and quality of the evidence
submitted, the following Biomarker Panel will be considered medically
reasonable and necessary:

  * ThyGeNEXT   
  

    * Xing, et al (2014),1 is a retrospective multicenter study that reviewed all known fusion and their prevalence in Papillary, poorly differentiated anaplastic, follicular, and medullary carcinomas. The study was a review and no new data was presented. The study conclusion demonstrates the prognostic value and perspectives of the utilization of gene fusions as therapeutic targets. The study conclusion is limited due to clinical utility not being achieved in reporting statistical findings, no available conflict of interest and no patient inhomogeneity. The quality of evidence for this study is moderate due to lack of peer review and the strength was conditional for the same reason.  
  

    * Xing, et al (2015),2 is a retrospective study to investigate the prognostic value of BRAF V600E mutation for the recurrence of papillary thyroid cancer in 2099 patients. The study conclusion demonstrates the overall BRAF V600E mutation prevalence was 48.5%. BRAF mutation was associated with poorer recurrence-free probability in Kaplan-Meier survival analyses in various clinicopathologic categories. The quality of evidence is high and the strength of recommendation is conditional for the population tested.  
  

    * Labourier, et al (2015),3 is a cross-sectional cohort study conducted at 12 endocrinology centers across the United States. The study results found that mutations were detected with malignant outcome. Among mutation negative specimens, miRNA testing correctly identified 64% of malignant cases and 98% of benign cases. The diagnostic sensitivity and specificity of the combined algorithm was 89% (95% confidence intervals (CI): 73 - 97%) and 85% (95% CI: 75 - 92%), respectively. At 32% cancer prevalence, 61% of the molecular results were benign with a negative predictive value of 94% (95% CI: 85 - 98%). Independently of variations in cancer prevalence, the test increased the yield of true benign results by 65% relative to mRNA-based gene expression classification and decreased the rate of avoidable diagnostic surgeries by 69%. This was purely supposition. The authors concluded: multi-platform testing for DNA, mRNA and miRNA can accurately classify benign and malignant thyroid nodules, increase diagnostic yield of molecular cytology, and further improve the preoperative risk-based management of benign nodules with AUS/FLUS or FN/SFN cytology. The quality of evidence is moderate as this was not peer reviewed, a conflict of interest was present in that one of the authors was employed by the company, and the clinical utility is implied but not proven.  
  

    * Giordano, et al (2014),4 is a case-control study conducted in 413 surgical cases comprising 17 distinct histopathologic categories. The study results found that, in the authors opinion, "standardized and validated multianalyte molecular panels can complement the preoperative and postoperative assessment of thyroid nodules and support a growing number of clinical and translational applications with potential diagnostic, prognostic, or theranostic utility." The quality of evidence is moderate as this was a validation study only and the clinical utility is not addressed. There is an obvious conflict of interest in that the laboratory represented in authors of this study and the correspondence is through the laboratory.  
  

    * Landa, et al (2013),5 is a retrospective study. The objectives of the study were: 1) to determine the prevalence of TERT promoter mutations C228T and C250T in different thyroid cancer histological types and cell lines; and 2) to establish the possible association of TERT mutations with mutations of BRAF, RAS, or RET/PTC. The study results found that TERT promoter mutations were found in 98 of 225 (44%) of specimens. TERT promoters C228T and C250T were mutually exclusive. The study conclusion demonstrates potential diagnostic, prognostic and therapeutic are suggested. TERT promoter mutations are highly prevalent in advanced thyroid cancers, particularly those harboring BRAF or RAS mutations which are most often TERT promoter wild type. Acquisition of a TERT promoter mutation could extend survival of BRAF- or RAS- driven clones and enable accumulation of additional genetic defects leading to disease progression. The quality of evidence is moderate as this is retrospective of variable tumor types and the clinical utility is only inferred.

**Leukemia**  
  
The literature submitted for the addition of several biomarkers for various
leukemia disease states was carefully reviewed. The literature submitted was
also reviewed and approved by the Molecular Testing Evaluation Committee
(MTEC). The MTEC reviews and votes on clinical requests for molecular testing
based upon levels of evidence, including publications in the medical
literature, and need for biomarkers in integral marker clinical trials. The
MTEC is charged with establishing evidence-based standard-of-care testing,
monitoring physician ordering of molecular tests, assuring documentation of
medical necessity, analyzing utilization data, and reviewing outcomes data
related to the use of molecular biomarkers. Taking into consideration the MTEC
approval and taking into account item 4 of the General Information section of
this policy, which allows for consideration of other independent, objective
evaluations or systematic literature reviews, the requested leukemia
biomarkers are considered reasonable and necessary.  
  
**ThyGeNEXT**  
  
The literature submitted for the requested addition of the ThyGeNEXT panel was
carefully reviewed. After consideration of the literature, NCCN rating, and
relevance to the Medicare population, the coverage of the ThyGeNEXT panel will
be added in replace of the ThyGenX panel. The coverage of this panel is being
added as there were enough genes requested in the panel achieving an NCCN 2A
rating that when combined with the genes covered in the ThyGenX panel with a
2A rating, a minimum total of 51 genes achieved the NCCN rating of 2A.
Further, the literature supported the clinical utility and clinical validity,
and was relevant to the Medicare population.