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Response to Comments: Molecular Pathology Procedures

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Article ID
A55334
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Article Title
Response to Comments: Molecular Pathology Procedures
Article Type
Response to Comments
Original Effective Date
12/01/2016
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As an important part of Medicare Local Coverage Determination (LCD) development, National Government Services solicits comments from the provider community and from members of the public who may be affected by or interested in our LCDs. The purpose of the advice and comment process is to gain the expertise and experience of those commenting.

We would like to thank those who suggested changes to the draft Molecular Pathology Procedures LCD. The official notice period for the final LCD begins on October 13, 2016, and the final determination will become effective on December 1, 2016.

Response To Comments

Number Comment Response
1 Requests were received in support of coverage of CPT 81445: Targeted genomic sequence analysis panel, solid organ neoplasm DNA and RNA analysis when performed, 5-50 genes (eg ALK, BRAF, CDKN2A, EGFR, ERBB2, KIT, KRAS, NRAS, MET, PDGFRA, PDGFRB, PGR, PIK3CA, PTEN, RET) seq variants and copy# or rearrangements if performed for assessment of indeterminate thyroid nodules. Commenters suggested that panel testing offered an appropriate and cost effective, tissue-saving, time-saving approach to providing this service and indicated that guidelines from professional societies (including NCCN) supported the direct impact on diagnosis, treatment, and management of the Medicare beneficiary. NGS carefully reviewed the submitted comments and accompanying literature and has concluded that Medicare coverage criteria are not yet met because of a lack of high quality evidence that such tests improve clinical outcomes in Medicare enrollees and the lack of a clear community standard as evidenced by disparate and/or weak recommendations from recognized relevant professional medical societies. The AACE (American Association of Clinical Endocrinologists) issued a disease state commentary for molecular diagnostic testing of thyroid nodules with indeterminate cytopathology in 2014 which concluded that, "molecular testing is meant to complement and not replace clinical judgment, sonographic assessment, and visual cytopathology interpretation" and "Prospective multicenter studies are required to validate all of these tests used either singly or in tandem." The American Thyroid Association (ATA) 2015 Management Guidelines for Adult Patients with Thyroid Nodules and Differentiated Thyroid Cancer offers the following recommendations for molecular testing in adults: “For nodules with AUS/FLUS (Atypia of Undetermined Significance/Follicular Lesions of Undetermined Significance) cytology, after consideration of worrisome clinical and sonographic features, investigations such as repeat FNA or molecular testing may be used to supplement malignancy risk assessment in lieu of proceeding directly with a strategy of either surveillance or diagnostic surgery. Informed patient preference and feasibility should be considered in clinical decision-making. (Weak recommendation, Moderate-quality evidence).” National Comprehensive Cancer Network (NCCN) Guidelines on the treatment of thyroid cancer (V1.2016) indicates that “molecular diagnostics may be employed (category 2B recommendation,” and noted that, “molecular markers should be interpreted with caution and in the context of clinical, radiographic, and cytologic features of each individual patient.” In general, NGS has not accepted NCCN 2B recommendations. Further research is warranted in order to meet requirements for Medicare coverage.
2 Requests were received in support of the PancraGen® (Interpace Diagnostics, Parsippany, N.J.), formerly known as Pathfinder® (RedPath Integrated Pathology, Pittsburgh, PA) test which uses topographic genotyping to provide a quantitative genetic mutational analysis of a specimen. PancraGen is being explored as an adjunctive tool when a definitive pathologic diagnosis cannot be determined from cytology specimens. NGS carefully reviewed the submitted comments and accompanying literature and has concluded that Medicare coverage criteria are not yet met because of a lack of high quality evidence that such tests improve clinical outcomes in Medicare enrollees and the lack of a clear community standard as evidenced by disparate and/or weak recommendations from recognized relevant professional medical societies. The American Society of Gastrointestinal Endoscopy (ASGE) recommendations used a “GRADE like methodology” and indicated the quality of evidence was low for the relevant recommendation, “We suggest that molecular testing of the cyst be considered when initial ancillary testing of cytology and CEA is inconclusive and when test results may alter management.” A low quality recommendation means that, “further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.” NGS agrees with the ASGE that the quality of evidence is low and that there remains a lack of quality evidence which shows that clinical care strategies which incorporate testing result in improved clinical outcomes compared to strategies without testing. Further research is warranted in order to meet requirements for Medicare coverage.
3 Multiple providers are concerned that DL35000 is extremely “broad” in scope, difficult to access, and difficult to target specific revisions. In an effort to be responsive to general comments from AMP-CAP and others, we acknowledge that the NGS policy L35000 is an unwieldy reference document regarding our molecular diagnostic coverage policies. To that end we have begun separating subject matter in separate policies. This process will extend through several policy making cycles.
4 Requests were received in support of coverage of genes in diagnosis and treatment of Myelodysplastic Syndrome (MDS). NGS appreciates the detailed effort in the Association for Molecular Patholgoy (AMP) and College of American Pathologists (CAP) commentary regarding multiple genetic tests used in the diagnosis and treatment of myelodysplastic syndromes and chronic myelomonocytic leukemia. Many of these tests are currently listed as Tier 2, some are reported with the unlisted code, 81479. AXSL1, EZH2, ETV6, RUNX, SF3B1, TP53 and JAK2 carry an NCCN 2A Category of Evidence recommendation in the diagnosis of myelodysplastic syndromes. Additional tests such as CEBPA (CPT 81218)) were also recommended, but do not share the same NCCN Category of Evidence. After deliberation, NGS is in agreement that genetic testing for MDS would be effectively addressed in a separate LCD. As such, we have conferred with our Carrier Advisory representatives (of relevant specialties), and with CAC appointed subject matter experts and have convened a policy initiative for the upcoming policy development cycle.
5 Requests were received in support of coverage of genes in the diagnosis and treatment of chronic myelomonocytic leukemia (CMML). AMP-CAP references the WHO guidelines (2016 revision) which state “the presence of mutations with genes often associated with CMML (e.g. TET2, SRSF2, AXL1 in >80% of cases, and SETBP1, NRAS/KRAS, RUNX1, CBL and EZT2in a lower frequency) in the proper clinical context can be used to support a diagnosis. Other molecular criteria for a CMML diagnosis include no evidence of BCR/ABL, PDGRA, PDGRB, FGFR1, PCM-JAK2 translocations, or JAK2, MPL1 or CALR mutations (see WHO 2016 revisions, Table 11, Diagnostic Criteria for CMML). The evidentiary base for these tests is not as firmly established in the NCCN guidelines. Nevertheless, as a clonal neoplasm with myelodysplastic and myeloproliferative features, it may be included in the policy development process for MDS outlined above. Therefore, NGS will also address genetic testing in CMML in an upcoming policy development cycle.
6 “Under Indications of Coverage, the statement, “Molecular pathology procedures (Tier1 and Tier 2) may be eligible for coverage when ALL of the following criteria are met”, We recommend that Bullet # 4: Results of the testing must directly impact treatment or management of the Medicare beneficiary;” be revised to read “Results of the testing must directly impact DIAGNOSIS, treatment or management of the Medicare beneficiary;” “Appropriate patient management is absolutely dependent on a correct DIAGNOSIS” SEC. 1862. [42 U.S.C. 1395y] (a) Notwithstanding any other provision of this title, no payment may be made under part A or part B for any expenses incurred for items or services— (1)(A) which, except for items and services described in a succeeding subparagraph, are not reasonable and necessary for the diagnosis or treatment of illness or injury or to improve the functioning of a malformed body member,” NGS will not revise bullet #4 because “diagnosis” is addressed in bullet #1.
7 Requests were received in support of coverage for 0008M (Prosigna®). NGS agrees and will provide coverage for the Prosigna® Breast Cancer Prognostic Gene Signature Assay based on FDA indications.
8 Requests were received in support of coverage for 81211, 81212, 81213, 81214, 81215, and 81217 BRCA testing for patients with a personal history of breast or another BRCA-related malignancy who do not have access to accurate family health information. Since this is a rare situation which is unlikely to apply to the Medicare population, NGS will not address in our policy at this time.
9 “ NCCN guidelines recommend obtaining “marrow to document remission status upon hematologic recovery including cytogenetics and molecular studies as appropriate. ” Consequently, mutation status must be determined to identify molecular markers to monitor therapeutic response. NCCN guidelines also instruct oncologists to “consider clinical trials for patients with targeted molecular abnormalities. ” It is only possible to follow these NCCN guidelines if gene panels of 5-50 genes are not denied automatically as not medically necessary”. Genetic testing to identify clinical trial eligibility is not a covered service.
10 Requests were received in support of coverage for CPT Code 81225 (CYP2C19 (cytochrome P450, family 2, subfamily C, polypeptide 19) (eg, drug metabolism), gene analysis, common variants (eg, *2, *3, *4, *8, *17)). NGS covers CYP2C619 to identify patients who are poor metabolizers of clopidogrel, particularly those with acute coronary syndrome or who are undergoing percutaneous coronary intervention.
11 Requests were received in support of coverage for CPT Code 81226 (CYP2D6 (cytochrome P450, family 2, subfamily D, polypeptide 6) (eg, drug metabolism), gene analysis, common variants (eg, *2, *3, *4, *5, *6, *9, *10, *17, *19, *29, *35, *41, *1XN, *2XN, *4XN). NGS provides coverage for a beneficiary who has Gaucher’s Disease or Huntington’s Chorea to guide therapeutic decision-making.
12 Requests were received in support of coverage for CPT Code 81227 (CYP2C9 (cytochrome P450, family 2, subfamily C, polypeptide 9) (eg, drug metabolism), gene analysis, common variants (eg, *2, *3, *5, *6)). NGS covers testing for warfarin response in accordance with NCD 90.1 (G9143}(Warfarin responsiveness testing by genetic technique using any method, any number of specimen(s))
13 Requests were received in support of coverage for CPT Code 81479 (ROS and MET; unlisted molecular pathology procedure). NGS covers Code 81479 (ROS and MET) for NSCLC. Also, ROS and MET are included in the Genomic Sequence Panels for Non-Small Cell Lung Cancer LCD under CPT code 81445.
14 Requests were received in support of coverage for CPT Code 81170 ABL1 (ABL proto-oncogene 1, non-receptor tyrosine kinase) (eg, acquired imatinib tyrosine kinase inhibitor resistance), gene analysis, variants in the kinase domain in patients with acute lymphoblasic leukemia (ALL) and chronic lymphoblastic leukemia (CLL) to guide therapeutic decision making. NGS agrees that ABL kinase domain sequencing is indicated in patients with ALL and chronic myeloid leukemia. The typographical error, chronic “lymphoblastic” leukemia (CLL), has been corrected.
15 Requests were received in support of coverage for CPT Code 81209 BLM (Bloom syndrome, RecQ helicase-like)(e.g. Bloom syndrome) gene analysis, 2281 del6ins7 variant. NGS agrees and will provide coverage for a beneficiary who may have Bloom syndrome to confirm diagnosis and guide medical decision-making.
16 Requests were received in support of coverage for CPT Codes 81220, 81221, 81222, 81223,81224 (cystic fibrosis transmembrane conductance regulator) (e.g.cystic fibrosis) gene analysis, common variants (e.g. ACMG/ACOG guidelines). NGS agrees and will provide coverage for a beneficiary who has or may have cystic fibrosis to guide therapeutic decision-making.
17 Requests were received in support of coverage for CPT Codes 81228 and 81229 Cytogenomic Microarray Analysis (CMA). While Cytogenomic Microarray Analysis (CMA) has applicability to fetal diagnostic studies, and in the initial post-partum evaluation of individuals with multiple congenital anomalies, with physical and intellectual developmental delay, and with autism spectrum disorders, it is not likely to be primarily ordered on Medicare beneficiaries. At present, NGS will maintain non-coverage.
18 Requests were received in support of coverage for CPT Code 81331 SNRPN/UBE3A (Prader-Willi syndrome or Angelman syndrome). Prader-Willi or Angelman’s Syndrome is a rare genetic disorder characterized by loss of function of specific genes on Chromosome 15. Phenotypic characterization is loss of muscle tone, weakness, intellectual impairment, decrease in sex hormones and statures and predisposition to diabetes and obesity. It is unlikely to be applied to Medicare beneficiaries. At present, NGS will maintain non-coverage.
19 Requests were received in support of coverage for CPT Codes 81410-81411 Aortic Dysfunction or Dilation. Disorders such as Marfan’s syndrome and Ehlers-Danlos syndrome are unlikely to be initially diagnosed or evaluated in the Medicare population. At present, NGS will maintain non-coverage.
20 Requests were received in support of coverage for CPT Codes 81430-81431 Hearing Loss Gene Panel (consisting of up to 100 gene tests). Unexplained sensorineural hearing loss, temporal bone abnormalities and Usher syndrome may require genetic diagnosis and confirmation. However, almost all of these patients require confirmation of diagnosis and clinical intervention in the pediatric age group. At present, NGS will maintain non-coverage.
21 Requests were received in support of coverage for CPT Codes 81280-81282 Long QT syndrome. The Long QT syndrome is an inherited disorder characterized by lengthening of the repolarization phase of the ventricular action potential. Recent work suggests abnormalities in the Na and K channels increasing excitability of the cardiac myocytes. This may result in clinical manifestations of syncope and sudden death. This diagnosis is almost always established at age 40 or younger and testing is unlikely to be applied to Medicare beneficiaries. At present, NGS will maintain non-coverage.
22 Requests were received in support of coverage for CPT Codes 81243-81244 FMR1, fragile X syndrome. FMR1, located on the X chromosome is associated with a protein necessary for the development of brain and reproductive organ tissues. Mutations of this gene can manifest as both impaired intellectual capacity, impaired ovarian function, and other developmental abnormalities, including autism and Parkinsonism. It is almost always diagnosed in childhood and adolescence. At present NGS will maintain non-coverage.
23 Requests were received in support of coverage for CPT Codes 81440, 81460, 81465 Mitochondrial Gene Panels. Mitochondrial diseases are characterized by abnormalities of the organelles providing cellular energy. They may be associated with mutations of the mitochondrial DNA or nuclear DNA. Most frequently, the clinical presentation is muscular weakness, coordination disturbance, cardiac and respiratory compromise, and may be associated with intellectual impairment. Almost always, these disorders are clinically manifested and diagnosed in childhood/adolescence, although more subclinical variants may have delayed presentation and diagnosis. At present, NGS will maintain non-coverage.
24 Requests were received in support of coverage for CPT Code 81442 Noonan syndrome disorder. Noonan’s Syndrome is a relatively common autosomal dominant congenital disorder. It is associated with congenital heart disease, facial abnormalities, short stature, intellectual impairment, pectus excavatum, and coagulation disturbance. Diagnosis is important in the management of this disorder, although there are no specific treatments. Again, this is a presentation of childhood, unlikely to relate to the Medicare population. At present, NGS will maintain non-coverage.
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