LCD Reference Article Response To Comments Article

Response to Comments: MolDX: NRAS Genetic Testing (L36797)

A55400

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Wisconsin Physicians Service Insurance Corporation	MAC - Part A	05101 - MAC A	J - 05	Iowa
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Article ID
A55400

Article Title
Response to Comments: MolDX: NRAS Genetic Testing (L36797)

Article Type
Response to Comments

Original Effective Date
02/16/2017

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This article summarizes the comments WPS received for Draft Local Coverage Determinations (LCD) MolDX: NRAS Genetic Testing. Thank you for the comments.

Response To Comments

Number	Comment	Response
1	We agree with your assessment that NRAS should be covered for patients with metastatic colorectal cancer. However we request that you also provide coverage for other cancers including thyroid cancer, myelodysplastic syndrome (MDS), and melanoma, of which each has a convincing body of evidence for clinical utility. NRAS testing should likely also be covered for some other hematopoietic malignancies, particularly myeloma and AML, based on a less mature, but still convincing body of evidence. The draft LCD’s review of the literature on the role of the NRAS gene mutations in thyroid cancer is limited and does not incorporate peer reviewed publications that demonstrate that NRAS mutations are the second most common mutation in thyroid cancer, informing the diagnosis in suspicious nodules. We disagree with your assessment that “the prognostic significance of NRAS mutations is still not well understood and further investigation of the histologic types of melanoma with specific NRAS mutations in a larger series is necessary to validate these apparent impacts on patient outcomes.” The commenter quoted Johnson, et al (Johnson DB et al. Circ, 2015) as saying that “immune therapies have become a mainstay in advanced melanoma treatment,” and that the presence of an NRAS mutation specifically predicted an enhanced clinical outcome benefit from immune-based therapies. The CAP further states that other literature supports the presence of activating NRAS mutations in melanomas and the great benefit to patients of the use of immune therapies in advanced melanoma treatment. The commenter disagrees with the statement in the policy stating the “significance of NRAS mutations is still not well understood and further investigation of the histologic types of melanoma with specific NRAS mutations in a larger series is necessary to validate these apparent impacts on patient outcomes.” Recent NCCN guidelines for the diagnosis of Myelodysplastic syndrome (MDS) specifically mention the detection of common NRAS mutations as one of several common mutations that can prove clonal hematopoiesis and thus confirm the diagnosis of MDS, as opposed to other benign causes of cytopenias. There is a significant body of evolving evidence on the clinical utility of NRAS mutation status in several hematopoietic malignancies, most notably myeloma and acute myeloid leukemia.	We received identical comments to those submitted to Noridian in December 15, 2015, and provided no new information. Clinical utility for NRAS testing for thyroid cancer, melanoma, MDS or other myeloid malignancies has not been established in the scientific literature. Response regarding Thyroid Cancer: While the studies submitted demonstrate specific gene associations with follicular indeterminate lesions, none of the articles demonstrates clinical utility – that molecular testing improves patient outcomes or changes physician management. In fact, Cantara et al. note that RAS mutations are mainly associated with cancer (74%) but also with follicular adenoma (26%). As a singular mutation, RAS mutations have little clinical significance. The ATA Guidelines provide a detailed discussion on sensitivity and specificity of mutational testing. The guidelines report that BRAF V600E has been estimated to have a specificity of approximately 99% but that the sensitivity is too low to reliably rule-out the presence of malignancy. As a result, the authors state that “mutational panels have been expanded to include multiple mutations/translocations including BRAF, NRAS, HRAS, and KRAS point mutations, as well as RET/PTC1, RET/PTC3, with or without PAX8/PPARγ rearrangements and other gene rearrangements fusions.” In indeterminate cytology thyroid nodules, the sensitivity of the 7-gene mutational panel testing is variable, with reports ranging from 44% to 100%. The reported variability in sensitivity of mutational analysis with the 7-gene panel in indeterminate nodules suggests that traditional limited mutation panels may not reliably rule out malignancy with a negative test in this population. Next-generation sequencing of an expanded panel of point mutations, single base insertions/deletions (indels), and gene rearrangements fusions has been reported to have a sensitivity of 90% for FN/suspicious for FN FNA cytology specimens from a single center study. The guidelines authors note multiple study limitations that may have biased the study findings. The ATA guideline authors note that “the currently available 7-gene mutational panels have been proposed to be most useful when surgery is favored”, but note that “this is based on the assumption that the surgical approach would be altered with a positive test”, and that “long-term outcome data proving the overall benefit of this therapeutic strategy are needed”. Finally, the ATA authors state that “long-term outcome data from a strategy of using molecular markers in indeterminate FNA specimens to stratify surgical approach are currently lacking”. In other words, the clinical utility of a multiple gene panel, inclusive of NRAS, is absent. We think this was incorrectly stated that ATA Recommendation #16 supports “mutational testing for NRAS and other genes to guide the management of patients with thyroid nodules with indeterminate cytology”. The ATA specifically states that “after consideration of clinical and sonographic features, molecular testing may be used to supplement malignancy risk assessment data” in conjunction with informed patient preference and feasibility. The ATA gave Recommendation #16 a “weak” recommendation, with moderate quality of evidence. UptoDate notes that RAS mutations are not specific to follicular thyroid cancer. RAS mutations account for a small portion of papillary thyroid cancer, particularly the follicular-variant papillary thyroid cancer, and have been identified in undifferentiated and anaplastic thyroid cancers. This observation suggests that RAS mutation genotyping may assist in identifying follicular thyroid cancer patients with a poor prognosis. However, this finding has not been confirmed. NCCN (Thyroid cancer, version 2.2016) does not address mutation testing for thyroid cancer. In summary, there is little to no evidence that supports the clinical utility for NRAS testing in thyroid cancer. Response regarding Melanoma: Johnson et al. state “Data from our multi-institutional retrospective analysis suggest that patients with NRAS-mutant melanoma experience higher rates of objective response or prolonged stable disease from immune therapy compared with those with BRAF-mutant and NRAS/BRAF WT melanoma,” and suggest that “One potential hypothesis is that NRAS mutations may occur in melanomas with higher mutational burden, a factor linked with higher response rates to immune therapy”. They also state “This analysis was exploratory only; the influence of NRAS mutations on OS will need additional follow-up in larger cohorts treated with immune therapy.” Response regarding MDS, Myeloma and AML: The most current NCCN guidelines for myeloma do not mention NRAS mutational testing. The current NCCN guidelines for acute myeloid leukemia mention NRAS testing in the context of mutational testing, but make no recommendation. Klco et al. JAMA, 2015 state regarding whole-genome and exome testing state “Analysis of comprehensive genomic data from the 71 AML patients did not improve outcome assessment over current standard-of-care metrics. In an analysis of 50 patients with both presentation and documented remission samples, 24 (48%) had persistent leukemia-associated mutations in at least 5% of bone marrow cells at remission. The 24 with persistent mutations had significantly reduced event-free and overall survival vs the 26 who cleared all mutations. Patients with intermediate cytogenetic risk profiles had similar findings; Conclusion: The detection of persistent leukemia-associated mutations in at least 5% of bone marrow cells in day 30 remission samples was associated with a significantly increased risk of relapse, and reduced overall survival. These data suggest that this genomic approach may improve risk stratification for patients with AML.” SUMMARY: As a result, there will be no additional CPT or ICD-10 codes added to the final policy.
2	The commenter recommended addition of CPT code 81445 for NGS of 5-50 genes be covered, and stated the ICD10 codes were incomplete and needed to be added to the policy.	The clinical utility of NRAS testing has not been established for any tumor except colon cancer. Because there is no multi-gene panel including NRAS with proven clinical utility, 81445 will not be added as a covered CPT code. Furthermore, no additional ICD10 codes will be added.

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LCDs
L36797 - MolDX: NRAS Genetic Testing

Updated On	Effective Dates	Status
12/20/2016	02/16/2017 - N/A	Currently in Effect	You are here

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Response to Comments: MolDX: NRAS Genetic Testing (L36797)

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