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Response to Comments: MolDX: NRAS Genetic Testing


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Response to Comments: MolDX: NRAS Genetic Testing
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Response to Comments
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Noridian’s Response to Provider Recommendations (for comment period ending 12/7/2015).

Response To Comments

1NRAS coverage for Thyroid Cancer The requestor states that NRAS is used to stratify thyroid nodules with indeterminate cytology into high risk and low risk of cancer groups. They state the direct treatment ramifications for this high vs low risk subgroup classification are immediate and substantial, with the high risk patients being offered upfront total thyroidectomy as the first line surgical management, and the low risk patients not needing this surgery. This direct molecularly-driven treatment impact on patients with thyroid nodules has been described in multiple peer reviewed publications (Nikiforov YE et al. JCEM, 2009; Cantara et al. JCEM 2010; Nikiforova MN et al. JCEM 2011). In addition the requestors state that the use of mutational testing for NRAS and other genes to guide the management of patients with thyroid nodules with indeterminate cytology has also been recommended by the 2015 guidelines from the American Thyroid Association (Haugen, Bryan R, M.D. 2015 American Thyroid Association American Thyroid Association Management Guidelines for Adult Patients with Thyroid Nodules and Differentiated Thyroid Cancer) These guidelines state that: “molecular testing may be used to supplement malignancy risk assessment data, in lieu of proceeding directly with surgery”.The publications cited by the requestor are observational studies because treatment selection was not based on the results of the testing. Consequently, while the studies 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/PPAR? 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. The requestor incorrectly states 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. Up-to-Date 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.
2NRAS coverage for Melanoma The requestor disagrees with the statement in the policy stating the “significant 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 requestor misstates Johnson, et al (Johnson DB et al. CIR, 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 requestor 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 cited study is retrospective. The authors state the findings “suggest that NRAS mutations in advanced melanoma correlate with increased benefit from immune-based therapies compared with other genetic subtypes.” Although the study’s authors state “the NRAS mutant cohort had superior or a trend to superior outcomes compared with the other cohorts in terms of response to first-line immune therapy, …” the authors also recognize their findings are hypothesis generating and affirm that prospective studies are warranted. The requestor’s citation of literature support misinterprets the published findings. Specific responses to the studies cited, highlights information that shows why none of these articles demonstrate medical necessity (clinical utility) for NRAS testing: Ascierto et al. Lancet , 2013 - enrolled 71 patients; median follow-up was 3·3 months; No patients had a complete response. Six (20%) of 30 patients with NRAS-mutated melanoma had a partial response (three confirmed) as did eight (20%) of 41 patients with BRAF-mutated melanoma (two confirmed); Interpretation: MEK162 is the first targeted therapy to show activity in patients with NRAS-mutated melanoma and might offer a new option for a cancer with few effective treatments. Coupe et al. Eur J Cancer, 2015 - 15 patients; 14 of 15 were wild-type for BRAF; trametinib can safely be given with weekly paclitaxel; small group promising progression free and overall survival in patients with melanoma lacking V600 BRAF mutation. THIS STUDY IS NOT RELEVANT TO NRAS. Jakob et al. Cancer, 2012 – Retrospective analysis; 677 melanoma samples; 47% BRAF and 20% NRAS mutations; 32% wild-type for BRAF and NRAS; Findings: BRAF or NRAS mutations were more likely than wild type patient to have central nervous system involvement at the time of diagnosis with distant metastases. NRAS was identified as an independent predictor of shorter survival after a diagnosis of stage IV melanoma. Johnson et al. CIR, 2015 – Retrospective analysis; 229 patients; Findings: “ This retrospective study suggests that NRAS mutations in advanced melanoma correlate with increased benefit from immune-based therapies compared with other genetic subtypes. If confirmed by prospective studies, this may be explained in part by high rate of PD-l1 expression.” Pfugfelder et al. J Dtsch Dermatol Ges, 2013 – German evidence-based guidelines for diagnosis, therapy and follow-up of melanoma. The only reference to NRAS in the guidelines is as follows: “In the presence of distant metastasis mutational screening should be performed for BRAF mutation, and eventually for CKIT and NRAS mutations.” THIS STUDY DOES NOT EVEN INCLUDE NRAS TESTING IN THEIR GUIDELINES. Romano et al. Clinical Cancer Research, 2013 – research study; evaluated the mechanism of acquired resistance in two subcutaneous metastases occurring in a patient with a BRAF v600E-mutated melanoma; Findings: Detected two mutually exclusive mechanism of resistance to vermurafenib; Study could serve as proof-of-principle for future prospective studies in a larger cohort of patients. In summary, the medical necessity for NRAS testing in thyroid cancer is not present in the literature.
3NRAS Coverage in Other Cancers: The requestor indicates a growing body of clinical utility for NRAS mutation status , notably myeloma and acute myeloid leukemia. The requestor specified that the Medicare contractor should always consider the current NCCN and professional practice guidelines as the definitive source of clinical utility for determining reimbursement. The requestor said the “evidence is ever-changing and must be constantly monitored to ensure payment policies always reflect the current state of the art science (Mulligan et al. Blood Journal, 2014; Dunna et al. Indian Journal of Biochemistry and Biophysics, 2014; Kadia et al. Cancer, 2012; Klco et al. JAMA, 2015).”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 – Whole-genome and exome testing; Results – “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: Clinical utility for NRAS testing for thyroid cancer and melanoma has not been established in the scientific literature. As a result, there will be no additional CPT or ICD-10 codes added to the final policy. The following references were submitted to support extended NRAS coverage for thyroid cancer, melanoma, myeloma, and acute myeloid leukemia: References Ascierto PA1, Schadendorf D, Berking C, et al. MEK162 for patients with advanced melanoma harbouring NRAS or Val600 BRAF mutations: a non-randomised, open-label phase 2 study. Lancet Onc. 2013 Mar 14; 14(3):249-56. doi: 10.1016/S1470-2045(13)70024-X. Epub 2013 Feb 13. Benson, A. B., Venook, A. P. & al, e. (2015/11/24), NCCN Guidelines Version 2.2016 Colon Cancer, [Online], National Comprehensive Cancer Network (NCCN), Available from: http://www.nccn.org/professionals/physician_gls/pdf/colon.pdf Bryan R. Haugen, M.D. 2015 American Thyroid Association American Thyroid Association Management Guidelines for Adult Patients with Thyroid Nodules and Differentiated Thyroid Cancer: 10.1089/thy.2015.0020 2015 Cantara S, Capezzone M, et al. Impact of Proto-Oncogene Mutation Detection in Cytological Specimens from Thyroid Nodules Improves the Diagnostic Accuracy of Cytology. J Clin Endocrinol Metab. March 2010, Vol 95 Issue 3. DOI: http://dx.doi.org/10.1210/jc.2009-2103 Center for Medicare and Medicaid Services, National Coverage Determination 310.1 Coupe N1, Corrie P2, et al. PACMEL: a phase 1 dose escalation trial of trametinib (GSK1120212) in combination with paclitaxel. European Journal of Cancer 2015 Feb;51(3):359-66. doi: 10.1016/j.ejca.2014.11.018. Epub 2014 Dec 24. Department of Clinical Effectiveness, MD Anderson Cancer Center, Thyroid Nodule Evaluation Practice Algorithm. Douillard JY, Oliner KS, Siena S, et al. Panitumumab-FOLFOX4 treatment and RAS mutations in colorectal cancer. N Engl J Med. 2013 Sep 12;369(11):1023-34. doi: 10.1056/NEJMoa1305275. PubMed PMID: 24024839. Dunna, N. R., Vuree, S., et al. NRAS mutations in de novo acute leukemia: prevalence and clinical significance. Indian Journal of Biochemistry & Biophysics, 2014 51(3), 207–10. http://www.ncbi.nlm.nih.gov/pubmed/25204082. Jakob JA1, Bassett RL Jr. NRAS mutation status is an independent prognostic factor in metastatic melanoma. Cancer. 2012 Aug 15;118(16):4014-23. doi: 10.1002/cncr.26724. Epub 2011 Dec 16. Johnson DB1, Lovly CM, et al. Impact of NRAS mutations for patients with advanced melanoma treated with immune therapies. Cancer Immunology Research 2015 Mar;3(3):288-95. doi: 10.1158/2326-6066.CIR-14-0207. Kadia, T. M., Kantarjian, H., et al. Clinical and proteomic characterization of acute myeloid leukemia with mutated RAS. Cancer, 2012. 118(22), 5550–9. doi:10.1002/cncr.27596 http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3416961/. Klco, J., Miller C., et al. Association Between Mutation Clearance After Induction Therapy and Outcomes in Acute Myeloid Leukemia. Journal of the American Medical Association, 2015 314(8):811-822. doi:10.1001/jama.2015.9643. Nikiforov YE, Steward DL, et al. Molecular Testing for Mutations in Improving the Fine-Needle Aspiration Diagnosis of Thyroid Nodules. J Clin Endocrinol Metab. June 2009, 94(6):2092–2098. Pflugfelder A1, Kochs C, et al. Malignant melanoma S3-guideline "diagnosis, therapy and follow-up of melanoma". Journal of Deutsch Dermatological Ges. 2013 Aug;11 Suppl 6:1-116, 1-126. doi: 10.1111/ddg.12113_suppl. Romano, E., Pradervand, S., et al, Identification of multiple mechanisms of resistance to vemurafenib in a patient with BRAFV600E-mutated cutaneous melanoma successfully rechallenged after progression. Clinical Cancer Research. 2013 < http://clincancerres.aacrjournals.org/content/19/20/5749.long> Tap WD1, Gong KW, et al. Pharmacodynamic characterization of the efficacy signals due to selective BRAF inhibition with PLX4032 in malignant melanoma. Neoplasia. 2010 Aug;12(8):637-49.

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