Local Coverage Determination (LCD)

MolDX: Melanoma Risk Stratification Molecular Testing

L37725

Expand All | Collapse All
Proposed LCD
Proposed LCDs are works in progress that are available on the Medicare Coverage Database site for public review. Proposed LCDs are not necessarily a reflection of the current policies or practices of the contractor.

Document Note

Note History

Contractor Information

LCD Information

Document Information

Source LCD ID
N/A
LCD ID
L37725
Original ICD-9 LCD ID
Not Applicable
LCD Title
MolDX: Melanoma Risk Stratification Molecular Testing
Proposed LCD in Comment Period
N/A
Source Proposed LCD
DL37725
Original Effective Date
For services performed on or after 12/03/2018
Revision Effective Date
For services performed on or after 07/03/2022
Revision Ending Date
N/A
Retirement Date
N/A
Notice Period Start Date
05/19/2022
Notice Period End Date
07/02/2022
AMA CPT / ADA CDT / AHA NUBC Copyright Statement

CPT codes, descriptions and other data only are copyright 2023 American Medical Association. All Rights Reserved. Applicable FARS/HHSARS apply.

Fee schedules, relative value units, conversion factors and/or related components are not assigned by the AMA, are not part of CPT, and the AMA is not recommending their use. The AMA does not directly or indirectly practice medicine or dispense medical services. The AMA assumes no liability for data contained or not contained herein.

Current Dental Terminology © 2023 American Dental Association. All rights reserved.

Copyright © 2023, the American Hospital Association, Chicago, Illinois. Reproduced with permission. No portion of the American Hospital Association (AHA) copyrighted materials contained within this publication may be copied without the express written consent of the AHA. AHA copyrighted materials including the UB‐04 codes and descriptions may not be removed, copied, or utilized within any software, product, service, solution or derivative work without the written consent of the AHA. If an entity wishes to utilize any AHA materials, please contact the AHA at 312‐893‐6816.

Making copies or utilizing the content of the UB‐04 Manual, including the codes and/or descriptions, for internal purposes, resale and/or to be used in any product or publication; creating any modified or derivative work of the UB‐04 Manual and/or codes and descriptions; and/or making any commercial use of UB‐04 Manual or any portion thereof, including the codes and/or descriptions, is only authorized with an express license from the American Hospital Association. The American Hospital Association (the "AHA") has not reviewed, and is not responsible for, the completeness or accuracy of any information contained in this material, nor was the AHA or any of its affiliates, involved in the preparation of this material, or the analysis of information provided in the material. The views and/or positions presented in the material do not necessarily represent the views of the AHA. CMS and its products and services are not endorsed by the AHA or any of its affiliates.

Issue

Issue Description

This LCD outlines limited coverage for this service with specific details under Coverage Indications, Limitations and/or Medical Necessity.

Issue - Explanation of Change Between Proposed LCD and Final LCD

Additional references were added in the final draft consistent with comments received. Minor edits were also made for clarity.

CMS National Coverage Policy

Title XVIII of the Social Security Act, §1862(a)(1)(A) allows coverage and payment for only those services that are considered to be reasonable and necessary.

42 Code of Federal Regulations (CFR) 410.32(a) Diagnostic x-ray tests, diagnostic laboratory tests, and other diagnostic tests: Conditions

CMS Internet-Only Manuals, Publication 100-04, Medicare Claims Processing Manual, Chapter 16, §50.5 Jurisdiction of Laboratory Claims, §60.1.2 Independent Laboratory Specimen Drawing, §60.2 Travel Allowance

Coverage Guidance

Coverage Indications, Limitations, and/or Medical Necessity

Molecular diagnostic tests used to assist in risk stratification of melanoma patients are covered when ALL of the following are true:

  1. The patient has a personal history of melanoma AND:
    1. Either:
      1. Has Stage T1b and above OR
      2. Has T1a with documented concern about adequacy of microstaging
    2. Is undergoing workup or being evaluated for treatment, AND
    3. Does not have metastatic disease AND
    4. Presumed risk for a positive Sentinel Lymph Node Biopsy (SLNB) based on clinical, histological, or other information is >5% AND
    5. Has a disease stage, grade, and Breslow thickness (or other qualifying conditions) within the intended use of the test
  2. The TEST has demonstrated, as part of a Technical Assessment:
    1. Clinical validity of analytes tested in predicting metastatic disease (or the absence of metastatic disease) in peer-reviewed scientific literature
    2. Utility beyond clinical, histological, and radiographical factors in the ability to accurately stratify patients into risk groups to manage patient care, such by precluding unnecessary sentinel lymph node biopsies
    3. Appropriate analytical validity
    4. Performance characteristics equivalent or superior to other covered, similar tests
Summary of Evidence

Cutaneous melanoma (CM) is increasing in incidence in the U.S., with an estimated 96,480 cases expected to be diagnosed in 2019 with 7,230 deaths.1

In the treatment of CM, the risk that a patient has or will develop metastatic disease is central to many of the decision management choices in cutaneous melanoma, with more aggressive management or treatment strategies recommended for patients who are at a higher risk.2 Per current national guidelines, a SLNB procedure is considered for all patients with melanoma pathologic Stage T1b and above, as well as those patients with T1a tumors in whom there is significant uncertainty about the adequacy of microstaging.2,3 Patients with a positive SLN are at substantially increased risk for distant metastatic disease and death;4 however, the procedure only provides prognostic information, and the MSLT-II study showed no survival benefit associated with completion lymphadenectomy in SLN positive patients.5 Currently, the identification of SLN positive patients helps identify Stage III patients who can potentially benefit from targeted and immunotherapeutic agents in the adjuvant setting.6-8 The procedure can be associated with complications in a substantial proportion of patients such as pain, seromas, nerve damage and edema, and requires a large team of dedicated personnel, including nuclear medicine physicians, surgeons, and pathologists.9-11 It has been estimated that the cost of a SLNB can be 10 times that of a wide excision alone, and the cost per life saved in a patient population with low prevalence of positive SLN can approach 1 million dollars.12 Overall, the likelihood of a positive SLN after the SLNB procedure is 16%,4,13 but this is variable for specific populations.13-16 Elderly patients account for a substantial proportion of CM patients, and 60% of melanoma-related deaths occur in patients ≥65 years-old. While older age is associated with a poor prognosis, fewer elderly patients are SLN positive,14-18 which indicates that the prognostic value of SLNB is limited in this population.19,20 In general, a 5% likelihood for a positive SLN is recommended as a threshold for performing this procedure in a patient population.13

Molecular diagnostic tests have been proposed to help managing clinicians risk stratify patients for selecting their most appropriate management based on their probability of developing metastatic disease; these tests may score patients’ probabilities of resultant metastatic disease by measuring tumor biomarkers such as relevant gene expression.21-24 One gene expression profile (GEP) test (DecisionDx Melanoma, Castle Biosciences) was evaluated in a retrospective cohort (n=782) to evaluate its ability to predict metastasis and ability to predict SLNB status with tumors with a Breslow thickness <2.0 mm (American Joint Committee on Cancer [AJCC] T1 T2).25

The ability of the test to identify a low-risk group was initially assessed and compared to SLNB in 2 contemporary, multi-center, prospective study cohorts: a 584 patient cohort from 2 published prospective studies (overall 14% SLN positive rate)23,26 and a 837 patient cohort from prospectively tested patients at 5 large academic institutions (overall 12% SLN positive rate).25 The rate of SLN positivity in both prospective study cohorts aligns with the SLN positivity rate in the general population of melanoma patients who have undergone SLNB. The results show that in patients from the Medicare-eligible population (65 years old and over) who were determined to be low-risk by this test, the concordance of a negative SLNB was 98.4%. These studies showed improved performance in other patient groups as well.

SLNB positivity rates for T3 tumors with low-risk score for this test is 8.7%. Importantly, the 5-year melanoma specific survival (MSS) rate for T1/T2 low-risk group remains favorable; with 99% MSS, comparable to that observed in T1a tumors and for which current guidelines do not recommend SLNB.2,27 Furthermore, T1/T2 low-risk patients show 5-year overall survival (OS) of 97% and distant metastasis free survival (DMFS) of 93%.28 The MSLT-II study demonstrated that a delay in lymph node dissection does not adversely affect survival, thus clinical follow up of low-risk patients and lymphadenectomy for those few who develop clinically detectable nodal disease should achieve similar outcomes to those who currently undergo a planned SLNB.5 Thus, the test identifies a patient population with <5% likelihood of a positive SLN and high survival rates and therefore, has utility in guiding SLNB decisions in patients 65 years-old and over with T1-T2 CM tumors. In this population, the test could potentially reduce the rate of SLNB by up to 78% while still maintaining an MSS survival rate of 99% in those patients with low-risk tumor biology who can safely avoid the procedure.

Clinical validation of this same test as a prognostic test for CM patients was performed in 3 multicenter, prospectively designed archival tissue studies including 782 patients.21,22,24 These studies have shown that the test accurately predicts risk for local/regional recurrence, distant metastasis, melanoma-related mortality, and all-cause mortality independent of clinicopathologic factors used in staging and that the test shows improved sensitivity and negative predictive value (NPV) for recurrence-free (RFS), distant metastasis-free (DMFS), melanoma-specific (MSS) and overall survival (OS) individually or in conjunction with established clinicopathologic factors. A study focused on patients with melanoma of the head and neck (H&N) demonstrated that patients with H&N melanoma have poorer outcomes and lower rates of SLN positivity which makes the prognostic value of the SLNB procedure limited and thus additional prognostic information provided by this test is important in this group of patients.28 Four prospective, independent studies (n=510) and an interim analysis of 2 prospective registries (n=322) have confirmed the prognostic accuracy of the assay.23,29-32 This suggests that the test may be useful in stratifying risk and patient treatment decisions.

A retrospective study directly compared the ability of DecisionDX Melanoma with the ability of AJCC melanoma staging to predict longer term outcomes.33 This study looked at 205 archived formalin-fixed, paraffin-embedded primary melanoma tissue blocks from 6 centers. This included 109 Stage I and 96 Stage II cancers, and median time to follow-up was 6.9 years. The median time to recurrence was 1.7 years, and the median time to distant metastasis was 1.6 years. In general, the test scoring alone had greater sensitivity to recurrence, distant metastasis, and death than AJCC staging. Alternatively, AJCC staging had greater specificity for these outcomes. The use of this assay with AJCC staging had a higher sensitivity to these adverse outcomes than either prognostic measurement alone. Studies have also suggested that clinicians value and use this test in their medical decision making regarding aggressiveness of melanoma management.34-36

Recent publications have provided further evaluation of these types of genetic risk stratification tests. Some studies and meta-analyses evaluating a host of clinical studies have cast doubt on the utility of gene expression profiles (GEPs) for risk stratification.37-38 Grossman et al37 described the findings of the National Melanoma Prevention Working Group, which evaluated 3 prognostic GEP tests. This included a review of online surveys, journal articles from 2015-2019, and relevant abstracts. One of the findings from the group was that it was difficult, due to a lack of clinical trial data reviewed, to clearly separate known clinical pathological factors that are associated with risk of recurrence/metastases from the GEP findings, stating that while some such factors were considered, not all such factors were considered in clinical studies that support GEP use. Additionally, it was noted that some of the staging used in the favorable studies were not using current AJCC8 staging criteria. Additionally, Marchetti et al38 performed a systematic review and meta-analysis of 7 GEP studies, including 5 that evaluated DecisionDx-Melanoma and 2 studies evaluating MelaGenix. They evaluated patients in these studies, who were characterized as high-risk or low-risk, dependent on staging, with recurrence (primary endpoint) or metastases (secondary endpoint). They determined that among patients with recurrence, DecisionDx-Melanoma correctly classified 29% of stage I patients and 82% of stage II as high-risk. Among patients without recurrence, this test identified 90% of stage I patients and 44% of stage II correctly as low-risk. The Melagenix test classified 32% of stage I and 76% of stage 2 patients with recurrence correctly as high-risk; and 77% of stage I and 43% of stage II patients without recurrence correctly as low-risk. The data evaluating metastasis as an endpoint was considered poor and not significantly evaluated.

Other studies, including meta-analyses, maintained and strengthened the evidence for the use of GEP tests. One example is Greenhaw et al42 that evaluated three studies that met criteria and analyzed raw data for a systematic review of 1479 patients. This study demonstrated that the Melanoma DecisionDX test was an independent predictor of both recurrence and distant metastasis-free survival based on multivariate analysis (including Breslow thickness, ulceration, age, and SLNB status; with the GEP having the highest Hazard Ratio of 2.9). The NPV of the GEP test was 92% (90-94% CI) for recurrence-free survival and 93% (91-95% CI) for distant metastasis-free survival, both outperforming SLNB. Although sensitivity for RFS and DMFS were 76%, this was superior to SLNB, although these data were not broken down by patient stage. Specificity for RFS and DMFS was similar to SLNB. Litchman et al46 evaluated 6 studies and noted high-risk GEP results correlated with poorer RFS and DMFS, as well as correlated with OS. A recent prospective study by Hsueh et al43 evaluated the use of DecisionDX Melanoma in 323 patients in two prospective trials with three years of follow-up (INTEGRATE and EXPAND registries), and demonstrated that a GEP high risk result was a significant predictor of RFS, DMFS, and OS in univariate analysis, and was demonstrated to be an independent predictor of RFS, DMFS, and OS in multivariate analysis, including AJCC 8th ed. staging (staging was also an independent predictor). Other studies had similar findings.47 Combining AJCC staging or other clinicopathological factors and GEP was also found to improve risk stratification.44,48-49 Other prospective and retrospective studies have subsequently been performed for GEP testing and demonstrate similar findings. Of importance, some studies have shown that the use of GEP has reduced some unnecessary SLNB, although these data are limited.45. It is understood that comprehensive data are currently being compiled.

Analysis of Evidence (Rationale for Determination)

For cutaneous melanoma, a well-established set of clinical pathways is available for patient management, which are heavily based on risk stratification of patients with higher risk patients being recommended to have a more intense diagnostic workup or more intensive treatment. While the consensus guidelines also give specific clinical, pathologic, and imagining findings that can help to risk stratify a patient, additional evidence suggests that molecular diagnostic tests can be used to further improve risk stratification, thereby improving the accuracy of the risk stratification that is key to deciding on the optimal patient management plan in these clinical pathways. This is particularly the case for identifying the patients at a higher risk of adverse outcomes as a result of the melanoma.

Although some recent publications and evidence has cast doubt in the clinical utility of these tests, it is important to consider these in light of the intended use of these tests as covered in this policy.37,38 The negative studies demonstrate disagreement in expert consensus on test use or question the predictive ability of the tests to accurately identify RFS in a stage dependent manner; however, other prospective trials and meta-analyses support the use of GEP testing and evaluate the evidence in univariate and multivariant analyses including AJCC 8th ed. staging criteria. Despite this, it is important to note that from a clinical utility perspective, a major of these GEP tests as described in this policy is to modify management of patients who have >5% likelihood of a positive SLN to preclude unnecessary SLNB. The data reviewed suggest not only that GEP tests can better predict SLN positivity than staging and clinicopathological criteria alone; they may be more predictive of DFS and DMFS than SLNB and may be even more effective when combined with clinicopathological factors. The Marchetti et al38 paper did not evaluate DMFS or SLB positivity because of limited data, and thus did not directly address the value this payor sees in these tests as a tool to help reduce the need for unnecessary SLNB in low-risk patients. Based on the evidence published and reviewed to date, this payor sees evidence that GEP testing may be used to better risk stratify and manage melanoma patients as defined in the coverage section of this policy. Specifically, this test has shown to be able to predict SLN status better than other methodologies, and thus likely reduce unnecessary SLNB in a low-risk population who would otherwise have received a SLNB as well as advocate for SLNB in those patients who may otherwise forgo the procedure based on staging criteria and clinical factors alone. Admittedly, the data supporting this test is limited and imperfect; however, the current alternative tools for assessing patient risk stratification in this population in accepted practice are even more so; with this policy we leave it to clinicians to use these services to mitigate a challenging clinical situation and hope that further evidence is developed to clearly guide melanoma patient management. We await more comprehensive published and peer-reviewed prospective data that support or refute changes in patient management based on the use of these or other similar tests.

Since the clinical utility of testing is dependent upon consensus-based management recommendations based on risk, this coverage decision is subject to change pending changes in the consensus recommended use of risk strata for patient management and the accuracy of alternative risk-stratification tools. This coverage decision will be periodically re-evaluated.

Proposed Process Information

Synopsis of Changes
Changes Fields Changed
N/A
Associated Information
Sources of Information
Bibliography
Open Meetings
Meeting Date Meeting States Meeting Information
N/A
Contractor Advisory Committee (CAC) Meetings
Meeting Date Meeting States Meeting Information
N/A
MAC Meeting Information URLs
N/A
Proposed LCD Posting Date
Comment Period Start Date
Comment Period End Date
Reason for Proposed LCD
Requestor Information
This request was MAC initiated.
Requestor Name Requestor Letter
View Letter
N/A
Contact for Comments on Proposed LCD

Coding Information

Bill Type Codes

Code Description
N/A

Revenue Codes

Code Description
N/A

CPT/HCPCS Codes

Group 1

Group 1 Paragraph

N/A

Group 1 Codes

N/A

N/A

ICD-10-CM Codes that Support Medical Necessity

Group 1

Group 1 Paragraph:

N/A

Group 1 Codes:

N/A

N/A

ICD-10-CM Codes that DO NOT Support Medical Necessity

Group 1

Group 1 Paragraph:

N/A

Group 1 Codes:

N/A

N/A

Additional ICD-10 Information

General Information

Associated Information

N/A

Sources of Information

N/A

Bibliography
  1. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2019. CA: a cancer journal for clinicians. 2019;69(1):7-34.
  2. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) Melanoma: Cutaneous. Accessed March 22, 2022.
  3. Wong SL, Faries MB, Kennedy EB, et al. Sentinel lymph node biopsy and management of regional lymph nodes in melanoma: American Society of Clinical Oncology and Society of Surgical Oncology clinical practice guideline update. J Clin Oncol. 2018;36(4):399-413.
  4. Morton DL, Thompson JF, Cochran AJ, et al. Final trial report of sentinel-node biopsy versus nodal observation in melanoma. N Engl J Med. 2014;370(7):599-609.
  5. Faries MB, Thompson JF, Cochran AJ, et al. Completion dissection or observation for sentinel-node metastasis in melanoma. N Engl J Med. 2017;376(23):2211-2222.
  6. Eggermont AM, Chiarion-Sileni V, Grob JJ, et al. Prolonged survival in stage III melanoma with ipilimumab adjuvant therapy. N Engl J Med. 2016;375(19):1845-1855.
  7. Eggermont AM, Chiarion-Sileni V, Grob JJ, et al. Adjuvant ipilimumab versus placebo after complete resection of high-risk stage III melanoma (EORTC 18071): A randomised, double-blind, phase 3 trial. Lancet Oncol. 2015;16(5):522-530.
  8. Long GV, Hauschild A, Santinami M, et al. Adjuvant dabrafenib plus trametinib in stage III BRAF-mutated melanoma. N Engl J Med. 2017;377(19):1813-1823.
  9. Ascha M, Ascha MS, Gastman B. Identification of risk factors in lymphatic surgeries for melanoma: A national surgical quality improvement program review. Ann Plast Surg. 2017;79(5):509-515.
  10. Bagaria SP, Faries MB, Morton DL. Sentinel node biopsy in melanoma: Technical considerations of the procedure as performed at the John Wayne Cancer Institute. Journal of Surgical Oncology. 2010;101(8):669-676.
  11. Moody JA, Ali RF, Carbone AC, Singh S, Hardwicke JT. Complications of sentinel lymph node biopsy for melanoma - A systematic review of the literature. Eur J Surg Oncol. 2017;43(2):270-277.
  12. Agnese DM, Abdessalam SF, Burak WE Jr, Magro CM, Pozderac RV, Walker MJ. Cost-effectiveness of sentinel lymph node biopsy in thin melanomas. Surgery. 2003;134(4):542-547; discussion 547-548.
  13. Han D, Zager JS, Shyr Y, et al. Clinicopathologic predictors of sentinel lymph node metastasis in thin melanoma. J Clin Oncol. 2013;31(35):4387-4393.
  14. Cavanaugh-Hussey MW, Mu EW, Kang S, Balch CM, Wang T. Older age is associated with a higher incidence of melanoma death but a lower incidence of sentinel lymph node metastasis in the SEER databases (2003–2011). Ann Surg Oncol. 2015;22(7):2120-2126.
  15. Sinnamon AJ, Neuwirth MG, Yalamanchi P, et al. Association between patient age and lymph node positivity in thin melanoma. JAMA Dermatol. 2017;153(9):866-873.
  16. Sondak VK, Taylor JM, Sabel MS, et al. Mitotic rate and younger age are predictors of sentinel lymph node positivity: Lessons learned from the generation of a probabilistic model. Ann Surg Oncol. 2004;11(3):247-258.
  17. Balch CM, Soong S-j, Gershenwald JE, et al. Age as a prognostic factor in patients with localized melanoma and regional metastases. Ann Surg Oncol. 2013;20(12):3961-3968.
  18. Balch CM, Thompson JF, Gershenwald JE, et al. Age as a predictor of sentinel node metastasis among patients with localized melanoma: An inverse correlation of melanoma mortality and incidence of sentinel node metastasis among young and old patients. Ann Surg Oncol. 2014;21(4):1075-1081.
  19. Fleming NH, Tian J, Vega-Saenz de Miera E, et al. Impact of age on the management of primary melanoma patients. Oncology. 2013;85(3):173-181.
  20. Macdonald JB, Dueck AC, Gray RJ, et al. Malignant melanoma in the elderly: Different regional disease and poorer prognosis. J Cancer. 2011;2:538-543.
  21. Gerami P, Cook RW, Russell MC, et al. Gene expression profiling for molecular staging of cutaneous melanoma in patients undergoing sentinel lymph node biopsy. J Am Acad Dermatol. 2015;72(5):780-785 e783.
  22. Gerami P, Cook RW, Wilkinson J, et al. Development of a prognostic genetic signature to predict the metastatic risk associated with cutaneous melanoma. Clin Cancer Res. 2015;21(1):175-183.
  23. Hsueh EC, DeBloom JR, Lee J, et al. Interim analysis of survival in a prospective, multi-center registry cohort of cutaneous melanoma tested with a prognostic 31-gene expression profile test. J Hematol Oncol. 2017;10(1):152.
  24. Zager JS, Gastman BR, Leachman S, et al. Performance of a prognostic 31-gene expression profile in an independent cohort of 523 cutaneous melanoma patients. BMC Cancer. 2018;18(1):130.
  25. Vetto JT, Hsueh EC, Gastman BR, et al. Guidance of sentinel lymph node biopsy decisions in patients with T1-T2 melanoma using gene expression profiling. Future Oncol. 2019;15(11):1207-1217.
  26. Dillon LD, Gadzia JE, Davidson RS, et al. Prospective, multicenter clinical impact evaluation of a 31-gene expression profile test for management of melanoma patients. SKIN The Journal of Cutaneous Medicine. 2018;2(2):111-121.
  27. Gershenwald JE, Scolyer RA, Hess KR, et al. Melanoma staging: Evidence-based changes in the American Joint Committee on cancer eighth edition cancer staging manual. CA Cancer J Clin. 2017;67(6):472-492.
  28. Gastman BR, Zager JS, Messina JL, et al. Performance of a 31-gene expression profile test in cutaneous melanomas of the head and neck. Head Neck. 2019;41(4):871-879.
  29. Greenhaw BN, Zitelli JA, Brodland DG. Estimation of prognosis in invasive cutaneous melanoma: An independent study of the accuracy of a gene expression profile test. Dermatol Surg. 2018;44(12):1494-1500.
  30. Keller J, Schwartz TL, Lizalek JM, et al. Prospective validation of the prognostic 31-gene expression profiling test in primary cutaneous melanoma. Cancer Med. 2019;8(5):2205-2212.
  31. Podlipnik S, Carrera C, Boada A, et al. Early outcome of a 31-gene expression profile test in 86 AJCC stage IB-II melanoma patients. A prospective multicentre cohort study. JEADV. 2019;33(5):857-862.
  32. Renzetti M, Farma J, Handorf E, et al. Combined experience of two tertiary referral centers with MelanomaDx GEP testing. Paper presented at: ANNALS OF SURGICAL ONCOLOGY. 2017;24:S137-138.
  33. Ferris LK, Farberg AS, Middlebrook B, et al. Identification of high-risk cutaneous melanoma tumors is improved when combining the online American Joint Committee on cancer individualized melanoma patient outcome prediction tool with a 31-gene expression profile–based classification. J Am Acad Dermatol. 2017;76(5):818-825. e813.
  34. Berger AC, Davidson RS, Poitras JK, et al. Clinical impact of a 31-gene expression profile test for cutaneous melanoma in 156 prospectively and consecutively tested patients. Curr Med Res Opin. 2016;32(9):1599-1604.
  35. Farberg AS, Glazer AM, White R, Rigel DS. Impact of a 31-gene expression profiling test for cutaneous melanoma on dermatologists' clinical management decisions. J Drugs Dermatol. 2017;16(5):428-431.
  36. Schuitevoerder D, Heath M, Cook RW, et al. Impact of gene expression profiling on decision-making in clinically node negative melanoma patients after surgical staging. J Drugs Dermatol. 2018;17(2):196-199.
  37. Grossman D, Okwundu N, Bartlett EK, et al. Prognostic gene expression profiling in cutaneous melanoma identifying the knowledge gaps and assessing the clinical benefit. JAMA Dermatol. 2020; 156(9):1004-1011.
  38. Marchetti MA, Coit DG, Dusza SW, et al. Performance of gene expression profile tests for prognosis in patients with localized cutaneous melanoma a systematic review and meta-analysis. JAMA Dermatol. 2020; 156(9):953-962.
  39. Cook RW, Middlebrook B, Wilkinson J, et al. Analytic validity of DecisionDx-Melanoma, a gene expression profile test for determining metastatic risk in melanoma patients. Diagnostic pathology. 2018;13(1):13.
  40. Fryback DG, Thornbury JR. The efficacy of diagnostic imaging. Med Decis Making. 1991;11(2):88-94.
  41. Centers for Disease Control and Prevention. ACCE Model List of 44 Targeted Questions Aimed at a Comprehensive Review of Genetic Testing. 2010. Accessed 3/22/2022.
  42. Greenhaw BN, Covington KR, Kurley SJ, et al. Molecular risk prediction in cutaneous melanoma: A meta-analysis of the 31-gene expression profile prognostic test in 1,479 patients. J Am Acad Dermatol.2020;83:745-753.
  43. Hsueh, EC, DeBloom JR, Lee JH, et al. Long-term outcomes in a multicenter, prospective cohort evaluating the Prognostic 31-Gene Expression Profile for cutaneous melanoma. JCO Precis Oncol.2021;5:589-601.
  44. Whitman ED, Koshenkov VP, Gastman BR, et al. Integrating 31-gene expression profiling with clinicopathologic features to optimize cutaneous melanoma sentinel lymph node metastasis prediction. JCO Precis Oncol. 2021;5:1466-1479.
  45. Scott AM, Dale PS, Conforti A, Gibbs JN. Integration of a 31-gene expression profile into clinical decision-making in the treatment of cutaneous melanoma. Am Surg . 2020;86(11):1561-1564.
  46. Litchman GH, Prado G, Teplitz RW, Rigel D. A systematic review and meta-analysis of gene expression profiling for primary cutaneous melanoma prognosis. SKIN J. Cutaneous Med. 2020; 4(3):221–237.
  47. Arnot SP, Han G, Fortino J, Han D, Fowler G, Vetto J. Utility of a 31-gene expression profile for predicting outcomes in patients with primary cutaneous melanoma referred for sentinel node biopsy. Am J Surg.2021;221:1195-1199.
  48. Kwatra SG, Hines H, Semenov Y, Trotter SC, Holland E, Leachman S. A dermatologist's guide to implementation of gene expression profiling in the management of melanoma. J Clin Aesthet Dermatol. 2020;13(11): S3-S14
  49. Bellomo D, Arias-Mejias SM, Ramana C,Heim JB, et al. Model combining tumor molecular and clinicopathologic risk factors predicts sentinel lymph node metastasis in primary cutaneous melanoma. JCO Precis Oncol. 2020;4:319-334.

Revision History Information

Revision History Date Revision History Number Revision History Explanation Reasons for Change
07/03/2022 R6

Under Coverage Indications, Limitations and/or Medical Necessity revised verbiage under 2a and 2b. Under Summary of Evidence second paragraph, added verbiage “American Joint Committee on Cancer.” Under third paragraph, first sentence, added verbiage, “initially.” Under fourth paragraph revised last sentence to read, “In this population, the test could potentially reduce the rate of SLNB by up to 78% while still maintaining an MSS survival rate of 99% in those patients with low-risk tumor biology who can safely avoid the procedure.” Under fifth paragraph, deleted the verbiage, “has been recently published", and added verbiage, “demonstrated that.” Under the sixth paragraph, first sentence, deleted the verbiage, “recent.” Under the seventh paragraph, first sentence, revised verbiage to read, “Recent publications have provided further evaluation of these types of genetic risk stratification tests." Revised second sentence to read, “Some studies and meta-analyses evaluating a host of clinical studies have cast doubt on the utility of gene expression profiles (GEPs) for risk stratification.” Revised the fifth sentence to read, “One of the findings from the group was that it was difficult, due to a lack of clinical trial data reviewed, to clearly separate known clinical pathological factors that are associated with risk of recurrence/metastases from the GEP findings, stating that while some such factors were considered, not all such factors were considered in clinical studies that support GEP use.” Under the seventh sentence, the verbiage, "Additionally" was added. The eighth paragraph was revised to read, “Other studies, including meta-analyses, maintained and strengthened the evidence for the use of GEP tests. One example is Greenhaw et al42 that evaluated three studies that met criteria and analyzed raw data for a systematic review of 1479 patients. This study demonstrated that the Melanoma DecisionDX test was an independent predictor of both recurrence and distant metastasis-free survival based on multivariate analysis (including Breslow thickness, ulceration, age, and SLNB status; with the GEP having the highest Hazard Ratio of 2.9). The NPV of the GEP test was 92% (90-94% CI) for recurrence-free survival and 93% (91-95% CI) for distant metastasis-free survival, both outperforming SLNB. Although sensitivity for RFS and DMFS were 76%, this was superior to SLNB, although these data were not broken down by patient stage. Specificity for RFS and DMFS was similar to SLNB. Litchman et al46 evaluated 6 studies and noted high-risk GEP results correlated with poorer RFS and DMFS, as well as correlated with OS. A recent prospective study by Hsueh et al43 evaluated the use of DecisionDX Melanoma in 323 patients in two prospective trials with three years of follow-up (INTEGRATE and EXPAND registries), and demonstrated that a GEP high risk result was a significant predictor of RFS, DMFS, and OS in univariate analysis, and was demonstrated to be an independent predictor of RFS, DMFS, and OS in multivariate analysis, including AJCC 8th ed. staging (staging was also an independent predictor). Other studies had similar findings.47 Combining AJCC staging or other clinicopathological factors and GEP was also found to improve risk stratification.44,48-49 Other prospective and retrospective studies have subsequently been performed for GEP testing and demonstrate similar findings. Of importance, some studies have shown that the use of GEP has reduced some unnecessary SLNB, although these data are limited.45. It is understood that comprehensive data are currently being compiled.”

Under Analysis of Evidence, first paragraph, revised the first sentence to read, "For cutaneous melanoma, a well-established set of clinical pathways is available for patient management, which are heavily based on risk stratification of patients with higher risk patients being recommended to have a more intense diagnostic workup or more intensive treatment." Second sentence, revised verbiage “imagining.” Second paragraph revised to read, "Although some recent publications and evidence has cast doubt in the clinical utility of these tests, it is important to consider these in light of the intended use of these tests as covered in this policy.37,38 The negative studies demonstrate disagreement in expert consensus on test use or question the predictive ability of the tests to accurately identify RFS in a stage dependent manner; however, other prospective trials and meta-analyses support the use of GEP testing and evaluate the evidence in univariate and multivariant analyses including AJCC 8th ed. staging criteria. Despite this, it is important to note that from a clinical utility perspective, a major of these GEP tests as described in this policy is to modify management of patients who have >5% likelihood of a positive SLN to preclude unnecessary SLNB. The data reviewed suggest not only that GEP tests can better predict SLN positivity than staging and clinicopathological criteria alone; they may be more predictive of DFS and DMFS than SLNB and may be even more effective when combined with clinicopathological factors. The Marchetti et al38 paper did not evaluate DMFS or SLB positivity because of limited data, and thus did not directly address the value this payor sees in these tests as a tool to help reduce the need for unnecessary SLNB in low-risk patients. Based on the evidence published and reviewed to date, this payor sees evidence that GEP testing may be used to better risk stratify and manage melanoma patients as defined in the coverage section of this policy. Specifically, this test has shown to be able to predict SLN status better than other methodologies, and thus likely reduce unnecessary SLNB in a low-risk population who would otherwise have received a SLNB as well as advocate for SLNB in those patients who may otherwise forgo the procedure based on staging criteria and clinical factors alone. Admittedly, the data supporting this test is limited and imperfect; however, the current alternative tools for assessing patient risk stratification in this population in accepted practice are even more so; with this policy we leave it to clinicians to use these services to mitigate a challenging clinical situation and hope that further evidence is developed to clearly guide melanoma patient management. We await more comprehensive published and peer-reviewed prospective data that support or refute changes in patient management based on the use of these or other similar tests.”

Under Bibliography changes were made to citations to reflect AMA citation guidelines, references number 42-49 were added. Formatting, punctuation and typographical errors were corrected throughout the LCD. Acronyms were inserted where appropriate throughout the LCD.

This revision is effective on 7/3/2022.

  • Provider Education/Guidance
12/10/2020 R5

Under CMS National Coverage Policy removed the regulation CMS On-Line Manual, Publication 100-02, Medicare Benefit Policy Manual, Chapter 15, §§80.0, 80.1.1, 80.2. Clinical Laboratory services. Under Bibliography corrected the link in reference #39. Typographical errors were corrected throughout the LCD.

At this time 21st Century Cures Act will apply to new and revised LCDs that restrict coverage which requires comment and notice. This revision is not a restriction to the coverage determination; and, therefore not all the fields included on the LCD are applicable as noted in this policy.

  • Provider Education/Guidance
11/22/2020 R4

Under LCD Title changed the LCD title from MolDX: DecisionDX Melanoma to MolDX: Melanoma Risk Stratification Molecular Testing.

Under CMS National Coverage Policy regulations regarding billing and coding were removed from this section and placed in the related billing and coding article.

Under Coverage Indications, Limitations and/or Medical Necessity the verbiage was revised and now reads:

Molecular diagnostic tests used to assist in risk stratification of melanoma patients are covered when:

  1. The patient has a personal history of melanoma AND:
    1. Either:
      1. Has Stage T1b and above OR
      2. Has T1a with documented concern about adequacy of microstaging
    2. Is undergoing workup or being evaluated for treatment, AND
    3. Does not have metastatic disease AND
    4. Presumed risk for a positive Sentinel Lymph Node Biopsy (SLNB) based on clinical, histological, or other information is >5% AND
    5. Has a disease stage, grade, and Breslow thickness (or other qualifying conditions) within the intended use of the test
  1. The TEST has demonstrated, as part of a Technical Assessment:
    1. Clinical validity of analytes tested in predicting metastatic disease in peer-reviewed scientific literature
    2. Utility beyond clinical, histological, and radiographical factors in the ability to accurately stratify patients into risk groups to manage patient care
    3. Appropriate analytical validity
    4. Performance characteristics equivalent to other covered, similar tests

Under Summary of Evidence the verbiage was revised and now reads:

Cutaneous melanoma (CM) is increasing in incidence in the U.S., with an estimated 96,480 cases expected to be diagnosed in 2019 with 7,230 deaths.1

In the treatment of CM, the risk that a patient has or will develop metastatic disease is central to many of the decision management choices in cutaneous melanoma, with more aggressive management or treatment strategies recommended for patients who are at a higher risk.2 Per current national guidelines, a SLNB procedure is considered for all patients with melanoma pathologic Stage T1b and above, as well as those patients with T1a tumors in whom there is significant uncertainty about the adequacy of microstaging.2,3 Patients with a positive SLN are at substantially increased risk for distant metastatic disease and death,4 however, the procedure only provides prognostic information, and the MSLT-II study showed no survival benefit associated with completion lymphadenectomy in SLN positive patients.5 Currently, the identification of SLN positive patients helps identify Stage III patients who can potentially benefit from targeted and immunotherapeutic agents in the adjuvant setting.6-8 The procedure can be associated with complications in a substantial proportion of patients such as pain, seromas, nerve damage and edema, and requires a large team of dedicated personnel, including nuclear medicine physicians, surgeons, and pathologists.9-11 It has been estimated that the cost of a SLNB can be 10 times that of a wide excision alone, and the cost per life saved in a patient population with low prevalence of positive SLN can approach 1 million dollars.12 Overall, the likelihood of a positive SLN after the SLNB procedure is 16%,4,13 but this is variable for specific populations.13-16 Elderly patients account for a substantial proportion of CM patients, and 60% of melanoma-related deaths occur in patients ≥65 years-old. While older age is associated with a poor prognosis, fewer elderly patients are SLN positive,14-18 which indicates that the prognostic value of SLNB is limited in this population.19,20In general, a 5% likelihood for a positive SLN is recommended as a threshold for performing this procedure in a patient population.13

Molecular diagnostic tests have been proposed to help managing clinicians risk stratify patients for selecting their most appropriate management based on their probability of developing metastatic disease; these tests may score patients’ probabilities of resultant metastatic disease by measuring tumor biomarkers such as relevant gene expression. 21-24 One gene expression profile (GEP) test (DecisionDx Melanoma, Castle Biosciences) was evaluated in a retrospective cohort (n=782) to evaluate its ability to predict metastasis and ability to predict SLNB status with tumors with a Breslow thickness <2.0 mm (AJCC T1 T2).25

The ability of the test to identify a low risk group was assessed and compared to SLNB in two contemporary, multi-center, prospective study cohorts: a 584 patient cohort from two published prospective studies (overall 14% SLN positive rate)23,26 and a 837 patient cohort from prospectively tested patients at 5 large academic institutions (overall 12% SLN positive rate).25 The rate of SLN positivity in both prospective study cohorts aligns with the SLN positivity rate in the general population of melanoma patients who have undergone SLNB. The results show that in patients from the Medicare-eligible population (65 years old and over) who were determined to be low risk by this test, the concordance of a negative SLNB was 98.4%. These studies showed improved performance in other patient groups as well.

SLNB positivity rates for T3 tumors with low risk score for this test is 8.7%. Importantly, the 5-year melanoma specific survival (MSS) rate for T1/T2 low risk group remains favorable; with 99% MSS, comparable to that observed in T1a tumors and for which current guidelines do not recommend SLNB.2,27 Furthermore, T1/T2 low risk patients patients show 5-year overall survival (OS) of 97% and distant metastasis free survival (DMFS) of 93%.28 The MSLT-II study demonstrated that a delay in lymph node dissection does not adversely affect survival, thus clinical follow up of low-risk patients and lymphadenectomy for those few who develop clinically detectable nodal disease should achieve similar outcomes to those who currently undergo a planned SLNB.5 Thus, the test identifies a patient population with <5% likelihood of a positive SLN and high survival rates and therefore has utility in guiding SLNB decisions in patients 65 years-old and over with T1-T2 CM tumors. In this population, the test could potentially reduce the rate of SLNB by up to 78% while still maintaining a MSS survival rate of 99% in those patients with low-risk tumor biology who can safely avoid the procedure.

Clinical validation of this same test as a prognostic test for CM patients was performed in three multicenter, prospectively designed archival tissue studies including 782 patients.21,22,24 These studies have shown that the test accurately predicts risk for local/regional recurrence, distant metastasis, melanoma-related mortality, and all-cause mortality independent of clinicopathologic factors used in staging and that the test shows improved sensitivity and negative predictive value (NPV) for recurrence-free (RFS), distant metastasis-free (DMFS), melanoma-specific (MSS) and overall (OS) survival individually or in conjunction with established clinicopathologic factors. A study focused on patients with melanoma of the head and neck (H&N) has been recently published. Patients with H&N melanoma have poorer outcomes and lower rates of SLN positivity which makes the prognostic value of the SLNB procedure limited and thus additional prognostic information provided by this test is important in this group of patients.28 Four prospective, independent studies (n= 510) and an interim analysis of two prospective registries (n=322) have confirmed the prognostic accuracy of the assay.23,29-32 This suggests that the test may be useful in stratifying risk and patient treatment decisions.

A recent retrospective study directly compared the ability of DecisionDX Melanoma with the ability of American Joint Committee on Cancer (AJCC) melanoma staging to predict longer term outcomes.33 This study looked at 205 archived formalin-fixed, paraffin-embedded primary melanoma tissue blocks from 6 centers. This included 109 Stage I and 96 Stage II cancers, and median time to follow-up was 6.9 years. The median time to recurrence was 1.7 years, and the median time to distant metastasis was 1.6 years. In general, the test scoring alone had greater sensitivity to recurrence, distant metastasis, and death than AJCC staging. Alternatively, AJCC staging had greater specificity for these outcomes. The use of this assay with AJCC staging had a higher sensitivity to these adverse outcomes than either prognostic measurement alone. Lastly, a number of recent studies have suggested that clinicians value and use this test in their medical decision making regarding aggressiveness of melanoma management.34-36

Under Analysis of Evidence the verbiage was revised and now reads:

For cutaneous melanoma, a well-established set of clinical pathways is available for the management of cutaneous melanoma, which are heavily based on risk stratification of patients with higher risk patients being recommended to have a more intense diagnostic workup or more intensive treatment. While the consensus guidelines also give specific clinical, pathologic, and imagining findings that can help to risk stratify a patient, additional evidence suggests that molecular diagnostic tests can be used to further improve risk stratification, thereby improving the accuracy of the risk stratification that is key to deciding on the optimal patient management plan in these clinical pathways. This is particularly the case for identifying the patients at a higher risk of adverse outcomes as a result of the melanoma. As such, tests such as the one evaluated above are considered reasonable and necessary for indications where it has both shown an ability to enhance accuracy of risk stratification and where this risk stratification may be used to select among a number of different consensus recommended management approaches.

Since the clinical utility of this test is dependent upon consensus-based management recommendations based on risk, this coverage decision is subject to change pending changes in the consensus recommended use of risk strata for patient management and the accuracy of alternative risk-stratification tools. This coverage decision will be periodically re-evaluated.

At this time 21st Century Cures Act will apply to new and revised LCDs that restrict coverage which requires comment and notice. This revision is not a restriction to the coverage determination; and, therefore not all the fields included on the LCD are applicable as noted in this policy.

  • Provider Education/Guidance
08/29/2019 R3

This LCD is being revised in order to adhere to CMS requirements per Chapter 13, Section 13.5.1 of the Program Integrity Manual, to remove all coding from LCDs. There has been no change in coverage with this LCD revision.

At this time 21st Century Cures Act will apply to new and revised LCDs that restrict coverage which requires comment and notice. This revision is not a restriction to the coverage determination; and, therefore not all the fields included on the LCD are applicable as noted in this policy.

  • Provider Education/Guidance
08/29/2019 R2

All coding located in the Coding Information section has been moved into the related Billing and Coding: MolDX: DecisionDx-Melanoma A56961 article and removed from the LCD.

At this time 21st Century Cures Act will apply to new and revised LCDs that restrict coverage which requires comment and notice. This revision is not a restriction to the coverage determination; and, therefore not all the fields included on the LCD are applicable as noted in this policy.

  • Provider Education/Guidance
05/30/2019 R1

Removed "b" from T1b in the first bullet of the Coverage Indications, Limitations, and/or Medical Necessity section and in the Summary of Analytical and Clinical Performance General table. These changes were inadvertently left out when finalizing the Local Coverage Determination.

  • Typographical Error
N/A

Associated Documents

Attachments
N/A
Related National Coverage Documents
N/A
Public Versions
Updated On Effective Dates Status
05/13/2022 07/03/2022 - N/A Currently in Effect You are here
Some older versions have been archived. Please visit the MCD Archive Site to retrieve them.

Keywords

  • Melanoma
  • Risk Stratification

Read the LCD Disclaimer