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Gene Expression Profiling for Uveal Melanoma

Policy Number: MP-585

ARCHIVED – Refer to AIM Genetic Testing Guidelines effective 3/1/20

Latest Review Date: February 2020

Category: Laboratory

Policy Grade: D

POLICY:

Effective for dates of service on or after February 24, 2017:

Gene expression profiling for uveal melanoma with DecisionDX-UM may be considered medically necessary for members with primary, localized uveal melanoma.

Gene expression profiling for uveal melanoma is considered not medically necessary and investigational for all other situations.


Effective for dates of service prior to February 24, 2017:

Gene expression profiling for uveal melanoma is considered not medically necessary and investigational.

DESCRIPTION OF PROCEDURE OR SERVICE:

Uveal melanoma is associated with a high rate of metastatic disease, and survival after the development of metastatic disease is poor. Prognosis following treatment of local disease can be assessed using various factors, including clinical and demographic markers, tumor stage, tumor characteristics, and tumor cytogenetics. Gene expression profiling (GEP) can be used to determine prognosis and gene expression profile testing is commercially available.

Uveal Melanoma

The uveal tract is the middle layer of the wall of the eye, and has three main parts: the choroid (a tissue layer filled with blood vessels), ciliary body (muscle tissue that changes the shape of the pupil and the lens), and the iris (the colored part of the eye). Uveal melanoma arises from melanocytes in the stroma of the uveal tract. Approximately 90% of uveal melanomas arise in the choroid, 7% in the ciliary body, and 3% in the iris.

Uveal melanoma, although rare, is the most common primary intraocular malignancy in adults. Mean age-adjusted incidence of uveal melanoma in the United States is 6.3 per million people among whites, 0.9 among Hispanics, and 0.24 among blacks. Uveal melanoma has a progressively rising, age-specific, incidence rate that peaks near age 70. Host susceptibility factors associated with the development of this cancer include white race, fair skin, and light eye color.

Treatment

Treatment of primary, localized uveal melanoma can be by surgery or radiotherapy. In general, larger tumors require enucleation surgery and smaller tumors can be treated with radiotherapy, but specific treatment parameters are lacking. The most common treatment of localized uveal melanoma is radiotherapy, which is preferred because it can spare vision in most cases. For smaller lesions, randomized controlled trials have shown that patients receiving radiotherapy or enucleation progress to metastatic disease at similar rates after treatment. Radiotherapy can be delivered by a variety of mechanisms, most commonly brachytherapy and proton beam therapy. Treatment of primary uveal melanoma improves local control and spares vision. However, the five-year survival rate (81.6%) has not changed over the last three decades, suggesting that life expectancy is independent of successful local eye treatment.

Uveal melanomas disseminate hematogenously, and metastasize primarily to the liver and lungs. Treatment of hepatic metastases is associated with prolonged survival and palliation in some patients. Therapies directed at locoregional treatment of hepatic metastases include surgical and ablative techniques, embolization, and local chemotherapy.

Metastatic Disease

It is unusual for patients with uveal melanoma to have distant metastases at presentation, with less than 1% presenting with metastases when they are treated for their intraocular disease, but are at risk for distant metastases, particularly to the liver, for years after presentation. The prospective, longitudinal Collaborative Ocular Melanoma Study (COMS) study followed 2,320 patients with choroidal melanoma with no melanoma metastasis at baseline who were enrolled in randomized controlled trials to evaluate forms of radiotherapy for choroidal melanoma for five to ten years. During follow-up, 739 patients were diagnosed with at least one site of metastasis, of which 660 (89%) were liver. Kaplan-Meier estimates of two-, five-, and ten-year metastasis rates were 10% (95% CI, 9% to 12%), 25% (95% CI, 23% to 27%), and 34% (95% CI, 32% to 37%), respectively.

Prognosis

Metastatic disease is the leading cause of death in patients with uveal melanoma, and approximately 50% of patients will develop distant metastasis. A number of factors may be used to determine prognosis, but the optimal approach is uncertain. The most important clinical factors that predict metastatic disease are tumor size measured in diameter or in thickness, ciliary body involvement, and transcleral extension. Clinical staging according to the American Joint Committee on Cancer (AJCC) recommendations allows risk stratification for metastatic disease. In a retrospective study of 3,377 patients with uveal melanoma, in which staging was performed using AJCC classifications, the rate of metastases-free survival at five years was 97% for Stage I, 89% for Stage IIA, 79% for Stage IIB, 67% for Stage IIIA, 50% for Stage IIIB, and 25% for Stage IIIB.

Genetic Analysis

Genetic analysis of uveal melanoma can provide prognostic information for the risk of developing metastatic disease. In 1996, Prescher et al showed that monosomy of chromosome three correlated strongly with metastatic death, with a five-year survival reduction from 100% to 50%. Subsequent studies reported the initial idea that, based on genetic analysis, there were two distinct types of uveal melanomas—those with monosomy chromosome three associated with a very poor prognosis and those with disomy three and 6p gain associated with a better prognosis. The BAP1 gene has been identified as an important marker of disease type. In one study, 89% of tumors with monosomy three had a BAP1 mutation, and no tumors without monosomy three had a BAP1 mutation.

Gene expression profiling (GEP) determines the expression of multiple genes in a tumor and has been proposed as an additional method to stratify patients into prognostic risk groups.

KEY POINTS:

The most recent literature review was updated through December 9, 2019.

Summary of Evidence

For individuals who have localized uveal melanoma who receive a gene expression profiling (GEP) test for uveal melanoma (DecisionDx-UM), the evidence includes cross-sectional studies of assay validation and clinical validity. Relevant outcomes are overall survival, disease-specific survival, test accuracy and validity, other test performance measures, functional outcomes, health status measures, and quality of life. One commercially available test identified (DecisionDx-UM) has published data related to its clinical validity, and is the focus of this review. Three studies of clinical validity identified used the GEP score to predict melanoma metastases and melanoma-specific survival. All three reported that GEP class correlated strongly with metastatic disease and melanoma mortality. Two studies compared GEP class to other prognostic markers, and GEP class had the strongest association among the markers tested. GEP class appears to be a strong predictor of metastatic disease and melanoma death. There are no studies directly showing clinical utility. In the absence of direct evidence, an indirect chain of evidence to determine whether using the results of GEP testing for management decisions improves the net health outcome of patients with uveal melanoma. Aaberg et al (2014) have shown an association between GEP classification and treatment, reporting that patients classified as low risk were managed with less frequent and intensive surveillance and were not referred for adjuvant therapy. It is uncertain whether stratification of patients into higher risk categories has the potential to improve outcomes by allowing patients to receive adjuvant therapies or through the detection of metastases earlier. However, classification into the low-risk group would allow reduction in the burden of surveillance without apparent harm. The evidence is sufficient to determine that the technology results in a meaningful improvement in the net health outcome.

Practice Guidelines and Position Statements

National Comprehensive Cancer Network (NCCN)

National Comprehensive Cancer Network (NCCN) guidelines for uveal melanoma (v.1.2019) state that biopsy specimens 'should be sent for histology, chromosome analysis, and/or gene expression profiling.' The guidelines include DecisionDx-UM classes as one of the factors used to risk stratify patients for systemic imaging.

Melanoma Focus

Melanoma Focus, a British medical nonprofit that focuses on melanoma research, for uveal melanoma was published in 2015. These guidelines, which were created through a process accredited by the National Institute for Health and Care Excellence, contain the following statements related to prognosis and surveillance:

“3.5.1 Prognostic factors/tools

  1. Prognostic factors of uveal melanoma are multi-factorial and include clinical, morphological and genetic features. The following features should be recorded:
  • Age
  • Gender
  • Tumour location
  • Tumour height
  • Tumour Largest [sic] basal diameter
  • Ciliary body involvement
  • Extraocular melanoma growth (macroscopic)

The following features should be recorded if tissue is available:

  • Cell type (modified Callender system)
  • Mitotic count (number/40 high power fields in H&E [hematoxylin and eosin] stained sections)
  • Presence of extravascular matrix patterns (particularly closed connective tissue loops; enhanced with Periodic acid Schiff staining). Grade A
  • Presence of extraocular melanoma growth (size, presence or absence of encapsulation). Grade A

3.5.2 Prognostic biopsy

  1. There should be a fully informed discussion with all patients, explaining the role of biopsy including the benefits and risks. The discussion should include:
  • Risk of having the biopsy
  • Limitations of the investigation
  • Benefits for future treatments (including possible recruitment to trials)
  • Impact on quality of life
  • Follow-up [GPP]
  1. Use of the current (i.e. 7th) Edition of the TN staging system for prognostication is highly recommended. Grade A
  2. Use of multifactorial prognostication models incorporating clinical, histological, immunohistochemical and genetic tumour features – should be considered. Grade D

3.6 Surveillance

  1. Prognostication and surveillance should be led by a specialist multidisciplinary team that incorporates expertise from ophthalmology, radiology, oncology, cancer nursing and hepatic services. [GPP]
  2. Prognostication and risk prediction should be based on the best available evidence, taking into account clinical, morphological and genetic cancer features. [GPP]
  3. All patients, irrespective of risk, should have a holistic assessment to discuss the risk, benefits and consequences of entry into a surveillance programme. The discussion should consider risk of false positives, the emotional impact of screening as well as the frequency and duration of screening. An individual plan should be developed. [GPP]
  4. Patients judged at high-risk of developing metastases should have six-monthly life-long surveillance incorporating a clinical review, nurse specialist support and liver specific imaging by a non-ionising modality. [GPP] …
  5. Liver function tests alone are an inadequate tool for surveillance. Grade C”

Note that Melanoma Focus defined GPP as: recommended best practice based on the clinical experience of the guideline development group.

U.S. Preventive Services Task Force Recommendations

Not applicable.

KEY WORDS:

Uveal melanoma, DecisionDx-UM®, GEP, gene expression profile

APPROVED BY GOVERNING BODIES:

Clinical laboratories may develop and validate tests in-house and market them as a laboratory service; laboratory-developed tests (LDTs) must meet the general regulatory standards of the Clinical Laboratory Improvement Amendments (CLIA). The DecisionDx-UM test is available under the auspices of CLIA. Laboratories that offer LDTs must be licensed by CLIA for high-complexity testing. To date, the U.S. Food and Drug Administration has chosen not to require any regulatory review of this test.

BENEFIT APPLICATION:

Coverage is subject to member’s specific benefits. Group specific policy will supersede this policy when applicable.

ITS: Home Policy provisions apply.

FEP: Special benefit consideration may apply. Refer to member’s benefit plan. FEP does not consider investigational if FDA approved and will be reviewed for medical necessity.

CURRENT CODING:

CPT Codes:

For DecisionDX®-UM:

81552

Oncology (uveal melanoma), mRNA, gene expression profiling (Effective 1/1/2020)

PREVIOUS CODING:

CPT codes:

0081U

Oncology (uveal melanoma), mRNA, gene-expression profiling by real-time RT-PCR of 15 genes (12 content and 3 housekeeping genes), utilizing fine needle aspirate or formalin-fixed paraffin-embedded tissue, algorithm reported as risk of metastasis. (Effective 01/01/19- Deleted 12/31/19)

81599

Unlisted multianalyte assay with algorithmic analysis

84999

Unlisted chemistry procedure

REFERENCES:

  1. Aaberg TM, Jr., Cook RW, Oelschlager K, et al. Current clinical practice: differential management of uveal melanoma in the era of molecular tumor analyses. Clin Ophthalmol. 2014; 8:2449-2460.
  2. AJCC Ophthalmic Oncology Task Force. International validation of the American Joint Committee on Cancer's 7th Edition Classification of Uveal Melanoma. JAMA Ophthalmol. Apr 2015; 133(4):376-383.
  3. Augsburger JJ, Correa ZM, Augsburger BD. Frequency and implications of discordant gene expression profile class in posterior uveal melanomas sampled by fine needle aspiration biopsy. Am J Ophthalmol. Feb 2015; 159(2):248-256.
  4. Augsburger JJ, Correa ZM, Shaikh AH. Effectiveness of treatments for metastatic uveal melanoma. Am J Ophthalmol 2009; 148(1):119-27.
  5. Choudhary MM, Gupta A, Bena J, et al. Hepatic ultrasonography for surveillance in patients with uveal melanoma. JAMA Ophthalmol. Feb 2016; 134(2):174-180.
  6. Correa ZM, Augsburger JJ. Independent prognostic significance of gene expression profile class and largest basal diameter of posterior uveal melanomas. Am J Ophthalmol. Feb 2016; 162:20-27 e21.
  7. Correa ZM. Assessing prognosis in uveal melanoma. Cancer Control. Apr 2016; 23(2):93-98.
  8. Decatur CL, Ong E, Garg N, et al. Driver mutations in uveal melanoma: associations with gene expression profile and patient outcomes. JAMA Ophthalmol. Apr 28 2016.
  9. Diener-West M, Reynolds SM, Agugliaro DJ, et al. Development of metastatic disease after enrollment in the COMS trials for treatment of choroidal melanoma: Collaborative Ocular Melanoma Study Group Report No. 26. Arch Ophthalmol. Dec 2005; 123(12):1639-1643.
  10. Desjardins L, Dorval T, Levy C, et al. Etude randomize de chemiotherapy adjuvant par le Delicense dans le melanoma choroidei (Randomized study of adjuvant therapy by DTIC in choroidal melanoma). Ophthalmology. 1998; 12(3):168-173.
  11. Finger PT, AJCC-UICC Ophthalmic Oncology Task Force. The 7th edition AJCC staging system for eye cancer: an international language for ophthalmic oncology. Arch Pathol Lab Med. Aug 2009; 133(8):1197-1198.
  12. Finger RL. Intraocular melanoma. In: DeVita VT, Lawrence TS, Rosenberg SA, eds. Cancer: Principles & Practice of Oncology. 10th ed. ed. Philadelphia, PA: Wolters Kluwer Health/Lippincott Williams & Wilkins; 2014: 1770-1779.
  13. Francis JH, Patel SP, Gombos DS, et al. Surveillance options for patients with uveal melanoma following definitive management. Am Soc Clin Oncol Educ Book. 2013: 382-387.
  14. Hawkins BS. Collaborative ocular melanoma study randomized trial of I-125 brachytherapy. Clin Trials 2011; 8(5):661-73.
  15. McLean IW, Berd D, Mastrangelo MJ, et al. A randomized study of methanol-extraction residue of bacille Calmette-Guerin as postsurgical adjuvant therapy of uveal melanoma. Am J Ophthalmol. Nov 15 1990; 110(5):522-526.
  16. Nathan P, Cohen V, Coupland S, et al. Melanoma Focus: Uveal Melanoma National Guidelines: Summary. 2015; Available at: www.melanomafocus.com/wp-content/uploads/2015/06/Uveal-Melanoma-National-Guidelines-Summary-v1.3.pdf.
  17. National Comprehensive Cancer Network (NCCN). NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines): Melanoma. 2017; Version 1.2018:www.nccn.org/professionals/physician_gls/pdf/melanoma.pdf. Accessed January 6, 2020.
  18. National Comprehensive Cancer Network (NCCN). NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines): Melanoma. 2019; Version 1.2018:www.nccn.org/professionals/physician_gls/pdf/melanoma.pdf. Accessed January 28, 2019.
  19. Onken MD, Worley LA, Char DH et al. Collaborative Ocular Oncology Group report number 1: prospective validation of a multi-gene prognostic assay in uveal melanoma. Ophthalmology 2012; 119(8):1596-603.
  20. Onken MD, Worley LA, Ehlers JP et al. Gene expression profiling in uveal melanoma reveals two molecular classes and predicts metastatic death. Cancer Res 2004; 64(20):7205-9.
  21. Onken MD, Worley LA, Tuscan MD et al. An accurate, clinically feasible multi-gene expression assay for predicting metastasis in uveal melanoma. J Mol Diagn 2010; 12(4):461-8.
  22. Pereira PR, Odashiro AN, Lim LA, et al. Current and emerging treatment options for uveal melanoma. Clin Ophthalmol. 2013; 7:1669-1682.
  23. Plasseraud KM, Cook RW, Tsai T, et al. Clinical Performance and Management Outcomes with the DecisionDx-UM Gene Expression Profile Test in a Prospective Multicenter Study. J Oncol. 2016; 2016:5325762.
  24. Prescher G, Bornfeld N, Hirche H et al. Prognostic implications of monosomy 3 in uveal melanoma. Lancet 1996; 347(9010):1222-5.
  25. Spagnolo F, Caltabiano G, Queirolo P. Uveal melanoma. Cancer Treat Rev 2012; 38(5):549-53.
  26. van de Nes JA, Nelles J, Kreis S, et al. Comparing the prognostic value of BAP1 mutation pattern, chromosome 3 status, and BAP1 immunohistochemistry in uveal melanoma. Am J Surg Pathol. Jun 2016; 40(6):796-805.
  27. Walter SD, Chao DL, Feuer W, et al. Prognostic Implications of tumor diameter in association with gene expression profile for uveal melanoma. JAMA Ophthalmol. Apr 28 2016.

POLICY HISTORY:

Medical Policy Panel, May 2014

Medical Policy Group, February 2015 (3): Creation of individual policy with all references related to Uveal Melanoma removed from medical policy #133-Genetic Testing for Inherited Cancer Predisposition and/or Pharmacogenetics related to Cancer Treatment

Medical Policy Administration Committee, March 2015

Medical Policy Panel, May 2015

Medical Policy Group, May 2015 (3): 2015 Updates to Key Points & Coding; no change in policy statement

Medical Policy Panel, July 2016

Medical Policy Group, July 2016 (3): 2016 Updates to Description, Key Points, Key Words & Coding; no change in policy statement

Medical Policy Panel, February 2017

Medical Policy Group, February 2017 (3): 2017 Updates to Description, Key Points & References; updated policy statements to reflect coverage criteria for GEP for uveal melanoma for members with primary, localized uveal melanoma, effective February 24, 2017

Medical Policy Administration Committee March 2017

Available for comment February 24 through April 9, 2017

Medical Policy Panel, February 2018

Medical Policy Group, March 2018 (2): 2018 Updates to Key Points and References; no change in policy statement.

Medical Policy Panel, February 2019

Medical Policy Group, March 2019 (9): 2019 Updates to Description, Key Points, References; no change in policy statement.

Medical Policy Group, November 2019: 2020 Annual Coding Update. Added CPT code 81552 to Current Coding section. Created Previous Coding section to include code 0081U.

Medical Policy Panel, February 2020

Medical Policy Group, February 2020 (9): 2020 Minor updates to Key Points and References; no change in policy statement.


This medical policy is not an authorization, certification, explanation of benefits, or a contract. Eligibility and benefits are determined on a case-by-case basis according to the terms of the member’s plan in effect as of the date services are rendered. All medical policies are based on (i) research of current medical literature and (ii) review of common medical practices in the treatment and diagnosis of disease as of the date hereof. Physicians and other providers are solely responsible for all aspects of medical care and treatment, including the type, quality, and levels of care and treatment.

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  1. The technology must have final approval from the appropriate government regulatory bodies;
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