Gene Expression Profiling for Uveal Melanoma

POLICY NUMBER

L.2.04.463

DESCRIPTION

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; it has 3 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. The mean age-adjusted incidence of uveal melanoma in the United States is 6.3 per million people among White individuals, 0.9 among Hispanic individuals, and 0.24 among Black individuals. 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 various mechanisms, most commonly brachytherapy and proton beam therapy. Treatment of primary uveal melanoma improves local control and spares vision, however, the 5-year survival rate (81.6%) has not changed over the last 3 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 they are at risk for distant metastases, particularly to the liver, for years after presentation. The prospective, longitudinal Collaborative Ocular Melanoma 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 5 to 10 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 2-, 5-, and 10-year metastasis rates were 10% (95% confidence interval [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 thickness), ciliary body involvement, and transcleral extension. Clinical staging using the American Joint Committee on Cancer recommendations allows risk stratification for metastatic disease. In a 2015 retrospective study of 3,377 patients with uveal melanoma, in which staging was performed using the American Joint Committee on Cancer classifications, the rate of metastasis-free survival at 5 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 IIIC.

Genetic Analysis

Genetic analysis of uveal melanoma can provide prognostic information for the risk of developing metastatic disease. In 1996, Prescher and colleagues showed that monosomy of chromosome 3 correlated strongly with metastatic death, with a 5-year survival reduction from 100% to 50%. Subsequent studies have reported that, based on genetic analysis, there were two distinct types of uveal melanomas—those with monosomy chromosome 3 associated with a very poor prognosis and those with disomy 3 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 3 had a BAP1 variant, and no tumors without monosomy 3 had a BAP1 variant.

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

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 (Castle Biosciences, Phoenix, AZ) is available under the auspices of the CLIA. Laboratories that offer LDTs must be licensed by the 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.

Related policies -

• Charged-Particle (Proton or Helium Ion) Radiotherapy for Neoplastic Conditions

POLICY

Gene expression profiling for uveal melanoma with DecisionDx-UM is medically necessary for individuals with primary, localized uveal melanoma.

Gene expression profiling for uveal melanoma that does not meet the above criteria is investigational.

POLICY EXCEPTIONS

Federal Employee Program (FEP) may dictate that all FDA-approved devices, drugs or biologics may not be considered investigational and thus these devices may be assessed only on the basis of their medical necessity.

POLICY GUIDELINES

The coverage guidelines outlined in the Medical Policy Manual should not be used in lieu of the Member's specific benefit plan language.

Medically Necessary is defined as those services, treatments, procedures, equipment, drugs, devices, items or supplies furnished by a covered Provider that are required to identify or treat a Member's illness, injury or Mental Health Disorders, and which Company determines are covered under this Benefit Plan based on the criteria as follows in A through D:

A. consistent with the symptoms or diagnosis and treatment of the Member's condition, illness, or injury; and

B. appropriate with regard to standards of good medical practice; and

C. not solely for the convenience of the Member, his or her Provider; and

D. the most appropriate supply or level of care which can safely be provided to Member. When applied to the care of an Inpatient, it further means that services for the Member's medical symptoms or conditions require that the services cannot be safely provided to the Member as an Outpatient.

For the definition of medical necessity, “standards of good medical practice” means standards that are based on credible scientific evidence published in peer-reviewed medical literature generally recognized by the relevant medical community, and physician specialty society recommendations, and the views of medical practitioners practicing in relevant clinical areas and any other relevant factors. BCBSMS makes no payment for services, treatments, procedures, equipment, drugs, devices, items or supplies which are not documented to be Medically Necessary. The fact that a Physician or other Provider has prescribed, ordered, recommended, or approved a service or supply does not in itself, make it Medically Necessary.

Investigative is defined as the use of any treatment procedure, facility, equipment, drug, device, or supply not yet recognized as a generally accepted standard of good medical practice for the treatment of the condition being treated and; therefore, is not considered medically necessary. For the definition of Investigative, “generally accepted standards of medical practice” means standards that are based on credible scientific evidence published in peer-reviewed medical literature generally recognized by the relevant medical community, and physician specialty society recommendations, and the views of medical practitioners practicing in relevant clinical areas and any other relevant factors. In order for equipment, devices, drugs or supplies [i.e, technologies], to be considered not investigative, the technology must have final approval from the appropriate governmental bodies, and scientific evidence must permit conclusions concerning the effect of the technology on health outcomes, and the technology must improve the net health outcome, and the technology must be as beneficial as any established alternative and the improvement must be attainable outside the testing/investigational setting.

POLICY HISTORY

07/17/2014: Approved by Medical Policy Advisory Committee.

07/20/2015: Code Reference section updated for ICD-10.

09/24/2015: Policy description updated. Policy statement unchanged. Investigative definition updated in Policy Guidelines.

06/07/2016: Policy number A.2.04.120 added.

08/24/2016: Policy description updated regarding treatment and prognosis of uveal melanoma. Policy statement unchanged.

08/15/2017: Policy description updated regarding surveillance for metastatic disease and available testing. Added statement that gene expression profiling for uveal melanoma with DecisionDx-UM is medically necessary for patients with primary, localized uveal melanoma. Policy statement revised to add that gene expression profiling for uveal melanoma not meeting the criteria is investigational. Code Reference section revised to update the coding table: "Investigational" changed to "Medically Necessary." Added diagnosis codes C69.30 - C69.32, C69.40 - C69.42, and C69.80 - C69.82.

02/28/2018: Policy description updated to remove information regarding surveillance for metastatic disease. Policy statements unchanged.

03/19/2019: Policy reviewed; no changes.

12/19/2019: Code Reference section updated to add new CPT code 81552 effective 01/01/2020.

03/09/2020: Policy description updated. Policy statements unchanged.

04/06/2021: Policy reviewed. Policy statement unchanged. Policy Guidelines updated to change "Nervous/Mental Conditions" to "Mental Health Disorders" and "Medically Necessary" to "medical necessity."

04/07/2022: Policy reviewed; no changes.

03/14/2023: Policy description updated with minor wording changes and regarding prognosis. Policy statement updated with minor wording change.

03/15/2024: Policy reviewed; no changes.

04/15/2025: Policy number changed from "A.2.04.120" to "L.2.04.463." Policy reviewed. Policy statements unchanged.

SOURCE(S)

Blue Cross and Blue Shield Association Policy # 2.04.120

CODE REFERENCE

This may not be a comprehensive list of procedure codes applicable to this policy.

The code(s) listed below are ONLY medically necessary if the procedure is performed according to the "Policy" section of this document.

Medically Necessary Codes

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