Medical Policy: 02.04.53
Original Effective Date: December 2015
Reviewed: October 2017
Revised: October 2017
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This Medical Policy document describes the status of medical technology at the time the document was developed. Since that time, new technology may have emerged or new medical literature may have been published. This Medical Policy will be reviewed regularly and be updated as scientific and medical literature becomes available.
The purpose of gene expression profiling assays (DecisionDx-UM) is to assist in the risk stratification and clinical management of individuals with uveal melanoma.
Uveal melanoma, although rare, is the most common primary intraocular malignancy in adults and is associated with a high rate of metastatic disease, predominantly to the liver. Management is complex and requires experienced specialists with training in ophthalmologic oncology. Survival after the development of metastatic disease is poor. Certain clinical factors and tumor genetic alterations (gene expression profiling) are being used to determine risk of metastases in individual patients, although it has not been shown that adjuvant treatment for patients who are considered to be at high risk for metastases alters survival outcomes, nor has it been shown that screening for the detection of early metastases has any effect on patient outcomes.
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 in the lens), and the iris (the colored part of the eye). Uveal melanoma arises from the 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. Iris melanomas have the best prognosis; melanomas of the ciliary body have the worst prognosis.
Modern diagnostic tools, including indirect funduscopic examination, optical coherence tomography, computed tomography (CT), and magnetic resonance imaging (MRI) of the globe and the orbital tissues, have led to significant advances in the ability to diagnose primary uveal melanoma. The clinical diagnosis of uveal melanoma has an accuracy of 99%, and therefore, biopsies and/or tumor resection with histopathologic examination are not essential for diagnosis.
Metastatic disease is the leading cause of death in patients with uveal melanoma, and approximately 50% of patients will develop distant metastasis. 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 is guided by the American Joint Committee on Cancer (AJCC) recommendations which allows risk stratification for metastatic disease. Staging requires intraocular examination, serum tests (complete blood count and liver function tests), and diagnostic imaging (CT of chest and abdomen, whole body PET-CT or liver MRI and chest CT). In a retrospective study of 3377 patients with uveal melanoma, in which staging was performed using AJCC classifications, the rate of metastases-free survival at 5 years was 97% for stage I, 89% for stage IIA, 79% for stage IIB, 67% for stage IIIA, and 50% for stage IIIB.
Local treatment of uveal melanoma is well established and is termed “conservative” if conservation of the eye is attempted. Conservative treatments include brachytherapy and proton beam radiation therapy. Radical therapy consists of enucleation. Both strategies offer the same prognosis, both in terms of survival rates and risk of metastasis, as shown by randomized trials from the Collaborative Ocular Melanoma Study (COMS).
However, despite the established treatment protocols for primary uveal melanoma, no decrease in the mortality rate of this tumor has been observed. The five-year survival rate has not changed over the last three decades (81.6%), suggesting that the life expectancy is independent of successful local eye treatment. Therefore, it has been suggested that the identification of patients at high risk for metastatic disease may assist in selecting patients who might benefit from adjuvant treatment, or that regular screening for the presence of metastatic disease may lead to improved outcomes. Adjuvant treatment may consist of radiotherapy or systemic therapy, such as chemotherapy, immunotherapy, hormone therapy, biological therapy or target therapy. However, randomized trials of patients with high risk of uveal melanoma recurrence showed no difference in survival between patients treated with adjuvant therapy versus no adjuvant treatment. In addition, regular screening tests for the development of liver metastases, including measurement of liver function tests, CT scan or MRI, have not shown evidence of any effect on patient outcomes.
The clinical course of patients with hepatic metastases is highly dependent on disease progression in the liver, and treatment of hepatic metastases has shown to be associated with prolonged survival in some patients. Therapies directed at locoregional treatment of hepatic metastases include surgical and ablative techniques, embolization and local chemotherapy.
In 2016, Weis et. al. developed a consensus based guideline to inform practitioners on the management of uveal melanoma. Eighty four publications, including five existing guidelines formed the evidence base. Consensus discussions by a group of content experts from medical, radiation, and surgical oncology were used to formulate the recommendations. Key recommendations highlight that, for uveal melanoma and its indeterminate melanocyte lesions in the uveal tract, management is complex and requires experienced specialists with training in ophthalmologic oncology. Staging examinations include serum and radiologic investigations. Large lesions are still most often treated with enucleation, and yet radiotherapy is the most common treatment for tumors that qualify. Adjuvant therapy has yet to demonstrate efficacy in reducing the risk of metastasis, and no systemic therapy clearly improves outcomes in metastatic disease. Where available, enrollment in clinical trials is encouraged for patients with metastatic disease. Highly selected patients might benefit from surgical resection of liver metastases.
Uveal melanoma is associated with a high rate of metastatic disease, predominantly to the liver. Survival after the development of metastatic disease is poor. Certain clinical factors and tumor genetic alterations (gene expression profiling) are being used to determine risk of metastases in individual patients, although it has not been shown that adjuvant treatment for patients who are considered to be at high risk for metastases alters survival outcomes, nor has it been shown that screening for the detection of early metastases has any effect on patient outcomes. Although, gene expression profiling of uveal melanoma has been shown to be an independent predictor of risk of metastasis, it is uncertain how risk stratification based upon this type of testing would improve net health outcomes. There is lack of published data from well-designed, prospective studies of sufficient sample size and follow-up that supports the clinical utility of gene expression profile testing for uveal melanoma. There appears to be no incremental benefit in its use over currently established prognostic clinical markers for predicting the risk of metastases, nor is there evidence that the use of this test will alter treatment decisions that will lead to improved outcomes. The evidence is insufficient to determine the effects of this testing on net health outcomes.
DecisionDx-UM® test (Castle Biosciences Inc., Friendswood, TX) is a proprietary, multigene expression profiling (GEP) test intended to assess 5 year metastatic risk in uveal melanoma. The test was introduced in 2009, and claims to identify the molecular signature of a tumor and its likelihood of metastasis within 5 years. The assay determines the expression of 15 genes, which stratify a patient’s individual risk of metastasis into 2 classes.
Based on the clinical outcomes from the prospective, 5 year multicenter Collaborative Ocular Oncology Group (COOG) study, the DecisionDx-UM test reports class 1A, class 1B, and class 2 phenotype:
Class 1A: Very low risk, with a 2% chance of the eye cancer spreading over the next 5 years
Class 1B: Low risk, with a 21% chance of metastasis over 5 years
Class 2: High risk, with 72% odds of metastasis within 5 years.
According to Castle Biosciences Inc., the DecisionDx-UM test results are used for the following:
Gene expression profiling assays (DecisionDx-Melanoma) are being investigated as a tool to assist in the risk stratification and clinical management of individuals with cutaneous melanoma.
Cutaneous melanoma represents less than 5% of skin malignancies but results in the most skin cancer deaths. The incidence of cutaneous melanoma continues to increase, and it is currently the sixth most common cancer in the United States. Mortality and most morbidity are directly related to metastatic events and not the primary tumor. As with nearly all malignancies, the outcome of melanoma depends on the stage at presentation. In the United States, it is estimated that 84% of patients with melanoma initially present with localized disease, 9% with regional disease, and 4% with distant metastatic disease. In general, the prognosis is excellent for patients who present with localized disease and primary tumors 1.0 mm or less in thickness, with 5 year survival achieved in more than 90% of patients. For patients with localized melanomas more than 1.0 mm in thickness, survival rates range from 50% to 90% depending on tumor thickness, ulceration, and mitotic rate. The likelihood of regional nodal involvement increases with increasing tumor thickness, as well as the presence of ulceration and mitotic rate. When regional nodes are involved, survival rates are roughly halved. However, within stage III, 5 year survival rates range from 20% to 70%, depending primarily on the nodal tumor burden. Historically, long term survival in patients with distant metastatic melanoma, taken as a whole, has been less than 10%. However, even within stage IV, some patients have more indolent clinical course that is biologically quite distinct from most patients with advanced disease. Furthermore the impact of emerging effective systemic therapies on the survival of patients with stage IV melanoma, either at presentation or recurrence, has made long-term remission possible for a larger portion of patients (NCCN 2017).
Patients can be clinically staged after histopathologic micro-staging of the primary tumor, and a complete history and physical examination (H&P). Patients are staged according to the American Joint Committee on Cancer (AJCC) criteria. Patients with in-situ melanoma are stage 0. Patients with invasive (not in-situ) melanoma and clinically negative nodes are stage I-II. Patients with palpable regional nodes, as well as those with in-transit disease or microsatellites are clinical stage III. Patients with distant metastases are clinical stage IV, and should be further assigned to a sub-stage by recoding all sites of metastatic disease. The AJCC analyzed 39,918 patients to determine factors significantly predictive of survival for patients with cutaneous melanomas. This and other studies have shown that in addition to patient-specific factors of age, and gender, tumor-specific factors of Breslow tumor thickness, ulceration and mitotic rate were found to be the three most important characteristics independently predictive of outcome by multivariate analysis (NCCN 2017).
Standard treatment options for Stage I and II cutaneous melanoma is surgical excision with or without sentinel lymph node examination. Current risk factors to predict localized tumor aggression include Breslow’s tumor thickness, tumor ulceration and mitotic rate of the tumor cells. Regional lymph node involvement, the likelihood of which increases the increasing tumor thickness, significantly negatively impacts the rate of survival.
The purpose of using gene expression profiling (GEP) testing (DecisionDx-Melanoma) in patients with stage I and II cutaneous melanoma is to measure risk of metastases. In those patients with high risk stage I and II disease they can possibly undergo more aggressive surveillance treatment than they would have otherwise received.
The clinical validity of the DecisionDx-Melanoma test was evaluated in a prospective, multicenter study of class 1 cutaneous melanoma tumors which analyzed microarray expression data to identify a prognostic 28-gene signature to predict risk of metastasis (Gerami, 2015). Based on modeling analysis of cohorts of primary cutaneous melanoma tumor tissue and Kaplan-Meier analysis, the study reported the 5-year disease-free survival (DFS) rates in the development set were 100% and 38% for predicted classes 1 and 2 tumors, respectively (p<0.0001). DFS rates for the validation set were 97% and 31% for predicted classes 1 and 2 tumors, respectively (p<0.0001). The investigators suggested their preliminary analysis indicates the 28-gene signature is an independent predictor of metastasis risk in the studied cohort of cutaneous melanoma tumors.
Gerami and colleagues (2015) assessed the prognostic accuracy of gene expression profiling for molecular staging of cutaneous melanoma in a multicenter cohort study of 217 individuals undergoing sentinel lymph node biopsy (SLNB). The prognostic accuracy of each test was determined using Kaplan-Meier and Cox regression analysis of disease-free, distant metastasis-free, and overall survival. For individuals with a negative SLNB and a class-2 gene expression profile signature (that is, a high risk outcome), Kaplan-Meier 5-year disease-free, distant metastasis-free, and overall survival rates were 35%, 49%, and 59%, respectively; however, there was no statistical difference in disease-free survival, or overall survival rates for individuals with class-2 gene expression profile signature and a negative SLNB result and individuals with a class-2 gene expression profile score and a positive SLNB result. A limitation of the study is the lack of data obtained from a randomized sample of cases, which the authors conclude as resulting "in a higher rate of distant metastasis than commonly observed or reported in the SLNB-negative group." Additional study is need in a randomized sample of individuals to determine how gene expression profiling combined with SLNB would contribute to the accurate staging and treatment planning of individuals with cutaneous melanoma.
To date, there is insufficient evidence in the peer-reviewed medical literature evaluating the clinical utility of the DecisionDx-Melanoma test.
Berger et. al. (2016) published a retrospective study of 156 consecutive patients from six institutions who had cutaneous melanoma and were evaluated with DecisionDX-Melanoma test. This study used chart review to describe changes in management, and examined whether management changes were associated with DecisionDX-Melanoma results. The frequency of clinic visits, imaging tests, referrals, and blood work was measured before and after results of DecisionDX-Melanoma were available. For patients with class 1 results, there was reduced utilization in 40 of 42 patients; for patients with class 2 results, there was increased utilization for 74 of 79. The difference in management changes by test class was statistically significant (p<0.001). However, the follow-up data was not collected for this patient cohort, the study is limited for the assessment of the impact of gene expression profile based on management changes on healthcare resource utilization and patient outcome. Future studies would benefit from the collection of follow-up data to show the impact of clinical practice adjustments on patient outcomes.
Based on review of the peer reviewed medical literature, there is insufficient evidence to evaluate the clinical validity and clinical utility of gene expression profile (GEP) testing (DecisionDx-Melanoma). Additional studies are needed to further validate if gene expression profiling of cutaneous melanoma will accurately identify which individuals are likely to have aggressive disease and how the results of this testing would alter treatment plans and improve health outcomes in the surveillance and treatment of high-risk cutaneous melanoma. NCCN guidelines for Melanoma state gene expression profiling is not recommended outside of clinical study. The evidence is insufficient to determine the effects of this testing on net health outcomes and therefore is considered investigational.
DecisionDx-Melanoma® test (Castle Biosciences Inc., Friendswood, TX), is a gene expression profile test that is a signature 31 genes, 28 discriminating genes and 3 control genes. The test is used to measure risk of metastasis in patients with stage I or II cutaneous melanoma and classifies tumors into two groups of risk or metastasis. The test is purported to give an independent prediction of risk of tumor metastases, independent of currently used metrics of risk assessment such as Breslow’s thickness, ulceration status (present or absent), mitotic rate, American Joint Committee on Cancer (AJCC) stage, and sentinel lymph node biopsy status. It is suggested this information would add to a comprehensive baseline evaluation and determination of the initial surveillance and treatment of individual with high risk stage I or II disease than they would have otherwise received.
"While there is interest in newer prognostic molecular techniques such as gene expression profiling to help differentiate benign from malignant neoplasms, or to help distinguish melanomas at low versus high risk for metastasis, routine (baseline) genetic testing of primary cutaneous melanomas (before or following sentinel lymph node biopsy (SLNB)) is not recommended outside of clinical study."
“Mucosal and uveal melanomas differ significantly from cutaneous melanoma in presentation, genetic profile, staging, response to treatment, and patterns of progression. Ideally, mucosal and uveal melanoma should be treated as disease distinct from cutaneous melanoma, with care tailored to the individual. The NCCN guidelines for Melanoma do not include recommendations for the diagnostic work-up or treatment of early-stage mucosal or uveal melanoma.”
American Academy of Dermatology in 2011 issued a guideline regarding care for the management of primary cutaneous melanoma which states: Recommendations for staging workup and follow-up:
In 2014, the American Brachytherapy Society consensus guidelines for plaque brachytherapy of uveal melanoma and retinoblastoma state the following: “Select centers routinely biopsy uveal melanomas for pathologic, genetic, and molecular biologic analyses. However, patients must be counseled that studies of the ocular and metastatic risks of biopsy have been small, limited in follow-up, single center, and thus did not reach Level 2 Consensus (uniform panel consensus, based on clinical experience).”
Note: Currently there are no evidence based clinical practice guidelines which specifically recommend the use of gene expression assays, specifically the DecisionDx assays, to guide the clinical management of patients with malignant tumors.
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). Genetic tests evaluated in this evidence review are 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 these tests.
Gene expression profiling (GEP) testing including but not limited to DecisionDx-UM ® (Castle Biosciences Inc.) for uveal melanoma is considered investigational.
Uveal melanoma is associated with a high rate of metastatic disease, predominantly to the liver. Survival after the development of metastatic disease is poor. Certain clinical factors and tumor genetic alterations (gene expression profiling) are being used to determine risk of metastases in individual patients, although it has not been shown that adjuvant treatment for patients who are considered to be at high risk for metastases alters survival outcomes, nor has it been shown that screening for the detection of early metastases has any effect on patient outcomes. Although, gene expression profiling of uveal melanoma has been shown to be an independent predictor of risk of metastasis, it is uncertain how risk stratification based upon this type of testing would improve net health outcomes. There is lack of published data from well-designed, prospective studies of sufficient sample size and follow up that supports the clinical utility of gene expression profile testing for uveal melanoma. There appears to be no incremental benefit in its use over currently established prognostic clinical markers for predicting the risk of metastases, nor is there evidence that the use of this test will alter treatment decisions that will lead to improved outcomes. The evidence is insufficient to determine the effects of this testing on net health outcomes.
Gene expression profiling (GEP) including but not limited to DecisionDx Melanoma® (Castle Biosciences Inc.) for cutaneous melanoma is considered investigational.
Based on review of the peer reviewed medical literature, there is insufficient evidence to evaluate the clinical validity and clinical utility of gene expression profile (GEP) testing (DecisionDx-Melanoma). Additional studies are needed to further validate if gene expression profiling of cutaneous melanoma will accurately identify which individuals are likely to have aggressive disease and how the results of this testing would alter treatment plans and improve net health outcomes in the surveillance and treatment of high-risk cutaneous melanoma. National Comprehensive Cancer Network (NCCN) guidelines for melanoma state gene expression profiling is not recommended outside of clinical study. The evidence is insufficient to determine the effects of this technology on net health outcomes and therefore is considered investigational.
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