Coverage Policy Manual
Policy #: 2012012
Category: Laboratory
Initiated: March 2012
Last Review: April 2019
  Genetic Test: Uveal Melanoma, Gene Expression Profile To Predict Risk Of Metastasis

Description:
Uveal melanoma
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 (Spagnolo, 2012).
 
Uveal melanoma has a progressively rising, age-specific, incidence rate that peaks near the age of 70 years. Host susceptibility factors associated with the development of this cancer include white race, fair skin and light eye color.
 
The uveal tract is the middle layer of the wall of the eye, and 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 (Spagnolo, 2012). Iris melanomas have the best prognosis; melanomas of the ciliary body have the worst prognosis.
 
Clinical diagnosis/prognosis
Modern diagnostic tools, including indirect fundoscopic examination, optical coherence tomography, computed tomography (CT), and magnetic resonance imaging (MRI) of the globe and 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 (Pereira, 2013).
 
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 in thickness, ciliary body involvement and transcleral extension.
 
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 3 correlated strongly with metastatic death, with a 5-year survival reduction from 100% to 50% (Prescher, 1996). Subsequent studies reported the initial idea that, based on genetic analysis, there were 2 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 (Spagnolo, 2012).
 
Genetic 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.
 
Treatment
Local treatment of uveal melanoma is well-established and is termed “conservative” if conservation of the eye is attempted. Conservative treatments include brachytherapy and external (proton beam) irradiation (Spagnolo, 2012). “Radical” therapy consists of enucleation. Both strategies offer the same prognosis, both in terms of survival rates and risk of metastasis, as shown by the randomized trials from the Collabortive Ocular Melanoma Study (COMS) (Hawkins, 2011).
 
However, despite the established treatment protocols for primary uveal melanoma, no decrease in the mortality rate of this tumor has been observed. The 5-year survival rate has not changed over the last 3 decades (81.6%), suggesting that life expectancy is independent of successful local eye treatment (Pereira, 2013). Therefore, it has been suggested that the identification of patients at high risk of 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, liver ultrasound, CT scan, or MRI, have not shown evidence of any effect on patient outcomes (Augsburger, 2009).
 
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 loco-regional treatment of hepatic metastases include surgical and ablative techniques, embolization and local chemotherapy.
 
Commercially available testing for:
The DecisionDx-UM® test (Castle Biosciences Inc, Phoenix, AZ) is a GEP test intended to assess 5-year metastatic risk in uveal melanoma. The test was introduced in late 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.
 
Regulatory Status
No U.S. Food and Drug Administration -cleared genotyping tests were found. Thus, genotyping is offered as a laboratory-developed test. Clinical laboratories may develop and validate tests in-house and market them as a laboratory service; such tests must meet the general regulatory standards of the Clinical Laboratory Improvement Act.
 
Coding
Effective January 01, 2019, there is a specific CPT PLA code for the Decision Dx- UM test:
 
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

Policy/
Coverage:
EFFECTIVE APRIL 2019
 
Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria
 
Gene expression profiling for uveal melanoma with DecisionDx-UM for patients with primary, localized uveal melanoma meets member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness.
 
Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria
 
Gene expression profiling for uveal melanoma not meeting the criteria listed above does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness.
 
For members with contracts without primary coverage criteria, gene expression profiling for uveal melanoma not meeting the criteria listed above is considered investigational. Investigational services are specific contract exclusions in most member benefit certificates of coverage.
 
EFFECTIVE PRIOR TO APRIL 2019
 
Gene expression profile testing of uveal melanoma with the DecisionDX test or any other gene expression profile methodology does not meet member certificate of benefit Primary Coverage Criteria for effectiveness because the test is presently under study to determine effectiveness, and at present the test has not been shown to improve health outcomes, and is not a covered benefit.
  
Gene expression profile testing of cutaneous melanoma does not meet member certificate of benefit Primary Coverage Criteria for effectiveness and is not a covered benefit.
  
For members with certificate of benefits which do not include Primary Coverage Criteria, gene expression profile measurement for uveal melanoma or cutaneous melanoma would be considered investigational, and would not be a covered benefit.
 

Rationale:
The published data on the use of a gene expression profiling (GEP) assay for risk stratifying uveal melanoma consist mainly of a 2010 study of the technical performance of a 15-gene assay and a 2012 study of a prospective validation of the assay.
 
In 2012, Onken et al conducted a prospective, multicenter study to evaluate the prognostic performance of a 15-GEP assay that assigned posterior (choroidal or ciliary body) uveal melanomas to 1 of 2 prognostic subgroups (Onken, 2012). Prognostic groups were class 1 (low risk of metastasis) or class 2 (high risk of metastasis). The first 260 cases were also assessed for status of chromosome 3. The clinical diagnosis of uveal melanoma was determined by the presence of clinical features typical of uveal melanoma. 459 cases were enrolled from 12 centers, between June 2006 and November 2010. Patients were treated for their primary tumors, and monitored for liver metastasis with a liver function panel every 6 months and liver imaging once a year if the liver panel was abnormal or there were clinical symptoms suspicious for metastasis. Mean patient age was 61.7 years (median, 61.0 years). Mean tumor diameter was 12.8 mm (median, 12.7 mm), and mean tumor thickness 6.3 mm (median, 5.5 mm). Involvement of the ciliary body
was absent in 308 cases, present in 139 cases, and unknown in 12. Tumor samples were obtained by fine needle aspiration in 359 cases, postenucleation fine needle aspiration in 92, and local tumor resection in 8 cases. The GEP assay rendered a classification in 97.2% of cases. The GEP was class 1 in 276 cases (61.9%) and class 2 in 170 cases (38.1%). Mean follow-up was 18.0 months (median 17.4 months). Metastasis was detected in 3 of class 2 cases.  By univariate Cox proportional hazard analysis, factors that were associated with metastatic disease included advanced patient age, ciliary body involvement, tumor diameter, tumor thickness, chromosome 3 status, and GEP class. The study did not report if the classification status determined by the GEP assay was used in clinical management of the study participants.
 
In 2010, Onken et al validated the GEP assay from a microarray platform to a polymerase chain reaction (PCR)-based 15-gene assay comprised of 12 discriminating genes and 3 endogenous control genes from previously published data sets (Onken, 2010; Onken, 2004). Technical performance of the assay was analyzed in a prospective study of 609 previously untreated rumors. Tumor samples were obtained by fine needle aspiration (n=553) or after enucleation (n=56). Samples were used for cytologic examination and RNA analysis. The genes were tested on the authors' training set of 28 uveal melanomas (15 considered to be of prognostic class 1 and 13 in class 2), with clinical follow-up of at least 5 years. The gene assay was demonstrated to be of sufficient sensitivity and failed on 1 of 51 samples with a cytologic diagnosis of quantity not sufficient, and preliminary outcome data affirmed the prognostic accuracy of the assay. The authors stated that preliminary outcome data were available on samples collected from 172 patients with a median follow up of 16 months, and the assay identified which patients would develop metastatic disease.
 
Conclusions
Preliminary studies suggest that the gene expression classifier may be able to accurately predict which patients with uveal melanoma are at greatest risk for developing metastasis. However, 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 use of the test will change clinical management or alter treatment decisions that will lead to improved clinical outcomes.
 
Summary
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 are 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.
 
Gene expression profiling has been proposed as another method to risk stratify patients, and preliminary studies have suggested that it may accurately identify patients at high risk for developing metastases. However, the clinical utility of the test has not been established.
 
2016 Update
A literature search was conducted using the MEDLINE database through December 2015. There was no new literature identified that would prompt a change in the coverage statement.
 
2017 Update
A literature search conducted through December 2016 did not reveal any new information that would prompt a change in the coverage statement. The key identified literature is summarized below.
 
Uveal Melanoma
Modern diagnostic tools, including indirect fundoscopic examination, optical coherence tomography, computed tomography (CT), and magnetic resonance imaging (MRI) of the globe and orbital tissues, have led to significant advances in the ability to diagnose primary uveal melanoma. The diagnosis of uveal melanoma can sometimes be made clinically without biopsy, however the diagnosis is not always certain from noninvasive testing and a tissue biopsy may be required for diagnosis (Pereir, 2013; Correa, 2016).
 
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 radiotherapy and enucleation have equivalent rates of metastatic disease (Finger, 2014; Hawkins, 2011). Radiotherapy can be delivered by a variety of mechanisms, most commonly brachytherapy and proton beam therapy (Spagnolo, 2012; Finger, 2014). 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 (Perria, 2013).
 
Analytic Validity
Augsburger and colleagues reported on the reliability of repeat GEP testing from the same tumor sample (Augsburger, 2015). This prospective, single-center study enrolled 80 patients who had uveal melanoma resection. Tumor samples were taken from 2 different sites and GEP testing was performed independently on both samples. The primary measure reported was the rate of discordance between the 2 samples on GEP class. Nine (11.3%) cases (95% confidence interval [CI], 9.0% to 13.6%) were definitely discordant, and 13 (16.3%) cases were definitely or possibly discordant (95% CI, 13.0% to 19.6%).
 
Section Summary: Analytic Validity
There is very little published data on the analytic validity of GEP testing. One study reported validation data of tumor samples compared to a training set of 28 samples. A second study examined the discordance of GEP class when 2 samples of the same tumor were tested, and reported discordance in 11.3% to 16.3% of cases.
 
Clinical Validity
Three studies reported data on the association of GEP score with clinical outcomes; they are summarized below. All studies showed strong and positive associations between GEP class and clinical outcomes.
 
The first study was published in 2012 by Onken and colleageus This prospective, multicenter study evaluated the prognostic performance of a 15-gene GEP assay (Walter, 2016). Prognostic groups were class 1 (low risk of metastasis) or class 2 (high risk of metastasis). 459 cases were enrolled from 12 centers between June 2006 and November 2010. The GEP assay rendered a classification in 97.2% of cases. GEP testing results were class 1 in 276 (61.9%) cases and class 2 in 170 (38.1%) cases. Mean follow-up was 18.0 months (median, 17.4 months). Metastasis was detected in 3 (1.1%) of class 1 cases and 44 (25.9%) of class 2 cases (p<10-14). By univariate Cox proportional hazard analysis, factors associated with metastatic disease included advanced patient age (p=0.02), ciliary body involvement (p=0.03), tumor diameter (p<0.001), tumor thickness (p=0.006), chromosome 3 status (p<0.001), and GEP class (p<107). The study did not report if the classification status determined by the GEP assay was used in clinical management of study participants.
 
Two other studies reporting data on clinical validity were published in 2016 (Decatur, 2016; Aaberg, 2014).  Walter and colleagues evaluated 339 patients from 2 clinical centers who underwent resection for uveal melanoma (Decatur, 2016).  This study had similar methodology to Onken (2012) (Walter, 2016), and the patient populations of both studies partially overlapped. GEP results were class 1 in 190 (56%) patients and class 2 in 149 (44%) patients. Cox proportional hazards analysis was used to examine GEP class together with other clinic-pathologic factors (tumor diameter, tumor thickness, age, gender, ciliary body involvement, pathologic class). GEP class 2 was the strongest predictor of metastases and mortality. Tumor diameter was also an independent predictor of outcomes, using a diameter of 12 mm as the cutoff value. Decatur and colleagues was a smaller, retrospective study of 81 patients who had tumor samples available from resections occurring between 1998 and 2014 (Aaberg, 2014). GEP was class 1 in 35 (43%) patients, class 2 in 42 (52%) patients, and unknown in 4 (5%) patients. GEP class 2 was strongly associated with BAP1 mutations (r=0.70; p<0.001). On Cox proportional hazards analysis, GEP class 2 was the strongest predictor of metastases and melanoma mortality
 
Summarized Studies of Clinical Validity
Onken (2012); patient population 459 patients with UM from 12 clinical centers; rate of metastases GEP Class 1 of 1.1%, GEP Class 2 of 25.9% p<0.001; melanoma mortality GEP Class 1 not reported, GEP Class 2 not reported.
 
Walter (2016); patient population 339 patients from single center with UM arising in ciliary body or choroid; rate of metastases GEP Class 1 5.8, GEP Class 2 39.6%; melanoma mortality GEP Class 1, GEP Class 2 25.9%.
 
Decatur (2016) patient population 81 patients from a single center with available tumor samples of UM arising from ciliary body or choroid; rate of metastases GEP Class 1 --, GEP Class 2 9.4 (3.1 to 28.5) p<0.001 (reported as a relative risk [95% confidence interval] for metastases [or melanoma mortality] in group 2 vs group 1), melanoma mortality GEP Class 1 --, CEP Class 2 15.7 (3.6 to 69.1) p<0.001 (reported as a relative risk [95% confidence interval] for metastases [or melanoma mortality] in group 2 vs group 1)
 
Section Summary: Clinical Validity
There are a small number of published studies on clinical validity. These studies have reported that GEP class 2 is a strong predictor of metastases and melanoma survival, and also strongly correlates with PAB1 mutations. Two studies have compared GEP class to a limited set of clinic-pathologic features and have reported that GEP class is the strongest predictor of clinical outcomes. Further evidence on clinical validity is needed to define the relation more precisely. Further data are needed to corroborate the predictive ability of GEP class with a larger set of clinical, pathologic and genetic mutation information.
 
Clinical Utility
There is no direct published evidence on the clinical utility of GEP testing. An indirect chain of evidence can be used to demonstrate clinical utility if each link in the chain is intact. The following indirect chain of evidence is derived from review 2.04.91 (general approach to genetic testing).
  • Does the GEP test for uveal melanoma have an association with prognosis of disease?
  • Does GEP testing provide prognostic information that is at least as good as alternative methods?
  • Does the genetic testing information allow for classification of patients into clinically credible prognostic groups? Have these prognostic groups been defined clinically a priori?
  • Are different prognostic groups associated with different management interventions?
  • Has treatment according to prognostic group been demonstrated to improve outcomes?
 
Does the GEP test for uveal melanoma have an association with prognosis of disease?
 
Yes. There are a limited number of studies that associate GEP class with risk of metastases and/or melanoma death. In 3 studies identified for this review, GEP class was strongly associated with risk of metastatic disease and melanoma death (see Table 1).
 
Does GEP testing provide prognostic information that is at least as good as alternative methods?
 
Uncertain. Numerous factors provide prognostic information. The studies that examined GEP score in a multivariate analysis did not include the full range of demographic, clinical, tumor, and genomic factors that influence prognosis. There are no direct comparisons of different prognostic measures with the GEP score. As a result, it is not possible to determine whether the GEP score is at least as good as other prognostic methods. Further prospective studies are needed that evaluate the full range of prognostic factors in conjunction with GEP score.
 
Does the genetic testing information allow for classification of patients into clinically credible prognostic groups? Have these prognostic groups been defined clinically a priori?
 
Yes. The classification by GEP testing corresponds to the 2 different subtypes of uveal melanoma. These 2 subtypes of uveal melanoma are well described in the literature and differ substantially in risk of metastatic disease.
 
Are different prognostic groups associated with different management interventions?
 
Uncertain. There is limited evidence on this question, and there is a lack of standardized management guidelines. As a result, it is difficult to determine when management deviates from the standard of care and which factors influence management changes.
 
Aaberg and colleagues retrospectively analyzed Medicare claims data submitted to Castle BioSciences by 37 ocular oncologists in the United States.19 Data were abstracted from charts on demographics, tumor pathology and diagnosis, and clinical surveillance patterns. High-intensity surveillance was defined as a frequency of every 3 to 6 months and low-intensity surveillance was a frequency of every 6 to 12 months. Of 195 patients with GEP test results, 88 (45.1%) patients had evaluable tests and adequate information on follow-up surveillance, 36 (18.5%) had evaluable tests and adequate information on referrals, and 8 (4.1%) had evaluable tests and adequate information on adjunctive treatment recommendations. Of the 191 evaluable GEP tests, 110 (58%) were class 1 and 81 (42%) were class 2. For patients with surveillance data available (n=88), all patients in GEP class 1 had low-intensity surveillance, and all patients in GEP class 2 had high-intensity surveillance (p<0.001 vs class 1).
 
For the survey portion of the study, 72 physicians were surveyed and 35 (49%) responded. The survey consisted of 24 questions related to practice patterns for fine-needle aspiration and molecular diagnostic testing for uveal melanoma. Most respondents (82%) reported that they performed some type of molecular analysis that required tumor tissue. GEP testing was the most common test performed (89%), followed by cytogenetics (49%), and chromosome analysis (20%). Most survey respondents (74%) reported that they made management changes based on either cytogenetics or GEP testing. These management changes were either in the frequency of surveillance, referrals to oncologists, or consideration for adjuvant therapy. Twenty-one percent of respondents reported that they did not use these tests to make treatment decisions.
 
Has treatment according to prognostic group been demonstrated to improve outcomes?
 
No. No management interventions are associated with improved outcomes for patients with metastatic uveal melanoma. The potential change in surveillance associated with GEP testing is unlikely to improve outcomes in the absence of effective treatment for metastatic disease.
 
Section Summary: Clinical Utility
The clinical utility of GEP testing has not been demonstrated. There is a strong association between GEP score and metastatic disease and melanoma death. However, many factors influence prognosis in uveal melanoma, and it is not possible to determine the optimal method. The available studies do not examine GEP score in relation to the full complement of demographic, clinical, tumor, and genomic markers associated with prognosis. One retrospective study of a selected sample of ocular oncologists reported that GEP class was associated with intensity of surveillance; however, this single study is insufficient to establish that management changes are made as a result of GEP score. While clinicians may change surveillance intensity based on GEP score, it is unlikely that changes in surveillance lead to improvements in health outcomes.
 
 
Summary of Evidence
For individuals who have uveal melanoma who receive a GEP test for uveal melanoma, 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. There is limited published data on the analytic validity of GEP testing. One study reported a 11% to 16% rate of discordance when 2 different samples from the same tumor were tested. Three studies of clinical validity were identified that used the GEP score to predict metastases and melanoma survival. All 3 studies 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. However, these studies included only a limited range of prognostic markers, and there are no studies that compare
GEP class to a full range of demographic, clinical, tumor, and genomic markers. There is limited evidence on whether GEP testing leads to changes in management. One retrospective study of a selected population of ocular oncologists reported that surveillance intensity was associated with GEP class. All patients in GEP class 1 received low-intensity surveillance and all patients in GEP class 2 received high intensity surveillance. It is uncertain whether intensity of surveillance improves outcomes, and there is no evidence that treatment changes are made based on GEP testing. The evidence is insufficient to determine the effects of the technology on health outcomes.
 
2019 Update
Annual policy review completed with a literature search using the MEDLINE database through January 2019. No new literature was identified that would prompt a change in the coverage statement.
 
2019 Update
Annual policy review completed with a literature search using the MEDLINE database through March 2019. No new literature was identified that would prompt a change in the coverage statement. The key identified literature is summarized below.
 
 Uveal Melanoma
 
Clinical Context and Test Purpose
The purpose of using the DecisionDx-UM test in individuals with localized uveal melanoma is to inform a decision about how often patients should undergo follow-up for metastases, based on their likelihood of developing metastases.
The optimal method and interval for surveillance are not well-defined, and it has not been established in prospective trials whether surveillance identifies metastatic disease earlier. Potential methods for metastases include magnetic resonance imaging, ultrasound, liver function testing, and positron emission tomography scans. One retrospective study (2016) of 262 patients estimated that use of hepatic ultrasound and liver function testing every 6 months in individuals with treated local uveal melanoma would yield a sensitivity and specificity for a diagnosis of metastasis of 83% (95% confidence interval [CI], 44% to 97%) and 100% (95% CI, 99% to 100%), respectively (Choudhary, 2016).
 
Identifying patients at high-risk for metastatic disease might assist in selecting patients for adjuvant treatment and more intensive surveillance for metastatic disease, if such changes lead to improved outcomes. Adjuvant treatment for metastatic disease consists of radiotherapy or systemic therapy, such as chemotherapy, immunotherapy, hormone therapy, biologic therapy, or targeted therapy. Randomized trials of patients with high-risk for uveal melanoma recurrence have shown no differences in survival rates between patients treated with and without adjuvant therapy. However, these trials were reported in 1990 and 1998, and may not represent current treatment and risk stratification methods (McLean, 1990; Desjardins, 1998).
 
Identifying patients at low-risk for metastatic disease might assist in selecting patients who could safely reduce frequency or intensity of surveillance, which could lead to improved outcomes through reduced burden.
 
Uveal melanomas may present with visual symptoms or be detected incidentally. The diagnosis is based on funduscopic examination and other noninvasive tests, such as ultrasound and fluorescein angiography. A biopsy may be useful to collect additional information about the molecular characteristics of the tumor. Treatment of primary, localized uveal melanoma can be by surgery or radiotherapy. While treatment is effective at preventing local recurrence, patients are at risk for distant metastases for many years. Approximately 50% of patients will develop distant metastasis, which is the leading cause of death in patients with uveal melanoma.
 
DecisionDx-UM is a gene expression profile (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 risk of metastasis into 3 classes. The 15-gene signature was originally developed based on a hybridization-based microarray platform; the current commercially available version of the DecisionDx-UM test is a polymerase chain reaction-based test that can be performed on fine-needle aspirate samples.
 
Based on the clinical outcomes from the prospective, 5-year multicenter Collaborative Ocular Oncology Group study, the DecisionDx-UM test reports class 1A, class 1B, and class 2 phenotypes:
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.
 
National Comprehensive Cancer Network guidelines for melanoma do not address the prognosis and management of uveal melanoma (NCCN, 2019). Melanoma Focus (2015), a British medical nonprofit that focuses on melanoma research, published guidelines on uveal melanoma that state that prognostication and risk prediction should be based clinical, morphologic, and genetic cancer features (Nathan, 2015).
 
Observational studies have reported data on the association between GEP score and clinical outcomes.  All studies showed strong and positive associations between GEP classification and clinical outcomes.
 
Onken et al published the first study. (Onken, 2012). This prospective, multicenter study evaluated the prognostic performance of a 15-gene GEP assay in patients with posterior (choroidal and ciliary body) uveal melanoma. Prognostic groups were class 1 (low-risk of metastasis) or class 2 (high-risk of metastasis). A total of 459 cases were enrolled from 12 centers between June 2006 and November 2010. The GEP assay rendered a classification in 97.2% of cases. GEP test results were class 1 in 276 (61.9%) cases and class 2 in 170 (38.1%) cases. Mean follow-up was 18.0 months (median, 17.4 months). Metastasis was detected in 3 (1.1%) of class 1 cases and 44 (25.9%) of class 2 cases (p <0.001). By univariate Cox proportional hazard analysis, factors associated with metastatic disease included advanced patient age (p=0.02), ciliary body involvement (p=0.03), tumor diameter (p<0.001), tumor thickness (p=0.006), chromosome 3 status (p<0.001), and GEP class (p<0.001). The GEP test was associated with a significant net reclassification index over TNM classification for survival at 2 years (NRI=0.37, p=0.008) and 3 years (NRI=0.43, p=0.001).
 
Two other studies reporting data on clinical validity were published in 2016 (Walter, 2016; Decatur, 2016). Walter et al evaluated 2 cohorts of patients at 2 clinical centers who underwent resection for uveal melanoma (Walter, 2016). This study had a similar methodology to Onken. The primary cohort included 339 patients, of which 132 patients were also included in the Onken study, along with a validation cohort of 241 patients, of which 132 were also included in the Onken study, the latter group of which was used to test a prediction model using the GEP plus pretreatment largest basal diameter. Cox proportional hazards analysis, was used in the primary cohort to examine GEP classification and other clinicopathologic factors (tumor diameter, tumor thickness, age, sex, ciliary body involvement, pathologic class). GEP class 2 was the strongest predictor of metastases and mortality. Tumor diameter was also an independent predictor of outcomes, using a diameter of 12 mm as the cutoff value. In the validation cohort, GEP results were class 1 (61.4%) in 148 patients and class 2 (38.6%) in 93 patients. Again, GEP results were most strongly associated with progression-free survival.
 
Decatur et al was a smaller, retrospective study of 81 patients who had tumor samples available from resections occurring between 1998 and 2014 (Decatur, 2016). GEP was class 1 in 35 (43%) patients, class 2 in 42 (52%) patients, and unknown in 4 (5%) patients. GEP class 2 was strongly associated with BAP1 variants (r=0.70; p<0.001). On Cox proportional hazards analysis, GEP class 2 was the strongest predictor of metastases and melanoma mortality.
The GEP test is associated with risk of metastatic disease and melanoma death. Although the three available studies reporting on clinical validity do not all specifically report on rates of survival or metastasis risk by risk group, there is clearly an association between risk category and metastasis and death. For a rare cancer, the studies on clinical validity include a large proportion of annual incident cases.
 
Plasseraud et al reported on metastasis surveillance practices and patient outcomes using data from a prospective observational registry study of DecisionDx-UM conducted at 4 centers, which included 70 patients at the time of reporting (Plasseraud, 2016). Surveillance regimens were documented by participating physicians as part of registry data entry. “High-intensity” surveillance was considered to be imaging and/or liver function testing every 3 to 6 months and “low-intensity” surveillance was considered to be annual imaging and/or liver function testing. The method for following patients for clinical outcomes was not specified. Of the 70 enrolled patients, 37 (53%) were class 1. Over a median follow-up of 2.38 years, more class 2 patients (36%) than class 1 patients (5%; p=0.002) experienced a metastasis. The 3-year metastasis-free survival rate was lower for class 2 patients (63%; 95% CI, 43% to 83%) than class 1 patients (100%; CI not specified; p=0.003). Most class 1 patients (n=30) had low-intensity surveillance and all (n=33) class 2 patients had high-intensity surveillance. Strengths of this study included a relatively large population given the rarity of the condition, and an association between management strategies and clinical outcomes. However, it is not clear which outcome measures were prespecified or how data were collected, making the risk of bias high.
 
Aaberg et al reported on changes in management associated with GEP risk classification. They analyzed Medicare claims data submitted to Castle Biosciences by 37 ocular oncologists in the United States (Aaberg, 2014). Data were abstracted from charts on demographics, tumor pathology and diagnosis, and clinical surveillance patterns. High-intensity surveillance was defined as a frequency of every 3 to 6 months, and low-intensity surveillance was a frequency of every 6 to 12 months. Of 195 patients with GEP test results, 88 (45.1%) patients had evaluable tests and adequate information on follow-up surveillance, 36 (18.5%) had evaluable tests and adequate information on referrals, and 8 (4.1%) had evaluable tests and adequate information on adjunctive treatment recommendations. Of the 191 evaluable GEP tests, 110 (58%) were class 1, and 81 (42%) were class 2. For patients with surveillance data available (n=88), all patients in GEP class 1 had low-intensity surveillance and all patients in GEP class 2 had high-intensity surveillance (p<0.001 vs class 1).
 
It is likely that treating liver metastasis affects local symptoms and survival, for at least a subset of patients. However, it is uncertain whether the surveillance interval has an effect on the time to detection of metastases.
There is the potential for patients considered to be at high-risk for metastases to undergo adjuvant treatment, but to date, no adjuvant therapies for nonmetastasized uveal melanomas have been shown to reduce the risk of metastasis.
 
For individuals who have localized uveal melanoma who receive a 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 classification correlated strongly with metastatic disease and melanoma mortality. Two studies compared GEP classification with other prognostic markers, and GEP class had the strongest association among the markers tested. GEP classification appears to be a strong predictor of metastatic disease and melanoma death. There are no studies directly showing clinical utility. Absent direct evidence, a chain of evidence can be constructed 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 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 (Aaberg, 2014). It is uncertain whether stratification of patients into higher risk categories has the potential to improve outcomes by allowing patients to receive adjuvant therapies through detection of metastases earlier. However, classification into the low-risk group would support a 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
National Comprehensive Cancer Network (NCCN) guidelines for uveal melanoma (v.1.2018) 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 (NCCN 2018).https://www.evidencepositioningsystem.com/_w_c87188ea52a833e91c1430538fc0f2b577770960212ca462/
 
Melanoma Focus
Melanoma Focus, a British medical nonprofit that focuses on melanoma research, published guidelines on uveal melanoma in 2015 Nathan, 2015). These guidelines, which were created using a process accredited by the National Institute for Health and Care Excellence, contained the following statements on prognosis and surveillance.
 
3.5.1Prognostic 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]…
2.     Use of the current (i.e. 7th) Edition of the TN staging system for prognostication is highly recommended. Grade A
3.     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 program. 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 6-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 a recommended best practice based on the clinical experience of the guideline development group.
 
Ongoing and Unpublished Clinical Trials
Some currently unpublished trials that might influence this review are listed below
 
NCT 02376920 5year Registry Study to Track Clinical Application of DecisionDX-UM Assay Results and Associated Patient Outcomes (CLEAR). Planned Enrollment: 2800  Completion Date: Oct. 2020

CPT/HCPCS:
0081UOncology (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
81479Unlisted molecular pathology procedure
81599Unlisted multianalyte assay with algorithmic analysis

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