| Coverage Policy Manual | |
| Policy #: | 2012012 |
| Category: | Laboratory |
| Initiated: | March 2012 |
| Last Review: | March 2024 |
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| Genetic Test: Uveal Melanoma, Gene Expression Profile To Predict Risk Of Metastasis | |
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| 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 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).
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.
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 (Pereira, 2013). The prospective, longitudinal Collaborative Ocular Melanoma Study (2005) followed 2320 patients with choroidal melanoma with no melanoma metastasis at baseline who were enrolled in RCTs to evaluate forms of radiotherapy for choroidal melanoma for 5 to 10 years (Francis, 2013). During follow-up, 739 patients were diagnosed with at least 1 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.
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 (Diener-West, 2005; Correa, 2016). 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 using the American Joint Committee on Cancer recommendations allows risk stratification for metastatic disease. In a retrospective study of 3377 patients with uveal melanoma (2015), 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 IIIB (Finger, 2009).
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). The BAP1 gene has been identified as an important marker of disease type. In 1 study, 89% of tumors with monosomy 3 had a BAP1 variant, and no tumors without monosomy 3 had a BAP1mvariant (Prescher, 1996).
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
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 (RCTs) have shown that patients receiving radiotherapy or enucleation progress to metastatic disease at similar rates after treatment (Spagnolo, 2012; Hawkins, 2011). Radiotherapy can be delivered by various 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 (Hawkins, 2011).
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.
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
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. The DecisionDx-UM® test (Castle Biosciences, Phoenix, AZ) is available under the auspices of the CLIA. Laboratories that offer laboratory-developed tests 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.
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
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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.
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| 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?
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?
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:
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
3.5.2 Prognostic biopsy
3.6 Surveillance
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
2020 Update
A literature search was conducted through March 2020. There was no new information identified that would prompt a change in the coverage statement.
2021 Update
Annual policy review completed with a literature search using the MEDLINE database through March 2021. No new literature was identified that would prompt a change in the coverage statement. The key identified literature is summarized below.
Similar outcomes were reported by Demirci et al in a retrospective review of 293 patients with choroidal melanoma (Demirci, 2018). Class 2 tumors with largest basal diameter ≥ 12 mm and class 2 and 1B tumors with American Joint Committee on Cancer (AJCC) stage III showed significantly worse prognosis. At a median follow-up of 26 months, the probability of metastasis-free survival was lowest in patients with class 2 tumors (HR 0.60; 95% CI, 0.44 to 0.72) compared to patients with class 1A (HR 0.99; 95% CI, 0.94 to 0.99) or class 1B (HR 0.90; 95% CI, 0.77 to 0.96) tumors.
Davanzo et al. conducted a retrospective review of 107 consecutive uveal melanoma patients, including 39, 31, and 37 patients with unknown, low-, and high-risk GEP results (Davanzo, 2019). Low-risk patients were followed with hepatic ultrasonography every 6 months, whereas high-risk patients were managed with more frequent hepatic imaging. High-risk patients (8/37) were significantly more likely to develop metastasis (P < 0.001) compared to patients in the low/unknown risk group (0/70).
Aaberg et al. published updated 5-year outcomes for 89 patients (Aaberg, 2020). Of these 89 patients, 49 (55%) were class 1, of which 39 (80%) received low-intensity management. The 5-year metastasis-free survival was 90% for class 1 patients compared to 40.7% for class 2 patients (P < 0.0001). The 5-year melanoma-specific survival was 94.3% for class 1 patients compared to 63.4% for class 2 patients (P = 0.0007). 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.
2022 Update
Annual policy review completed with a literature search using the MEDLINE database through March 2022. No new literature was identified that would prompt a change in the coverage statement. The key identified literature is summarized below.
Schefler et al. reported on risk-appropriate changes in management following testing with DecisionDx-UM in a prospective, multicenter cohort (N=93) enrolled in the Clinical Application of DecisionDx-UM Gene Expression Assay Results (CLEAR II) registry study (Schefler, 2020). Following testing, 44 (98%) of class 2 patients received a referral to another provider, of which 42 (93%) received referrals to medical oncology. For class 1 patients, 55 (59%) received a referral to another provider, of which 47 (51%) were referred to medical oncology. Medical oncology referral was more common for high-risk class 2 patients compared to class 1 (p<.001). Class 2 patients were 3.3 times more likely to receive high-frequency chest imaging (p<.001) and 4.3 times more likely to received high-frequency abdominal imaging (p<.001). Health outcomes resulting from changes in management were not reported.
2023 Update
Annual policy review completed with a literature search using the MEDLINE database through March 2023. No new literature was identified that would prompt a change in the coverage statement. The key identified literature is summarized below.
The National Comprehensive Cancer Network guidelines for uveal melanoma (v2.2022) address the prognosis and management of uveal melanoma, stating that biopsy of the primary tumor for molecular/chromosomal testing for prognostication is preferred over cytology alone and that the risk/benefits of biopsy for prognostic analysis for risk stratification should be carefully considered and discussed with the patient. Risk stratification to determine the frequency of follow-up should be based on the highest risk factor present (NCCN, 2022).
The National Comprehensive Cancer Network guidelines (v2.2022) for uveal melanoma state that if biopsy is performed, "molecular/chromosomal testing for prognostication is preferred over cytology alone." The guidelines include DecisionDx-UM classes as 1 of the factors used to risk-stratify patients for systemic imaging and note that risk stratification to determine the frequency of follow-up should be based on the highest risk factor present (NCCN, 2022).
Demirci et al completed a retrospective review of 293 patients with choroidal melanoma (Demirci, 2018). Class 2 tumors with largest basal diameter ≥ 12 mm and class 2 and 1B tumors with American Joint Committee on Cancer (AJCC) stage III showed significantly worse prognosis. At a median follow-up of 26 months, the probability of metastasis-free survival was lowest in patients with class 2 tumors (Hazard Ratio [HR] 0.60; 95% CI, 0.44 to 0.72) compared to patients with class 1A (HR 0.99; 95% CI, 0.94 to 0.99) or class 1B (HR 0.90; 95% CI, 0.77 to 0.96) tumors. The authors subsequently analyzed a scoring system combining AJCC stage and GEP in the same dataset (including 3 additional patients since the 2018 publication), with results indicating better estimate of prognosis with the combined score than with use of AJCC stage or GEP alone (Stacey, 2022).
Roelofs et al performed a retrospective analysis of 343 patients with uveal melanoma who underwent GEP classification, including 255 patients with class 1 and 88 patients with class 2 results (Roelofs, 2022). Patients were classified as being at low (GEP class 1 and tumor thickness <8 mm) or high risk of metastasis (GEP class 2 or tumor thickness ≥8mm); low-risk patients underwent annual surveillance abdominal ultrasound, while high-risk patients underwent alternating surveillance liver ultrasound and abdominal magnetic resonance imaging every 6 months according to institutional protocol. The mean follow-up was 40 ± 26 months. In univariate Cox proportional hazard regression, enucleation, ciliary body involvement, extraocular extension, tumor thickness, largest basal tumor diameter (as a continuous and categorical [>12mm] variable), and GEP class 2 were associated with future metastasis. Multivariate Cox proportional hazards regression indicated GEP class 2 and longest basal diameter >12mm remained independently predictive of metastasis-free survival, and stratified analysis further indicated longest basal diameter >12mm remained predictive of metastasis-free survival in both GEP class 1 and 2 tumors.
Singh et al performed a retrospective analysis of metastasis-free survival in patients with uveal melanoma, with a focused analysis comparing predicted (according to DecisionDx-UM metastasis-free survival prediction for GEP class 2 [ie, 50% at 3 years, 28% at 5 years]), observed (via analysis of a cohort of consecutive patients with uveal melanoma treated at the authors' 2 institutions), and published (via a meta-analysis of patients with uveal melanoma from 7 retrospective or prospective studies utilizing GEP published between 2012 and 2021) metastasis-free survival in GEP class 2 subgroups (Singh, 2022). The overall retrospective cohort consisted of 343 patients, of whom 121 were GEP class 2, while the meta-analysis pooled data from 667 GEP class 2 patients. In the analysis of GEP class 2 patients, both observed and meta-analysis-derived published metastasis-free survival at 3 and 5 years were longer than the corresponding DecisionDx-UM-predicted survival, with point estimate differences ranging from 12% to 19%. The predicted metastasis-free survival estimate was below the lower limit of the 95% confidence interval for both observed and published survival estimates at both time points.
Khan et al conducted a multicenter, single-arm study of crizotinib as adjuvant therapy in adults with localized high-risk uveal melanoma (defined as GEP class 2 and longest basal tumor diameter >12mm) (Khan, 2022). This was the first published clinical trial of crizotinib in uveal melanoma. Patients received crizotinib 250 mg by mouth twice daily for a total of 48 weeks, beginning within 90 days of primary enucleation or radiotherapy. The primary outcome was 32-month relapse-free survival (RFS) rate; planned enrollment was 30 patients to provide 90% power to detect a 75% RFS rate at 32 months relative to a 50% RFS rate based on historical data. The analysis included a comparison of the primary outcome in the study cohort to a 2:1 propensity score-matched historical control. Among the 34 patients enrolled, the median age was 60 years, and all patients had an Eastern Cooperative Oncology Group performance status of 0 or 1. The mean relative dose intensity per cycle was 84%; 4 patients did not complete 48 weeks of treatment with crizotinib due to toxicity despite dose reduction. In 32 evaluable patients, at a median follow-up of 47.1 months, the estimated 32-month RFS rate was 50% (95% CI 23% to 67%). There was no difference in the primary outcome between the study cohort and the propensity score-matched historical control cohort, in whom the estimated 32-month RFS rate was 57% (95% CI 40% to 73%). All patients experienced at least 1 treatment-related adverse event, the most common of which were nausea, transaminase elevation, diarrhea, fatigue, and sinus bradycardia.
In 2015, Melanoma Focus, a British medical nonprofit that focuses on melanoma research, published guidelines on uveal melanoma (Nathan, 2015). These guidelines, which were created using a process accredited by NICE, contained the following statements on prognosis and surveillance. A 2022 guideline update included several additional relevant statements, which are denoted below (2022) (Melanoma Focus, 2022). A separate update to the guidance for surveillance is underway at the time of this review.
"2.5 Genetic and molecular features (2022)
Prognostic factors/tool
28. Prognostic factors of uveal melanoma are multi-factorial and include clinical, morphological and genetic features. The following features should be recorded:
The following features should be recorded if tissue is available:
29. The following features should be recorded if cytology of tumour is available:
Prognostic biopsy
30. There should be a fully informed discussion with all patients, explaining the role of biopsy including the benefits and risks. The discussion should include:
31. The minimum dataset for uveal melanoma from the Royal College of Pathology (or national official equivalents) should be recorded in the pathology reports. [...]
32. Use the most up-to-date edition of the Tumor Node Metastasis staging system for prognostication and include in pathology/clinical reports. (2022)
33. Collect molecular genetic and/or cytogenetic data for research and prognostication purposes, where tumour material is available and where patient consent has been obtained, as part of an ethically-approved research programme. (2022)
34. The use of multifactorial prognostication models incorporating clinical, histological, immunohistochemical and genetic tumour features should be considered. (2022)
35. Where available the results of state-of-the-art molecular analysis should be combined with clinical features and standard anatomical and pathological staging for prognostication. (2022)
36. Tests for novel circulating blood-borne biomarkers should only be used within clinical trials or research programmes. (2022)
[...]
2.7 Surveillance
40. Prognostication and surveillance should be led by a specialist multidisciplinary team that incorporates expertise from ophthalmology, radiology, oncology, cancer nursing and hepatic services.
41. Prognostication and risk prediction should be based on the best available evidence, taking into account clinical, morphological and genetic cancer features.
42. 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.
43. 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.
44. Liver function tests alone are an inadequate tool for surveillance. "
2024 Update
Annual policy review completed with a literature search using the MEDLINE database through February 2024. No new literature was identified that would prompt a change in the coverage statement.
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