Medical Policy: 02.04.53
Original Effective Date: December 2015
Reviewed: October 2017
Revised: May 2018
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This Medical Policy document describes the status of medical technology at the time the document was developed. Since that time, new technology may have emerged or new medical literature may have been published. This Medical Policy will be reviewed regularly and be updated as scientific and medical literature becomes available.
Gene expression profiling determines the expression of multiple genes in a tumor and has been proposed as an additional method to stratify patients into prognostic risk groups. Gene expression profiling has been proposed in the clinical management of individuals with uveal melanoma. Gene expression profile testing is commercially available (DecisionDx-UM, Castle Biosciences Inc., Friendswood, TX).
Uveal melanoma, although rare, is the most common primary intraocular malignancy in adults and is associated with a high rate of metastatic disease, predominantly to the liver. Management is complex and requires experienced specialists with training in ophthalmologic oncology. Survival after the development of metastatic disease is poor. Certain clinical factors and tumor genetic alterations (gene expression profiling) are being used to determine risk of metastases in individual patients, although it has not been shown that adjuvant treatment for patients who are considered to be at high risk for metastases alters survival outcomes, nor has it been shown that screening for the detection of early metastases has any effect on patient outcomes.
The uveal tract is the middle layer of the wall of the eye, and has three main parts: the choroid (a tissue layer filled with blood vessels), ciliary body (muscle tissue that changes the shape of the pupil in the lens), and the iris (the colored part of the eye). Uveal melanoma arises from the melanocytes in the stroma of the uveal tract. Approximately 90% of uveal melanomas arise in the choroid, 7% in the ciliary body, and 3% in the iris. Iris melanomas have the best prognosis; melanomas of the ciliary body have the worst prognosis.
Modern diagnostic tools, including indirect funduscopic examination, optical coherence tomography, computed tomography (CT), and magnetic resonance imaging (MRI) of the globe and the orbital tissues, have led to significant advances in the ability to diagnose primary uveal melanoma. The clinical diagnosis of uveal melanoma has an accuracy of 99%, and therefore, biopsies and/or tumor resection with histopathologic examination are not essential for diagnosis.
Metastatic disease is the leading cause of death in patients with uveal melanoma, and approximately 50% of patients will develop distant metastasis. The most important clinical factors that predict metastatic disease are tumor size measured in diameter or thickness, ciliary body involvement, and transcleral extension. Clinical staging is guided by the American Joint Committee on Cancer (AJCC) recommendations which allows risk stratification for metastatic disease. Staging requires intraocular examination, serum tests (complete blood count and liver function tests), and diagnostic imaging (CT of chest and abdomen, whole body PET-CT or liver MRI and chest CT). In a retrospective study of 3377 patients with uveal melanoma, in which staging was performed using AJCC classifications, the rate of metastases-free survival at 5 years was 97% for stage I, 89% for stage IIA, 79% for stage IIB, 67% for stage IIIA, and 50% for stage IIIB.
Local treatment of uveal melanoma is well established and is termed “conservative” if conservation of the eye is attempted. Conservative treatments include brachytherapy and proton beam radiation therapy. Radical therapy consists of enucleation. Both strategies offer the same prognosis, both in terms of survival rates and risk of metastasis, as shown by randomized trials from the Collaborative Ocular Melanoma Study (COMS).
However, despite the established treatment protocols for primary uveal melanoma, no decrease in the mortality rate of this tumor has been observed. The five-year survival rate has not changed over the last three decades (81.6%), suggesting that the life expectancy is independent of successful local eye treatment. Therefore, it has been suggested that the identification of patients at high risk for metastatic disease may assist in selecting patients who might benefit from adjuvant treatment, or that regular screening for the presence of metastatic disease may lead to improved outcomes. Adjuvant treatment may consist of radiotherapy or systemic therapy, such as chemotherapy, immunotherapy, hormone therapy, biological therapy or target therapy. However, randomized trials of patients with high risk of uveal melanoma recurrence showed no difference in survival between patients treated with adjuvant therapy versus no adjuvant treatment. In addition, regular screening tests for the development of liver metastases, including measurement of liver function tests, CT scan or MRI, have not shown evidence of any effect on patient outcomes.
The clinical course of patients with hepatic metastases is highly dependent on disease progression in the liver, and treatment of hepatic metastases has shown to be associated with prolonged survival in some patients. Therapies directed at locoregional treatment of hepatic metastases include surgical and ablative techniques, embolization and local chemotherapy.
DecisionDx-UM® test (Castle Biosciences Inc., Friendswood, TX) is a proprietary, multigene expression profiling (GEP) test intended to assess 5 year metastatic risk in uveal melanoma. The test was introduced in 2009, and claims to identify the molecular signature of a tumor and its likelihood of metastasis within 5 years. The assay determines the expression of 15 genes, which stratify a patient’s individual risk of metastasis into 2 classes.
Based on the clinical outcomes from the prospective, 5 year multicenter Collaborative Ocular Oncology Group (COOG) study, the DecisionDx-UM test reports class 1A, class 1B, and class 2 phenotype:
According to Castle Biosciences Inc., the DecisionDx-UM test results are used for the following:
Three studies have reported data on the association between GEP score and clinical outcomes.
In 2012, Onken et. al., in a prospective multicenter study evaluated the prognostic performance of a 15 gene expression profiling (GEP) assay that assigns primary posterior uveal melanomas to prognostic subgroups: class 1 (low metastatic risk) and class 2 (high metastatic risk). 459 patients with posterior uveal melanoma were enrolled from 12 independent centers between June 2006 and November 2010. De-identified patient information was collected from each center, including patient age, gender, tumor thickness (measured by ultrasound), tumor diameter (defined as the largest basal tumor dimension measured by indirect ophthalmoscopy or ultrasound), ciliary body involvement (defined as any portion of the tumor extending anterior to the ora serrata), date tumor sample was obtained, cytopathologic cell type (predominatly spindle, mixed, eiptheloid, unspecified melanoma cell type, acellular/quantity not sufficient for diagnosis, or information not available), last known patient survival status (alive with no metastasis, alive with metastasis, dead of metastatic disease, or dead of other causes), presence or absence of metastatic disease, date metastatic disease was first detected and date of death or most recent follow-up. The 7th edition Tumor Node Metastasis (TNM) clinical classification for uveal melanoma was performed using basal tumor diameter, thickness, and ciliary body involvement as described elsewhere. 224 patients were female and 235 were male. Mean age was 61.7 years (median 61.0 years). Mean tumor diameter was 12.8 mm (median 12.7 mm), and mean tumor thickness was 6.3 mm (median 5.5 mm). Ciliary body involvement was absent in 308 cases, present in 139 cases and unknown in 12 cases. Tumor samples were obtained by FNAB (fine needle aspiration biopsy) in 359 cases, post-enucleation FNAB in 92 cases, and local tumor in 8 cases. The cytopathologic diagnosis was spindle cell melanoma in 143 cases, mixed cell melanoma in 95 cases, epitheloid cell melanoma in 87 cases, unspecified melanoma cell type in 41 cases, acellular/quantity not sufficient for diagnosis is 60 cases, and sample not obtained for cytopathology in 33 cases. The status of chromosome 3 was assessed by multi-SNP assay in the first 260 cases. 34 deaths occurred, 28 (82.4%) of which were due to metastatic disease. Another 19 patients developed metastases but were still alive at the time of last follow-up. The 15 gene classification was performed at the Washington University site. The GEP assay was successful in rendering a classification in 446/459 (97.2%) cases. Among the 13 samples that failed to yield a GEP result, 5 did not adhere to study protocol (improper buffer, handling or shipping). Of the 446 cases, 276 (61.9%) were class 1 and 170 (38.1%) were class 2. Median follow was 18 months. Metastasis was detected in 3 (1.1%) patients with class 1 tumors and 44 (25.9%) patients with class 2 tumors (p < 0.0001). By Kaplan-Meier analysis, GEP class 2 was more strongly associated with metastasis than any of the other prognostic factors that were analyzed, including chromosome 3 status. By univariate Cox proportional hazards analysis, factors associated with metastasis included advanced patient age (p=0.02), ciliary body involvement (p=0.03), tumor diameter (p=0.0003), tumor thickness (p=0.006), tumor cell type (p=0.04), chromosome 3 status (p=0.0002) and GEP class (p=10-7). By multivariate Code modeling, GEP class (p=0.006) was the only variable that contributed independent prognostic information. A significant association was observed between TNM classification and metastasis (p=0.003). Chromosome 3 status did not contribute additional prognostic information that was independent of GEP (p=0.2). The GEP test was associated with a significant net reclassification index (NRI) over TNM classification for survival at 2 years (NRI=0.37, p=0.008) and 3 years (NRI=0.43, p=0.001). The authors concluded the GEP assay had a high technical success rate and was the most accurate prognostic marker among all the factors analyzed. GEP provided a highly significant improvement in prognostic accuracy over clinical TNM classification and chromosome 3 status. Chromosome 3 status did not provide prognostic information that was independent of GEP.
In 2016, Walter et. al., retrospective observational study performed at 2 ocular oncology referral centers (Washington University in St. Louis and Tumori Foundation at California Pacific Medical Center) to determine whether any clinicopathologic factors provide independent prognostic information that may enhance the accuracy of the GEP classification. There were 339 patients in the primary cohort and 241 patients in the validation cohort. All patients underwent tumor biopsy for GEP prognostic testing. Clinicopathologic variables included patient age and sex, tumor thickness, largest basal tumor diameter (LBD), ciliary body involvement, and pathologic cell type. Patients from the primary cohort were enrolled From November 1, 1998 to March 16, 2012; the validation cohort from November 4, 1996 to November 7, 2013. Follow-up for the primary cohort was completed August 18, 2013 and for the validation cohort December 10, 2013. Data was analyzed from November 12, 2013 to November 25, 2015. The primary outcome measure was progression free survival (PFS), defined as the interval from UM diagnosis to the detection of metastatic disease. The secondary outcome measure was overall survival, defined as the interval from UM diagnosis to death due to any cause. The primary cohort consisted of 339 patients (175 women [51.6%]; 164 men [48.4%]; mean age 61.8 years) diagnosed as having uveal melanoma (UM) arising in the ciliary body and/or choroid, 132 whom were included in the initial COOG study (Onken et. al. 2012 above). The GEP prognostic test results included class 1 in 190 cases (56.0%) and class 2 in 149 cases (44.0%). First assessed the prognostic contribution of each clinical, pathologic, and molecular feature to PFS using multivariate Cox proportional hazards analysis in the primary cohort. The most significant prognostic factor was the GEP class (exp[b] = 10.33; 95% CI, 4.30-24.84; P < .001). The only other variable that provided independent prognostic information was LBD (exp[b] = 1.13; 95% CI, 1.02-1.26; P = .02). With the use of all-cause mortality as the end point, GEP class was the only significant prognostic factor (exp[b] = 7.99; 95% CI, 3.29-19.40; P < .001). To evaluate the independent prognostic value of LBD within each GEP class, we performed univariate Cox proportional hazards analysis with PFS as the end point. Among class 1 UMs, the association of LBD with PFS was exp (b) = 1.16 (95% CI, 0.99-1.37; P = 07). Among class 2 Ums, LBD showed a modest but significant association with PFS (exp[b] = 1.13; 95% CI, 1.04-1.24; P = .005). A stepwise log-rank testing was used to determine whether a threshold LBD could be identified that best separated UMs of each GEP class into groups at lower and higher risk for metastasis. For class 1 Ums, no LBD threshold provided a significant separation of tumors with respect to metastatic risk. However, 9 of 11 class 1 Ums (82%) that metastasized had an LBD of at least 12 mm. For class 2 Ums, a significant difference in metastatic risk was observed when cases were separated based on LBD of less than 12 mm vs at least 12 mm. The mean PFS was 68.9% (95% CI, 59.3-78.4) months for class 2 UMs with an LBD of less than 12 mm vs 42.1 (95% CI, 36.4-47.8) months for class 2 UMs with an LBD of at least 12 mm (log rank test, P = 0.4). The 5 year actuarial PFS estimates were 97% (3%) for class 1 UMs with an LBD of less than 12 mm, 90% (4%) for class 1 UMs with an LBD of at least 12 mm, 90% (9%) for class 2 UMs with an LBD of less than 12 mm, and 30% (7%) for class 2 UMs with an LBD of at least 12 mm. Similar results were obtained for all-cause mortality, where the 5-year actuarial overall survival estimates were 96% (4%) for class 1 UMs with an LBD of less than 12 mm, 91% (4%) for class 1 UMs with an LBD of at least 12 mm, 100% for class 2 UMs with an LBD of less than 12 mm, and 26% (7%) for class 2 UMs with an LBD of at least 12 mm.
To determine whether this 2 term predictive model consisting of GEP class plus LBD could be applied to other patients with UM, the validation cohort was analyzed. This cohort consisted of 241 patients diagnosed with UM arising in the ciliary body and/or choroid, 132 of whom were included in the initial COOG report (Onken et. al. above). This cohort did not differ significantly from the primary cohort with respect to patient age, sex, tumor thickness, ciliary body involvement, or pathologic cell type. However, the median LBD in the primary cohort was 14.6 (mean 14.6; interquartile range 12.0-17.0) mm compared with 11.5 (mean 11.5; interquartile range 9.0-13.5) mm for the validation cohort (Mann-Whitney test, P < .001). The GEP was class 1 in 148 cases (61.4%) and class 2 in 93 cases (38.6%). As with the primary cohort, GEP classification was the factor most strongly associated with PFS (exp[b], 8.25; 95% CI, 3.79-17.94; P < .001), and LBD provided independent but modest prognostic information (exp[b], 1.19; 95% CI, 1.05-1.34; P = .005). The most significant LBD partition within each GEP class with respect to metastatic risk was LBD of less than 12 mm vs at least 12 mm. The 5 year actuarial PFS survival estimates was 100% for class 1 UMs with an LBD of less than 12 mm vs 74% (14%) for class 1 UMs with an LBD of at least 12 mm (log-rank test, P = .07). The 5 year PFS survival estimates was 69% (14%) for class 2 UMs with an LBD of less than 12 mm vs 20% (9%) for class 2 UMs with an LBD of at least 12 mm (log-rank test, P = .004).
In the initial prospective multicenter COOG validation study (Onken et. al. 2012 above), no clinicopathologic feature was found to provide prognostic information that was independent of the GEP classification. In the present study, it was re-investigated whether any clinicopathologic feature may have independent prognostic value in a cohort treated by a single surgeon that included smaller tumors and longer follow-up times than were contributed by the same surgeon to the original COOG study. It was confirmed that GEP class was by far the most accurate prognostic feature and that patient age, ciliary body involvement, tumor thickness, and tumor cell type provided no prognostic information that was independent of GEP class. However, in class 2 UMs, LBD (largest basal diameter) provided modest but significant prognostic information that was independent of GEP class and that the optimal threshold between lower and higher metastatic risk was an LBD of approximately 12 mm. A statistically significant association between LBD and outcome was not observed in class 1 UMs. A weakness of this study included the retrospective study design, which likely led to small differences in clinical tumor measurements, metastatic surveillance, follow-up intervals and other factors, as well as the relatively short follow-up, which could have preferentially underestimated the rate of metastasis in class 1 tumors. The authors concluded, we confirmed that GEP class was by far the most accurate prognostic feature and that patient age, ciliary body involvement, tumor thickness and tumor cell type provided no diagnostic information that was independent of GEP class. However, we found that in class 2 UMs, LBD provided modest but significant prognostic information that was independent of GEP class and that the optimal threshold between lower and higher metastatic risk was an LBD of approximately 12 mm. A statistically significant association between LBD and outcome was not observed for class 1 UMs. These findings have important implications for patient counseling, primary tumor treatment, clinical trial enrollment, metastatic surveillance and adjuvant therapy. We are planning a prospective, multicenter study to validate these findings and to determine the optional use of LBD in guiding primary tumor treatment, clinical trial inclusion criteria, and systemic adjuvant therapy.
Decatur et. al. (2016) was a smaller retrospective study on patients with uveal melanoma (UM) treated by enucleation by a single ocular oncologist between November 1, 1998 and July 31, 2014. The objective of the study was to determine the associations between driver mutations, gene expression profile (GEP) classification, clinicopathologic features and patient outcomes in UM. Frequent mutations have been described in the following 5 genes in uveal melanoma: BAP1, EIF1AX, GNA11, GNAQ, and SF3B1. Understanding the prognostic significance of these mutations could facilitate their use in precision medicine. The study cohort comprised 81 participants. Their mean age was 61.5 years and 37% (30 of 81) were female. The GEP classification was class 1 in 35 of 81 (43%), class 2 in 42 of 81 (52%), and unknown in 4 of 81 (5%). BAP1 mutations were identified in 29 of 64 (45%), GNAQ mutations in 36 of 81 (44%), GNA11 mutations in 36 of 81 (44%), SF3B1 mutations in 19 of 81 (24%) and EIF1AX mutations in 14 of 81 (17%). Sixteen of the mutations in BAP1 and 6 of the mutations in EIF1AX were previously unreported in UM. GNAQ and GNA11 mutations were mutually exclusive. BAP1, SF3B1, and EIF1AX mutations were almost mutually exclusive with each other. Using multiple regression analysis, BAP1 mutations were associated with class 2 GEP and older patient. EIF1AX mutations were associated with class 1 GEP and the absence of ciliary body involvement. SF3B1 mutations were associated with younger patient age. GNAQ mutations were associated with the absence of ciliary body involvement and greater largest basal diameter (LBD). GNA11 mutations were not associated with any of the analyzed features. Using Cox proportional hazards modeling, class 2 GEP was the prognostic factor most strongly associated with metastasis (relative risk 9.4; 95% CI, 3.1-28.5) and melanoma-specific mortality (relative risk 15.7; 95% CI, 3.6-69.1) (P < .001 for both). After excluding GEP class, the presence of BAP1 mutations was the factor most strongly associated with metastasis (relative risk, 10.6; 95% CI, 3.4-33.5) and melanoma-specific mortality (relative risk 9.0; 95% CI 2.8-29.2) (P < .001 for both). A limitation of this study was that it included only UMs treated by enucleation, which was a matter of necessity to obtain adequate amounts of tumor tissue for the various molecular analyses that were performed. As such, the findings of the study and others that are limited to enucleation specimens may not be representative of smaller UMs that are treated by globe-sparring procedures. The authors concluded, consistent with previous work, class 2 GEP demonstrated prognostic accuracy that was superior to all other variables that were examined. After excluding GEP class, the next most accurate prognostic factor was the presence of BAP1 mutations for both time to metastasis and to melanoma-specific mortality. These findings suggest that mutational analysis of BAP1 may have value as a biomarker for poor prognosis, whereas EIF1AX and SF3B1 may be useful markers of good prognosis. These mutations may have value as prognostic markers in uveal melanoma (UM).
Three published studies on clinical validity were included in this review, these studies have reported that GEP class 2 is a strong predictor of metastases and melanoma survival. Two studies have compared GEP class to clinicopathologic features and have reported that GEP classification is the strongest predictor of clinical outcomes.
Direct evidence of clinical utility is provided by studies that compare health outcomes for patients managed with and without the test. Preferred evidence comes from randomized clinical trials (RCTs).
Aaberg et. al. (2014) reported on changes in management associated with GEP (gene expression profiling) risk classification. They analyzed Medicare claims data submitted to Castle BioSciences by 37 ocular oncologists in the United States. Data was 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. There were 191 evaluable patients, 88 (46%) had evaluable tests and adequate information on follow-up surveillance, 36 (19%) 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 were treated with low intensity surveillance and all patients in GEP class 2 were treated with high intensity surveillance (P < 0.0001 versus class 1). For patients with referral data (n=36), all 23 class 2 patients were referred to medical oncology; however, none of the 13 class 1 patients were referred (P < 0.0001 versus class 1). For patients with adjunctive treatment data only class 2 patients were recommended for adjunctive treatment regimens. The authors concluded, overall the data in this report support the conclusion that molecular analysis, including GEP (gene expression profiling) and chromosomal analysis have been widely accepted and adopted for uveal melanoma treatment decisions. In addition to the impact on surveillance and referral management, such information is likely to be required for entry into future clinical trials involving adjuvant therapy at major medical center. The authors recognize that there is no strong data suggesting that more intensive surveillance improves survival outcomes.
Plasseraud et. al. (2016) reported 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. 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 (LFTs) every 3 to 6 months and low-intensity surveillance was considered to be annual imaging and/or LFTs. The method for following patients for clinical outcomes was not specified. Of the 70 enrolled patients, 37 (53%) were class 1 and 33 (47%) were class 2. Over a median follow-up of 2.38 years, more class 2 patients (36%) than class 1 patients (5%; p=0.002) experienced metastatis. The 3 year metastasis free survival (MFS) 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 outcomes were pre-specified or how data was collected, making the risk of bias high.
In 2016, Weis et. al. developed a consensus based guideline to inform practitioners on the management of uveal melanoma. Eighty four publications, including five existing guidelines formed the evidence base. Consensus discussions by a group of content experts from medical, radiation, and surgical oncology were used to formulate the recommendations. Key recommendations highlight that, for uveal melanoma and its indeterminate melanocyte lesions in the uveal tract, management is complex and requires experienced specialists with training in ophthalmologic oncology. Staging examinations include serum and radiologic investigations. Large lesions are still most often treated with enucleation, and yet radiotherapy is the most common treatment for tumors that qualify. Adjuvant therapy has yet to demonstrate efficacy in reducing the risk of metastasis, and no systemic therapy clearly improves outcomes in metastatic disease. Where available, enrollment in clinical trials is encouraged for patients with metastatic disease. Highly selected patients might benefit from surgical resection of liver metastases.
There are no studies directly showing clinical utility. It is uncertain whether stratification into higher risk categories has the potential to improve outcomes by allowing patients to receive adjuvant therapies or through the detection of metastases earlier. To date no adjuvant therapies for non-metastasized uveal melanomas have been shown to reduce the risk of metastases. It is uncertain whether the surveillance interval has an effect on time to detection of metastases. To date there is no strong data suggesting that more intensive surveillance improves survival outcomes.
Uveal melanoma is associated with a high rate of metastatic disease, predominantly to the liver. Survival after the development of metastatic disease is poor. Certain clinical factors and tumor genetic alterations (gene expression profiling) are being used to determine risk of metastases in individual patients, although it has not been shown that adjuvant treatment for patients who are considered to be at high risk for metastases alters survival outcomes, nor has it been shown that screening for the detection of early metastases has any effect on patient outcomes. Although, gene expression profiling of uveal melanoma has been shown to be an independent predictor of risk of metastasis, it is uncertain how risk stratification based upon this type of testing would improve net health outcomes. There is lack of published data from well-designed, prospective studies of sufficient sample size and follow-up that supports the clinical utility of gene expression profile testing for uveal melanoma. There appears to be no incremental benefit in its use over currently established prognostic clinical markers for predicting the risk of metastases, nor is there evidence that the use of this test will alter treatment decisions that will lead to improved outcomes. Well-designed randomized controlled trials (RCTs) are needed to determine the clinical utility of gene expression profiling of uveal melanoma compared with traditional clinical factors to guide medical management and improve clinical outcomes. The evidence is insufficient to determine the effects of this testing on net health outcomes.
Consider biopsy of primary tumor for prognostic analysisd.
d. Biopsy of the primary tumor does not impact outcome, but may provider prognostic information that can help inform frequency of follow-up and may be needed for eligibility for clinical trials. Specimen should be sent for histology, chromosome analysis, and/or gene expression profiling. The risks/benefits of biopsy for progression analysis should be carefully considered and discussed.
Discussion section of the NCCN guideline is still under development.
In 2014, the American Brachytherapy Society consensus guidelines for plaque brachytherapy of uveal melanoma and retinoblastoma state the following: “Select centers routinely biopsy uveal melanomas for pathologic, genetic, and molecular biologic analyses. However, patients must be counseled that studies of the ocular and metastatic risks of biopsy have been small, limited in follow-up, single center, and thus did not reach Level 2 Consensus (uniform panel consensus, based on clinical experience).”
Clinical laboratories may develop and validate tests in-house and market them as a laboratory service; laboratory-developed tests (LDTs) must meet the general regulatory standards of the Clinical Laboratory Improvement Amendments (CLIA). Genetic tests evaluated in this evidence review are available under the auspices of CLIA. Laboratories that offer LDTs must be licensed by CLIA for high-complexity testing. To date, the U.S. Food and Drug Administration has chosen not to require any regulatory review of these tests.
See also the following medical policies:
Gene expression profiling (GEP) for uveal melanoma including but not limited to DecisionDx-UM is considered investigational.
Although, gene expression profiling of uveal melanoma has been shown to be an independent predictor of risk of metastasis, it is uncertain how risk stratification based upon this type of testing would improve net health outcomes. There is lack of published data from well-designed, prospective studies of sufficient sample size and follow up that supports the clinical utility of gene expression profile testing for uveal melanoma. There appears to be no incremental benefit in its use over currently established prognostic clinical markers for predicting the risk of metastases, nor is there evidence that the use of this test will alter treatment decisions that will lead to improved outcomes. Well-designed randomized controlled trials (RCTs) are needed to determine the clinical utility of gene expression profiling of uveal melanoma compared with traditional clinical factors to guide medical management and improve clinical outcomes. The evidence is insufficient to determine the effects of this testing on net health outcomes.
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