Gene Expression Profiling has been proposed as a method of risk stratification for uveal melanoma.

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1 Last Review Status/Date: September 2014 Description Page: 1 of 5 Gene Expression Profiling has been proposed as a method of risk stratification for uveal melanoma. Background 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 Caucasians, 0.9 among Hispanics and 0.24 among African-Americans. (1) 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 Caucasian race, fair skin and light eye color. 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), the 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. (1) 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. (2) 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

2 Page: 2 of 5 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 and colleagues showed that monosomy of chromosome 3 correlated strongly with metastatic death, with a 5-year survival reduction from 100% to 50%. (3) Subsequent studies reported the initial idea that, based on genetic analysis, there were two distinct types of uveal melanomas- those with monosomy chromosome 3 associated with a very poor prognosis, and those with disomy 3 and 6p gain associated with a better prognosis. (1) 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. (1) 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 Study (COMS). (4) 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. (2) Therefore, it has been suggested that the identification of patients at high risk of metastatic disease may assist in selecting patients that 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. (5) 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 gene expression profile (GEP) test intended to assess five-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 five

3 Page: 3 of 5 years. The assay determines the expression of 15 genes which stratify a patient s individual risk of metastasis into two classes. Based upon the clinical outcomes from the prospective, 5-year multi-center 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 five years; Class 1B: Low risk, with a 21% chance of metastasis over five years; Class 2: High risk, with 72% odds of metastasis within five years. Regulatory Status No U.S. Food and Drug Administration (FDA)-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 (CLIA). Related Policy Charged-Particle (Proton or Helium Ion) Radiation Therapy Policy *This policy statement applies to clinical review performed for pre-service (Prior Approval, Precertification, Advanced Benefit Determination, etc.) and/or post-service claims. Gene expression profiling for uveal melanoma is considered investigational. Rationale The published data on the use of a gene expression profiling 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 and colleagues conducted a prospective, multi-center study to evaluate the prognostic performance of a 15 gene expression profiling (GEP) assay that assigned posterior (choroidal or ciliary body) uveal melanomas to one of two prognostic subgroups. (6) 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 Patients were treated for their primary tumor, 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

4 Page: 4 of 5 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, post-enucleation 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 (1.1%) of class 1 cases and 44 (25.9%) of class 2 cases (p<10-14). By univariate Cox proportional hazard analysis, factors that were associated with metastatic disease included advanced patient age (p=0.02), ciliary body involvement (p=0.03), tumor diameter (p=0.0003), tumor thickness (p=0.006), chromosome 3 status (p=0.0002), and GEP class (p<10 7). 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 and colleagues validated the GEP assay from a microarray platform to a PCR-based 15-gene assay comprised of 12 discriminating genes and 3 endogenous control genes from previously published data sets. (7, 8) The 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 (p=1.9 x 10-6). 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. Practice Guidelines and Position Statements National Comprehensive Cancer Network (NCCN) guidelines do not address ocular melanoma. 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.

5 Page: 5 of 5 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, and it is considered investigational References 1. Spagnolo F, Caltabiano G, Queirolo P. Uveal melanoma. Cancer treatment reviews 2012; 38(5): Pereira PR, Odashiro AN, Lim LA et al. Current and emerging treatment options for uveal melanoma. Clinical ophthalmology 2013; 7: Prescher G, Bornfeld N, Hirche H et al. Prognostic implications of monosomy 3 in uveal melanoma. Lancet 1996; 347(9010): Hawkins BS. Collaborative ocular melanoma study randomized trial of I-125 brachytherapy. Clinical trials 2011; 8(5): Augsburger JJ, Correa ZM, Shaikh AH. Effectiveness of treatments for metastatic uveal melanoma. American journal of ophthalmology 2009; 148(1): Onken MD, Worley LA, Char DH et al. Collaborative Ocular Oncology Group report number 1: prospective validation of a multi-gene prognostic assay in uveal melanoma. Ophthalmology 2012; 119(8): Onken MD, Worley LA, Tuscan MD et al. An accurate, clinically feasible multi-gene expression assay for predicting metastasis in uveal melanoma. The Journal of molecular diagnostics: JMD 2010; 12(4): Onken MD, Worley LA, Ehlers JP et al. Gene expression profiling in uveal melanoma reveals two molecular classes and predicts metastatic death. Cancer research 2004; 64(20): Policy History Date Action Reason September 2014 New Policy Keywords This policy was approved by the FEP Pharmacy and Medical Policy Committee on September 12, 2014 and is effective October 15, Signature on File Deborah M. Smith, MD, MPH