Solving the Riddle of Advanced Uveal Melanoma

Bercin Tarlan, MD 

Matthew G. Field, MS 

J. William Harbour, MD 

Bascom Palmer Eye Institute
Sylvester Comprehensive Cancer Center and Interdisciplinary Stem Cell Institute
University of Miami Miller School of Medicine

Conflict of Interest:  Dr. Harbour is the inventor of intellectual property related to subjects mentioned in this article. He is a paid consultant for Castle Biosciences, which licensed this intellectual property, and he receives royalties from its commercialization. 

Uveal melanoma is the most common primary intraocular malignancy and the second most common form of melanoma.1 It has many similarities to cutaneous melanoma, such as their common ancestry from neural crest-derived melanocytes and their strong tendency for metastasis. There are also striking differences. Whereas cutaneous melanoma demonstrates regional lymphatic dissemination as well as distant metastasis to the liver, lungs, bone, brain and other sites, uveal melanoma exhibits a strong proclivity for hematogenous metastasis to the liver. 

The mutation landscape of cutaneous melanoma is also extraordinarily different than that of uveal melanoma. And whereas metastatic cutaneous melanoma frequently responds to immune checkpoint inhibitors, metastatic uveal melanoma rarely does. 

However, recent advances in understanding the molecular pathogenesis of uveal melanoma are beginning to impact on management of advanced disease.

iris melanoma
Figure 1. Typical clinical presentations of uveal melanoma
(A) Iris melanoma arising from neural crest-derived melanocytes residing within the iris stroma (see arrow heads).

Difficulties in Detection

Uveal melanoma can arise in the iris, where it is readily discovered by inspection of the external eye (Figure 1A). However, about 95 percent of these lesions arise posterior to the pupil, in the ciliary body and/or choroid, where they cannot be visualized without special equipment such as slit lamp biomicroscopy and indirect ophthalmoscopy (Figure 1B). Only about half of uveal melanomas are discovered during a routine eye exam, when they are still asymptomatic. The other half present with symptoms such as light flashes, floaters, blind spots and blurriness, none of which are specific to uveal melanoma. 

For borderline or indeterminate lesions that overlap in size between small uveal melanomas and large uveal nevi, certain clinical features, such as subretinal fluid, orange autofluorescent lipofuscin pigment deposition and tumor thickness greater than 2 mm are used to help estimate malignant potential.2 However, these features are far from perfect predictors, and more accurate biomarkers are needed. 

posterior uveal melanoma
Figure 1. Typical clinical presentations of uveal melanoma
(B) Posterior uveal melanoma arising from the choroidal component of the uveal tract (see arrow heads).

The Need for Enhanced Prognosis

The 5-year mortality rates for patients with uveal melanoma are about 15 percent for small tumors, 30 percent for medium tumors and 50 percent for large tumors.3 Remarkably, there has been no demonstrable improvement in survival since the 1970s, despite substantial progress in diagnosis and treatment of the primary tumor.4 Scientists now attribute this to a propensity for early micrometastasis prior to treatment.As such, most specialists have adopted a systemic approach to management that involves some form of prognostic testing. Certain clinical and pathologic factors, such as tumor diameter, thickness and ciliary body involvement are associated with increased metastatic risk. However, these variables are susceptible to inter- and intra-observer variability and exhibit poor positive and negative predictive value for individual patients. For example, the AJCC TNM staging system, which is valuable for comparing cohorts of patients between different centers, is ill-suited for routine clinical prognostic testing. Alternatively, most leading centers now use molecular biomarkers for prognostic testing.  The earliest molecular biomarkers to be used were chromosomal gains and losses, with monosomy 3 being strongly associated with metastasis.6 However, the frequent intratumoral heterogeneity and potential for sampling error for monosomy 3,7 along with the need for large biopsy samples to perform chromosomal analysis, led to exploration of other molecular biomarkers. 

Gene expression profiling (GEP) revealed two basic molecular subtypes of uveal melanoma that correspond to their metastatic risk. About two-thirds of tumors have a class 1 profile (low metastatic risk), and about one-third have the class 2 profile (high metastatic risk).8  Several groups have shown that GEP is a more accurate predictor of metastasis than chromosomal gains and losses.9-11  As a result, our group developed a clinical-grade test for routine clinical use, utilizing a 12-gene expression signature performed using real-time PCR on a microfluidics platform.12 This GEP prognostic assay requires much smaller biopsy samples and is less prone to sampling error than chromosomal testing. Validated in a prospective multicenter study, the GEP assay is now commercially available under the trade name DecisionDx-UM,® and most ocular oncology centers in North America have used it.13

Recently, we discovered a new biomarker that enhances the prognostic accuracy of the GEP assay. A small percentage of tumors with the low-risk class 1 profile give rise to metastasis, and we recently showed that mRNA expression of the cancer-testis antigen PRAME identifies this subset of class 1 tumors.14 PRAME is now being added to the DecisionDx-UM® test and allows class 1 patients to be divided into those with minimal versus intermediate metastatic risk (Table I, below). 

Gene Expression Profile-Based Prognostic Classification

Percentage of Patients


Estimated 5-Year
Metastatic Risk

Class 1/PRAME-negative

53 percent


0-5 percent

Class 1/PRAME-positive

14 percent


30-35 percent

Class 2

33 percent


70-75 percent


Therapeutic Challenges for Advanced Disease

The lack of broadly effective treatments for metastatic uveal melanoma has been a major barrier to progress.15 Unlike cutaneous melanoma, where immune checkpoint inhibitors and targeted molecular therapies have ushered in a new era of improved treatments, no comparable breakthroughs have occurred for uveal melanoma. 


To date, immune-based therapy with single agent checkpoint inhibitors has had disappointing efficacy in uveal melanoma. Response rates to ipilimumab (Yervoy®) and PD-1 blockades have been estimated in the single digits.16 This may be due to the lower mutational burden of uveal melanoma, which could reasonably be inferred to correlate with lower rates at baseline of CD8+ T cell infiltration, which in cutaneous melanoma has been associated with responses to PD-1 blockade monotherapy.

A role remains for immune-based therapy in uveal melanoma, but future efforts should focus on improving immune infiltration and modulating the microenvironment. One reasonable approach may be combining ipilimumab with nivolumab (a successful FDA-approved combination for metastatic cutaneous melanoma). Another approach is a CD3 antibody fused to an engineered MHC Class 1 molecule that recognizes the surface protein gp100 (IMCgp100). The ongoing phase 1 trial of this agent reported that two of five patients with metastatic uveal melanoma achieved objective responses.

Another possible experimental approach to treatment is utilizing regional hepatic-directed therapy. Hepatic artery embolization could be investigated as an adjunct to other immune-based or targeted therapies. Hepatic artery embolization with granulocyte-macrophage colony stimulating factor led to objective responses in 10 of 31 patients in a phase 1 trial.17 Another approach is hepatic perfusion, where the portal venous system is isolated to perfuse the liver with higher doses of cytotoxic agents than would be possible systemically.

Molecular Pathogenesis and Targeted Therapy

Targeted molecular therapies have similarly fallen short. We most likely will need a better understanding of the mutational landscape of uveal melanoma to develop more effective targeted therapies. Uveal melanomas rarely harbor mutations in BRAF, KIT, NRAS and other genes that are commonly mutated in cutaneous melanoma. Rather, they demonstrate a distinctive set of driver mutations.18,19 The vast majority of uveal melanomas contain single nucleotide mutations in GNAQ or GNA11, which are thought to represent early or initiating events in tumorigenesis.19-21 Mutations in BAP1, SF3B1 and EIF1AX, almost mutually exclusive, are thought to occur later in tumor progression and to be associated with high, intermediate and low metastatic risk, respectively.19,22-24 BAP1 mutations are strongly associated with class 2 tumors,22 SF3B1 mutations with class 1/PRAME+ tumors,14 and EIF1AX mutations with class 1/PRAME- tumors.  The discovery of these mutations provides a framework for targeted molecular therapy. 

GNAQ/11 mutations activate the MEK, PI3-kinase/AKT, Hippo-YAP and other pathways that are amenable to pharmacologic modulation.25-30 BAP1 mutations may render tumor cells susceptible to inhibitors of epigenetic regulators such as HDAC and EZH2. 31,32 Also, since PRAME encodes an immunogenic protein that has been successfully targeted for immunotherapy in other cancers, PRAME expression in uveal melanoma may serve as a “companion prognostic” test that identifies patients with increased metastatic risk who may respond to immunotherapy.

Currently a phase 1b trial is open to accrual utilizing the protein kinase C inhibitor AEB071 (which in phase 1 trials led to a median PFS of 16 weeks33) in combination with the Phosphoinositol-3-Kinase alpha inhibitor BYL719 (NCT02273219). In addition, an ongoing randomized trial of the MEK inhibitor trametinib with or without the Akt inhibitor GSK2141795 (NCT01979523) has matched baseline and in-treatment biopsies that should provide additional pharmacodynamic and epigenetic analyses to fuel further trials. Ongoing preclinical work has identified novel targets, such as YAP/Hippo signaling, EZH2 and BRD4, which should lead to new clinical trials.

Moving forward, these novel treatment targets and an increasing understanding of the role of immune surveillance in this disease offer patients with advanced disease hope for improved therapeutic options. 

Key Considerations

Uveal melanoma differs in important ways from cutaneous melanoma in its metastatic pattern, prognostication, mutation landscape and responsiveness to targeted molecular therapy and immunotherapy. Recent discoveries in the molecular pathogenesis of uveal melanoma may pave the way to more effective therapies and more personalized management of high-risk patients.


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