Prognostic Biomarkers in Uveal Melanoma: The Status Quo, Recent Advances and Future Directions

SIMPLE SUMMARY: Although rare, uveal melanoma (UM) is the most common cancer that develops inside adult eyes. The prognosis is poor, since 50% of patients will develop lethal metastases in the first decade, especially to the liver. Once metastases are detected, life expectancy is limited, given that the available treatments are mostly unsuccessful. Thus, there is a need to find methods that can accurately predict UM prognosis and also effective therapeutic strategies to treat this cancer. In this manuscript, we initially compile the current knowledge on epidemiological, clinical, pathological and molecular features of UM. Then, we cover the most relevant prognostic factors currently used for the evaluation and follow-up of UM patients. Afterwards, we highlight emerging molecular markers in UM published over the last three years. Finally, we discuss the problems preventing meaningful advances in the treatment and prognostication of UM patients, as well as forecast new roadblocks and paths of UM-related research. ABSTRACT: Uveal melanoma (UM) is the most common malignant intraocular tumour in the adult population. It is a rare cancer with an incidence of nearly five cases per million inhabitants per year, which develops from the uncontrolled proliferation of melanocytes in the choroid (≈90%), ciliary body (≈6%) or iris (≈4%). Patients initially present either with symptoms like blurred vision or photopsia, or without symptoms, with the tumour being detected in routine eye exams. Over the course of the disease, metastases, which are initially dormant, develop in nearly 50% of patients, preferentially in the liver. Despite decades of intensive research, the only approach proven to mildly control disease spread are early treatments directed to ablate liver metastases, such as surgical excision or chemoembolization. However, most patients have a limited life expectancy once metastases are detected, since there are limited therapeutic approaches for the metastatic disease, including immunotherapy, which unlike in cutaneous melanoma, has been mostly ineffective for UM patients. Therefore, in order to offer the best care possible to these patients, there is an urgent need to find robust models that can accurately predict the prognosis of UM, as well as therapeutic strategies that effectively block and/or limit the spread of the metastatic disease. Here, we initially summarized the current knowledge about UM by compiling the most relevant epidemiological, clinical, pathological and molecular data. Then, we revisited the most important prognostic factors currently used for the evaluation and follow-up of primary UM cases. Afterwards, we addressed emerging prognostic biomarkers in UM, by comprehensively reviewing gene signatures, immunohistochemistry-based markers and proteomic markers resulting from research studies conducted over the past three years. Finally, we discussed the current hurdles in the field and anticipated the future challenges and novel avenues of research in UM.