Uveal melanoma is a rare type of melanoma, but it is the most common intraocular cancer in adults. It has a great tendency to spread, especially in the liver, which gives it an aggressive nature that the statistics of recent years confirm: despite advances in research, approximately 50% of patients develop metastasis.

With such a high incidence of metastasis, it is essential to deepen the research and characterization of this tumor in the metastatic stage to better understand it and to be able to design effective diagnostic and therapeutic strategies for patients who are in this phase of the disease. Along these lines, a team of researchers led by Dr. Josep Maria Piulats, co-leader of the Cancer Immunotherapy research group at  IDIBELL-ICO and also a researcher at CIBERONC (Center for Biomedical Research in Cancer Network), and Dr. Luís del Carpio, first author of the study, medical oncologist and researcher at ICO-IDIBELL, has recently published a study in the European Journal of Cancer in which they propose a new favourable prognostic marker in metastatic uveal melanoma that could serve to clarify the prognostic outlook of patients with metastasis.

The study is based on a cohort of 220 patients treated at Bellvitge University Hospital, the largest series analyzed to date for this type of tumor. Staff from the Ophthalmology, Pathology, and Liver Surgery Departments at Bellvitge University Hospital also participated prominently in the study.

Characterize uveal melanoma in all its phases

The landscape of mutations that describe primary, nonmetastatic uveal melanoma has been quite clear for some time. Typically, a pair of initial mutually exclusive mutations occur that are characteristic of the early stages of the disease. From there, additional mutations in several genes that define the course and progression of cancer are added.

Thus, for example, mutations in the EIF1AX gene are at low risk for metastasis, while mutations in BAP1 are generally more problematic and are associated with a higher risk of dissemination. This information is key to personalising the therapeutic strategy, since knowing the type of mutations that each patient has helps to stratify their individual risk of developing metastases and to adjust, based on this, the strategy to be followed.

This is known and useful information for defining the risk of patients with primary uveal melanoma, but there are currently no prognostic markers for patients with metastases. Now, more than ever, with the approval of tebentafusp as a drug to treat metastatic uveal melanoma, the need to identify new factors that characterize metastasis is underlined to optimize the clinical plan to be followed.

SF3B1: A New Favorable Forecast Marker

To delve deeper into this aspect, Dr. Piulats’ team characterized the genetic profile of 220 patients with primary uveal melanoma treated at Bellvitge Hospital, of which 36% (79) ended up developing metastases. Based on the results, chromosomal abnormalities that typically report the prognosis of the primary tumor did not predict survival in metastatic tumors.

Instead, the researchers found, as Dr. Piulats points out, that “mutations in the SF3B1 gene are useful as predictors of survival in patients with metastases and, in fact, have a protective role.” Mutations in this gene confer almost 3 times longer survival (31.7 months average survival for those with the mutation vs. 11.8 months for those without it), regardless of the chromosomal alterations that the patients may have and whether they were being treated with tebentafusp or not. Some previous studies had already suggested that these mutations were favourable, but this is the first time that it has been confirmed in a large cohort of patients with metastasis.

Reconfiguring the forecast

In short, the published study transforms the understanding of prognosis in metastatic uveal melanoma, revealing that the markers used in the prognosis of primary tumors lose their predictive capacity once metastases appear. Instead, mutations in SF3B1 emerge as a new marker of favourable prognosis, independent of other risk factors.

This discovery opens the door to future research, essential to validate the results in larger cohorts and understand the molecular mechanisms that explain the protective effect of SF3B1. If confirmed, treatment selection and therapeutic stratification could change substantially to improve patient survival.

The Bellvitge Biomedical Research Institute (IDIBELL) is a research centre created in 2004 and specialising in cancer, neuroscience, translational medicine and regenerative medicine. It has a team of more than 1,500 professionals who, from 73 research groups, publish more than 1,400 scientific articles a year. L’IDIBELL is participated by the Bellvitge University Hospital and the Viladecans Hospital of the Catalan Health Institute, the Catalan Institute of Oncology, the University of Barcelona and the City Council of L’Hospitalet de Llobregat.

IDIBELL is a member of the Campus d’Excelencia Internacional of the University of Barcelona HUBc and is part of the CERCA institution of the Generalitat de Catalunya. In 2009 it became one of the first five Spanish research centres accredited as a health research institute by the Carlos III Health Institute. In addition, it is part of the HR Excellence in Research program of the European Union and is a member of EATRIS and REGIC. Since 2018, IDIBELL has been an Accredited Centre of the AECC Scientific Foundation (FCAECC).