Uveal melanoma and risk of metastasis

With between 500 and 600 cases of uveal melanoma diagnosed in France each year, it is the most common form of eye cancer in adults. It is generally discovered by coincidence, during a routine exam such as a funduscopic exam. Sometimes patients consult due to decreased visual acuity, light flashes or spots in the visual field, which are symptoms of retinal detachment caused by the tumor. When the tumor is small enough, conservative treatment relies on proton therapy. Institut Curie is one of only two cancer centers in France to use this form of ultra-precise radiotherapy. It allows local control of the primary tumor in almost 100% of cases, but 30 to 50% of patient develop metastases, most frequently in the liver, sometimes more than 10 years after the initial treatment. These metastases are associated with a negative vital prognosis since current treatments are not very effective in controlling them.

It is therefore a question of early detection of patients at risk of metastasis, in order to be able to offer various therapeutic options as early as possible. "The risk of metastatic relapse increases with the size of the tumor. It becomes significant from 15 mm

explains Dr. Manuel Rodrigues, medical oncologist at Institut Curie

A tumor sample can also be taken on tumors smaller than 15 mm via biopsy, and analyzed to detect genomic anomalies: "uveal melanoma cells may present a loss of chromosome 3 or a gain of chromosome 8. We know that if none of these alterations are present, the risk of metastasis is very low," he adds. Once patients at risk of relapse have been identified - those with a tumor measuring more than 15 mm and/or presenting one of these genomic alterations - their liver is monitored by MRI every six months. Starting in 2020, a dedicated course of treatment will be offered to these patients at Institut Curie as part of the SALOME protocol.                                                                

If metastases are detected there are several therapeutic options, including surgery, interventional radiology, chemotherapy and more recently, immunotherapy.

The response rate to these treatments, in other words the percentage of chance that they are effective, is low. In reality, some patients will be very sensitive to one or another of these therapies, but we are not able to tell which ones. Being able to predict this and offer truly "personalized" medicine would help increase this response rate. This is one of the major leads currently.

This is why clinical trials are so important: Institut Curie is taking part in two international trials. "It is a phase I-II assessing a targeted therapy such as a C kinase protein inhibitor on the one hand, and a phase II, which tests a dedicated immunotherapy," explains Dr. Sophie Piperno-Neumann, a medical oncologist who is principal investigator for these trials at Institut Curie. This involves several dozen of our patients."

Furthermore, Dr. Piperno-Neumann is coordinating a third trial which will start in 2020 and will assess not a medication but the method of treating patients. The aim of "Early together" is to assess whether it is possible to improve the experience of patients and their quality of life by offering them support care from the start of treatment of metastases, in the absence of specific symptoms.

Lastly, basic research has not been slacking, with the UM Cure 2020 European research program launched in 2016. Coordinated by Institut Curie, it is the only large-scale research program currently on metastatic uveal melanoma. It involves fourteen European partners. "We created a virtual liver metastases bio-bank," explains Sergio Roman-Roman, head of the translational research department at Institut Curie and coordinator of this project. The samples are stored in different countries but all the clinical and biological data are shared. In addition, "we have created new cell and animal models. The aim is to better understand the metastatic disease in order to identify and test new therapeutic approaches," says Sergio Roman-Roman.

This program involves all the European specialists of this very rare type of cancer, and has enabled us to forge ties with American experts. It is very encouraging, even though much remains to be done, including convincing pharmaceutical laboratories to launch clinical trials with therapeutic combinations that we have identified as being promising.