20 May 2021

Rethinking rare eye melanomas

Clinical Rare cancers Uveal melanomas

Two sequencing studies published a year apart have revealed genetic signatures of UV damage in a small subset of rare eye melanomas which stand to benefit from treatments currently used for skin melanoma, researchers say.  

Richard Marais, a professor of molecular oncology at Cancer Research UK Manchester Institute, presented the findings from his research on mucosal melanomas and another Australian-led study of uveal melanomas at the 2021 AACR Annual Meeting in April. 

Taken together, the two studies suggest that immunotherapy might be an option for some patients with these rare and understudied melanomas that generally, have very low response rates to immunotherapies.

“With increased understanding of these rarer subtypes of melanomas, we’re finding subgroup of patients who may have better response rates to immunotherapy and similarities to cutaneous melanomas,” said oncologist Dr Jenny Lee, who was not involved in either study. 

Professor Marais outlined results from his recent study, published in January 2021, which showed that melanomas that originate in the conjunctiva, a mucosal membrane of the eye, bear signatures of UV radiation. 

“When you start looking at mutation burden, you see that clearly, the conjunctival melanomas have many more mutations that mucosal melanomas from other sites,” and their mutation burden is comparable to the average sun-exposed skin melanoma, Professor Marais said in his presentation. 

He added that the UV signature, detected in nine out the 10 conjunctival tumours studied, sits atop of other oncogenic drivers, such as BRAF mutations, common in cutaneous melanomas, which gives clinicians an extra line of treatment. 

But of course, clinicians are eager to know which patients are responding to immunotherapies. Professor Marais also presented work, published in Nature Cancer, showing how DNA from T cell receptors circulating in the blood of metastatic melanoma patients may indicate treatment response after just one cycle of immunotherapy.

The second whole-genome sequencing study, published last year in Nature Communications by melanoma researcher Dr Kelly Brooks and her colleagues at QMIR Berghofer Medical Research Institute in Brisbane, found that similarly, tumours of the iris had a much higher mutation burden than the other 95% of uveal melanomas. 

“Like cutaneous melanomas, they have a high number of mutations and a very strong UV damage signature,” Dr Brooks told Oncology Republic about the study which included eight iris tumours.

Added to Professor Marais’ work, the research suggests that patients with metastatic iris or conjunctival melanomas could be good candidates for immunotherapy, Dr Brooks said. 

“They have a much higher chance of responding than the rest of the eye melanomas,” she said.

Dr Lee noted that although treatment strategies are unlikely to change based on this research – patients with these rare melanomas typically receive PD-1 inhibitors and molecular testing for mucosal melanomas is standard practice – it will help clinicians inform their patients about likely prognosis on treatment. 

“Where it will make a difference is when we counsel that patients, when we talk about potentially response rates to immunotherapy, or in terms of clinical trial eligibility,” said Dr Lee from the Chris O’Brien Lifehouse in Sydney.

“At the moment, especially with the conjunctival melanomas, they’re often excluded from cutaneous melanoma trials so it may be important in that regard.”

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