Researchers say they have found out how some skin cancers stop responding to treatment at the end of life. An analysis of 14 patients who died from incurable melanoma has revealed that changes to the order, structure, and number of copies of tumor DNA could cause some skin cancers to resist treatment. These changes also explain how melanoma can spread to other parts of the body.

The study “Late-stage metastatic melanoma emerges through a diversity of evolutionary pathways,” published in Cancer Discovery, was led by scientists and clinicians at the Francis Crick Institute, University College London (UCL), and The Royal Marsden.

“Understanding the evolutionary pathways to metastasis and resistance to immune checkpoint inhibitors (ICI) in melanoma is critical for improving outcomes. Here we present the most comprehensive intra-patient metastatic melanoma dataset assembled to date as part of the PEACE research autopsy program, including 222 exome, 493 panel-sequenced, 161 RNA-seq, and 22 single-cell whole-genome sequencing samples from 14 ICI-treated patients,” write the investigators.

“We observed frequent whole-genome doubling and widespread loss of heterozygosity, often involving antigen presentation machinery. We found KIT extrachromosomal DNA may have contributed to the lack of response to KIT inhibitors of a KIT-driven melanoma. At the lesion-level, MYC amplifications were enriched in ICI non-responders. Single-cell sequencing revealed polyclonal seeding of metastases originating from clones with different ploidy in one of the patients. Finally, we observed that brain metastases that diverged early in molecular evolution emerge late in disease. “Overall, our study illustrates the diverse evolutionary landscape of advanced melanoma.”

The study analysis showed that immune checkpoint inhibitor drugs had stopped working in all 14 patients who had died from advanced melanoma. [Andrew Brookes/Getty Images]
In the study, the scientists took 573 samples from 387 tumors from 14 patients with advanced melanoma. All of the patients in the study had been treated with immune checkpoint inhibitor (ICI) drugs, which help the immune system to recognize and attack cancer cells. In all 14 patients, ICI drugs had stopped working by the time of their deaths.

The scientists read the genetic code of individual cells within the tumor samples, looking for patterns in how the code changed when the tumors spread and resisted treatment.

They found that 11 out of the 14 patients in the study had lost functioning genes that enable ICI drugs to help the immune system recognize and attack the cancer. This loss occurs because the cancer can either make multiple copies of defective versions of the genes, or use extrachromosomal DNA to override normal copies of the genes.

“Treatment options for patients whose melanoma that returned or spread have improved dramatically in the last decade. But sadly, almost half of melanoma patients still lose their lives to their cancer,” says Samra Turajlic, PhD, consultant medical oncologist in the melanoma unit at the Royal Marsden and Research Group Leader at the Francis Crick Institute. “To understand why existing treatments sometimes fail, we need to know what happens in the final stages of their cancer. It’s difficult, but the only practical way to do this is to analyze tumor samples after people have died from their cancer.

“We found that melanoma can profoundly alter its genome to hide from the immune system and spread around the body. These profound changes are highly complex, but we’re hopeful that we can now find ways to target them in the clinic.”

The researchers involved are currently analyzing samples from people who died from other types of incurable cancer to find out how cancers spread and why they stop responding to treatment.

“These results present the most detailed picture yet of what melanoma looks like at the final stages of life. We can now see how the cancer evolves to spread to the brain and the liver, and how it can beat the most common treatment currently available for people with advanced disease,” notes Mariam Jamal-Hanjani, PhD, clinical associate professor at University College London. “We now have a huge opportunity to look for new ways to treat advanced cancer.”

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