A new analysis published in the journal Cancer Discovery reveals how some skin cancers stop responding to treatment at the end of life.

The 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, according to Cancer Research UK.

The research was led by scientists and clinicians at the Francis Crick Institute, UCL and The Royal Marsden in the UK. It is part of the Cancer Research UK-funded PEACE study, which is shedding light on the final stages of life with cancer by analyzing tumor samples taken from autopsies with informed consent.

“Many people with advanced cancers had previous treatment which wasn’t successful because the cancer found ways to overcome it. Scientists hope that this new information about melanoma’s resistance to current treatments will ultimately deliver new treatments which give people with advanced cancer more time with their loved ones,” according to a Cancer Research UK news release.

In the study, the scientists took 573 samples from 387 tumors from 14 patients with advanced melanoma. Research autopsies were carried out soon after death at University College London Hospitals and Guys and St Thomas’ Mortuary, with samples analyzed at the Francis Crick Institute and UCL. 

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. The researchers says this loss occurs because the cancer can either make multiple copies of defective versions of the genes, or use circular rings of DNA from outside the chromosome (called 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. 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,” said Consultant Medical Oncologist at the Melanoma Unit at the Royal Marsden and Research Group Leader at the Francis Crick Institute, Professor Samra Turajlic.

“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,” Dr. Turajlic said. “None of this would have been possible without our patients and their families who were willing to take part in this study at the hardest point in their cancer journey. Their selfless commitment to helping others through science is a huge source of inspiration to our clinical and research teams.”

To date, this is the largest study of its kind to find out in detail the changes that occur within melanoma tumors at the final stages of life. So far, almost 400 patients have consented to the PEACE study and the scientists have performed over 230 autopsies. 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.

Additional funding for this research was provided by Melanoma Research Alliance, The Royal Marsden Cancer Charity and Rosetrees Trust.