Melanoma cells viewed under the microscope

The results of new research have revealed how some skin cancers stop responding to treatment at the end of life.

As part of the Cancer Research UK-funded PEACE study, 14 patients with advanced melanoma skin cancer consented to have their tumours analysed after their death.

Those samples were analysed using advanced genome sequencing techniques to map out the final stages of their cancer. The analysis uncovered changes to the order, structure and number of copies of tumour DNA that could allow melanoma to develop resistance to treatment.

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.

The research, published today in the journal Cancer Discovery, was led by scientists and clinicians at the Francis Crick Institute, University College London (UCL) and The Royal Marsden.

“These results present the most detailed picture yet of what melanoma looks like at the final stages of life,” said Dr Mariam Jamal-Hanjani, lead investigator of the PEACE study and clinical associate professor at UCL.

What did the study do?

Many people with advanced cancers have had previous treatment that wasn’t successful because the cancer found ways to resist it.

In the study, the scientists took 573 samples from 387 tumours from 14 patients with advanced melanoma.

Research autopsies were carried out soon after death at University College Hospital and Guys and St Thomas’ Mortuary, with samples analysed at the Francis Crick Institute and UCL.

All the patients in the study had been treated with a type of immunotherapy called checkpoint inhibitors (ICIs), which help the immune system to recognise and attack cancer cells. In all 14 patients, these ICIs had stopped working by the time of their deaths.

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

They found that 11 out of the 14 patients in the study had lost functioning genes that enable ICIs to help the immune system recognise and attack the cancer.

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 has returned or spread have improved dramatically in the last decade. But sadly, almost half of melanoma patients still lose their lives to their cancer,” said Professor Samra Turajlic, consultant medical oncologist at 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 analyse tumour 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.”

A selfless commitment

To date, this is the largest study of its kind to find out in detail the changes that occur within melanoma tumours 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 analysing samples from people who died from other types of incurable cancer, to find out how cancers spread and why they stop responding to treatment.

“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,” said Turajlic.

“Their selfless commitment to helping others through science is a huge source of inspiration to our clinical and research teams.”

“I am in awe of the people who have taken part in the PEACE study,” Jamal-Hanjani added.

“Faced with the life-altering news of a terminal cancer diagnosis, they have shown huge courage by deciding to help science after their death in the hope that this will benefit future generations of patients.

“We now have a huge opportunity to look for new ways to treat advanced cancer. I’m excited about the prospect of more people with cancer having the precious gift of a longer life thanks to research.”


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