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Study reveals how incurable skin cancer resists treatment



Scientists have uncovered how some skin cancers stop responding to treatment at the end of life.

An in-depth analysis of 14 patients who died from incurable melanoma showed that changes to the order, structure and number of copies of tumour DNA could cause some skin cancers to resist treatment.

These changes also explain how melanoma can spread to other parts of the body.

The research was led by scientists and clinicians at the Francis Crick Institute, UCL and The Royal Marsden.

It is part of the Cancer Research UK-funded PEACE study, which aims to shed light on the final stages of life with cancer by analysing tumour samples taken from autopsies with informed consent.

Clinical Associate Professor at University College London and lead investigator of the PEACE study, Dr Mariam Jamal-Hanjani, said:

“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.”

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

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

All of the patients in the study had been treated with immune checkpoint inhibitor (ICI) drugs, which enable the immune system to recognise and attack cancer cells.

In all 14 of the patients, ICI drugs had stopped working by the time of their deaths.

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

They found that 11 out of the 14 participants had lost functioning genes that enable ICI drugs 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 these genes, or use circular rings of DNA from outside the chromosome (called extrachromosomal DNA) to override normal copies of the genes.

Consultant Medical Oncologist at the Melanoma Unit at the Royal Marsden and Research Group Leader at the Francis Crick Institute, Professor Samra Turajlic, said:

“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.

“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.”

The findings have been welcomed by relatives of people who consented to take part in the PEACE study.

Dave Sims, originally from Bristol, lost his twin brother Mark to melanoma when he was just 28.

London-based doctor Mark, a doctor was first diagnosed with melanoma at the age of 15.

Dave said:

“Mark always thought about others more than himself.

“He wanted to do everything he possibly could to ensure that no-one else ever has to go through the same thing that he did.

“Research takes a long time, but the wait has been worth it.

“I feel that I now have some answers about what happened with Mark’s cancer and I am heartened that this knowledge is moving us closer to the day where no family has to face the same pain and heartache that we have endured.”

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, with scientists performing over 230 autopsies.

The scientists 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.

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