Scientists uncover how incurable skin cancer resists treatment at the end of life

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.

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.”