Researchers have revealed the potential mechanisms contributing to treatment resistance in patients with melanoma at the end of life, according to a new study published by Spain et al in Cancer Discovery.
“These results present the most detailed picture yet of what melanoma looks like at the final stages of life,” explained study author Mariam Jamal-Hanjani, MD, PhD, Clinical Associate Professor of Oncology and Group Leader of the Cancer Metastasis Lab at the University College London Cancer Institute.
Background
“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,” revealed senior study author Samra Turajlic, BA, MBBS, MRCP, PhD, Group Leader at the Francis Crick Institute and a consultant medical oncologist in the Skin and Urology units at the Royal Marsden Hospital.
“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 [patients] have died from their cancer,” she continued.
Study Methods and Results
In the new Posthumous Evaluation of Advanced Cancer Environment (PEACE) study, researchers analyzed the tumors of 14 patients with advanced melanoma—who consented to provide tumor samples for study following their deaths—using advanced genome sequencing techniques to map out the final stages of their cancer. All of the patients involved in the study had received immune checkpoint inhibitors, which had stopped being effective before their deaths. The researchers uncovered how changes to the order, structure, and number of copies of tumor DNA enabled melanoma cells to develop treatment resistance.
After collecting 573 samples of 387 tumors from the patients, the researchers conducted autopsies shortly following the patients’ deaths. They then searched for patterns in the genetic code that could help them understand how it changed when the tumors metastasized and resisted treatment.
They found that 78.6% of patients (n = 11) had lost functioning genes that allow immune checkpoint inhibitors to help the immune system recognize and attack cancer cells. The researchers explained that this loss may have occurred as a result of the cancer cells either duplicating defective versions of the genes or using extrachromosomal DNA to override normal copies of the genes.
“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.
Conclusions
The researchers emphasized that the new study is one of the largest of its kind to examine the detailed changes that occur within melanoma tumors at the final stages of life. They reported that, to date, almost 400 patients have consented to be involved in the PEACE study—and that the researchers have performed over 230 autopsies. Currently, they are looking to analyze samples from patients who have died from other types of incurable cancers in order to uncover how tumors spread and why they become resistant 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 [patients] who have taken part in the PEACE study,” Dr. Jamal-Hanjani commented. “Faced with the life-altering news of a terminal cancer diagnosis, they have shown huge courage by deciding to help science after their deaths 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 [patients] with cancer having the precious gift of a longer life thanks to [this] research.”
The researchers hope that their new findings will ultimately encourage the development of new treatment options to increase survival in patients with different types of advanced cancers.
Disclosure: For full disclosures of the study authors, visit aacrjournals.org.
