PEACE Study Offers New Clues About How Cancer Resists Treatment
By Deborah Borfitz
April 26, 2023 | Research autopsies are nothing new—the use of post-mortem tissues for cancer research has been ongoing since the end of the nineteenth century—but the Cancer Research UK-sponsored PEACE (posthumous evaluation of advanced cancer environment) study stands apart by virtue of its scope and scale. The pan-cancer initiative intends to enroll 500 patients across the country in hopes of understanding cancer evolution, drug resistance and why patients die of their disease, according to Mariam Jamal-Hanjani, M.D., Ph.D., clinical associate professor at University College London and lead investigator for the study.
Among those who consented to participate were 14 patients with metastatic late-stage melanoma, from whom researchers have been able to map genomic landscape changes after their treatment with immunotherapy drugs. Results of that analysis, published recently in Cancer Discovery (DOI: 10.1158/2159-8290.CD-22-1427), produced the most comprehensive intra-patient metastatic melanoma dataset ever assembled.
Each autopsy can provide “tens if not hundreds of samples,” explains Jamal-Hanjani, which is the real selling point of the approach. The same learnings could not be obtained from individual biopsies, let alone multiple biopsies from multiple metastases.
“The fact that tumors evolve means a single needle biopsy at one site in a tumor gives you a glimpse; it does not give you the full picture,” she says. Samples from across the body are required to capture the spatial heterogeneity of cancer and to identify the common features as well as the unique “subclones” of cancer cells with distinct features of their own.
Patients themselves have been the biggest advocates and supporters of research autopsies. “It is pure altruism on their part,” she says. PEACE is their legacy and comes with the assurance that their samples will fuel scientific discovery.
A consortium of more than 300 EU-wide investigators, scientists, clinicians, nurses, and tissue collectors, need samples for specific research projects, Jamal-Hanjani continues. “We’ve tried to lead with the science... [meaning] we recruit patients we know will contribute to scientific questions addressing areas of clinical unmet need, which sadly means we can’t take on all comers.”
The PEACE initiative is not to be confused with biobanks, which will often accept all patients who want to donate their body to medical science, says Jamal-Hanjani. Biobanks aren’t even an option in the UK and, for patients with metastatic cancer, neither are medical school anatomy departments since the disease can distort the normal anatomy of organs.
Research autopsies through PEACE are done “in conjunction with family wishes and what the patient had wanted before death,” she says. “We work with funeral homes, caretakers, undertakers, [and] mortuary technicians, so it is done when it can be done but always with the intention of understanding how an aggressive cancer has behaved.”
Since 2016, almost 400 patients have consented to participate in the PEACE research autopsy program and over 230 autopsies have been performed, Jamal-Hanjani reports. PEACE-enabled studies sometimes dovetail with other studies, such as the Cancer Research UK-funded TRACERx (tracking cancer evolution through therapy (Rx)) study where early-stage lung cancer patients are followed from diagnosis to death starting with the capture of fresh tissue at the time of surgery.
Many patients with metastatic disease have approached researchers about participation in PEACE studies even if their disease is well controlled, she says, notably after a story about the program runs in the local news. Projects are all seeking answers to specific research questions and recruitment efforts around those focused on why immunotherapy drugs don’t always work would therefore be seeking only patients where such therapies have stopped or potentially could stop working.
“Sometimes I’ve had to say no to a patient ... (for example) if they’ve undergone surgery many times, have tissue we’ll never be able to analyze before death, or there’s no investigator in the PEACE consortium that is specifically looking at their type of cancer,” continues Jamal-Hanjani. The rationale is the significant amount of money and time required to do the research autopsies, and the promise made to participants that every sample taken from their body at autopsy will be part of a preplanned research study.
While scientists know the physiological terminal events associated with cancer, including organ failure and thrombosis, they don’t yet understand the preceding biology and mechanisms leading to metastases or why cancer spreads to certain anatomical sites or develops drug resistance, says Jamal-Hanjani. These are shared goals of the PEACE and TRACERx programs.
Since many cancer patients present with advanced or metastatic disease, it would be unethical and invasive to take tissue biopsies from multiple sites where the cancer has spread, she continues. Research autopsies are an answer to that dilemma, but most such programs are small and may be focused on a particular type of cancer.
In the U.S., the Johns Hopkins-led PELICAN (project to eliminate lethal cancer) autopsy study of 33 men with lethal metastatic prostate cancer ended nearly two decades ago. One of the lead investigators, G. Steven Bova (now at the University of Tampere in Finland), is part of the PEACE consortium. Similar programs have been established for colorectal, breast, and esophageal cancer, Jamal-Hanjani says.
In Australia, the CASCADE (cancer tissue collection after death) research program is enrolling patients with advanced metastatic disease who consent to undergo rapid autopsy following death, which is leveraging a team of on-call pathologists and mortuary staff, she adds. The University of Cambridge also ran an autopsy program focused on metastatic breast cancer, which published results in Cell Reports (DOI: 10.1016/j.celrep.2019.04.098) in 2019.
The infrastructure (e.g., staff and tissue collection protocol) had to be established in the UK for the ambitions of the PEACE study program. As proposed to Cancer Research UK, the world’s largest charitable funder of cancer research, the initiative approaches patients undergoing treatment to ask them about donating their body—provided, when they die, it harbors cancer, says Jamal-Hanjani.
To set up the program on a national scale, across multiple centers, was logistically complicated since this was not to be a rapid autopsy service where post-mortem examinations are performed four to six hours after the death of a patient. “It was almost like putting together a puzzle and establishing the program in a real-world setting within a national health service,” she says.
Once patients die, multiple fresh samples are taken from all sites in their body where the cancer has spread and are frozen with liquid nitrogen. Together with blood and clinical data collected while they were still alive, the preserved tissues aid understanding of cancer and its progression at different treatment time points. In some cases, researchers must hunt down where earlier biopsies were done or to learn if additional preserved samples are available from pathology departments elsewhere.
For the metastatic melanoma study, patients when alive had all been treated with immune checkpoint inhibitor drugs. In all but three of the 14 patients, cells in their tumor had lost functioning genes that enabled the drugs to help their immune system recognize and attack the cancer, explains Jamal-Hanjani. The cancer succeeded in either making multiple copies of defective versions of the genes or using extrachromosomal DNA (ecDNA) to override normal copies of the genes. Patients treated with drugs targeting a gene called KIT were particularly subject to developing resistance.
Study results provide clues to genetic changes acquired later in the evolution of the disease, so researchers can begin to hypothesize that these may be in response to an intervention, says Jamal-Hanjani. The changes correlate to the development of resistance but aren’t necessarily causal because the study has no living patients to serve as controls and this would require further mechanistic studies. The number of patients with late-stage metastatic melanoma in the PEACE program continues to grow and, with it, confidence in the conclusions that might be reasonably drawn.
“We’re trying to find the mechanism of resistance to specific drugs,” she says, adding that a study specific to lung cancer combining TRACERx and PEACE is now underway. In this case, researchers have the added benefit of looking at the primary cancer before treatment begins.
Interest in research autopsies is burgeoning within the research community, says Jamal-Hanjani. “Probably the most difficult aspect has been the need for clinicians to approach patients... [due to] the stigma of talking about death and the logistics of it, so it really needs championing and encouragement.” Every study site and team member need to be on board, and “a little bit selective” about the patients with whom they have conversations about death.
The PEACE consortium wants as much as possible to leverage work already done when patients were alive, she stresses. “The autopsies then allow us to start putting the story together all the way from diagnosis through relapse and death... [about how] the behavior of a particular cancer allows it to survive and resist often several lines of therapy.”
In a separate paper newly published in Nature (DOI: 10.1038/s41586-023-05874-3), which involved PEACE, researchers found that air pollutants act on cells that harbor mutations in healthy lung tissue and may predispose people who have never smoked to lung cancer. Here again, autopsies could lend themselves to the study of uninvolved normal tissue as well as tumor tissue to identify any background changes that might play a role, Jamal-Hanjani says.
Of course, cancer cells don’t work by themselves, she adds. The potential role of the tumor microenvironment in the metastatic process also needs to be mapped out. Her lab is additionally interested in looking more closely at cachexia, the wasting syndrome seen with people with advanced cancer for which there is currently no effective treatment, by analyzing muscle and fat tissue taken at autopsy using sequencing or single-cell technologies.
Research autopsies make possible a seemingly endless variety of investigative paths, says Jamal-Hanjani. But her immediate next step is work on the cohort of 20-plus lung cancer patients followed from diagnosis to death to start mapping out the routes by which the disease spreads and describe the genetic makeup of primary and metastatic tumors. Findings could be published in the next year, she hopes.
Last year, Jamal-Hanjani was part of the teams that won two of the four Cancer Grand Challenges jointly sponsored by Cancer Research UK and the National Cancer Institute. One of the projects, involving an international team led by Eileen White, Ph.D. (Rutgers Cancer Institute), is exploring the hypothesis that cachexia is driven by the tumor itself, activating neurohormonal sickness pathways that lead to anorexia, metabolic dysfunction, and tissue wasting.
The other project, led by Paul Mischel, M.D. (Stanford University), is seeking to understand the biology of ecDNA generation and action, and developing ways to target mechanisms in cancer. DNA found off the chromosomes “do their own thing and do not follow the normal Mendelian rules of cell division and replication,” Jamal-Hanjani points out.
Thanks to the PEACE initiative and work led by others, a theory has emerged that ecDNA—known to be present in about one-quarter of all cancers and predictive of a poor prognosis—is what drives resistance to therapies, Jamal-Hanjani says. The autopsy of one patient, whose primary cancer had no ecDNA, revealed a clear connection between cancer spread and accumulation of ecDNA that could be playing a role in suppressing response to immune therapy.
“[Extrachromosomal DNA] is really exciting biology,” she says. “Suddenly, autopsies have become relevant in understanding ecDNA, metastases, and knowing which tumors are getting bigger or smaller... and might give us some clue as to how [it] is driving drug resistance.”