A new blood test that analyzes DNA shed by metastatic cancers could reveal characteristics unique to each patient’s tumor and allow physicians to develop more personalized treatment plans, according to a new report.
The blood test focuses on circulating tumor DNA (ctDNA). By sequencing the complete genome of ctDNA, researchers can learn about the different metastases spread throughout the body.
“A key goal in cancer research is to better understand metastatic cancer in each affected person so we can select the best treatments and avoid giving toxic therapies to people who will not derive benefit,” senior author Alexander Wyatt, MD, DPhil, assistant professor of genitourinary cancer genomics at the University of British Columbia, Vancouver, Canada, and senior research scientist at the Vancouver Prostate Center, told Medscape Medical News.
“However, biopsies of metastatic cancer are rarely performed since they are invasive and have risks of complications,” he said. “In the past, this major barrier has prevented the widespread study of metastatic cancer and progress to better treatment of this lethal disease.”
The study was published in Nature on July 20.
Blood-based biopsy technology, also known as “liquid biopsy,” has emerged as a tool for clinical cancer genotyping and longitudinal disease monitoring. Tests that use ctDNA have begun to influence the clinical management of people with cancer, the study authors write, though the full potential for understanding metastatic cancer biology hasn’t yet been unlocked.
Wyatt and colleagues analyzed serial plasma and synchronous metastases in patients with aggressive, treatment-resistant prostate cancer through deep whole-genome sequencing, which allows for a comprehensive assessment of every part of the genetic code within the cancer cells.
The researchers assessed all classes of genomic alterations and found that ctDNA contains multiple dominant populations, indicating that most people with metastatic cancer have different metastases spread around the body. They found that the whole-genome sequencing process provides a host of information about these different metastases.
The research team used newly developed computer programs to provide information about the genetic makeup of each cancer population, which can tell researchers about a person’s overall disease rather than about one metastatic tumor. In the future, this information could allow clinicians to make better decisions about managing a patient’s cancer.
The researchers studied multiple ctDNA samples collected over time to understand how a patient’s cancer evolved in response to treatment. They focused on inhibitors of the androgen receptor pathway. They found that current therapies for metastatic prostate cancer actively change the composition of cancer populations in the body and that treatment often selects for biologically aggressive cancer populations that underlie clinical resistance. This allowed them to pinpoint new genetic resistance mechanisms to the most common treatments for metastatic prostate cancer. The technique could be applied to other cancers as well.
The research team used nucleosome footprints in ctDNA to infer mRNA expression in metastases upon which biopsies were synchronously performed. They identified treatment-induced changes in androgen receptor transcription factor signaling activity. This means whole-genome sequencing of ctDNA can reveal the active processes occurring within cells, allowing clinicians to predict which treatments will be effective or ineffective in each patient.
“Our research significantly expands the breadth of cancer information that can be obtained from only a few drops of blood,” said Wyatt. “From a clinical perspective, this extra information can be used in new clinical trials that are testing strategies to direct cancer treatments only to those whose quality or whose length of life will be improved.”
The study authors write that whole-genome ctDNA sequencing technology, which is minimally invasive, inexpensive, and scalable, is now being deployed in large clinical trials to help discover new treatment resistance mechanisms. These include precision oncology clinical trials that are being conducted with Canadian cancer patients at the Vancouver Prostate Centre and BC Cancer.
The technology can also be implemented in existing commercial ctDNA testing platforms, which means that patients could soon directly benefit from more comprehensive liquid biopsy testing. The research team has made the methods and computer code publicly and freely available so that the technology can be applied to other cancer types and clinical settings.
“Understanding how clonal evolution occurs and what drives it is one of the key questions that need to be addressed in almost all cancers, and this study provides that level of insight for advanced prostate cancer, as well as a model and tools for how to carry out this work,” Christopher Mueller, MD, PhD, a cancer biologist and geneticist at Queen’s Cancer Research Institute and a professor of biomedical and molecular sciences at Queen’s University, told Medscape Medical News.
Mueller, who wasn’t involved with this study, has researched biomarkers and ctDNA as avenues for more precise management of advanced prostate cancer. He and colleagues have developed blood tests for detecting and monitoring metastatic breast cancer, uveal melanoma, and prostate, pancreatic, and lung cancer.
“The expansion of treatment-resistant clones is how we lose almost all cancer patients, and they clearly demonstrate that in castrate-resistant prostate cancer, changes in the androgen receptor locus almost always drive this process,” Mueller said. “Understanding clonal evolution will allow us to design treatment strategies that overcome or limit their expansion, hopefully extending the lives of these patients.”
The study was funded by the Canadian Institutes of Health Research, the Canadian Cancer Society Research Institute, the Prostate Cancer Foundation, Prostate Cancer Canada, the Movember Foundation, the Jane and Aatos Erkko Foundation, the Academy of Finland Center of Excellence program, the Terry Fox New Frontiers Program, and the BC Cancer Foundation. Wyatt has served on advisory boards or has received honoraria from AstraZeneca, Astellas, Janssen, and Merck, and his research lab has a contract research agreement with ESSA Pharma. Mueller has disclosed no relevant financial relationships.
Nature. Published online July 20, 2022. Full text
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