Blood test could provide insight into patients’ metastatic cancer

According to a new report, a new blood test that analyzes DNA shed by metastatic cancer could reveal unique characteristics of each patient’s tumor and allow doctors to develop more personalized treatment plans.

The blood test focuses on circulating tumor DNA (ctDNA). By sequencing the full genome of ctDNA, researchers can learn more about the various metastases found throughout the body.

“A major goal of cancer research is to better understand metastatic cancer in each affected person so that we can select the best treatments and avoid giving toxic therapies to people who will not benefit,” senior author Alexander Wyatt, MD, DPhil , assistant professor of urogenital cancer genomics at the University of British Columbia, Vancouver, Canada, and senior research scientist at the Vancouver Prostate Center Medscape Medical News.

“However, biopsies of metastatic cancer are rarely performed because they are invasive and carry the risk of complications,” he said. “In the past, this major barrier prevented the widespread study of metastatic cancer and progress toward better treatments of this deadly disease.”

The study was published in Nature on the 20th of July.

test methods

Blood-based biopsy technology, also known as “liquid biopsy,” has emerged as a tool for clinical genotyping of cancer and longitudinal disease monitoring. Tests using ctDNA have begun to influence the clinical management of people with cancer, the study authors write, although the full potential for understanding the biology of metastatic cancer has not yet been realised.

Wyatt and colleagues analyzed serial plasma and synchronous metastases in patients with aggressive, treatment-resistant prostate cancer using deep whole genome sequencing, which allows for a comprehensive assessment of every part of the genetic code in the cancer cells.

The researchers evaluated all classes of genome alteration and found that ctDNA contains multiple dominant populations, suggesting that most people with metastatic cancer have different metastases spread throughout the body. They found that the process of whole genome sequencing provides a wealth 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 more about a person’s overall disease than a metastatic tumor. In the future, this information could allow doctors to make better decisions about how to manage a patient’s cancer.

Researchers examined several 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 alter the composition of cancer populations in the body and that treatment often targets biologically aggressive cancer populations that harbor clinical resistance. This allowed them to localize novel genetic resistance mechanisms for the most common treatments for metastatic prostate cancer. The technique could also be applied to other types of cancer.

The research team used nucleosome footprints in ctDNA to infer mRNA expression in metastases that were biopsied synchronously. They identified treatment-induced changes in androgen receptor transcription factor signaling activity. This means that whole genome sequencing of ctDNA can reveal the active processes going on in cells, allowing doctors to predict which treatments will or will not work in each patient.

“Our research greatly expands the breadth of cancer information that can be gleaned from just a few drops of blood,” Wyatt said. “From a clinical perspective, this additional information can be used in new clinical trials testing strategies to target cancer treatments only to those whose quality or longevity will be improved.”

Clinical Trials

The study authors write that whole genome ctDNA sequencing technology, which is minimally invasive, inexpensive and scalable, is now being used in large clinical trials to help discover new treatment resistance mechanisms. This includes precision oncology clinical trials being conducted in Canadian cancer patients at the Vancouver Prostate Center and BC Cancer.

The technology can also be implemented into existing commercial ctDNA testing platforms, meaning patients could soon directly benefit from more comprehensive liquid biopsy testing. The research team has made the methods and computer code public and freely available so the technology can be applied to other cancer types and clinical settings.

Dr Christopher Mueller

“Understanding how clonal evolution occurs and what drives it is one of the key questions that must be addressed in almost all cancers, and this study provides that level of understanding for advanced prostate cancer, as well as a model and tools for carrying out this work,” said Christopher Mueller, MD, PhD, cancer biologist and geneticist at Queen’s Cancer Research Institute and Professor of Biomedicine and Molecular Sciences at Queen’s University Medscape Medical News.

Mueller, who was not involved in this study, explored biomarkers and ctDNA as avenues to more precisely treat advanced prostate cancer. He and colleagues have developed blood tests to detect and monitor metastatic breast cancer, uveal melanoma, and prostate, pancreatic, and lung cancer.

“With the proliferation of treatment-resistant clones, we lose almost all of our cancer patients, and they clearly show that in castration-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 will overcome or limit its spread and hopefully prolong 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 and the Terry funded Fox New Frontiers Program and the BC Cancer Foundation. Wyatt has served on advisory boards or received honoraria from AstraZeneca, Astellas, Janssen and Merck, and his research laboratory has a contract research agreement with ESSA Pharma. Mueller has not disclosed any relevant financial relationships.

Nature. Published online 20 July 2022. Full text

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