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Blood Test Could Provide Insight Into Patients’ Metastatic Cancer

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A new blood test that analyzes DNA released from metastatic cancer could reveal characteristics unique to each patient’s tumor and allow doctors to develop more personalized treatment plans, according to a new report.

The blood test focuses on circulating tumor DNA (cDNA). By sequencing the complete ctDNA genome, researchers can learn about the various metastases spreading throughout the body.

Dr. Alexander Wyatt

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“A key goal in cancer research is to better understand metastatic cancer in every sick person so that we can choose the best treatments and avoid prescribing toxic treatments to people who will not benefit,” Senior Author Alexander Wyatt, MD, MD, Associate Professor of Genitourinary Cancer Genomics at the University of British Columbia, Vancouver, Canada, and Senior Research Fellow at the Vancouver Prostate Center, told Medscape Medical News.

“However, metastatic cancer biopsy is rarely performed because it is invasive and carries a risk of complications,” he said. “In the past, this major barrier has hampered the widespread study of metastatic cancer and progress in improving the treatment of this deadly disease.”

The study was published in Nature on July 20.

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Test Methods

Blood-based biopsy technology, also known as “liquid biopsy”, has become a tool for clinical cancer genotyping and dynamic disease monitoring. The authors of the study write that tests using ctDNA have begun to influence the clinical management of people with cancer, although the full potential for understanding the biology of metastatic cancer has yet to be unlocked.

Wyatt and colleagues analyzed serial plasma metastases 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 cancer cells.

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The researchers assessed all classes of genomic alterations and found that cDNA contained several dominant populations, indicating that in most people with metastatic cancer, metastases spread throughout the body. They found that the whole genome sequencing process provides a wealth of information about these various metastases.

The research team used newly developed computer programs to provide information about the genetic makeup of each cancer population, which could tell researchers about a person’s overall disease rather than a single metastatic tumor. In the future, this information may allow clinicians to make more informed decisions about treating a patient’s cancer.

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The researchers studied several ctDNA samples collected over time to understand how a patient’s cancer developed in response to treatment. They focused on androgen receptor pathway inhibitors. They found that current therapies for metastatic prostate cancer actively alter the composition of cancer populations in the body and that treatments often target biologically aggressive cancer populations that underlie clinical resistance. This allowed them to identify new mechanisms of genetic resistance to the most common treatments for metastatic prostate cancer. This technique can be applied to other types of cancer as well.

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The research team used traces of nucleosomes 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 ctDNA sequencing can reveal active processes occurring in cells, allowing clinicians to predict which treatment will or will not work for each patient.

“Our study greatly expands the range of information about cancer that can be obtained from just a few drops of blood,” Wyatt said. “From a clinical perspective, this additional information could be used in new clinical trials that test strategies to treat cancer only in those whose quality of life or life expectancy would be improved.”

Clinical Trials

The study authors write that ctDNA whole genome sequencing technology, which is minimally invasive, inexpensive and scalable, is currently being used in large clinical trials to help discover new mechanisms of treatment resistance. These include the Precision Oncology Clinical Trial, which is being conducted with Canadian cancer patients at the Vancouver Prostate and Cancer Center of British Columbia.

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This technology can also be implemented on existing commercial ctDNA testing platforms, meaning that patients will soon be able to directly benefit from more comprehensive liquid biopsy testing. The research team has made the methods and computer code public and free so the technology can be applied to other types of cancer and clinical settings.

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Dr. Christopher Muller

“Understanding how clonal evolution occurs and what drives it is one of the key questions that needs to be addressed in almost all cancers, and this study provides this level of understanding of advanced prostate cancer, as well as a model and tools for how to work,” Christopher Muller, MD, an oncological biologist and geneticist at the Royal Institute for Cancer Research and professor of biomedical and molecular sciences at Queen’s University, told Medscape Medical News.

Mueller, who was not involved in this study, was investigating biomarkers and ctDNA as a means to more accurately 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 cancers.

“The expansion of treatment-resistant clones is how we lose almost all cancer patients, and they clearly demonstrate 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 develop treatment strategies that overcome or limit their spread, which will hopefully prolong the lives of these patients.”

The study was funded by the Canadian Institutes for Health Research, Canadian Cancer Society Research Institute, Prostate Cancer Foundation, Prostate Cancer Canada, Movember Foundation, Jane and Aatos Erkko Foundation, Finnish Academy Center of Excellence Program, Terry Fox New Frontiers Program and Cancer Foundation British Columbia. Wyatt has served on advisory boards or received honoraria from AstraZeneca, Astellas, Janssen and Merck, and his research lab has a research contract with ESSA Pharma. Mueller did not disclose any relevant financial relationships.

Nature. Published online July 20, 2022 Full text

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