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Treatment-Resistant Prostate Cancer Clues Drawn From Circulating Tumor DNA Dynamics

NEW YORK – A University of British Columbia-led team has demonstrated that the "chronology" of cell-free tumor DNA circulating in blood plasma over time can offer a look at tumor evolution and resistance mechanisms in patients with aggressive, difficult-to-treat forms of prostate cancer.

"Our results provide insights into cancer biology and show that liquid biopsy can be used as a tool for comprehensive multiomic discovery," co-senior and corresponding author Alexander Wyatt, a cancer genomics researcher in urologic sciences with the University of British Columbia's Vancouver Prostate Centre and BC Cancer's Michael Smith Genome Sciences Centre, and his colleagues wrote in Nature on Wednesday.

Using deep whole-genome sequencing, the researchers tracked circulating tumor DNA (ctDNA) dynamics in dozens of blood samples collected sequentially from 33 men with metastatic, castration-resistant prostate cancer, including 16 prostate cancer patients with corresponding metastatic tumor tissue samples. They also assessed matched white blood cell samples, along with plasma samples from two metastatic neuroendocrine prostate cancer patients, two individuals with metastatic bladder cancer, and five cancer-free control individuals.

The team's findings suggested that it is possible to tap into ctDNA to follow the evolution of tumor populations, including shifts in the representation of distinct clonal populations, cancer drivers, and the advent of resistance-related mutations.

"This resolution was only previously achievable through invasive and repeated profiling of fresh tissue biopsies," the authors explained, noting that "our work advances ctDNA profiling from an emerging tool for the detection of selected clinically actionable gene mutations, towards a modality for genome-scale discovery and deep clinical-biological insight in progressing metastatic cancers."

In prostate cancer cases marked by the ability to dodge androgen receptor inhibitor treatment, for example, the team identified resistance-related alterations by comparing ctDNA profiles in blood plasma samples collected before and after treatment.

The most prominent resistance-related shifts involved a rise in tumor populations with enhanced AR gene activity, the researchers noted, and AR-related transcription factor signaling appeared to shift as androgen receptor inhibitor resistance increased — detected with the help of nucleosome footprints gleaned from deep ctDNA sequences and cell-free DNA fragment patterns.

All told, the team identified almost 687,300 somatic mutations and some 16,200 structural variants across the ctDNA and metastatic tumor samples tested, including inactivating tumor suppressor alterations, DNA repair gene mutations, and gene fusions.

Mutations in the metastatic tumors typically turned up through deep sequencing on a patient's ctDNA, the investigators reported. But the ctDNA collection tended to be more complex and comprehensive than mutation profiles for individual tumors since the tumor DNA in circulation included driver mutations and snippets of clones found across all of the metastatic tumors present.

"Although tissue and ctDNA showed concordant clonally expanded cancer driver alterations, most individual metastases contributed only a minor share of total ctDNA," the authors explained.