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What Can Be Learned From ctDNA About Treatment-Resistant Prostate Cancer? Researchers Say a Lot

By: Victoria Kuhr, BA
Posted: Tuesday, August 30, 2022

Circulating tumor DNA (ctDNA) in blood plasma may be used as a tool for comprehensive multiomic discovery for patients with treatment-resistant prostate cancer. Alexander W. Wyatt, PhD, of the Vancouver Prostate Centre, University of British Columbia and the Michael Smith Genome Sciences Centre, BC Cancer, Vancouver, and colleagues demonstrated that the use of ctDNA revealed mRNA expression in synchronously biopsied metastases, including treatment-induced changes in androgen receptor transcriptional activity. These findings were published in Nature.

“This technology can be applied across other types of cancer to understand how those tumors metastasize and how they eventually evade treatment,” said Dr. Wyatt in a University of British Columbia press release. “It will also help us design the next generation of cancer therapies that more effectively target resistant disease.”

The study performed deep whole-genomic sequencing of 61 plasma ctDNA samples and 15 metastatic tissue biopsies from 33 patients with metastatic castration-resistant prostate cancer. An additional nine ctDNA samples were collected: two from patients with metastatic neuroendocrine prostate cancer, two from patients with metastatic bladder cancer, and five from control individuals with no detectable ctDNA.

In total, 687,293 somatic mutations and 16,200 structural rearrangements were identified across the 61 ctDNA and 15 tissue samples. Although tissue and ctDNA samples showed consistent clonally expanded cancer driver alterations, most patients’ metastases contributed a small amount of the total ctDNA. Serial ctDNA was compared before and after clinical disease progression on inhibitors of the androgen receptor pathway. The study authors observed that population restructuring converged on androgen receptor augmentation as the dominant genomic driver of acquired treatment resistance. In several patients, a nondominant ancestral lineage that was present at baseline outcompeted daughter lineages at treatment progression during a selective search. This finding suggests that ancestral tumor lineages may contain clinically important information in treating late-stage diseases.

Disclosure: For full disclosures of the study authors, visit www.nature.com.


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