LIQUID BIOPSY AFTER CYSTECTOMY

Measuring tumor-specific mutations in blood and urine samples may be useful for monitoring response to treatment and identifying early signs of metastases after radical cystectomy in patients with advanced bladder cancer, researchers in Denmark suggest.

Up to 80% of patients who undergo radical cystectomy experience relapse, and minimally invasive methods to detect it early as well as monitor treatment response, are needed, according to Drs. Lars Dyrskjoet Andersen and Karin Birkenkamp-Demtroeder, both of Aarhus University Hospital.

The team previously showed that circulating tumor DNA (ctDNA) is detectable in liquid biopsies from patients with bladder cancer and that rising levels of ctDNA are associated with disease progression.

Therefore, they investigated whether the marker could be used to detect metastatic relapse after cystectomy and measure treatment efficacy in 60 patients with muscle-invasive bladder cancer recruited prospectively between 2013 and 2017. Fifty were scheduled for neoadjuvant chemotherapy and 10 for chemotherapy due to metastatic disease.

DNA from all patients was screened for mutations. In addition, exome sequencing was done on tumor and germline DNA from 24 selected patients, from which digital droplet polymerase-chain-reaction assays targeting genetic variants and mutations were designed. In total, 84 tumor-specific assays targeting 61 genes were tested for specificity in 370 liquid biopsies (271 from plasma, 99 from urine).

As reported in European Urology, online September 25, patients with metastatic relapse had significantly higher ctDNA levels than disease-free patients. The median positive lead time between ctDNA detection in plasma and a relapse diagnosis was 101 days after cystectomy.

The authors conclude that “early detection of metastatic relapse and treatment response using liquid biopsies represents a novel, highly sensitive tool for monitoring patients, supporting clinicians, and guiding treatment decisions.”

However, Drs. Andersen and Birkenkamp-Demtroeder told Reuters Health in a joint email that before the tool can be used in the clinic, “we need to initiate new clinical trials on more patients to determine test cut-off values, as well as the clinical benefit of, for example, earlier therapeutic treatment upon tumor DNA detection in blood.”

“In addition,” they said, “analysis pipelines need to be established for fast analysis and reporting for routine clinical use.”

Dr. Shikha Jain of Northwestern Medicine in Chicago told Reuters Health, “A ctDNA analysis may be a way to detect minimal residual disease with the possibility of uncovering treatment failure earlier than was possible previously.”

“This may allow for earlier treatment changes directed by disease that was previously undetectable by other interventions,” she said by email. “This may result in improving progression free and overall survival.”

However, she agreed that “further studies are needed in order for this type of testing to be utilized in a clinical setting.”

“Low levels of ctDNA may be evidence of minimal residual disease, or may not be clinically significant,” she noted. “The concern would be that in patients with low levels of ctDNA, systemic therapy may be changed unnecessarily or prematurely.”

“The study is limited by its small size,” she added, “as well as the inability to monitor for novel mutations that developed during evolution of the tumors.”