Joshua Linscott, MD, PhD, discusses the use of utDNA to predict MRD prior to repeat TURBT in patients with high-risk non-muscle invasive bladder cancer.

Dr Linscott on the Use of Urinary Cell-free Tumor DNA to Predict MRD in High-Risk NMIBC

Joshua Linscott, MD, PhD, urologic oncologist, Moffitt Cancer Center, discusses the background of a clinical trial that investigated the use of urinary cell-free tumor DNA (utDNA) to predict minimal residual disease (MRD) prior to repeat transurethral resection of bladder tumors (rTURBT) in patients with high-risk non-muscle invasive bladder cancer (NMIBC).

This prospective study focused on patients who underwent either initial TURBT or, more commonly, rTURBT, as part of their treatment for high-risk NMIBC, Linscott begins. Investigators at Moffitt Cancer Center collect urine samples from these patients throughout their treatment. The goal of this study was to assess the use of utDNA to detect MRD and evaluate its potential role in ongoing surveillance, Linscott explains. The study investigated whether tumor fraction and copy number burden (CNB) from utDNA can serve as reliable biomarkers for detecting MRD prior to rTURBT, he adds.

The field of cell-free DNA is rapidly advancing, with implications across various cancer types, and it is especially promising in bladder cancer, Linscott continues. Numerous studies have demonstrated that bladder tumors release cell-free DNA into the urine, making the urine an accessible source for detecting genomic alterations in localized disease, he emphasizes. In early-stage bladder cancer, plasma or circulating tumor DNA levels tend to be lower and less detectable, Linscott expands. However, since urine is constantly in contact with bladder tumors, it provides a more reliable source for detecting utDNA and assessing tumor activity, he adds. This study used whole-genome sequencing to detect utDNA and estimate CNB, along with MRD sequencing probes that were personalized to each patient and derived from somatic variants in their initial tissue samples, Linscott notes. Ultimately, this approach could revolutionize the way oncologists monitor MRD and disease progression, offering a non-invasive and highly sensitive method for assessing tumor activity in patients with bladder cancer, he concludes.

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Dr Linscott on the Need for Improved MRD Detection in High-Risk NMIBC

Joshua Linscott, MD, PhD, urologic oncology fellow, Moffitt Cancer Center, discusses the rationale for a study evaluating a urinary cell-free tumor DNA (utDNA) assay for minimal residual disease (MRD) detection in patients with high-risk non–muscle-invasive bladder cancer (NMIBC).

Patients with high-risk, NMIBC frequently experience disease recurrence, although progression to muscle-invasive disease is relatively uncommon, Linscott begins. Current recurrence surveillance strategies involve invasive procedures, primarily cystoscopy, conducted every 3 to 6 months until a recurrence occurs, he notes. These monitoring strategies underscore the need for more efficient and less invasive diagnostic tools that can accurately detect disease recurrence and assess the risk of progression, Linscott emphasizes. Additionally, there is a pressing need to identify predictive biomarkers that can guide treatment decisions and personalize therapeutic approaches for this population, he says. Understanding which patients are at risk of progression can inform clinical decision-making, allowing for more personalized treatment approaches, Linscott explains.

, Linscott and colleagues presented findings from a study evaluating the use of a utDNA assay to predict MRD prior to repeat transurethral resection of bladder tumor patients with high-risk NMIBC. In this setting, patients have undergone primary tumor resection, resulting in a lower tumor burden and reduced levels of circulating cell-free DNA, according to Linscott. This scenario mirrors early recurrence, where tumor presence remains minimal, he adds. By selecting high-risk patients who have undergone initial tumor resection and are scheduled for a standard repeat resection, this study targeted those likely to harbor MRD. Accordingly, this is an ideal population for assessing the efficacy of the utDNA assay, he explains.

This study aimed to determine the accuracy and reliability of noninvasive testing for detecting residual disease in this population. Investigators hypothesized that success in this population would validate the test’s utility in identifying MRD and support its potential application for detecting early recurrence in patients with NMIBC, Linscott says.

Joshua Linscott, MD, PhD, discusses a study evaluating a utDNA assay for minimal residual disease detection in patients with high-risk NMIBC.

Dr Linscott on Future Directions for utDNA Research in Bladder Cancer

Joshua Linscott, MD, PhD, urologic oncology fellow, Moffitt Cancer Center, discusses the use of tumor fraction and copy number burden from urinary cell-free tumor DNA (utDNA) to predict minimal residual disease (MRD) prior to standard repeat transurethral resection of bladder tumors (rTURBT) in high-risk non–muscle-invasive bladder cancer (NMIBC).

A study enrolled and collected urine samples from 53 patients with high-risk NMIBC prior to undergoing rTURBT. Investigators then measured tumor fraction and copy number burden levels in utDNA derived from the samples. Findings from this study, which were presented at the 

, demonstrated that the utDNA technology detected MRD in 68% of patients. Furthermore, the copy number burden score detected MRD with an overall area under the curve (AUC) of 0.86. In patients with personalized tumor fraction (n = 34), MRD was detected with an AUC of 0.89.

The findings from this study are broadly applicable across bladder cancer research, Linscott begins, adding that this approach could improve patient surveillance and treatment personalization. Although this study was conducted in patients with NMIBC, utDNA results could also be extrapolated to patients with muscle-invasive bladder cancer (MIBC), including those receiving neoadjuvant chemotherapy, he explains.

In the future, Linscott and colleagues may investigate different prognostic signatures to predict which patients with bladder cancer may respond to certain treatments, including those with advanced disease who receive neoadjuvant chemotherapy, he notes. utDNA surveillance may also be used to evaluate whether certain patients with MIBC who achieve a complete response with neoadjuvant chemotherapy may be candidates for bladder-sparing treatment, Linscott emphasizes.

Overall, analysis of utDNA prior to transurethral resection may benefit patients with bladder cancer, ensuring more precise and effective treatment plans, Linscott says. Despite the nascent stage of this technology, its potential is vast and relatively untapped, Linscott concludes.

Joshua Linscott, MD, PhD, discusses a study investigating the use of utDNA to predict MRD prior to rTURBT in NMIBC.

Dr Linscott on Urinary Cell-free Tumor DNA to Predict MRD in High-risk NMIBC

Joshua Linscott, MD, PhD, urologic onologist, Moffitt Cancer Center, discusses findings from a study investigating the use of urinary cell-free tumor DNA (utDNA) to predict minimal residual disease (MRD) prior to repeat transurethral resection of bladder tumors (rTURBT) in patients with high-risk non-muscle invasive bladder cancer (NMIBC).

The study investigated the efficacy of using tumor fraction and copy number burden (CNB) from utDNA as biomarkers for detecting MRD. Linscott explains that genomic alterations detected in utDNA are concordant with those from tissue samples in urothelial carcinoma. This study evaluated whether utDNA alterations and CNB could serve as reliable indicators of MRD before standard-of-care rTURBT.

, Linscott and colleagues presented data from 53 patients with high-risk NMIBC, comparing utDNA from urine samples collected before rTURBT with tissue samples from initial TURBT (iTURBT). Low-pass whole-genome sequencing was used to detect utDNA and estimate CNB. Tumor fraction was measured using personalized ultra-deep sequencing MRD probes designed from somatic variants in iTURBT tissue.

Key findings revealed that MRD was detected in 68% of patients through pathologic evaluation. The CNB score from urine samples collected prior to rTURBT showed an area under the curve (AUC) of 0.85, with a CNB threshold of 6.14, yielding a positive likelihood ratio of 11.7 and a negative likelihood ratio of 0.37 for detecting MRD. For personalized urinary tumor fraction (n = 34), the AUC was approximately 0.89. The median urinary tumor fraction was approximately 3.5% for patients with MRD and was undetectable in disease-free patients (

< 0.001). Combining CNB and tumor fraction in a step-wise model improved the performance of the assay, achieving approximately 85.7% sensitivity, 100.0% specificity, and 90% overall accuracy.

Linscott highlights the significance of these findings, noting that utDNA is a robust tool for detecting MRD in patients with high-risk NMIBC. He emphasizes that the combination of structural changes detected by CNB and specific point mutations measured by tumor fraction resulted in high levels of MRD detection accuracy.

The study observed that MRD can be detected with high accuracy using utDNA prior to rTURBT, providing a promising noninvasive biomarker. If validated, this approach could identify patients needing maximal resection before intravesical therapy, ultimately improving patient outcomes.

Joshua Linscott, MD, discusses using urinary cell-free tumor DNA to predict minimal residual disease in high-risk non-muscle invasive bladder cancer.

Joshua Linscott, MD

Articles

Dr Linscott on the Use of Urinary Cell-free Tumor DNA to Predict MRD in High-Risk NMIBC

Dr Linscott on the Need for Improved MRD Detection in High-Risk NMIBC

Dr Linscott on Future Directions for utDNA Research in Bladder Cancer

Dr Linscott on Urinary Cell-free Tumor DNA to Predict MRD in High-risk NMIBC