The American Society of Clinical Oncology Genitourinary Cancers Symposium (ASCO-GU 2023) kicked off in San Francisco on February 16, 2023. On the second day of the conference, during a special session on urothelial carcinoma, Professor Kyle M. Rose from the H. Lee Moffitt Cancer Center presented a prospective study on using cfDNA/utDNA for MRD detection in NMIBC patients undergoing repeat-transurethral resection of bladder tumor (rTURBT).

01 Non-Muscle-Invasive Bladder Cancer (NMIBC) MRD Detection using Urine Tumor Cell-Free DNA before Second Transurethral Resection: A Prospective Study (Abstract No: LBA445)

Recently, liquid biopsies have become an important tool for tumor screening and monitoring. Cell-free DNA (cfDNA) has emerged as a novel biomarker for urothelial carcinoma, showing great potential in detecting minimal residual disease (MRD) in muscle-invasive bladder cancer (MIBC) and metastatic bladder cancer. Urine tumor DNA (utDNA) can be directly shed from tumors into urine and can pass through kidney glomerular filtration. It is suitable for tumors with less circulating tumor DNA (ctDNA), such as non-muscle invasive bladder cancer (NMIBC). This prospective study aimed to assess the efficacy of utDNA for MRD detection in NMIBC patients undergoing second transurethral resection (rTURBT).

The study included 11 high-risk NMIBC patients. Whole exome sequencing (WES) was performed on the index tumor and rTURBT tumor tissues. Before rTURBT, urine was collected for utDNA detection. The utDNA test was carried out through ultra-deep sequencing of urine cfDNA, using a customized panel of up to 50 baseline mutations for each patient, as well as through the PredicineBEACON panel that covers hotspot regions and actionable variants. The primary endpoint was the detection of utDNA to predict MRD at the time of the second resection..

In the WES (Whole Exome Sequencing) testing: Residual tumors were detected in 8 out of 11 patients (73%) who underwent the second resection. The WES tests of the index tumor and the tumor from the second resection identified 146 and 91 non-synonymous (NS) mutations, respectively.

The consistency of WES (Whole Exome Sequencing) testing between the index tumor and the tumor from the second resection was 83%. The highest consistency was found in tumors with muscle-invasive features, while the lowest consistency was observed in carcinoma in situ (CIS) of the bladder.

In the utDNA (urine tumor DNA) testing: Tumor-characteristic variations were detected in 10 out of 11 patients (91%). All patients with visible tumor lesions during the second resection had positive utDNA tests. The most commonly detected mutations in utDNA were: TP53 (45%), KMT2D (36%), RB1 (27%), CDKN1A (18%), and PIK3CA (18%).

In general, 50% of utDNA mutations were consistent with the index tumor tissue, 39% were consistent with the rTURBT tissue, and 33% were consistent with all three. In patients with visible tumors during the second resection surgery, a higher utDNA tumor score was observed (2.5% vs. 0.2%, P=0.10). The utDNA score for predicting MRD had an area under the receiver operating characteristic curve (AUC) of 0.85, sensitivity of 75%, and specificity of 100%.

In summary, these research findings indicate that there are highly consistent mutation characteristics found in index tumors and secondary resection tumors. Additionally, utDNA demonstrates better consistency with index tumors compared to the consistency between secondary resection tissue and index tumors. The use of utDNA tumor scores for predicting Minimal Residual Disease (MRD) shows high specificity (75%) and sensitivity reaching 100%. Therefore, utDNA holds promise as an alternative biomarker for MRD detection in patients undergoing secondary resection, and it may have the potential to predict the pathology of Transurethral Resection of Bladder Tumor (TURBT) in Non-Muscle-Invasive Bladder Cancer (NMIBC). Future research will require larger cohorts and long-term follow-up to determine whether utDNA can be used to stratify patients before rTURBT and predict recurrence and long-term outcomes.

Reference :

[1]Kyle M.Rose,et al.Cell-free urinary tumor DNA to detect minimal residual disease prior to repeat-transurethral resection of bladder tumor in non–muscle-invasive bladder cancer:A prospective study.J Clin Oncol 41,2023(suppl 6;abstr LBA445)

[2]Zhang R,Zang J,Xie F,et al.Urinary Molecular Pathology for Patients with Newly Diagnosed Urothelial Bladder Cancer.J Urol.2021;206(4):873-884.doi:10.1097/JU.0000000000001878