The Potential of Urine Biomarkers: A New Horizon in Non-Invasive Cancer Detection and Monitoring

The concept of liquid biopsy has revolutionized cancer diagnosis and treatment monitoring. Unlike traditional tissue biopsies, which provide a limited snapshot of the tumor, liquid biopsies can better capture intratumor heterogeneity. They have the advantage of being minimally invasive or even noninvasive, with urine being a prime example of the latter. Urine collection is simple, can be done at home or in a clinical setting, and allows for serial sampling and multiomic analysis. Urine’s role in liquid biopsy is gaining traction across various cancer types due to these advantages​​. Urinary biomarkers fall into several categories: diagnostic, monitoring, predictive, and prognostic. Diagnostic biomarkers identify the presence of disease, monitoring biomarkers assess disease status or treatment response, predictive biomarkers forecast the likelihood of benefit or harm from a specific therapy, and prognostic biomarkers predict disease progression or recurrence. Urine has been primarily utilized for detecting diagnostic biomarkers, followed by prognostic, monitoring, and predictive biomarkers. The analytes detected in urine, including cell-free or cellular DNA and RNA, extracellular vesicles, proteins, and metabolites, highlight urine’s potential as a multiomic sample type, encompassing genomics, epigenomics, transcriptomics, proteomics, metabolomics, and metallomics​​.

In a new expert opinion review published in the International Journal of Cancer by PhD graduate Stephanie Jordaens, Karen Zwaenepoel, Wiebren Tjalma, Christophe Deben, Koen Beyers, Vanessa Vankerckhoven, Patrick Pauwels, and led by Professor Alex Vorsters from the University of Antwerp conducted a comprehensive and systematic analysis of the current state of urine sampling as a liquid biopsy tool for noninvasive cancer research. They focused on exploring the use of urine in detecting various cancer types, examining the preanalytical parameters and methodologies employed in this emerging field. They reviewed a vast array of literature, searching through major health and life sciences databases, including PubMed and ISI Web of Science, covering publications from 2010 to 2022. From the eligible publications, they extracted data on various aspects such as study population characteristics, cancer types, urine preanalytics, analyte classes, isolation and detection methods, and the types of biomarkers used. They organized their findings to present a comprehensive overview of urine as a liquid biopsy tool, covering its application in different cancer types, the variety of biomarkers investigated, and the methods used in these studies.

According to the authors, a significant challenge in the field is the lack of standardization in preanalytical parameters like sample collection, preservation, and storage. Most publications in this area fail to report these critical parameters, even though they significantly impact biomarker stability and accuracy. When preservation methods are mentioned, ethylenediaminetetraacetic acid (EDTA) or commercial methods are commonly used. The presence of nucleic acid-hydrolyzing enzymes in urine necessitates careful consideration of preservation methods to prevent DNA degradation​​.

The authors discussed some interesting cancer-specific applications. For instance, in urological cancers, particularly prostate cancer (PCa) and bladder cancer, there have been significant advances in the use of urinary biomarkers. There are FDA-approved or CLIA tests available for these cancers, highlighting the clinical utility of urine-based biomarkers in this field​​. Whereas in urothelial cancer, various analytes like cells, DNA (cell-free and cellular), exosomes, metabolites, proteins, and RNA have been investigated. About 30% of the studies focused on protein biomarkers. Studies have shown that urinary cellular DNA in urothelial cancer originates from cancer cells shed directly into the urine​​. While in prostate cancer research a wide range of urinary biomarkers were explored, though there is limited information on urine type or preservation methods used in these studies​​. Additionally, the authors discussed current research on gynecological cancers, particularly cervical cancer, endometrial cancer, and ovarian cancer, has primarily focused on Human Papillomavirus (HPV) detection. The majority of these studies used commercially available methods or EDTA for preservation. According to the authors, first-catch urine samples offer higher accuracy in HPV detection compared to other types​​.

The review highlights the increasing interest in using urine as a noninvasive, easily accessible sample type for cancer detection and monitoring, expanding beyond traditional blood-based liquid biopsies. By pointing out the lack of standardization in preanalytical methods, the review highlights a critical gap in current research practices, suggesting that addressing these inconsistencies is essential for advancing the field. Moreover, the authors illustrated the versatility of urine biomarkers across a wide range of cancers, not limited to the urogenital tract. This broad applicability underlines the potential of urine biomarkers in advancing cancer diagnostics and personalized medicine. The detailed analysis of current practices and methodologies in the review serves as a valuable resource for guiding future research, aiding in the development of standardized protocols, and paving the way for clinical applications. The challenge ahead lies in standardizing methodologies and ensuring consistency across studies to fully realize the potential of urine biomarkers in clinical oncology. Furthermore, the review’s insights into the noninvasive nature, ease of collection, and the potential for serial sampling of urine biomarkers underscore their significance in improving cancer diagnosis, monitoring treatment responses, and possibly enhancing patient quality of life.