Clinical Implementation of Minimal Residual Disease Testing in Genitourinary Cancers: Bridging Promise and Practice

Detection of minimal residual disease (MRD) represents a significant advance for precision oncology across many cancer types. In this issue of European Urology, Barata and colleagues [1] provide a comprehensive review of emerging technologies for detecting and monitoring MRD in genitourinary cancers. The emergence of highly sensitive molecular assays and novel imaging modalities offers unprecedented opportunities to detect occult disease and to monitor treatment responses more precisely. As these technologies move closer to clinical implementation, careful navigation of technical and practical challenges will be required for successful integration into practice.

The applications of MRD biomarkers span the entire disease continuum, offering potential benefits at multiple critical decision points in patient care. At initial diagnosis, enhanced detection sensitivity could significantly improve staging accuracy and facilitate more precise selection of treatment modality and intensity. In the post-treatment setting, early detection of recurrence might allow more timely intervention, while sophisticated response monitoring could help in optimizing both treatment duration and selection. In the metastatic setting, these biomarkers may provide deeper insights into treatment responses and disease progression and could potentially add value to conventional imaging and clinical biomarker to allow earlier detection of treatment resistance and more precise assessment of disease burden. Such findings suggest a future in which treatment decisions are increasingly guided by molecular evidence of disease status.

In general, MRD testing in oncology can span a broad range of assays, including tissue-based evaluation in the neoadjuvant setting, molecular imaging with sensitive, tumor-specific positron emission tomography (PET) tracers, and liquid biopsies such as circulating tumor DNA (ctDNA) detected and quantified in blood, urine, and other fluids. As MRD assays enter clinical practice, they are increasingly driving changes in treatment decisions, from therapy escalation and de-escalation to metastasis-directed approaches and local treatment modifications. Clinical adoption has outpaced evidence that treatment changes based on these biomarkers improve patient outcomes, creating a concerning gap between technological capability and clinical validation. While the potential to augment treatment decisions exists, robust data demonstrating that biomarker-driven changes actually improve patient outcomes are largely lacking. This disconnect between implementation and validation represents a critical challenge that can only be addressed via carefully designed prospective clinical trials.

To realize what has been achieved in the management of some hematological malignancies, several fundamental challenges must be addressed before these promising technologies can be widely adopted in clinical practice for patients with genitourinary malignancies. Heterogeneity in biomarker expression presents a multidimensional challenge that spans cellular, spatial, temporal, and interpatient domains [2]. In prostate cancer, recent studies have revealed extensive heterogeneity in prostate-specific membrane antigen (PSMA) expression that manifests across multiple levels, from varying expression between different cells within the same tumor to differences across metastatic sites and changes over time during treatment. This complexity is particularly evident in advanced disease, in which PSMA expression can be suppressed in treatment-emergent neuroendocrine variants and show marked variability in liver metastases in comparison to other sites [3]. Even within PSMA-positive tumors, the degree and pattern of expression can vary significantly, affecting both imaging characteristics and the potential efficacy of PSMA-targeted therapeutics. Similar challenges exist in renal cell carcinoma (RCC), for which there are limited data on the modulation of CA9 expression in response to VEGF-targeted therapies and immunotherapy, resulting in uncertainty about the reliability of CA9 as a biomarker over the course of treatment. An understanding of these various dimensions of heterogeneity is crucial in improving our ability to accurately detect and monitor MRD.

As imaging and molecular MRD assays evolve to guide clinical decision-making, standardization of detection thresholds, sensitivity, specificity, and positive and negative predictive values across diverse patient populations remains a crucial challenge. For PSMA-based PET imaging, the definition of positivity varies across studies and clinical contexts, with different criteria using varying reference standards such as liver or parotid uptake to define positivity when evaluating disease in localized, biochemically recurrent, or metastatic settings or determining candidacy for radioligand therapy. In parallel, the technical definition of molecular MRD positivity on the basis of ctDNA varies significantly across genitourinary malignancies, reflecting their distinct biological behaviors and DNA shedding patterns. Plasma testing for MRD typically requires deep sequencing to achieve the high sensitivity and specificity needed to detect low amounts of ctDNA. Urothelial carcinoma has emerged as a prototype for ctDNA detection, with studies using a tumor genotype–informed bespoke assay demonstrating excellent sensitivity and specificity in detecting MRD. In addition, ctDNA positivity is emerging as a potential predictive marker of benefit from adjuvant immunotherapy, as demonstrated in the IMvigor010 trial [4]. Novel approaches are being developed to overcome detection challenges, particularly in RCC, which is characterized by low rates of DNA shedding. These include DNA methylation profiling using cell-free methylated DNA immunoprecipitation sequencing and analysis of fragmentomic features such as fragment size distribution and end motifs, which have shown promise in improving detection beyond conventional mutation-based approaches that have been limited by detection rates [5,6]. In testicular cancer, microRNA (miRNA)-based testing, particularly for miR-371a-3p, has shown excellent diagnostic performance, with >90% sensitivity and specificity across multiple clinical settings including primary diagnosis, post-treatment monitoring, and early detection of relapse, significantly outperforming traditional serum markers [7]. miR-371a-3p levels also have utility in discriminating viable cancer from teratoma in postchemotherapy residual masses [8]. Looking ahead, successful clinical implementation of these emerging biomarker platforms will require careful standardization of detection methods and definitions of both negativity and positivity criteria for each assay.

The experience with prostate-specific antigen (PSA) offers valuable lessons for the development and implementation of new MRD biomarkers. While PSA revolutionized prostate cancer detection and monitoring, it also led to instances of overdiagnosis and overtreatment with noncurative therapies, highlighting the critical importance of establishing clinically meaningful thresholds via prospective validation studies. In the metastatic setting, treatment decisions are not based on PSA changes alone but require integration with clinical assessment and radiologic findings, underscoring the need to interpret even well-established biomarkers within a broader clinical context. The PSA experience emphasizes the need to establish relevant diagnostic parameters, account for leadtime bias in outcome interpretation, and maintain the crucial distinction between detecting disease and improving clinically meaningful patient outcomes.

The bar for clinical implementation of new MRD biomarkers must be appropriately high. The level of evidence required should match the clinical impact of decisions being guided by the biomarker. Use of MRD status to de-escalate therapy, for instance, requires particularly robust validation to ensure treatment efficacy is not compromised. The ongoing MODERN trial in bladder cancer exemplifies the type of rigorous study needed, and is prospectively evaluating whether MRD status can safely guide treatment decisions to improve outcomes for patients.

Practical considerations for implementation present additional challenges that must be addressed. Cost and access remain significant concerns, as novel imaging and molecular tests are often expensive and may not be uniformly available, potentially exacerbating existing health care disparities in underserved and under-represented populations. Health care systems must consider both the direct costs of testing and potentially longitudinal evaluation, and the broader economic implications of implementing MRD-guided treatment strategies. Scalability, turnaround time, and integration with clinical workflows must also be carefully considered to ensure that these technologies can be effectively implemented in real-world practice and made accessible across diverse health care settings.

As we move forward, the development of MRD biomarkers represents a crucial advance in genitourinary cancer care, but successful implementation requires careful attention to multiple factors. Future research should focus not just on technical validation but also on demonstrating clinical utility via well-designed trials. The promise of MRD detection to facilitate more personalized treatment approaches is significant, but realization of this potential requires a balanced approach that learns from past experiences while embracing new technologies. Success will ultimately require continued collaboration between researchers, clinicians, and health care systems to ensure these promising tools truly deliver a benefit in patient care.