Youssef J, Yehya A, Salhab Z, Bitar R, Ghamlouche F, Bahmad HF, Abou-Kheir W. Liquid biopsy in genitourinary cancers: Diagnostic and prognostic implications. World J Clin Oncol 2025; 16(12): 113578 [DOI: 10.5306/wjco.v16.i12.113578]
Corresponding Author of This Article
Wassim Abou-Kheir, PhD, Full Professor, Department of Anatomy, Cell Biology and Physiological Sciences, American University of Beirut, Bliss Street, Hamra, Beirut 1107-2020, Lebanon. wa12@aub.edu.lb
Research Domain of This Article
Oncology
Article-Type of This Article
Review
Open-Access Policy of This Article
This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
Joe Youssef, Amani Yehya, Zahraa Salhab, Ricardo Bitar, Fatima Ghamlouche, Wassim Abou-Kheir, Department of Anatomy, Cell Biology and Physiological Sciences, American University of Beirut, Beirut 1107-2020, Lebanon
Hisham F Bahmad, Department of Pathology and Laboratory Medicine, University of Miami, Miller School of Medicine, Miami Beach, FL 33136, United States
Co-corresponding authors: Hisham F Bahmad and Wassim Abou-Kheir.
Author contributions: Youssef J, Yehya A, Salhab Z, Bitar R, and Ghamlouche F contributed investigation, methodology, and wrote the original draft; Youssef J, Bahmad HF, and Abou-Kheir W contributed to conceptualization and visualization; Youssef J, Yehya A, Salhab Z, Bitar R, Ghamlouche F, Bahmad HF, and Abou-Kheir W contributed to validation, reviewed and edited the manuscript; Bahmad HF and Abou-Kheir W contributed to project administration, supervision, gave final approval, and made equal contributions as co-corresponding authors; all authors have read and approved the final manuscript.
Conflict-of-interest statement: All the authors report no relevant conflicts of interest for this article.
Open Access: This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: https://creativecommons.org/Licenses/by-nc/4.0/
Corresponding author: Wassim Abou-Kheir, PhD, Full Professor, Department of Anatomy, Cell Biology and Physiological Sciences, American University of Beirut, Bliss Street, Hamra, Beirut 1107-2020, Lebanon. wa12@aub.edu.lb
Received: September 2, 2025 Revised: September 30, 2025 Accepted: November 10, 2025 Published online: December 24, 2025 Processing time: 112 Days and 12.8 Hours
Abstract
Genitourinary neoplasms, including bladder, prostate, renal, and testicular cancers, represent 25% of all solid tumors worldwide. Great advances have been achieved in the last few decades in diagnostic and therapeutic modalities. Among these, liquid biopsy (LB) technology has evolved during the past few years and offers emerging and novel modalities in the field of oncology. LB is performed by withdrawing bodily fluids (i.e., blood or urine) and looking for circulating tumor DNA, circulating tumor cells, extracellular vesicles, and non-coding RNAs, among others. Over the past years, several technologies have been developed to isolate and analyze the tumor burden. LB is less invasive than traditional biopsies and has many applications, including early screening, providing diagnostic cues, predicting disease severity and survival outcomes, assessing response and resistance to treatment, detecting minimal tumor burden before radiological evidence, and monitoring for disease recurrence. However, multiple challenges still need to be addressed, including reduction in variability between assays, standardization of protocols, and validation in large trials to ensure reliability. This review will focus on the latest advancements in LB applications for diagnostic and prognostic characterization of genitourinary cancers.
Core Tip: Liquid biopsy (LB) is emerging as a new tool to help the oncologist for early screening and prognostication. The diagnostic accuracy of the different LB modalities is improving with newer techniques, showing promises in the future for early detection of malignancies. In specific, genitourinary cancers can be screened and followed up through urine LB, offering a non-invasive longitudinal tool for patient monitoring. LB offers new ways to predict disease progression, treatment response and early recurrence, reshaping the future of oncology.
Citation: Youssef J, Yehya A, Salhab Z, Bitar R, Ghamlouche F, Bahmad HF, Abou-Kheir W. Liquid biopsy in genitourinary cancers: Diagnostic and prognostic implications. World J Clin Oncol 2025; 16(12): 113578
Urological cancers form a major part of the global burden of cancer, contributing to 2.25 million cases and over 800000 deaths in 2021[1]. Prostate cancer (PC) accounted for the largest share of incidence and mortality, followed by bladder cancer (BC) and renal cell carcinoma (RCC)[1]. Finally, testicular cancer (TC), while less common overall, holds unique importance as the most frequent solid tumor in young men[2]. Each of these cancers presents with distinct epidemiological and clinical characteristics, and thus unique challenges.
As the second most common cancer in men globally and the most common cause of cancer-related death in around a quarter of the world’s countries[3], PC contributed to 1.32 million cases and around 432000 deaths in 2021[1]. Because of its prevalence, screening for PC is gaining acceptance, with the main tools including prostate-specific antigen (PSA), multiparametric magnetic resonance imaging, and targeted or systematic biopsy[4]. BC is a much less prevalent but still significant disease globally being the 9th most commonly diagnosed cancer and the 13th leading cause of cancer-related mortality[5]. Most new cases of BC are classified as non-muscle invasive (NMIBC), a diagnosis that carries a low risk of progression (15%) but a high risk of recurrence (70%-80%)[5]. As a result, patients with BC need follow-up, mainly with cystoscopy which is an invasive and expensive procedure[6]. RCC forms the majority of kidney cancers and is the 12th most common cancer worldwide, excluding blood neoplasms[7]. Early RCC has a much better prognosis than RCC with metastases (5-year survival rate of 93% vs 12%)[7]. Moreover, this cancer is generally resistant to chemotherapy[7], making early detection and monitoring essential. Testicular germ cell tumors (TGCT) are an even rarer form of cancer, constituting approximately 1% of male cancers, but are the most frequent cancer in adolescents and young adults, with incidence increasing in recent decades[2]. With modern therapy, prognosis is excellent, with localized disease reaching essentially a 100% cure rate and metastatic disease yielding long-term survival of around 80%-90%[8]. Despite these advances, 15%-20% of patients relapse or develop treatment-refractory disease[8]. Thus, early detection of relapses is essential. A common theme among these four neoplasms is the presence of diagnostic challenges. As early stage tumors tend to be asymptomatic (PC[3]) or easier to treat (RCC[7]), and as repeated testing might be needed to detect recurrence (BC[6], TC[8]), there is a definite need for better biomarkers.
The emergence of liquid biopsy (LB) technologies offers one promising solution to the aforementioned issues. LB refers to a minimally invasive sampling of blood or other bodily fluids to detect tumor components and metabolites[9]. This approach enables detection of molecular alterations associated with cancer. Common LB analytes include circulating tumor cells (CTC), circulating tumor DNA (ctDNA), extracellular vesicles (EVs)/exosomes and non-coding RNAs (ncRNAs)[9,10].
CtDNA consists of small fragments of DNA released by tumor cells following apoptosis or necrosis[9]. It represents a small fraction of total cell-free DNA, but is important as it carries tumor-specific genetic and epigenetic alterations (point mutations, copy changes, methylation) that can be detected with polymerase chain reaction (PCR) or sequencing[9,10]. It is already used for genotyping advanced cancers and shows promise in urologic tumors for detecting mutations or minimal residual disease (MRD). Moreover, ctDNA have very short half-lives (minutes to hours) allowing its use to reflect the tumor burden in near real-time[9]. In urological cancers, urine ctDNA is particularly informative since the urothelium is in direct contact with urine. This is particularly relevant in BC. For instance, in the muscle-invasive variant of this disease, tumor DNA was detected in approximately 89% of urine samples as opposed to approximately 43% of matched plasma samples, with urine ctDNA levels significantly higher than plasma (P value < 0.001)[11]. This trend is not applicable to all urological tumors, as illustrated by the lower detection rate of ctDNA in urine of patients with RCC. In patients with this disease, only approximately 28% of plasma-detected alterations were also found in matched urine samples, showcasing lower detection rates, likely due to technical difficulties and biological heterogeneity in ctDNA shedding[12]. CTC are intact cells shed from the main tumor and circulating in the blood. They are exceedingly rare (around 1 per 106-107 leukocytes) and die quickly, but their presence correlates to metastatic potential[9]. As such, they can provide valuable information on tumor dissemination and prognosis.
Tumor cells release exosomes, which circulate freely in bodily fluids. These exosomes, a subtype of EV, originate from multivesicular bodies and carry cargo [DNA, mRNA, microRNA (miRNA), proteins] from the parent cell[9]. Because they protect their contents, exosomal nucleic acids and proteins are more stable than their free counterparts and thus can reflect the tumor microenvironment[9]. MiRNAs are around 18-23 nucleotide ncRNAs that regulate gene expression at a post-transcriptional level[9]. Circulating miRNAs, either free or encapsulated in exosomes, are remarkably stable in blood and urine. Dysregulated miRNAs are common in cancers and can serve as diagnostic or prognostic markers[9].
There are several advantages to the various LB techniques discussed. LB uses blood or urine samples instead of tissue, enabling frequent sampling without increased risk or discomfort[9]. Moreover, tumor-specific alterations can be detected at very low levels, allowing earlier detection than currently possible with available technologies[10]. Seeing as LB markers reflect the current tumor burden and biology, this allows dynamic tracking of the tumor. For example, ctDNA levels often drop rapidly after effective therapy and rise with recurrence, while CTC counts and phenotypes can alert to metastatic progression[9]. Such benefits are especially useful in urological cancers, seeing as their screening and diagnosis present various challenges[4,6,7]. Thus, we will be reviewing the diagnostic and prognostic applications of the different LB modalities in urogenital cancers.
BC
CtDNA
Diagnostic applications: The use of ctDNA in detection and prognostication of BC has been gaining momentum in the past few years. Indeed, several techniques such as next generation sequencing or PCR have allowed the identification of BC ctDNA in both serum and urine (utDNA). While ctDNA gets into the serum through tumor cell apoptosis, necrosis or active secretion, utDNA is a result of both renal clearance and BC direct shedding from the urinary epithelium. In fact, two different sizes of DNA have been identified in urine, pointing out to a dual origin: Low molecular weight utDNA (150 and 250 base pairs) that is filtrated, and high molecular weight utDNA (size above 1k base pairs) that originates from cell shedding[13,14].
The genetic aberrances in BC were extensively studied in the last few years. We now have a better understanding of the genes commonly involved in the tumorigenesis of BC, including but not restricted to FGFR3, ERBB2, PIK3CA, tumor protein P53, and STAG2[15,16]. In light of these findings, a recent meta-analysis examined (Figure 1 and Table 1) showed that ctDNA has moderate diagnostic value compared to traditional gold standards like cystoscopy and pathology, with a sensitivity of 68%, specificity of 76%, positive likelihood ratio of 2.8 and negative likelihood ratio of 0.43[17]. These results showed the limitations of ctDNA use in BC detection. However, since urothelial tumor cells are in direct contact with urine, it was suggested that utDNA would have a better yield in terms of cancer detection[18].
Figure 1 Diagnostic accuracy of liquid biopsy analytes in genitourinary malignancies.
The error bars represent the 95% confidence intervals. To note, all values and 95% confidence interval are derived from the latest meta-analyses looking at these diagnostic markers. No meta-analysis looked at circulating tumor cells for diagnosis in prostate cancer. The bars without error values in positive likelihood ratio and negative likelihood ratio were derived from sensitivity and specificity values. This error bar plot outlines the variation seen in the diagnostic accuracy of the different liquid biopsy analytes, showcasing the limitations in screening and diagnosing genitourinary cancers. It also highlights that these analytes are overall more specific than sensitive. Finally, the error bars demonstrate the variability and lack of standardization of the liquid biopsy modalities, stressing the need for internationally regulated protocols.
Table 1 Diagnostic parameters of liquid biopsy analytes in genitourinary malignancies as reported by meta-analyses.
Indeed, Xu et al[19] studied the expression ratio of an upregulated gene (IQGAP3) to two other downregulated genes (bone morphogenetic protein 4 and family with sequence similarity 107 member A) in utDNA to predict BC in patients with hematuria. The combined use of IQGAP3/bone morphogenetic protein 4 and IQGAP3/family with sequence similarity 107 member A ratio yielded a sensitivity of 71% and specificity of 88.6% in the detection of BC in this population[19]. On the other hand, Cheng et al[20] focused on studying the methylation pattern and copy number aberrations in utDNA. Since utDNA has filtered DNA from different cells in the body, it is essential to first determine the contribution from each type of cell to the overall methylomic. Thus, they demonstrated that BC cells, especially high grade and muscle invasive subtypes, were the main contributors to the difference in methylation pattern in utDNA between healthy and BC patients, ensuring specificity of this test. Cheng et al[20] also showed statistically significant differences in hypomethylation and copy number aberrations between cases and controls. By combining the three approaches, they reached an overall sensitivity of 93.5% and specificity of 95.8% in the detection of BC[20]. Similarly, Xiao et al[21] focused on the DNA methylation signature of BC to differentiate healthy from NMIBC and muscle invasive BC (MIBC) patients. They first demonstrated the high sensitivity of the PCR next generation sequencing assay, as it can distinguish between healthy individuals’ urine and 0.25% utDNA concentrated urine. They also showed that sensitivity and specificity of the assay increased with the stage and grade of the tumor, reaching 100% sensitivity and specificity for high grade BC. Of note, compared to urine sedimentary cells fluorescence in situ hybridization, utDNA next generation sequencing assay was more specific (100% vs 81%; P < 0.001) and more sensitive (low grade BC: 62% vs 28%; P value < 0.01, high grade BC: 100% vs 73%; P value < 0.001)[21]. Similarly, Feber et al[22] developed a 150 loci UroMark assay with 98% sensitivity and 97% specificity. Finally, a subgroup analysis from a meta-analysis demonstrated that urine sediment ctDNA, as compared to urine supernatant ctDNA, has better sensitivity (77% vs 68%) and specificity (87% vs 74%)[23] (Figure 1; Table 1).
Several commercial urine kits are available in the market for BC detection. A recent German multicenter study with a sample size of 732 evaluated the diagnostic characteristics of four kits: BTA stat, NMP22 BladderChek [both Food and Drug Administration (FDA) approved], UBC Rapid Test, and Cancer and Check UBC rapidVISUAL (approved in Europe). The sensitivity ranged from 13.4% to 62.4% for low-grade BC and from 49.5% to 83.4% in high-grade BC, whereas the specificity ranged from 67.9% to 95.5% in overall BC[24]. These kits performed similarly if not better than classical cytology (sensitivity for low-grade BC 36.2%, high-grade BC 71.2% and specificity 67.7%)[24]. Several ongoing studies are prospectively assessing the diagnostic accuracy of ctDNA methylation pattern (NCT06878027; NCT06310759) and detect MRD (NCT05366881).
Prognostic applications: CtDNA and utDNA are also being investigated as prognostic markers of disease recurrence, metastasis, treatment response and resistance. In fact, Christensen et al[25] showed that ctDNA detection at three specific timepoints after diagnosis was prognostic of future recurrence. First, positive ctDNA after transurethral resection of bladder tumor (before chemotherapy) was a marker of residual disease and was associated with 42% 12 months recurrence compared to 3% with negative ctDNA. Furthermore, positive ctDNA after chemotherapy was associated with 75% 12-month recurrence compared to the negative counterpart with 11%. Finally, and most importantly, detection of ctDNA after cystectomy led to 76% overall recurrence compared to 0% in ctDNA negative patients[25]. Besides, in the phase III IMvigor010 trial, ctDNA status in MIBC identified patients who would benefit from atezolizumab adjuvant therapy post cystectomy, with ctDNA positive patients having a worse overall survival (OS) but would have prolonged survival on atezolizumab[26]. Additionally, trends of ctDNA during chemotherapy were associated with therapy response: Patients with no clearance of ctDNA showed no response to therapy[25]. Moreover, Crupi et al[27] showed in their systematic review that ctDNA clearance after two cycles of immunotherapy with atezolizumab was associated with improved disease-free survival and OS.
Similarly, the use of utDNA methylation pattern has also enabled stratification of patients pre-surgically into low and high risk of recurrence of the disease. Indeed, Xiao et al[21] were able to predict BC recurrence using their urine cancer score model (UCAS). 100% of patients (n = 13) with negative UCAS were disease free after 3 years whereas 37% (n = 57) of patients with positive UCAS had disease recurrence at 3 years[21]. Moreover, post-surgical utDNA analysis has also been shown to predict disease recurrence, although with lower sample sizes[21].
CTCs
Diagnostic applications: CTCs are another modality currently being researched as a less invasive diagnostic and prognostic tool in BC. Compared to ctDNA, CTC allow for multi-omics analysis and offer the possibility of studying the tumor biology and metastatic potential[28]. CTC have been mainly investigated for their prognostic value; however, a few studies have investigated their diagnostic potential. In fact, Zhang et al[29] conducted a meta-analysis showing that CTC have a sensitivity of 34%, specificity of 97%, positive likelihood ratio 11.8 and negative likelihood ratio 0.68 in diagnosing BC (Figure 1; Table 1). Therefore, CTC should not be used as an initial screening tool. The poor sensitivity could be partly explained by the difficulty of isolating CTC and differentiating them from normal circulating cells. Indeed, the isolation methods rely on epithelial cell adhesion molecule (EpCAM) and cytokeratin antigen detection to isolate BC-specific CTC, failing to isolate CTC mesenchymal features[30]. Thus, many centers are now working on developing new technologies to enhance CTC detection, which could provide better tools in the future for CTC use in BC diagnosis[30,31].
Prognostic applications: It is now agreed that CTC play a crucial role in metastasis and disease recurrence; therefore, their use as a prognostic marker would give key indications about disease status and evolution. Niu et al[31] recently developed a graphene oxide chip conjugated with antibodies against epidermal growth factor receptor and EpCAM to enhance detection and isolation CTC, allowing them to study the transcriptomic profile of these cells and identifying markers with increased metastatic potential such as a disintegrin and metalloproteinase 15, CD31, epidermal growth factor receptor and human epidermal growth factor receptor 2. Additionally, CTC concentration correlates with the burden of disease and the OS of patients[31]. Indeed, Carrasco et al[32] showed in their study that MIBC patients with high CTC burden (> 52 CTC per 7.5 mL blood) were at higher risk of disease recurrence and metastasis at 12 months post radical cystectomy (P value = 0.009). Additionally, an increase in CTC was indicative of disease recurrence more than 4 months before radiological evidence [120 days vs 255 days (P value = 0.001)][32]. In the CirGuidance open label trial, Beije et al[33] studied CTC as a prognostic marker in patients with non-metastatic MIBC to determine the need for neo-adjuvant chemotherapy (NAC). CTC-negative patients did not receive NAC, while CTC-positive patients were assigned to NAC on an individual basis. In contrast to previous studies, they demonstrated no difference in OS regardless of CTC status (P value = 0.1). However, cancer-specific mortality (mortality attributable to cancer) was higher in CTC-positive patients (P value = 0.03), potentially outlining higher rates of non-cancer related mortality in this study. Relapse rate was similarly shown to be higher in this subcategory of BC patients (P value = 0.001)[33]. Interestingly, CTC-positive patients receiving neoadjuvant chemotherapy had better survival outcomes than CTC-positive patients who directly underwent radical cystectomy. However, the trial did not reach pre-defined thresholds to use CTC as marker for determining NAC need prior to surgery[33]. Finally, CTC have been used as a marker of disease progression in a study evaluating the role of opioids in BC metastasis. Wang et al[34] studied the effect of opioids in mice, and showed that opioids enhance CTC formation by activating the mu-opioid receptor/phosphoinositide 3-kinase/protein kinase B/Slug signaling pathway, thus leading to an increased rate of metastasis. The team then also conducted a randomized control trial, where patients would be assigned to general anesthesia group (GA) receiving opioids during and after surgery, or to GA + epidural group, whereby patients would receive epidural ropivacaine for pain relief. They showed that both groups had similar numbers of CTC immediately after surgery; however, a higher number of CTC was detected in the GA group after 3 days and 1 month than the GA + epidural group[34]. This study demonstrates the use of CTC as a surrogate for early post-surgical disease monitoring, and its use as a marker for intervention outcomes.
EVs and ncRNA
Diagnostic applications: Bladder tumor cells secrete EV as a means of communication; these vesicles hold ncRNA that are stable enough to be extracted and studied, adding an additional tool to the armamentarium of LB[35,36]. A recent meta-analysis conducted by Zhao et al[37] looked at the diagnostic profile of EV in BC (Figure 1; Table 1). Two long ncRNA (lncRNA) have been especially studied in the literature: UCA1 and MALAT1. UCA1 plays a role in cell proliferation, invasion and chemoresistance to cisplatin, while MALAT1 is involved in metastasis[38]. UCA1 and MALAT1 have a sensitivity of 75% and 74% and specificity of 78% and 74% respectively[37]. Moreover, the diagnostic accuracy increases with the analysis of multi-lncRNA panel, with sensitivity of 81% and specificity of 80%. Furthermore, when looking at exosomal miRNA, the sensitivity and specificity were higher (80% and 87% respectively), with an area under the curve (AUC) of 0.91[37].
Similarly to ctDNA, BC tissues release EC into the urine (uEV), making them a valuable tool for non-invasive serial follow-up. In a recent meta-analysis pooling 77 studies (Figure 1; Table 1), the overall sensitivity and specificity of uEV in diagnosing BC were 75% and 77% respectively[39]. Moreover, in the subgroup analysis, they showed that lncRNA are the most sensitive (78%) while miRNAs are the most specific (0.81%). However, it is important to be cautious while interpreting these results since the number of studies looking at miRNA was much smaller compared to lncRNA. Finally, as for serum lncRNA, multi-lncRNA analysis had higher sensitivity and specificity than each individual lncRNA[39]. Moreover, Sun et al[40] recently looked at a combination of three uEV mRNA (SRGN, FLI1, and MACROH2A2), reaching a high level of accuracy (sensitivity 92.8%; specificity 96.4%). This combination distinguished early stage BC from healthy controls with an AUC of 0.969[40].
Prognostic applications: The different ncRNA present in EV have also been associated with prognostic outcomes in BC patients. For instance, increased levels of MALAT-1 and PCAT-1 lncRNA in uEV were associated with lower recurrence free survival rates in NMIBC but not in MIBC[41]. Similarly, serum EV lncRNA H19 is increased in healthy individuals compared to BC patients (P value < 0.001). Furthermore, higher levels of H19 correlated with poorer survival (hazard ratio = 2.7; P value < 0.001)[42]. Moreover, several EV and uEV miRNAs have been studied as prognostic markers of BC. For instance, decreased levels of miR-214, miR-185-5p, and miR-106a-5p and increased levels of miR-10b-5p were linked to worse survival in BC patients[43,44].
On the other hand, EV play a role in modulating tumor response to therapy. In fact, Luo et al[45] incubated BC cells with exosomes containing LINC00355 which was previously shown to contribute to tumor proliferation and invasion. BC cells incubated with LINC00355 had a higher rate of resistance to cisplatin than control. On a molecular level, LINC00355 sponges miR-34b-5p therefore leading to ABCB1 upregulation and cisplatin resistance[45]. Similarly, Yang et al[46] demonstrated that circTRPS1 sponges miR-141-3p and thus modulates glutamine metabolism, leading to CD8+ T cells exhaustion. EV thus play a key role in immunomodulation and can influence patients’ response to immunotherapy by hindering the activity of CD8+ T cells on tumor cells[46].
PC
CtDNA
Diagnostic applications: As in BC and other malignancies, the management of PC has significantly evolved with the integration of LB. PC was among the first cancers to adopt a blood-based biomarker, PSA, into routine clinical practice, which revolutionized the detection of prostate adenocarcinoma[41]. However, its utility is debated, as PSA is organ- but not cancer-specific, and levels may rise in benign conditions such as prostatitis or benign prostatic hyperplasia, leading to false positives, overdiagnosis, and unnecessary invasive biopsies[42,43].
Multiple studies have demonstrated the diagnostic potential of ctDNA beyond PSA. Bang et al[47] performed ctDNA sequencing in 100 patients with metastatic PC and identified clinically relevant somatic alterations in 63% and pathogenic/likely pathogenic germline alterations in 12% of cases, most commonly in androgen receptor (AR), tumor protein P53, retinoblastoma 1, phosphatase and tensin homolog, adenomatous polyposis coli, and breast cancer 1/2 (BRCA1/2). CtDNA positivity was correlated with radiographic and clinical progression and showed greater sensitivity than PSA in identifying aggressive subtypes[47]. Similarly, Mandel et al[48] reported that ctDNA sequencing achieved a 100% success rate compared with 88% for tumor tissue (TT) sequencing, detecting BRCA1/2 alterations in 20% of patients vs 9% with TT.
Beyond mutational profiling, methylation-based assays also demonstrated strong diagnostic performance. Bryzgunova et al[49] analyzed plasma ctDNA from PC, benign prostatic hyperplasia, and healthy individuals, and achieved 100% sensitivity and specificity in distinguishing PC from non-malignant conditions. Similarly, Mahal et al[50] analyzed a targeted methylation-based multicancer early detection blood test in the Circulating Cell-Free Genome Atlas and PATHFINDER studies. The assay preferentially detected high-grade PC with stage-dependent detection rates, reaching 81.5% in stage IV disease[50]. Moreover, Chen et al[51] demonstrated that the ctDNA methylome could robustly distinguish localized from metastatic PC with 98.9% prediction accuracy. For more aggressive subtypes, Franceschini et al[52] validated a targeted ctDNA methylation assay for identifying castration-resistant neuroendocrine PC (NEPC), achieving an AUC > 0.93 and correlating methylation-defined tumor fraction with outcomes in two prospective trials.
Fragmentomics is emerging as an additional layer of information in PC diagnostics. De Sarkar et al[53] used whole-genome sequencing to map nucleosome positioning patterns in plasma ctDNA from advanced PC, enabling accurate classification of AR-positive and NEPC phenotypes, with performance comparable to tissue-based approaches. Finally, a meta-analysis of 29 studies by Chen et al[54] confirmed the overall diagnostic utility of ctDNA, reporting a pooled specificity of 92% and emphasizing the added value of quantitative vs qualitative evaluation (Figure 1; Table 1).
Prognostic applications: CtDNA has also shown strong potential as a prognostic biomarker in PC. Zang et al[55] applied a tumor-informed, enriched amplicon sequencing approach to detect MRD following prostatectomy. Patient-specific founder mutations were identified through tumor exome sequencing, and ctDNA was detectable in 45% of patients pre-operatively, 64% immediately post-operatively, and 62.5% at one month. Notably, persistent ctDNA detection at one month was associated with subsequent PSA relapse[55]. In another real-world observational study, Fei et al[56] assessed pre-operative ctDNA in 161 patients undergoing radical prostatectomy for non-metastatic PC. CtDNA was detectable in 65.5% of pre-operative plasma samples and was strongly associated with biochemical progression-free survival (PFS) and biochemical recurrence[56].
In the nationwide SCRUM-Japan MONSTAR SCREEN, ctDNA profiling using FoundationOne® Liquid CDx in patients with metastatic castration-sensitive PC (mCSPC) and metastatic castration-resistant PC (mCRPC) identified higher frequencies of AR alterations and homologous recombination repair defects in mCRPC compared with mCSPC. Homologous recombination repair defects in mCSPC predicted earlier castration resistance while AR amplification or mutations in mCRPC predicted shorter responses to AR pathway inhibitors[57].
Importantly, the phase III PROfound trial utilizing plasma samples from patients with mCRPC, tested by FoundationOne® Liquid CDx, showed that BRCA1/2 or ataxia telangiectasia mutated alterations detected in ctDNA could identify patients who derived significant prolonged radiographic PFS compared with olaparib. These findings, alongside supporting evidence, contributed to the FDA approval of FoundationOne® Liquid CDx as a comprehensive pan-tumor test with multiple companion diagnostic indications[58]. Moreover, the ProBio trial evaluated the prognostic value of baseline ctDNA fraction in 220 patients with mCRPC. Patients with undetectable ctDNA were shown to have significantly increased OS compared to those with detectable ctDNA[59]. Fonseca et al[60] analyzed 738 plasma samples from 491 men with mCRPC across two randomized phase II trials and a biobanking program. Their study found that ctDNA percentage correlated with serum and radiographic disease burden and was highest in patients with liver metastasis. Elevated ctDNA% strongly predicted shorter OS, PFS, and poorer treatment response[60]. Additionally the phase 3 TALAPRO-2 trial (NCT03395197) evaluated the prognostic utility of baseline ctDNA burden and early on-treatment changes in patients with mCRPC receiving talazoparib plus enzalutamide (ENZ) or placebo plus ENZ as first-line therapy. Among 678 evaluable patients, high baseline ctDNA burden was associated with significantly shorter radiographic PFS in both treatment arms. Patients converting from high to low ctDNA burden at week 9 had improved radiographic PFS compared with those remaining high, while persistently low ctDNA burden was associated with the most favorable outcomes[61].
CTCs
Diagnostic applications: CTC represent another minimally invasive biomarker source that enables real-time tumor characterization and longitudinal disease monitoring in PC, particularly in the metastatic setting. In a recent study, Løppke et al[62] developed a combined microfluidic enrichment and on-cartridge staining workflow for detecting and characterizing CTC in metastatic PC. Using the FDA-cleared Parsortix size-based enrichment system, they detected CTC in 67% of cases among 12 metastatic patients. Single CTC genomic profiling revealed aberrations linked to treatment response and clinical outcomes, demonstrating the potential of integrating CTC-based genomic monitoring into clinical decision-making[62]. CTC detection is also feasible in earlier disease stages. Kilercik et al[63] combined the Cellsway® high-throughput microfluidic enrichment platform with multiparametric flow cytometry to detect CTC in 85% of localized PC patients, with zero false positives in healthy donors. Moreover, in a large multi-institutional prospective study, Sharifi et al[64] developed a high-purity CTC isolation workflow enabling RNA sequencing of 273 samples from 117 patients with metastatic PC. Tumor purity in 146 samples matched that of tissue biopsies, allowing transcriptomic classification into four phenotypes mirroring lineage states seen in TT[64]. Similarly, Bergmann et al[65] profiled 102 blood samples from 76 metastatic PC patients, including androgen-variant PC and therapy-induced NEPC and demonstrated that CTC transcriptional signatures could distinguish NEPC from metastatic hormone-sensitive PC (mHSPC) with 95.5% specificity and from androgen-variant PC with 88.2% specificity. Finally, ongoing studies (NCT04556916, NCT06981377, and NCT05366881) are currently recruiting participants to assess for early PC detection through CTC, ctDNA and exosomes analysis.
Prognostic applications: In the same study by Sharifi et al[64], pretreatment luminal-B-like CTC phenotype predicted early progression on 177 Lu-PSMA-617, underscoring the potential of CTC transcriptional profiling for real-time lineage characterization and therapeutic decision-making. In another prospective cohort of 52 PC patients receiving definitive, adjuvant, or salvage radiotherapy (RT), Schott et al[66] evaluated epithelial CTC detected via EpCAM-based enrichment as a dynamic biomarker of relapse risk. They were identified in 96% of patients at baseline, and serial counts were measured before, mid-treatment, and at the end of RT. A significant decline in counts during RT, particularly in post-prostatectomy patients, was associated with reduced relapse risk, whereas increases during or after RT correlated with markedly higher risk. Notably, PSA levels did not reliably predict relapse in this cohort, suggesting CTC monitoring may provide superior prognostic insight[66]. Besides, Antonarakis et al[67] demonstrated that AR splice variant 7 (AR-V7) detection in CTC correlated with lower PSA response to ENZ or abiraterone and shorter PFS, highlighting the role of CTC in prediction response to treatment. A systematic review by Enikeev et al[68] confirmed that in metastatic PC, higher CTC counts and AR-V7 positivity consistently correlated with shorter OS and PFS. Finally, an ongoing study (NCT03601143) is further assessing the optimal method to determine AR-V7 status to predict treatment resistance.
Additionally, the PROPHECY trial evaluated baseline and progression CTC prostate specific membrane antigen (PSMA) expression in 97 men with mCRPC treated with abiraterone or ENZ. At baseline, CTC were detectable in 80% of patients, with 55% having any PSMA-positive (PSMA+) CTC and 21% showing ≥ 2 PSMA+ CTC/mL. At progression, CTC detection increased to 88%, with PSMA positivity in 68% of cases. Using the optimal threshold of ≥ 2 PSMA+ CTC/mL, median OS was 26 months (no CTC), 21 months (PSMA- CTC), and 11 months (PSMA+ CTC). These findings highlight CTC PSMA profiling as a potential prognostic tool and companion biomarker for PSMA-targeted therapies[69]. In the phase III S1216 trial, Goldkorn et al[70] assessed baseline CTC counts in 503 men with newly diagnosed mHSPC. Counts were stratified as 0, 1-4, or ≥ 5 CTC/7.5 mL. Baseline CTC counts ≥ 5 were observed in 11.9% of patients and were associated with markedly worse outcomes: Median OS 27.9 months vs 56.2 months (1-4 CTC) and not reached for 0 CTC. Adding CTC count to known prognostic factors improved 3-year survival prediction, validating baseline CTC enumeration as a robust prognostic biomarker in mHSPC and supporting its integration into risk stratification and trial design[70]. Likewise, in the PRESIDE phase 3b biomarker substudy, Ruiz-Vico et al[71] examined plasma ctDNA and CTC-AR-V7 in 157 men with mCRPC initiating docetaxel with or without continued ENZ. Patients positive for a composite resistance biomarker (AR gain and/or CTC-AR-V7) derived no PFS benefit from continuing ENZ with docetaxel, whereas biomarker-negative patients experienced significantly prolonged PFS. These results suggest integrating ctDNA and CTC-based AR-V7 status to identify patients unlikely to benefit from AR-targeted therapy with chemotherapy[71].
EVs and ncRNA
Diagnostic applications: Exosomal biomarkers are emerging as promising tools for PC detection and risk stratification. A recent systematic review reported disease-specific alterations in exosomal cargo capable of distinguishing malignant from benign prostate conditions, predicting tumor aggressiveness, and tracking treatment efficacy. Notably, miRNAs were the most studied and demonstrated superior diagnostic and prognostic accuracy compared to PSA, with several panels associated with therapeutic response[72]. Similarly, in a systematic review and meta-analysis of 19 studies (976 PC cases; 676 controls), Li et al[73] reported pooled sensitivity/specificity of 70%/79% for individual EV RNAs and 85%/83% for individual EV proteins, with EV panels performing best at 84%/86% (Figure 1; Table 1). Frequently studied markers included miR-141, miR-221, and PSMA. The authors noted variability in EV isolation/detection methods as a key source of heterogeneity, an important consideration for clinical translation[73].
The ExoDx Prostate IntelliScore (EPI) test analyzes exosomal RNA expression of ERG, prostate cancer antigen 3, and SPDEF from first-catch urine without the need for digital rectal examination. In a prospective, CE-marked validation study (EPI-CE; NCT04720599) involving 109 biopsy-naive men with PSA 2-10 ng/mL, EPI-CE demonstrated a negative predictive value of 89% and sensitivity of 92% for detecting high-grade PC (grade group ≥ 2). The assay outperformed the PC Prevention Trial and European Randomized Study of Screening for PC risk calculators, with an AUC of 0.67 vs 0.59 and 0.60, respectively, and provided additional predictive value beyond standard clinical parameters, even prior to magnetic resonance imaging[74].
Beyond single modality approaches, Tomeva et al[75] developed a multi-analyte assay that combined ctDNA mutations, methylation markers, and circulating miRNAs. In a cohort of 97 cancer patients (including 27 with PC) and 15 healthy controls, the assay detected the AR p.H875Y mutation in over half of the cancer cases, but in none of the controls. A model integrating two ctDNA mutations (COSM10758, COSM18561), four methylation markers (MLH1, MDR1, GATA5, SFN), and 13 miRNAs achieved 95.4% accuracy, 97.9% sensitivity, and 80% specificity for cancer detection[75].
Besides, a prospective trial (NCT04556916) is evaluating the combined use of CTC, ctDNA, and EV-derived markers from a single blood sample to improve diagnostic accuracy and risk stratification in men with elevated PSA. In parallel, the ExoPLA assay (NCT03694483) is under clinical investigation as a non-invasive test for detecting plasma prostasomes, prostate-derived EV enriched in PSA and PSMA, using a proximity ligation approach to distinguish malignant from benign prostatic conditions.
Prognostic applications: EV also demonstrate prognostic utility as biomarkers in pooled analysis. Brokāne et al[76] validated 15 candidate RNA biomarkers in plasma and uEV from PC patients using droplet digital PCR. Several RNAs, including NKX3-1 in plasma EV and tRF-Phe-GAA-3b, tRF-Lys-CTT-5c, piR-28004, and miR-375-3p in uEV, significantly decreased after radical prostatectomy, indicating their prostate/PC origin[76]. Besides, Bhagirath et al[77] performed serum EV small RNA sequencing in castration-resistant PC (CRPC) patients and identified 182 known and 4 novel miRNAs dysregulated between adenocarcinoma CRPC and NEPC. Using machine learning, they developed an EV-miRNA classifier that robustly discriminates NEPC from CRPC-adenocarcinoma. Proteomic profiling of NEPC-derived exosomes revealed thrombospondin-1 as a candidate specific biomarker. These findings provide the first EV-based biomarker panel for detecting therapy-induced NEPC[77]. Additionally, Bryzgunova et al[78] investigated changes in plasma EV-associated miRNAs in PC patients before and one week after radical prostatectomy. Using an aggregation-precipitation EV isolation method and reverse transcription-quantitative PCR analysis, they assessed 14 target miRNAs and identified 11 miRNA ratios with significant postoperative changes. Notably, miR-125b and miR-30e were recurrently involved across altered ratios, suggesting a central role in the molecular response to radical therapy[78]. Besides, Casanova-Salas et al[79] performed genomic and transcriptomic profiling of EV-DNA and EV-RNA from longitudinal plasma samples of metastatic PC patients receiving AR signaling inhibitors or taxane therapy. EV-DNA recapitulated genomic alterations detected in matched biopsies and ctDNA, with specific features associated with clinical progression. Using their novel RExCuE workflow, they also profiled EV-RNA, which was enriched for tumor-associated transcripts and captured early transcriptomic adaptation changes during therapy[79]. Urinary exosomal miRNA profiling also holds prognostic value. In a study of 149 PC patients, expression levels of miR-21, miR-16, miR-142-3p, miR-451, and miR-636 were associated with metastatic disease. Multivariate analysis identified miR-21, miR-451, miR-636, and preoperative PSA as independent predictors, forming the PC Metastasis Risk Scoring model. This model achieved superior stratification, compared with preoperative PSA or Gleason score, with high scores correlating with significantly worse biochemical recurrence-free survival[80].
EMERGING APPLICATIONS IN RENAL AND TCS
LB is a powerful cancer diagnosis and monitoring tool but so far has not been widely applied to testicular and renal cancer. Unlike other malignancies, the literature is limited and most research has been based on small patient cohorts with few of them conducted in the real-world clinical environment. Evidence of this sort underscores the need for more study to establish LB’s true diagnostic and prognostic utility in these urologic cancers.
RCC, ctDNA
Diagnostic applications: In RCC, ctDNA offers a noninvasive method for the detection of tumor specific mutations, monitoring disease, and assessing response to treatment, though RCC itself is generally considered a low-ctDNA cancer. Detection rates vary greatly by technique: Tumor guided sequencing is extremely sensitive for known mutations; targeted plasma sequencing can identify new variants but is tumor burden-dependent; global sequencing is less sensitive; targeted methylation analysis is very specific but less sensitive; and global methylation analysis, particularly cfMeDIP-seq, is most sensitive[81]. CtDNA methylation profiling has shown promising diagnostic potential, where multi-gene methylation panels separated RCC from controls and correlated with tumor stage, but heterogeneity of detection in localized disease and absence of standardized protocols currently limit their clinical use[82]. A meta-analysis reported blood-derived ctDNA to have 71% sensitivity, and 79% specificity[83] (Figure 1; Table 1). Supplementing these findings, another study assessed urinary ctDNA using quantitative and qualitative assays. Quantitative analysis had an AUC value of 0.784, sensitivity of 59%, and specificity of 88%, while qualitative assays had a slightly lower AUC value of 0.774, reduced sensitivity (47%), but increased specificity (92%). These results show that even if urine-based ctDNA assays are low in sensitivity, high specificity makes them effective confirmatory diagnostic tools[84]. Lastly, as mentioned previously, an ongoing case-control study (NCT05366881) in the United States is currently evaluating the role of cfDNA in early diagnosis and residual disease detection in several malignancies, including renal, prostate and BC.
Prognostic applications: CtDNA can detect spatial and temporal heterogeneity of tumors, correlate with poor prognosis and survival, and longitudinally track response to treatment with increased elevation before progression and decrease after effective therapy[81]. In metastatic RCC, patients with a ctDNA tumor fraction ≥ 1.2% experienced significantly poorer survival, while serial ctDNA monitoring detected arising resistance mutations on disease progression[85]. Furthermore, ongoing positivity of ctDNA on surveillance strongly predicted poorer outcomes compared with ctDNA-negative patients. Apart from prognosis, dynamic ctDNA profiling enables real-time measurement of response to immune checkpoint inhibitors and the detection of tumor heterogeneity and thus its utility in RCC personalization[86]. Lastly, ORACLE, an ongoing trial (NCT05059444) is evaluating the role of ctDNA in detecting recurrence in patients treated for early-stage solid tumors.
CTCs
Diagnostic applications: CTC offer theoretically specific and minimally invasive access to diagnose, track, and forecast cancers, including RCC[82]. However, clinical usefulness is now limited by low frequency of CTC in early cancers, morphological overlap with white cells, and reduced epithelial marker expression like EpCAM in RCC, making these less sensitive to conventional detection devices[87]. A meta-analysis and systematic review reported a sensitivity of 45% but a high specificity of 99% (Figure 1; Table 1). Although their low sensitivity limits their role as individual diagnostic tests, their high specificity makes them valuable as confirmatory or prognostic markers in RCC[88].
Prognostic applications: For RCC, higher numbers of CTC, especially CTC white blood cell aggregates, is linked with larger tumor size, poorer metastasis free survival, and decreased overall and progression free survival, particularly in metastatic disease[89]. Alternative enrichment methods have improved recoveries, and evidence suggests prognostic value in preoperative CTC count, dynamic variation post-surgery, mesenchymal phenotypes, and Beclin-1 expression[90]. In 54 studies reviewed, detection rates of CTC varied considerably by platform and markers used. In some studies, higher CTC density or positivity was linked to progression stage and decreased survival, and thus possibly useful as a prognostic marker, although findings are conflicting and insufficient to warrant clinical application[91].
EVs and ncRNA
Diagnostic applications: A comprehensive evaluation of EV in renal cancer demonstrates their prognostic, predictive, and diagnostic significance. EV, harvested from urine, blood, or other bodily fluids, carry tumor-specific proteins, RNAs, and metabolites that reflect the biology of their cell of origin. In RCC, serum EV cargo such as lncRNA, azurocidin, and miRNAs (miR-210, miR-1233, miR-15a, miR-21-5p, miR-126-3p, miR-449a) have been identified to be useful in discriminating patients from healthy controls, in metastasis prediction, and in potentially detecting early disease[92,93]. A few miRNAs, such as urinary miR-210, not only differentiate between patients and controls but also decrease significantly after surgical resection, proving a tumoral origin[94]. A meta-analysis conducted showed serum exosomal miR-1233 had 86% sensitivity and 80% specificity, in favor of its diagnostic utility[95] (Figure 1; Table 1). A study also demonstrated high diagnostic capability, wherein serum miR-21-5p had an AUC of 0.938 and 83% sensitivity[96]. Urinary EV also harbor diagnostic mRNAs (miR-126-3p, miR-449a, miR-30c-5p) and novel stage I clear cell RCC markers (NME2, AAMP, CAPNS1, VAMP8, and MYL12B)[97-99]. A study highlighted the combined diagnostic value of urinary miR-126-3p and miR-449a, which achieved an AUC of 0.84, 83.8% sensitivity, and 62.5% specificity. Urinary exosomal miR-30c-5p was also highly specific, having an AUC of 0.819, 68.6% sensitivity, and 100% specificity[94]. In terms of urine-based testing, a study showed miR-15a had a highly impressive AUC of 0.955, with perfect sensitivity (100%) and near-perfect specificity (98.1%), rendering it one of the most promising non-invasive biomarkers for renal cancer[100].
Prognostic applications: MiR-210 has been associated with tumor progression and poor prognosis in clear cell RCC[94]. Serum exosomal miR-210 was reported to have a sensitivity of 70% to 82.5%, and specificity of 62.2% to 80%, thus demonstrating its promise as well as inconsistency between studies[96]. In addition to diagnosis, EV cargo (miR-183/182/96, miR-224-5p, and miR-19b-3) plays mechanistic roles in angiogenesis, epithelial-mesenchymal transition, and pre-metastatic niche formation, which correlate with poor prognosis[97-99]. Exosomal miRNA, miR-224, have shown correlations with decreased progression-free, cancer-specific, and OS, indicating prognostic value[100]. Certain EV-derived RNAs (miR-549a) are involved in resistance to vascular endothelial growth factor and tyrosine kinase inhibitors, which suggests predictive potential as markers for both metastasis detection and response to therapy[101].
Plasma glycosaminoglycans
Diagnostic applications: Plasma glycosaminoglycans (GAGs) were discovered to possess excellent potential for RCC diagnosis and prognosis. A novel plasma GAG score differentiated non-metastatic RCC patients from normal subjects with over 93% sensitivity and specificity independent of tumor stage, grade, size, or histology. GAG alterations were identified even in tumors that were smaller than 4 cm, suggesting they may be a reflection of early systemic responses rather than tumor burden as such. Although very sensitive, this activity may limit specificity for RCC in early detection settings, though possibly beneficial for postoperative follow up[102]. Finally, an ongoing study (NCT05060783) is currently evaluating the specificity of GAG for RCC as compared to other types of renal cancers such as oncocytomas or angiomyolipomas.
Prognostic applications: One of the GAG components, chondroitin sulfate concentration, was an independent predictor of survival and recurrence free survival, and its combination with tumor size allowed patients to be divided into high and low risk groups for metastatic recurrence or death[102].
TC, ctDNA
Diagnostic applications: CtDNA is being investigated as a novel diagnostic reagent in TC, particularly among patients with no typical serum tumor marker expression [alpha-fetoprotein (AFP), human chorionic gonadotropin (hCG)]. Early studies demonstrated that actin-β DNA fragment analysis was able to distinguish seminoma and nonseminoma patients from healthy controls with 87% sensitivity and 97% specificity[103]. Similarly, mitochondrial DNA fragmentation analysis and hypermethylation panels (adenomatous polyposis coli, glutathione S-transferase P1, prostaglandin-endoperoxide synthase 2, p14, p16, Ras association domain family protein1 isoform A) were very accurate in all TC subtypes, and KIT ligand CpG methylation was a potential seminoma biomarker. These approaches detect the importance of ctDNA methylation and fragmentation patterns as highly specific, minimally invasive biomarkers for the diagnosis of TC[103].
Prognostic applications: Although ctDNA is still in development for TGCT, newer extremely sensitive tests such as molecular residual disease tests have proved to be capable of detecting micro-metastases through the application of tumor specific mutation profiles[104]. Research indicates that ctDNA levels are associated with TGCT stage and activity, and tend to surpass conventional serum tumor markers in both sensitivity and specificity[105]. Tumor-informed ctDNA assays build patient-specific panels of mutations and are capable of detecting micro-metastatic disease in the peri-orchiectomy time period as well as under surveillance. In a current multi-institutional publication, post-treatment positivity by ctDNA strongly correlated with relapse and worse event-free survival, while post-treatment ctDNA negativity after curative therapy correlated with non-recurrence. Reviews confirm that ctDNA levels are stage and activity correlated with TGCT and are still detectable when normal conventional serum markers are present. Although highly promising for detection and monitoring of MRD, ctDNA is not yet as well established as miR-371a-3p in diagnostic performance[106].
CTCs
Diagnostic applications: CTC have been investigated as a LB in TGCTs, although their clinical application is limited by low quantities in early disease, technical challenges in isolation, and a lack of GCT-specific surface markers. Advances such as microfluidic devices and immunomagnetic enrichment with GCT antigens have improved recovery rates[107].
Prognostic applications: Early reports indicate that elevated CTC counts can be linked to advanced stage and poor outcome, but evidence is scanty, and standardization does not exist. Integration with other LB methodologies (miRNA or ctDNA) may enhance their prognostic utility[107]. In a study of 143 patients, CTC were detected in 17.5% of peripheral blood samples, with positivity strongly associated with advanced stage and with relapsed/chemotherapy-refractory disease; detection of CTC was also associated with increased AFP/β-hCG/Lactate dehydrogenase. CTC numbers were significantly higher in the tumor-draining (testicular) vein than in peripheral blood, emphasizing the technical challenge for routine sampling[108].
MiRNA
Diagnostic applications: A number of studies have found certain miRNAs to be very promising biomarkers in TGCT with higher sensitivity and specificity than traditional serum tumor markers (AFP, β-hCG, lactate dehydrogenase)[109]. The best validated among them is miR-371a-3p, with a sensitivity 90%-96% and specificity 84%-100%, in seminomas and non-seminomas (but not teratomas). Its elevated diagnostic performance and reproducibility have established miR-371a-3p as the leading candidate biomarker in TGCT[106]. In multiple clinical trials, miR-371a-3p has demonstrated consistently high diagnostic accuracy, early clearance after orchiectomy, and direct correlation with active germ cell tumor burden but is not informative in pure teratoma. The evidence base consists of large clinic series, prospective trials, and confirming in vitro and in vivo experimentation on miRNA expression. With ongoing clinical trials and assay pipeline optimization, miR-371a-3p is on the threshold of readiness for use as a clinical diagnostic and disease monitoring liquid biomarker[110].
Prognostic applications: MiR-371a-3p is related to tumor burden, drops off rapidly after orchiectomy, and can diagnose minimal testicular masses, predict occult metastases in stage I-II disease, monitor treatment response, and detect relapse at potentially less requirement for imaging[106]. Other clusters such as miR-302/367, miR-517/519, and miR-223-3p have differentially expressed profiles in TGCT and may have either diagnostic or prognostic value, but miR-371a-3p is by far the most promising candidate for clinical application, pending further validation and standardization[111].
CHALLENGES
LB offer new perspectives on less invasive medicine. However, the different modalities have varying sensitivities and specificities, limiting their use as reliable diagnostic tools. To get a sense of the screening and diagnostic limitations, a hypothetical scenario with 1000 cases of BC among 1000000 individuals can be considered. Using utDNA (sensitivity 77%, specificity 87% as per Table 1), 230 cases of BC would be missed (false negatives) and almost 130000 healthy cases would wrongly be assigned to a positive screening test (false positives). More strikingly, if an individual turned out to have a positive test, they would only have a 0.6% chance of truly being diagnosed with BC using the gold standards. The non-invasive nature of utDNA is attractive, and it could identify up to 77% of BC new cases yearly, but would also subject a substantial number of false positive individuals to additional costs and psychosocial stress. Indeed, it was estimated that utDNA cost varied between 199 dollars and 9124 dollars based on platform, assay and testing volume[112]. Moreover, each LB modality faces specific challenges unique to its characteristics and method of extraction and analysis. For instance, CTC are not abundant in serum or urine with an approximate concentration of 1 to 100 for every 106-108 red blood cells, making it difficult to isolate and detect them, and explaining the high associated cost[113,114]. Moreover, CTC have heterogeneous antigen expression further complicating their identification[115]. This heterogeneity might also hinder our understanding of the whole tumor burden, as CTC only allow to sample the tumor cells that are shed into plasma and urine. On the other hand, in early diseases, only low concentrations of ctDNA can be detected in serum and urine due to low initial burden of disease. Additionally, pre-analytical handling of ctDNA can lead to unwanted errors, like dilution, fragmentation or destruction of the genetic material. Furthermore, there is a lack of standardization of the techniques to ensure reproducibility of results[116]. Similarly, the lack of universal protocols complicates the isolation and purification of EV from serum. Indeed, EV vary in size, origin and composition[117]. In addition, ncRNA are highly susceptible to degradation, requiring specialized laboratory handling and high throughput detection technologies[118]. Both tumors and normal cells secrete EV at different rates, and their content is highly heterogeneous, often leading to decreased specificity and sensitivity of this modality[119]. In the setting of the individual limitations of each analyte, it seems reasonable to consider combining these modalities together to obtain more accurate diagnostic and prognostic information. However, cost reduction and standardization of techniques are made possible. With the rapid evolution of artificial intelligence, integrating LB with clinical features could promise enhanced personalized prediction tools.
CONCLUSION
While tissue biopsy remains the gold standard for cancer diagnosis due to its high level of standardization and accuracy, LB modalities are emerging as a hotspot of cancer research, with promising diagnostic and prognostic applications. LB offer several advantages over the traditional methods, like low invasiveness and risk, regular follow-ups with repeated testing; and these advantages hold mostly true for urogenital cancers, where the urine sampling is of great value. However, the variable outcomes from different studies reflect the challenges facing LB modalities in the current era, and stress the need for protocol standardization. Moreover, LB only capture one aspect of tumors biology, and do not encompass the complex nature of the disease. Clinically, they will serve as adjuncts to the traditional biopsy, as screening tools or prognostic markers.
Footnotes
Provenance and peer review: Invited article; Externally peer reviewed.
Peer-review model: Single blind
Specialty type: Oncology
Country of origin: Lebanon
Peer-review report’s classification
Scientific Quality: Grade A, Grade B
Novelty: Grade A, Grade B
Creativity or Innovation: Grade A, Grade C
Scientific Significance: Grade A, Grade B
P-Reviewer: Chang YX, PhD, Associate Professor, China; Meng YK, MD, Associate Professor, China S-Editor: Wu S L-Editor: A P-Editor: Wang CH
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