CONSORT flow diagram for COBALT-RCC trial design schematic

546 Background: Artificial intelligence (AI)–based digital pathology has shown great promise in prostate and bladder cancer, but its application in renal cell carcinoma (RCC) remains limited. We applied the Computational Histology Artificial Intelligence (CHAI) platform, a deep learning-based pathology system, to develop and validate a novel prognostic biomarker for localized RCC. Methods: Hematoxylin and eosin stained whole-slide images from stage I-III RCC cases in The Cancer Genome Atlas (TCGA) were analyzed with CHAI to quantitatively extract histologic features from the tumor and microenvironment. All RCC subtypes within TCGA were included (clear cell, papillary, chromophobe). Cases were divided into development (30%) and validation (70%) cohorts using a stratified random split. In the development cohort, a continuous histologic risk signature for overall survival (OS) was derived and dichotomized into low- and high- risk groups with a 70-30 cutoff. We then tested the locked biomarker and evaluated its performance in the independent validation cohort. Multivariate Cox proportional hazards (CPH) models assessed associations with progression-free survival (PFS), disease-specific survival (DSS), and OS. Results: 801 RCC patients were available (236 in development, 565 in validation). In the validation cohort, the median age was 60 years (IQR 51-70), and 370 (65%) were male. Disease stage was I in 340 (60%), II in 86 (15%), and III in 139 (25%). Histologic subtypes in the validation cohort included clear cell in 307 (54%), papillary in 184 (33%), and chromophobe in 74 (13%). On validation, the biomarker stratified patients into 167 (29%) high-risk and 398 (70%) low-risk. High-risk status was significantly associated with inferior PFS (HR: 2.74 [95%CI: 1.81, 4.15]), DSS (HR: 3.37 [1.89, 6.03]) and OS (HR: 1.92 [1.25, 2.96]), all p<0.05. Associations remained significant after controlling for age, sex, stage, and subtype (p<0.05). At 1 year, high-risk patients demonstrated higher rates of progression (15% vs 4.6%), disease-specific mortality (4.8% vs 1.1%), and overall mortality (7.8% vs 2.9%). Conclusions: We developed and validated an AI-derived digital pathologic biomarker that prognosticates localized RCC by risk of progression, disease-specific death, and overall mortality--independent of histologic subtype. These findings support further investigation of CHAI-based digital biomarkers as tools to refine RCC risk assessment and guide personalized management. Multivariate CPH model of OS. Variable Factor HR (95% CI) p-value Biomarker (ref: Low-Risk) High-Risk 1.90 (1.22, 2.97) <0.01 Age 1.03 (1.01, 1.04) <0.01 Sex (ref: Female) Male 0.71 (0.45, 1.11) 0.12 Stage (ref: Stage I) II 1.61 (0.79, 3.29) 0.19 III 3.93 (2.43, 6.35) <0.01 Subtype (ref: Clear Cell) Papillary 0.74 (0.43, 1.25) 0.26 Chromophobe 0.43 (0.18, 1.02) 0.06

INTRODUCTION:Belzutifan, a HIF-2α inhibitor, is approved for von Hippel-Lindau (VHL)-tumors and sporadic metastatic renal cell carcinoma (mRCC) after prior immunotherapy (IO) and tyrosine kinase inhibitor (TKI) therapy. Real-world data on outcomes and adverse events (AEs) of belzutifan in patients not represented in clinical trial settings remain limited. PATIENTS AND METHODS:A multicenter retrospective study of patients with mRCC treated with belzutifan was performed. Clinical efficacy outcomes included objective response rate (ORR), progression-free survival (PFS), and overall survival (OS). Treatment-related AEs were also recorded. RESULTS:A total of 43 patients received belzutifan (26% Hispanic). Median age was 67 years (range, 21-86). Clear cell histology was predominant (91%); other histologies included mixed clear cell/papillary (n = 1); chromophobe with somatic VHL alteration (n = 1); unclassified RCC (n = 1). Common sites of metastases at belzutifan start included liver (33%), bone (30%), and peritoneum (19%). The median number of prior therapies was 3 (range, 0-6) including prior IO (95%) and TKI (88%). Among 36 evaluable patients, ORR was 25% (9 partial responses). At a median follow-up of 8.2 months, the median PFS was 5.7 months (95% CI, 3.3-10.7) and median OS was not reached (95% CI, 12.0-NR). Any AE was reported in 93% with all-grade anemia (79%), fatigue (30%); hypoxia (14%) being most common. The most frequent grade 3 to 5 AEs were anemia (30%) and hypoxia (7%). Discontinuation due to AE occurred in 12%. CONCLUSIONS:In this diverse, heavily pre-treated mRCC cohort with frequent visceral metastases, belzutifan had consistent clinical outcomes and toxicity profile with prior reports.

The seventh Kidney Cancer Research Summit was held as a hybrid virtual/in-person event in Boston, MA during July 17-18, 2025. This conference, which aims to help guide the design of kidney cancer clinical trials and research, centers around projects that showcase the most impactful basic, translational, and clinical data evolving in renal cell carcinoma (RCC), and brings together clinical oncologists, physician scientists, translational researchers, and patient advocates. The abstract presentations were published as a supplement in The Oncologist (https://academic.oup.com/oncolo/issue/30/Supplement_2). This perspective will provide the layout of the current RCC research landscape as discussed and debated among the stakeholders at the conference as well as more recent updates.

INTRODUCTION:The rapid integration of immune checkpoint inhibitor (ICI) based combination therapies in first-line treatment of metastatic renal cell carcinoma (mRCC) is raising questions about next-line treatments and outcomes of ICI rechallenge. METHODS:We performed a meta-analysis using the results from the phase-III RCTs, CONTACT-03 and TiNivo-2, to evaluate the effect of adding a PD-1/PD-L1 inhibitor rechallenge to a vascular endothelial growth factor (VEGF) tyrosine kinase inhibitor (TKI) vs a VEGF TKI alone in patients with mRCC who had progressed on ICI based combination therapy or ICI monotherapy. RESULTS:A total of 865 patients with mRCC were included in this meta-analysis. The meta-analysis showed no difference in progression free survival between ICI plus VEFG TKI combination and TKI monotherapy groups (HR = 0.96, 95% CI, 0.76-1.21; P = .75) in patients previously progressing on ICI. Furthermore, adding ICI to anti-VEGF TKI therapy was not associated with improve overall survival (HR = 1.06, 95% CI, 0.89-1.25; P = .52). CONCLUSION:In summary, PD-1/PD-L1 inhibitor rechallenge with a VEGF TKI in mRCC does not improve survival outcomes and should not be used in patients with prior progression to ICI. Understanding both intrinsic and acquired resistance mechanisms to ICI therapy is crucial for developing effective initial and sequential immunotherapy strategies in RCC.

Purpose Aberrant alternative splicing (AS) events have been implicated in cancer progression; however, their role in metastatic renal cell carcinoma (mRCC) remains underexplored. This study aims to identify AS events associated with clinical benefits from immune checkpoint inhibitors and targeted therapies in mRCC. Materials and methods We conducted a retrospective analysis on 101 patients with mRCC who received systemic therapy and underwent RNA sequencing. Patients were divided into subgroups based on ICIs (alone or in combination) and targeted therapies. Responders and non-responders were classified according to Response Evaluation Criteria in Solid Tumors V.1.1 criteria. Differential gene expression and splicing analyses were performed between responders and non-responders in each cohort. Novel AS events were analyzed for their potential to generate peptide neoantigens through major histocompatibility complex (MHC) class I binding predictions. Results Outlier splicing analysis identified 10 aberrant splice events specific to mRCC. AS analysis revealed 461 differentially spliced events between responders and non-responders in the ICI cohort and 253 in the targeted therapy cohort, with intron retention as the predominant motif. Thirteen unique AS events were enriched in responders, including PTPN6 and ACTN1. Predictive neoantigen analysis identified high MHC class I binding potential in peptides from AS events in IFFO1 and ZNF692. High splice burden was linked to an immunogenic tumor microenvironment, characterized by enriched antigen processing and adaptive immune responses. Conclusions This study provides a comprehensive analysis of AS events in mRCC, highlighting intron retention as potential biomarkers for treatment response. Identified AS-derived neoantigens may serve as potential targets for adoptive cell therapy strategies.

BACKGROUND:Lymphocyte activation gene-3 (LAG-3) is an immune checkpoint receptor that has emerged as a biomarker of interest but its relationship with outcomes in renal cell carcinoma (RCC) is poorly characterized. This study evaluates molecular and immune correlates of LAG-3 expression and its association with outcomes. METHODS:De-identified DNA-NGS data (xT) and RNA-NGS (xR) from patients (pts) with RCC (n = 566) within the Tempus multi-modal database were analyzed using Lens. Eligible pts had first-line (1 L) immunotherapy (IO) and biopsies collected within 1 year of IO. Samples were stratified into 4 quartiles by LAG-3 RNA expression (TPM). Immune cell proportions were estimated from RNA (quanTIseq). Real-world objective response rate (rwORR) was assessed within 90 days of IO. Real-world overall survival (rwOS), defined as time from 1 L IO start to death, lost to follow-up, or 5 years after 1 L, was analyzed using Cox proportional hazard models and P-values (Wald test). RESULTS:The median age was 61 and majority were male (72%), white (79%), with metastases at specimen collection (94%). BAP1 (P = .008) and NF2 (P = .015) were increased in the highest LAG-3 groups, while VHL, PBMR1, and SETD2 were not. LAG-3 correlated with higher CTLA4, PD1, PD-L1, PD-2, TIM3, and TIGIT RNA expression (all P < .001), and increased M1/M2 macrophages, NK, B, CD8 T, and Treg cell % (all P < .001). Higher LAG-3 expression was associated with improved rwORR and lower disease progression (P = .039). rwOS was not statistically significant (P = .2). CONCLUSIONS:LAG-3 is associated with distinct tumor immune features and may serve as a biomarker for early IO response in RCC.

Summary of Treatment-Related TEAEs in Safety Analysis Set by Dose Level

BACKGROUND:Patients with metastatic renal cell carcinoma (mRCC) treated with immune checkpoint inhibitors (ICIs), alone or in combination with tyrosine kinase inhibitors (TKIs), often experience significant treatment-related adverse events, including fatigue, that can impair health-related quality of life (HRQOL). Structured exercise interventions may mitigate these symptoms, but data in mRCC are limited. OBJECTIVE:To evaluate the feasibility and impact of a 12-week supervised remote exercise program on HRQOL, fatigue, and symptom burden in patients with mRCC receiving ICIs or ICI-TKI combinations. METHODS:Nineteen patients with mRCC (median age 67 years; 57.9% male) participated in a 12-week home-based exercise program, supervised via telehealth. The program included aerobic, resistance, and mobility exercises delivered through weekly virtual consultations and supported by the Vedius platform. Outcomes were assessed at baseline and post intervention using the Functional Assessment of Cancer Therapy-Immune Checkpoint Modulator (FACT-ICM), Brief Fatigue Inventory (BFI), and Edmonton Symptom Assessment System (ESAS). RESULTS:Participants demonstrated significant improvements in overall HRQOL (FACT-General mean increase, 9.8 points; P  = .001; Cohen d  = 0.8), treatment-related toxicity (ICM mean increase, 10.1 points; P  = .017), and fatigue (BFI mean decrease, 21.1 points; P  = .018; ESAS fatigue mean decrease, 5.0 points; P  = .001; Cohen d  = -1.5). Symptom burden (ESAS mean decrease, 12.3; P  = .001) and key patient-reported outcomes, including anxiety, depression, appetite loss, and sleep disturbances, also improved ( P  ≤ .02). CONCLUSIONS:A 12-week supervised remote exercise program was feasible and associated with meaningful improvements in HRQOL, fatigue, and symptom burden among patients with mRCC undergoing ICI-based therapies. These findings support the integration of structured exercise into supportive care for mRCC, highlighting the potential of remote interventions to enhance physical and emotional well-being. Future studies should confirm these results in larger randomized trials and identify the most effective program components.

Three landmark trials confirm that fecal microbiota transplantation is a promising approach to enhancing immunotherapy efficacy in advanced solid tumors. The trials also provide insights with major implications for microbiome therapeutic development.

Immunotherapy has been a pillar of the renal cell carcinoma (RCC) treatment landscape for over three decades. Some of the earliest cancer immunotherapies available, such as interleukin 2 and interferon-alpha, have resulted in complete responses, but only in a small number of patients. Immune checkpoint inhibitors (ICIs), however, have demonstrated improved response rates and prolonged survival for a greater number of patients, fully transforming the standard of care in first-line and subsequent-line settings. More recently, ICIs are also being used in the adjuvant setting for high-risk patients. However, treatment with ICIs requires a nuanced understanding of topics such as patient selection, histology and risk considerations, and integration with local therapies. As such, the Society for Immunotherapy of Cancer (SITC) convened a panel of experts to develop this clinical practice guideline (CPG) on immunotherapy for the treatment of RCC. Drawing from published data and clinical experience, the Expert Panel developed evidence-based and consensus-based recommendations. Topics include therapy selection in the adjuvant and metastatic settings, considerations for special patient populations, response monitoring, and patient education and quality of life considerations, among others, with the goal of improving patient care by providing guidance to the oncology community.

Background: Sarcomatoid carcinoma of the upper urinary tract (SCUT) is a rare and aggressive malignancy. Due to its rarity, the molecular landscape and the prevalence of potentially targetable alterations are poorly characterized. We aimed to compare the clinical, pathological, and genomic profiles of SCUT and upper tract urothelial carcinoma (UTUC). Methods: We leveraged the Tempus Lens clinically annotated genomic dataset to extract clinicopathologic and somatic genomic alteration data from patients with UTUC and SCUT. Patients with any-stage disease who underwent either blood- or tissue-based next-generation sequencing were included. Baseline clinical and demographic characteristics were summarized using descriptive statistics. Comparisons between groups were performed using Wilcoxon rank-sum test for continuous variables and the Chi-square test/Fisher’s exact test for categorical variables. Mutational frequencies and pairwise comparisons were performed to assess significant differences between groups. Results: In total, 1721 patients were included, of which 1600 (93%) had UTUC and 121 (7%) had SCUT. Patients with SCUT were younger at diagnosis, 61 years (interquartile range (IQR) 54, 70), compared to UTUC, 71 years (IQR 64, 77) (p < 0.001), and were more likely to have node-positive disease at presentation (all p < 0.001). SCUT patients were more likely to show visceral metastases to the lung (44% vs. 21%), bone (31% vs. 17%), and brain (7% vs. 1%), compared to UTUC (all p < 0.05). Among SCUT patients, the most common genomic alterations were TERT (30%), TP53 (29%), NF2 (19%), PTEN (13%), SETD2 (12%), PBRM1 (12%), and BAP1 (8%). Among UTUC patients, the most common were TERT (52%), TP53 (52%), KMT2D (30%), FGFR3 (25%), ARID1A (20%), and KDM6A (18%). Compared to UTUC, SCUT was significantly enriched with NF2, SETD2, PBRM1, PTEN, and BAP1 (all p < 0.05). SCUT was depleted in FGFR3 (0% vs. 25%) and FGF4 (0% vs. 8%) mutations compared to UTUC (both p < 0.05). Targetable alterations were observed in SCUT, including NF2, SETD2, and PTEN. Conclusion: Compared with UTUC, SCUT exhibits a more aggressive clinical and genomic phenotype, characterized by enrichment in NF2, SETD2, PBRM1, and PTEN. These findings underscore the divergent molecular landscape of SCUT and highlight potentially targetable genomic alterations.

Cytokine secretion during CAR T-cell activation upon coculture with CD70+ RCC cells

Importance:Geographic disparities in cancer clinical trial access are well described in the US, but patterns in bladder cancer remain poorly defined. Objective:To evaluate bladder cancer trial availability across US counties and its associations with epidemiologic and socioeconomic factors. Design, Setting, and Participants:This cross-sectional study of completed, open, or active bladder cancer clinical trials from June 1, 2019, to June 1, 2025, on ClinicalTrials.gov used data on county-level incidence, mortality, and Social Vulnerability Index (SVI) obtained from the Centers for Disease Control and Prevention, the National Cancer Institute, and the Agency for Toxic Substances and Disease Registry and included interventional bladder cancer clinical trials of adults at 1 or more US sites. Data were analyzed from July 1, 2025, to October 20, 2025. Exposures:Epidemiologic and socioeconomic characteristics of bladder cancer clinical trials. Main Outcome and Measures:Trial availability was defined as 1 or more bladder cancer trial sites per county. Trial volume (number of unique trials per county) was modeled using a multivariable zero-inflated negative binomial regression and reported as incidence rate ratios. Associations between trial characteristics and location in highest vs lowest bladder cancer mortality quintile counties were assessed using a generalized linear mixed-effects logistic regression model. Results:The study identified 436 bladder cancer trials across 713 US counties. Of 3145 counties, 713 (22.7%) had 1 or more trial sites, and 2432 (77.3%) had none. Most trials were sponsored by pharmaceutical companies (211 [48.4%]) or academic institutions (170 [39%]). Most trials were drug focused (350 [80.2%]) and early phase (phase 1 or phase 2; 314 [72%]). Higher bladder cancer incidence was associated with higher trial rates (incidence rate ratio [IRR], 1.03; 95% CI, 1.003-1.06). A higher bladder cancer mortality rate was associated with lower trial rates (IRR, 0.80; 95% CI, 0.73-0.88). Compared with counties with a high SVI, trial rates were higher in counties with a lower-middle (IRR, 1.57; 95% CI, 1.18-2.08), middle-high (IRR, 1.60; 95% CI, 1.22-2.11), and low SVI (IRR, 2.53; 95% CI, 1.89-3.38). Of 7091 trial sites, 225 (3.2%) were located in counties in the highest quintile for bladder cancer mortality. Pharmaceutical company-sponsored trials were less likely than academic trials to be in counties with the highest mortality rate (odds ratio, 0.11; 95% CI, 0.04-0.29; P < .001), as were trials enrolling fewer than 100 participants compared with more than 100 participants (odds ratio, 0.20; 95% CI, 0.09-0.46; P < .001). Conclusions and Relevance:In this cross-sectional study of 436 bladder cancer clinical trials across US counties, most counties lacked trials, with geographic availability concentrated in counties with a high bladder cancer incidence and low social vulnerability. Expanding trial sites to counties with a high mortality rate or a high SVI may improve the geographic availability of bladder cancer clinical trials.

Background Cabozantinib is approved as a subsequent therapy for patients with metastatic renal cell carcinoma (mRCC) based on the METEOR trial. However, only 5% of patients in this trial received prior immunotherapy. Objective Analyze the effectiveness of Cabozantinib in the second-line setting after different first-line treatments. Methods This retrospective study analyzed patients with mRCC who received second-line Cabozantinib between 2010 and 2023, using the International mRCC Database Consortium (IMDC). Patients were grouped by prior therapy and IMDC risk category. We assessed overall response rate (ORR), time to next treatment (TTNT), treatment duration (TD), and overall survival (OS). Results Among 603 patients (mean age 59 years), 31.5% had received IO-IO regimens, 24.5% IO-TKI combinations, and 34.3% TKI monotherapy as initial therapy. At Cabozantinib start, 13.8% were favorable-risk, 49.1% intermediate-risk, and 16.7% poor-risk per IMDC. The ORR for the overall cohort was 25.7%; median TTNT was 10.1 months; median TD was 8.9 months; and median OS was 19.0 months. Efficacy outcomes were consistent across first-line treatment groups. Conclusion This real-world analysis supports the effectiveness of Cabozantinib in the second-line setting, including among patients previously treated with immune checkpoint inhibitors. Prior treatment type did not significantly affect Cabozantinib outcomes.

Abstract Background: N/I is a standard first-line therapy for mRCC. Our group has shown that gut microbiome modulation may enhance immune checkpoint inhibitor (ICI) efficacy in mRCC (Dizman et al, 2022; Ebrahimi et al, 2024). In preclinical models, camu camu, a polyphenol-rich Amazonian berry, enriched Ruminococcus spp. in the gut microbiome and improved responses to ICI in mice (Messaoudene et al 2022). We prospectively evaluated the biological and clinical effects of adding camu camu to N/I for mRCC therapy. Methods: This single-center, randomized, phase I trial enrolled pts. ≥18 years with clear-cell mRCC, IMSC intermediate- or poor-risk disease, ECOG 0-1, measurable disease, and adequate organ function. Prior systemic therapy was not allowed, except adjuvant or neoadjuvant therapy completed ≥6 months without prior ICI exposure. Patients were randomized 2:1 to receive standard-dose N/I (3 mg/kg plus 1 mg/kg every 3 weeks for 4 doses, then N 480 mg every 4 weeks) with or without camu camu 1500 mg PO daily. The primary endpoint was the change in Ruminococcus spp. abundance in stool from baseline to week 13. Secondary endpoints included progression-free survival (PFS), overall survival (OS), objective response rate (ORR), safety, changes in microbiome diversity, and plasma cytokine assessment. A 2-group t-test with a 1-sided type I error of 0.05 was used to assess the primary endpoint, increase in Ruminococcus spp. with camu camu. Results: We enrolled 31 patients (21 N/I plus camu camu; 10 N/I alone) with a median follow-up of 15.9 months. Median age was 64 years (range 45-84),10% had sarcomatoid features, 35% had a nephrectomy, and 29% presented poor-risk disease. Median PFS was 16.4 months (95% CI 5.5-not estimable [NE]) in the camu camu arm vs 5.4 months (95% CI 2.6-NE) with N/I alone (p=0.04). ORR was 33% in the experimental and 10% in the control arm (p=.2). Median OS was not reached in either arm. No significant differences in Ruminococcus spp. abundance present. Alpha diversity as measured by species richness in the placebo arm decreased from baseline to week 13 (p=0.02), whereas it remained stable in the camu camu arm (p=0.5). In the N/I arm, there was an increased differential abundance at week 13 compared to baseline in deleterious bacteria such as Collinsella aerofaciens, Veillonella rogosae, and Enterococcus gallinarum, while beneficial bacteria including Ruminococcus lactaris remained enriched at week 13 in the camu camu arm. The proportion of beneficial SIG2 TOPOscore (Derosa et al., Cell 2024) bacteria significantly increased at week 13 in responders (15% vs. 29%, p<0.001), not observed in the N/I group. The most frequent adverse events (AEs) in both arms were fatigue and anemia. Patients in the camu camu arm displayed a distinct pattern of immune-related AEs (irAEs), including cerebritis (n=2),immune thrombocytopenic purpura (n=1), and adrenal insufficiency (n=6). Cytokine assessment showed significant changes at week 13 compared with baseline in this group, with increased IL-10 and IL-17A, and reduced IL-8 levels. Conclusion: In this first randomized trial evaluating a natural prebiotic with ICI in first-line mRCC, the addition of camu camu prolonged PFS and beneficially shifted the gut microbiome. The irAEs observed with camu camu, together with associated cytokine alterations, emphasize the need for close monitoring in future studies. Citation Format: Regina Barragan Carrillo, Miguel Zugman, Bertrand Routy, Mallia Geiger, Xiaochen Li, Nazli Dizman, Hedyeh Ebrahimi, Salvador Jaime-Casas, Nicholas Salgia, Joann Hsu, Daniela V. Castro, Benjamin D. Mercier, Koral Sha, Sreya Duttagupta, Tanya B. Dorff, Neal S. Chawla, Ruchi Agarawal, Ekta Kapoor, Marcin Kortylewski, Alex Chehrazi-Raffle, Arielle Elkrief, Sumanta K. Pal. Camu camu plus nivolumab/ipilimumab (N/I) as first-line therapy for metastatic renal cell carcinoma (mRCC): A randomized phase I trial [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(8_Suppl):Abstract nr CT182.

Precision oncology has fundamentally reshaped cancer treatment by enabling therapies to be matched to the molecular biology of individual tumors. Advances in next-generation sequencing (NGS) technologies, expanding biomarker discovery, and an increasing number of targeted therapies have made comprehensive molecular testing an integral component of modern oncology practice. Realizing the full clinical impact of these technologies requires understanding not only the biological alterations detected but also the diagnostic workflows through which genomic information is generated and interpreted. NGS-based assays differ substantially in their design, particularly in terms of sequencing breadth, depth, and the chemistry involved in library prep. These technical characteristics influence the types of genomic alterations that can be detected, the analytical sensitivity of testing, and the clinical confidence with which results can be interpreted. Preanalytic variables-including tissue adequacy, nucleic acid quality, and specimen handling-are equally critical, as they determine whether molecular testing can be successfully performed and whether the resulting data accurately reflect tumor biology. Once genomic results are available, clinicians must interpret a diverse range of molecular alterations, including single-nucleotide variants, copy number changes, structural rearrangements, and composite genomic signatures. Structured reporting practices, multidisciplinary interpretation through molecular tumor boards, and evidence-based actionability frameworks help translate these findings into clinically meaningful treatment decisions. Ultimately, maximizing the impact of precision oncology requires coordinated integration across molecular diagnostics, clinical interpretation, and health care delivery systems. By understanding each step of this pathway-from specimen acquisition to therapeutic decision making-clinicians can more effectively translate genomic insights into improved patient outcomes.

We previously reported initial results from a clinical trial testing a strategy in which patients with muscle-invasive bladder cancer (MIBC) achieving a clinical complete response after cystoscopic resection of the bladder tumor plus systemic therapy could forgo removal of their entire bladder (cystectomy). While the results were highly promising, a subset of patients omitting initial cystectomy developed recurrence highlighting the need for biomarkers to refine selection of patients for this approach. We here report long-term follow-up of these patients and investigate whether tumor DNA in the plasma (ctDNA) or urine (utDNA) could inform prognosis and the need for cystectomy. Three-year bladder-intact survival among patients with a complete clinical response following four rounds of systemic therapy was 69%. Metastatic risk was significantly higher for patients with detectable versus undetectable ctDNA presystemic therapy (HR 4.68; 95% CI 1.10-43.35; log-rank P = 0.036). Only 4.5% (1 of 22) of patients with undetectable baseline ctDNA developed metastatic disease. Undetectable ctDNA before or after systemic therapy was associated with extremely low metastatic risk. Urine utDNA was more sensitive than plasma ctDNA at detecting residual disease within the bladder, and detectable urine utDNA in patients with a complete clinical response was associated with shorter bladder-intact survival (HR 6.47, 95% CI 1.34-31.31; log-rank P = 0.008). These findings establish the conceptual and experimental foundation for incorporating ctDNA and utDNA assays into the management of patients with MIBC, particularly with respect to the need for cystectomy.