Background: Prostate cancer is a heterogeneous disease with variable clinical outcomes. If localized, the patient may be cured. However, prostate cancer is lethal if recurrence/progression to metastatic castrate resistant disease occurs. Thus, there is an unmet need to further understand the molecular underpinnings of this progression. Epidemiologic studies show that increased risk of developing and dying from prostate cancer has been associated with elevated serum IGF-1 levels, hyperinsulinemia and metabolic syndrome. Alterations in insulin pathway genes, such as PTEN, FOXO, and PIK3CA, are mutated in up to 32%, 15%, and 11% of localized prostate tumors, respectively. We aimed to further characterize expression of insulin pathway genes in localized prostate cancers in an effort to (1) provide insights into potential mechanisms of progression to metastatic disease and (2) try to further enrich for those prostate tumors that portend worse survival outcomes. Methods: Using the multi-institutional Oncology Research Information Exchange Network (ORIEN) database, gene expression data was analyzed from localized prostate cancer tumors. The raw counts were first normalized, and 176 genes related to the insulin receptor and its downstream pathways were then subset and used for clustering using the non-negative matrix factorization (NMF). The NMF cluster analysis was performed in an attempt to separate gene expression into two groups. Gene Set Enrichment Analysis (GSEA) was then performed between the two groups that had been separated by cluster analysis to determine homology between other GSEA sets. Kaplan-Meier curves were used to assess median overall survival. Cox analysis was performed to generate the adjusted KM curve. Mediation analysis was conducted to determine the relationship between cluster status, TN stage, and survival. Results: Cluster analysis revealed two distinct groups of insulin gene expression, cluster 1 (n = 96) and cluster 2 (n = 337). Compared with cluster 2, cluster 1 consisted of decreased expression of PTEN (p < 0.001) and PIK3R1 (p < 0.001), along with increases in the expression of AKT1 (p < 0.001), IRS1/2 (p < 0.001), FASN (p < 0.001), IGFBP2 (p < 0.001), and MTOR (p < 0.001). GSEA analysis revealed changes in lipid metabolism and WNT secretion pathways in cluster 1. Cluster 2 GSEA showed pathway changes related to DNA damage repair and testosterone. Patient characteristics between clusters differed significantly in the T and N stages of tumor but not in other ways. In unadjusted analysis, median overall survival was estimated at 117 months and 232 months for cluster 1 and cluster 2, respectively (p < 0.05). The proportion of patients who went on to develop metastases (p < 0.05) or need chemotherapy (p < 0.05) was increased in cluster 1 compared to cluster 2. Repeat survival analysis adjusted for confounders (T stage, N stage, age at diagnosis, pathologic grade) showed no difference in survival between clusters. Mediation analysis showed that the contribution of cluster status to survival was independent of T or N stage. Conclusions: A subset of localized prostate cancer patients demonstrated linked insulin pathway changes that are consistent with prior studies describing a pattern of insulin dysregulation. Though the group characterized by insulin dysregulation initially showed worse survival outcomes, this difference disappeared when controlling for confounders. Though baseline differences in tumor stage seemed to most readily explain the difference in survival between clusters, mediation analysis showed that the effect of cluster status on survival was independent of tumor stage. This suggests that other confounders, such as pathologic grade or baseline age, may explain the survival difference.

BACKGROUND AND OBJECTIVE:Histological subtypes and divergent differentiation are common in bladder cancer. Each subtype has distinct biology and clinical features. We aim to summarize pathology, molecular features, and outcomes of the most common bladder cancer subtypes to guide management. METHODS:We performed a narrative review of cohort studies, clinical trials, and population-based analyses assessing morphology, immunophenotype, genomic alterations, and outcomes following various localized and systemic therapies in patients with bladder cancer subtypes. KEY FINDINGS AND LIMITATIONS:Histological subtypes are often understaged on transurethral resection of bladder tumor and commonly demonstrate lymph node metastasis, supporting early radical cystectomy (RC) even for certain clinically non-muscle-invasive bladder cancers. Small cell urothelial carcinoma (UC) consistently benefits from platinum/etoposide-based chemotherapy regimens, whereas predominant squamous, plasmacytoid, sarcomatoid, and micropapillary tumors demonstrate variable response rates to systemic therapies used in conventional UC. Trimodality therapy may approximate RC in locoregional control for small cell UC and appears inferior in cases with predominant squamous and adenocarcinoma. Genomic profiling highlights actionable alterations, albeit with unclear clinical implications. Immune checkpoint blockade and antibody-drug conjugates have been used sparingly against subtype bladder cancers and have anecdotally demonstrated activity across several subtypes. CONCLUSIONS AND CLINICAL IMPLICATIONS:Histological subtypes and divergent differentiation of UC represent high-risk yet biologically distinct disease phenotypes that may not conform to the current "one-size-fits-all" treatment paradigm. More in-depth clinical and translational analyses with robust, adequately powered cohorts are required to further understand the clinical behavior of each unique bladder cancer subtype and to customize the optimal therapeutic strategies.

PURPOSE:Synchronous prostate and rectal cancers pose therapeutic challenges. Prostate external beam radiation therapy may increase rectal dose and impair anastomotic healing after chemoradiation (CRT). High-dose-rate brachytherapy (HDR-BT) enables prostate dose escalation, minimizing rectal exposure. We report outcomes of pelvic CRT plus HDR-BT boost and propose a treatment algorithm. METHODS:We retrospectively reviewed a multi-institutional database (2011-2023) to identify patients with synchronous prostate and rectal/anal cancers treated with curative intent. All received pelvic CRT (45-50.4 Gy/25-28 fractions) with concurrent 5-FU or capecitabine ± total neoadjuvant therapy. HDR-BT boosts were delivered to the prostate ± seminal vesicles, meeting objectives of prostate V100 ≥ 95%, rectum V75% < 1 cc, and urethra D10 ≤ 115%. Toxicities were graded per CTCAE v5.0; oncologic outcomes were assessed. RESULTS:Six men (age 60-78) completed CRT, HDR-BT, and surgery/nonoperative management without interruptions. At median 40 months (range 30-110) follow-up post-BT, no locoregional failures occurred; two rectal cancers achieved pathologic complete response, and four remained recurrence-free. All prostate cancers were biochemically controlled; two rectal cancers developed distant metastasis at ∼2-3 years. HDR-BT achieved excellent prostate coverage (V100 94.6%-97.7%, D90 103%-108%) and rectal sparing (D2cc 40%-72% of prescription, V75 ≤ 1.4 cc). One late grade 3 proctitis/urethral stricture occurred in a fractionated high-dose case; none ≥ grade 3 GU/GI in the single-fraction cohort. CONCLUSION:CRT followed by HDR-BT prostate boost is feasible, maintains anastomotic safety, and achieves excellent local control and dosimetry with minimal severe toxicity.

Histological subtypes of bladder cancer are generally associated with more aggressive disease, higher stage at presentation, and worse prognosis compared to conventional urothelial carcinoma. Recent updates in classification systems have further refined the distinction between true histologic subtypes and divergent differentiation, underscoring the complexity of these tumors. Emerging molecular profiling studies have identified subtype-specific genomic alterations, including ERBB2 amplification in micropapillary subtype carcinoma, CDH1 loss in plasmacytoid subtype carcinoma, and TP53 and RB1 co-alterations in neuroendocrine bladder cancer, which may contribute to differences in tumor biology and therapeutic response. Despite these advances, the histological subtypes of bladder cancer remain underrepresented in prospective clinical trials, leading to significant gaps in evidence-based management. Treatment responses vary widely across subtypes, with some demonstrating sensitivity to platinum-based chemotherapy or immunotherapy, while others appear less responsive to conventional approaches. This review summarizes the current understanding of the epidemiology, molecular landscape, and clinical behavior of major bladder cancer subtypes and highlights emerging opportunities for personalized treatment strategies, biomarker-driven therapies, and more inclusive clinical trial design to improve outcomes in this high-risk population.

Abstract Introduction Nectin-4 targeting antibody-drug conjugate (ADC) enfortumab vedotin (EV), in combination with pembrolizumab, is the first-line treatment for patients with locally advanced or metastatic urothelial carcinoma (UC). Optimal treatment strategies for patients who are non-responders or progress on EV with pembrolizumab remain an unmet clinical need. We sought to characterize ADC and immunotherapy (IO)-associated target expression profiles to identify candidate therapeutic vulnerabilities beyond EV. Methods We conducted a literature review to identify ADC and IO targets with approved or investigational relevance in UC. Unsupervised hierarchical clustering was used to identify clusters of target gene expression in RNA-seq data. Transcriptomic clustering analyses were performed in 434 patients from The Cancer Genome Atlas Bladder Urothelial Carcinoma cohort (TCGA-BLCA) and validated in an independent cohort of 478 patients from the Oncology Research Information Exchange Network (ORIEN) consortium. Proteomic interrogation of these targets was performed using mass spectrometry data from additional cohort of 116 patients. Differential gene expression analyses evaluated associations between target expression patterns, histologic variants, and consensus molecular subtypes of muscle-invasive bladder cancer (CMIBC). Results We identified 13 ADC and 10 IO-associated targets with translational relevance in UC. Transcriptomic analyses revealed three reproducible clusters of overexpressed target genes across independent cohorts: 1) a luminal/epithelial-associated cluster enriched for VTCN1, SLITRK6, FGFR3, NECTIN4, TACSTD2, ERBB2, and ERBB3; 2) an immune target predominant cluster enriched for BTLA, LAG3, PDCD1, TIGIT, CTLA4, TNFRSF9, TNFRSF18, TNFRSF4 ; and 3) a basal/neuroendocrine-associated cluster characterized by CD274, F3, NT5E, EGFR, MET and DLL3. Similar clusters were largely conserved at the proteomic level. Adenocarcinomas overexpressed ERBB3 compared to neuroendocrine and squamous cell carcinomas. Pure squamous cell carcinomas overexpressed TACSTD2 compared to adenocarcinomas. In CMIBC subtypes, basal/squamous tumors expressed higher levels of CD274, EGFR , F3 , LAG3 , NT5E , and TNFRSF18 , whereas luminal tumors demonstrated higher ERBB2 and ERBB3 expression. Neuroendocrine-like tumors showed higher DLL3 expression compared to all other subtypes. Tumors with low expression of NECTIN4 , TACSTD 2, and FGFR3 were enriched for alternative targets including DLL3, CD274, and CD276. Our findings provide a framework for hypothesis-driven therapeutic prioritization in advanced UC. Conclusions: UC is characterized by reproducible, biologically distinct patterns of ADC and IO target expressions. The degree of expression of NECTIN4 was positively associated with TACSTD2 , FGFR3 and inversely associated with DLL3 , CD276 , and CD274 , supporting alternative biologically informed treatment strategies besides EV . Histologic variants and molecular subtypes of UC also display distinct patterns of target expression. This study provides the first integrated transcriptomic framework linking ADC and IO target co-expression patterns for hypothesis-driven therapeutic prioritization. These findings provide a basis for rational ADC and immunotherapy development in advanced UC and support prospective proteomic validation in treatment stratified cohorts. Statement of Translational Relevance Enfortumab vedotin plus pembrolizumab has redefined first-line therapy for advanced urothelial carcinoma, yet treatment selection following resistance or progression remains undefined. In this study, we integrate transcriptomic and proteomic analyses across independent cohorts to define reproducible patterns of antibody–drug conjugate (ADC) and immunotherapy target co-expression in urothelial carcinoma. We identify biologically distinct target-expression patterns that are associated with histologic and molecular subtypes and demonstrate coordinated and, in some cases, mutually exclusive relationships among therapeutically actionable targets. These findings have direct translational implications. First, they provide biologic rationale for rational sequencing and combination strategies based on co-expressed targets in NECTIN4 -enriched tumors. Second, they identify alternative therapeutic vulnerabilities, including DLL3 - and CD274 -associated pathways, in tumors with low NECTIN4 expression, a population potentially enriched for resistance to EV-based therapy. Finally, this framework establishes a foundation for biomarker-driven clinical trials in urothelial carcinoma and supports the development of precision therapeutic approaches beyond current standards.

BACKGROUND:Grade group 5 (GG5) prostate cancer (PCa) carries a less favorable prognosis after standard-of-care (SOC) therapy, necessitating novel therapeutic approaches. High-dose rate brachytherapy (HDRBT) and androgen deprivation therapy (ADT) may modulate immune response in GG5 PCa, particularly in tumors with increased immune content. This study evaluated whether the addition of nivolumab to SOC was associated with improved disease control in patients with high-volume GG5 PCa, including those with oligometastatic disease. METHODS:In this non-randomized phase II trial, 31 patients with localized or oligometastatic GG5 PCa and >30% positive biopsy cores were evaluated between September 2018 and April 2021. Patients received four doses of nivolumab (240 mg every 2 weeks) beginning 4 weeks prior to HDRBT, alongside ADT, HDRBT, and external beam radiation. The primary endpoint was to evaluate whether the 2-year freedom from biochemical recurrence (FFBR) rate would exceed a prespecified historical control rate of 75%. RESULTS:Among the 31 patients, the median follow-up was 38.8 months (IQR 31.0-46.5 months). The addition of nivolumab to SOC RT with ADT was associated with a 2-year FFBR rate of 90.3% (95% CI 74.3% to 98.0%) (median FFBR not reached), exceeding the prespecified historical control rate of 75% (one-sided p value from binomial test=0.024). Definitive and probable nivolumab-related toxicity included 6.3% acute grade 2 and 6.3% acute grade 3 adverse events (AEs), with no grade 4+ AEs observed. A higher Decipher immunosuppression score at diagnosis correlated with early pathologic response (p=0.005) and was independently associated with time to metastatic failure (p=0.044). CONCLUSIONS:Nivolumab combined with SOC was associated with encouraging FFBR in this high-risk GG5 PCa population and may represent a promising therapeutic intensification strategy. The Decipher immunosuppression score may serve as a predictive biomarker for response. These findings warrant further investigation in randomized trials.

Abstract Background: Harmonizing patient longitudinal data is critical to uncovering variables and events that can influence outcomes or molecular data, yet existing tools have significant limitations in integrating multilayered time-series data, particularly in linking treatment events with survival outcomes. Due to their observational nature, real-world data (RWD) can be comprehensive and heterogeneous, posing a challenge when visualizing and interpreting the data. We developed ShinyEvents, an open-source tool and application to facilitate interaction and exploration of longitudinal data, which we demonstrate in the application of the AACR Project GENIE a global consortium that pools real-world cancer genomic and clinical data to advance precision oncology. Methods: ShinyEvents is a web-based framework that allows users to upload longitudinal data and generate interactive patient timelines to view clinical events and perform cohort-level analyses through treatment clustering and endpoint assignment. The tool provides informative cohort visualizations, such as a Sankey diagram of the treatment line, swimmer diagrams of the clinical course and treatment duration, as well as heatmaps to view unsupervised clustering on patient treatments. Our tool can infer real-world progression-free survival (rwPFS) based on user-defined endpoints and perform Kaplan-Meier and Cox proportional hazards regression analysis. We incorporated the AACR Project GENIE data on non-small cell lung cancer (NSCLC) and colorectal cancer (CRC) into a dedicated wed instance to visualize and interact with the data. The application is publicly accessible at the following link: https://shawlab-moffitt.shinyapps.io/ShinyEvents_AACR_GENIE/. Conclusions: ShinyEvents provides a unified framework integrating longitudinal real-world data with survival analytics to facilitate transparent and reproducible collaboration between clinicians and data scientists. Based on the GENIE data, the tool is able to provide dynamic longitudinal visualization on the patient treatment regimen and relate back to the molecular data by identifying complexities surrounding sample collection in relation to treatment regimens. This standardized approach to RWD analysis will facilitate additional collaboration across the global GENIE network. Citation Format: Alyssa Obermayer, Joshua Davis, Roger Li, Rodrigo Rodrigues Pessoa, Brandon J. Manley, G. Daniel Grass, Aik Choon Tan, Dung-Tsa Chen, Timothy Shaw. ShinyEvents: Harmonizing real-world longitudinal data for clinical insights and survival analytics [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 9.

Over a decade ago, collaborating academic cancer centers formed the Oncology Research Information Exchange Network® (ORIEN) to develop a patient-driven, federated infrastructure for oncology research. Aster Insights is the network’s operational, commercial, and research partner. Together ORIEN and Aster Insights have built a unique multimodal dataset on the active engagement and consent of patients who opted into the Total Cancer Care® (TCC) protocol to contribute their data and biospecimens for research. Over 400,000 cancer patients have been enrolled in TCC, >32,500 of which have an in silico “Avatar” generated to represent their individual patient experience and molecular profile to support a broad range of network and industry research use cases. We provide an overview of ORIEN’s evolution, demonstrate the power of our data resources through a landmark analysis of >37,000 tumors across all cancer types collected for the Avatar program, and provide a vision for ORIEN to fuel collaborative research.

Longitudinal data analysis of the patient’s treatment course is critical to uncovering variables that influence outcomes. However, existing tools have significant limitations in integrating multilayered time-series data, particularly in linking treatment events with survival outcomes. Here, we developed ShinyEvents, a web-based framework for complex longitudinal data analysis. ShinyEvents allows users to upload data and generate interactive timelines of clinical events, enabling cohort-level analyses such as treatment clustering and endpoint assignment. It also provides informative cohort visualizations, such as a Sankey diagram of the treatment line and a Swimmer diagram of the clinical course. Finally, our tool can infer real-world progression-free survival (rwPFS) based on user-defined endpoints and perform Kaplan-Meier and Cox proportional hazards regression analysis. With these features, the tool can then associate treatment lines with clinical outcomes. As a case study, we analyzed Moffitt patients with muscle-invasive bladder cancer treated with neoadjuvant chemotherapy followed by surgery. Patients treated with cisplatin and gemcitabine exhibited more favorable rwPFS and overall survival, which is consistent with prior reports. Altogether, ShinyEvents provides a unified framework for integrating longitudinal real-world data with survival analytics, fostering transparent and reproducible collaboration between clinicians and data scientists. A live demo is available at https://shawlab-moffitt.shinyapps.io/shinyevents/.

Purpose:SWI/SNF (BAF) chromatin remodeling complex alterations are common in urothelial carcinoma, yet no biomarker-directed therapeutic strategies have been established for this population. We investigated whether BAF alterations delineate a biologically distinct, therapeutically actionable urothelial carcinoma subtype. Experimental Design:We performed integrative genomic and transcriptomic analyses of 792 urothelial carcinoma tumors from the Oncology Research Information Exchange Network (ORIEN) and validated findings in the TCGA-BLCA cohort. Mechanistic studies incorporated RNA sequencing and ATAC-seq following histone deacetylase (HDAC) inhibition. Functional dependencies were assessed using patient-derived xenograft organoids and cell line models. Clinical relevance was explored in a biomarker-enriched investigator-initiated trial. Results:Approximately half of urothelial carcinoma tumors exhibited BAF alterations, defining a previously unrecognized chromatin-altered molecular subtype characterized by activation of proliferative programs, loss of lineage identity, and altered metabolic signaling. This subtype was enriched for transcriptomic programs associated with HDAC inhibitor sensitivity and depleted of HDAC inhibitor resistance signatures. Mechanistically, HDAC inhibition induced widespread chromatin remodeling with reduced accessibility at AP-1 and TEAD-associated regions, and downregulation of E2F- and MYC-driven transcriptional networks. Functional studies confirmed enhanced HDAC inhibition sensitivity in ARID1A -mutated cell lines and a patient-derived organoid model. Early clinical observations demonstrated a durable responder treated with HDAC inhibitors and immunotherapy. Conclusions:BAF alterations define a chromatin-dependent tumor state in urothelial carcinoma that is selectively vulnerable to HDAC inhibition. Integrating genomic, epigenomic, functional, and early clinical evidence, these findings provide a rationale for biomarker-enriched clinical trials and HDAC inhibitor-based combination strategies in urothelial carcinoma.

Prostate Artery Embolization (PAE) is a novel minimally invasive angiographic technique that has been used effectively to treat men with lower urinary tract symptoms (LUTS) from benign prostatic hyperplasia (BPH). However, applications of PAE for men with prostate cancer have been minimally studied. This review serves as an update on the status of PAE in men with prostate cancer, as well as a discussion of emerging indications.

MOTIVATION:Spatial transcriptomic (ST) technologies, such as GeoMx Digital Spatial Profiler, are increasingly utilized to investigate the role of diverse tumor microenvironment components, particularly in relation to cancer progression, treatment response, and therapeutic resistance. However, in many ST studies, the spatial information obtained from immunofluorescence imaging is primarily used for identifying regions of interest (ROIs) rather than as an integral part of downstream transcriptomic data analysis and interpretation. RESULTS:We developed ROICellTrack, a deep learning-based framework that better integrates cellular imaging with spatial transcriptomic profiling. By analyzing 56 ROIs from urothelial carcinoma of the bladder and upper tract urothelial carcinoma, ROICellTrack identified distinct cancer-immune cell mixtures, characterized by specific transcriptomic and morphological signatures and receptor-ligand interactions linked to tumor content and immune infiltrations. Our findings demonstrate the value of integrating imaging with transcriptomics to analyze spatial omics data, improving our understanding of tumor heterogeneity and its relevance to personalized and targeted therapies. AVAILABILITY AND IMPLEMENTATION:ROICellTrack is publicly available at https://github.com/wanglab1/ROICellTrack.

Introduction Organ-sparing surgery (OSS) for penile squamous cell carcinoma (PSCC) is the preferred treatment option for low-grade/low-stage tumors because despite higher recurrence rates, there is no impact on overall survival. Identifying factors associated with improved recurrence or survival can enhance personalized treatment options and improve outcomes. In this study, we examined the oncological outcomes of HPV-positive compared to HPV-negative PSCC at a single institution. Methods A retrospective analysis of patients with penile cancer (Ta, Tis, T1-3) treated with low-risk OSS from May 2013 to May 2024 was performed. Low-risk OSS was defined as wide local excision, circumcision, Mohs micrographic surgery, laser ablation, cryotherapy, partial glansectomy, and glans resurfacing. Patients who had total glansectomy, partial penectomy, or total penectomy at primary surgery, or who had nodal disease or metastasis at presentation, were excluded. P16 immunostaining and in situ hybridization of resected tissue were primarily used together to determine HPV status, with PCR done in 1 case.Baseline characteristics were compared using independent t-test for continuous variables and Chi-square for categorical. HPV status in relation to recurrence and mortality was analyzed using Chi-square and Fisher's exact test. Results 43 patients met study criteria, with the majority being HPV-positive (n=36, 83.7%). A total of 15 local recurrences, 7 regional recurrences, and 5 distant metastatic recurrences were recorded between the two groups. Baseline demographics and clinicopathologic characteristics were statistically insignificant between the two groups except for histologic subtype (Table 1).HPV-negative patients were noted to have higher rates of local recurrence (71.4% vs 27.8%, P=0.04) and distant metastatic recurrence (42.9% vs 5.6%, P=0.024) compared to HPV-positive patients. No significant difference was noted in overall or regional recurrence based on HPV status. HPV-negative status was associated with higher cancer-specific mortality compared to HPV-positive patients (42.9% vs 2.8%, P=0.01) (Table 2). Conclusions HPV-positive PSCC is associated with significantly lower rates of both local and distant metastatic recurrence, as well as lower cancer-specific mortality on univariate analysis. Overall recurrences likely weren't statistically significant due to low statistical power. Our data shows that low-risk OSS may have higher efficacy for HPV-positive tumors and suggests the potential for a tailored approach to the management of localized penile cancer that maximizes quality of life without compromising oncological outcomes.

BACKGROUND AND OBJECTIVE:Patient-centric management necessitates providing care aligned with patients' values, preferences, and expressed needs. Therefore, critical assessment of bladder preservation therapies (BPTs) as alternatives to radical cystectomy (RC) for muscle-invasive bladder cancer (MIBC) and practical recommendations on the optimal selection of patients for BPTs are needed urgently. METHODS:A global committee of bladder cancer experts was assembled to develop BPT recommendations for MIBC. Working groups reviewed the literature and drafted recommendations, which were voted on by International Bladder Cancer Group (IBCG) members using a modified Delphi process. During a live meeting in August 2023, voting results and supporting evidence were presented, and recommendations were refined based on discussions. Final recommendations achieved ≥75% agreement during the meeting, with further refinements through web conferences and e-mail discussions. KEY FINDINGS AND LIMITATIONS:Patients with newly diagnosed MIBC should be offered evaluation in a multidisciplinary setting for consideration of BPTs. The main alternative to RC is trimodal therapy (TMT), and favorable prognostic factors for TMT include unifocal cT2 stage, lack of hydronephrosis, and no multifocal carcinoma in situ (CIS). Other options should be reserved for very select patients who are ineligible for or who decline TMT or RC after thorough consideration of benefits versus risks. These include partial cystectomy (PC) for urachal adenocarcinoma and PC or radical transurethral resection alone for solitary tumors amenable to resection with adequate margins and without concomitant CIS or histologic subtypes. CONCLUSIONS AND CLINICAL IMPLICATIONS:The IBCG consensus recommendations provide practical guidance on BPTs for MIBC.

577 Background: Approximately 30% of patients with ccRCC present with metastatic disease (stage IV) and close to half of patients with stage III disease will recur during follow-up surveillance. Two of the most common and morbid sites of metastatic development are brain and bone metastasis. Existing treatment guidelines do not recommend routine brain or bone directed imaging during either initial staging or surveillance in the absence of clinical signs or symptoms. A group of recurrently altered aberrant splice variants in primary ccRCC tumors associated with metastatic progression have previously been identified. Our study aims to investigate metastatic organotropism of the FGD1 -splice variant ( FGD1 -SV) to refine risk stratification and therapeutic decision-making as cabozantinib is drug with activity at these disease sites. Methods: This study leveraged the ORIEN AVATAR network, a data-sharing alliance of 18 NCI-designated cancer centers, to evaluate the presence of FGD1 -SV in a cohort of 1,001 clear cell renal cell carcinoma (ccRCC) patients using bulk RNA-sequencing (RNA-seq). Samples with three or more FGD1 -SV reads were classified as positive. Clinical and survival data were collected, and Kaplan-Meier curves were generated. Odds ratios (ORs) evaluated the presence of FGD1 -SV on brain and bone metastases, while hazard ratios (HRs) assessed association with cabozantinib response. Of 1,037 RNA-seq samples, 84 were metastatic tumor specimens. The relationship between FGD1 -SV positivity and metastasis to common sites was assessed with Fisher's exact test. Results: Brain and bone metastases demonstrated the highest FGD1 -SV positivity (50% and 44%, respectively). A grouped comparison of brain and bone metastases versus all other common metastatic sites (adrenal, lymph node, pancreas, lung, and liver) revealed significant enrichment of FGD1 -SV in these metastases (OR 5.33, 95% CI [1.64 - 18.42], p=0.002). FGD1 -SV positivity in primary tumors was associated with greater risk of recurrence after surgical resection (p=0.0029). Furthermore, FGD1 -SV positive tumors were associated with poor survival when not treated with cabozantinib (HR 2.04, 95% CI [1.20 - 3.45], p=0.01). Conclusions: FGD1 -SV positivity is significantly associated with brain and bone metastatic organotropism in ccRCC. Our findings warrant prospective studies to validate these results and investigate the integration of FGD1 -SV into clinical decision-making, potentially guiding surveillance and therapeutic approaches in high-risk and metastatic patients.

222 Background: Androgen indifferent prostate cancer (AIPC) is increasingly common and particularly lethal. Data describing these tumors are sparse and AIPC remains a poorly understood malignancy. This study aims to characterize the clinical and genomic features of AIPC. Our work ultimately seeks to identify biomarkers with diagnostic and therapeutic potential. Methods: Utilizing the Oncology Research Information Exchange Network (ORIEN) database, we queried all prostate cancer (PC) patients, identified metastatic castrate resistant prostate cancer (MCRPC) samples, and aimed to enrich for tumors with features of AIPC using previously described characteristics. Our AIPC cohort included three subgroups: aggressive variant prostate cancer (AVPC) defined as having alterations in at least two of TP53, RB1, PTEN; neuroendocrine PC (NEPC) defined as small cell histology or NEPC signature score ≥ 0.25 (1); and double-negative PC (DNPC), defined as non-NEPC patients with low AR expression/AR signaling score. We compared clinical characteristics and genomic analysis of AIPC vs non-AIPC samples in patients who developed MCRPC. Clinical analysis was done using Wilcoxon rank sum test or Fisher's exact test. Gene expression analysis was performed using DESeq2 and GSEA. Results: Of 1,496 total PC patients available for analysis, we identified 323 (22%) as MCRPC. Of those, 39 (12%) met AIPC criteria (17 AVPC, 13 NEPC, 9 DNPC) and 284 (88%) were non-AIPC. Median age at diagnosis for AIPC was 62 years and 85% were white, compared to 62 years and 87% for non-AIPC. Fifty-seven percent of AIPC patients had ECOG ≥1 at diagnosis vs 16% of non-AIPC. Forty-three percent of AIPC patients had de novo metastatic disease vs 15% for non-AIPC (p=0.003). TMPRSS2-ERG gene fusions were found in a significantly higher proportion of AIPC samples vs non-AIPC (38.5% vs 16%, p=0.014). Homologous recombination deficiency (HRD) and tumor mutational burden (TMB) did not differ between cohorts, but microsatellite instability scores (MSI) were significantly higher in AIPC (p=0.019). Using Gene Set Enrichment Analysis (GSEA), we found that genes defining response to androgens and genes involved in oxidative phosphorylation were the most downregulated, whereas genes involved in epithelial mesenchymal transition (EMT), interferon response, and angiogenesis were significantly upregulated in AIPC vs non-AIPC samples. Conclusions: There was a significantly higher rate of de novo metastasis in the AIPC cohort. The downregulated androgen response and upregulated EMT pathways in AIPC suggest enrichment for androgen indifference with our methodology. Upregulated immune signaling and angiogenesis as well as higher MSI suggest opportunities for therapeutic investigation. Future directions include more focused in vitro and in vivo analysis to identify actionable targets. 1. Beltran H, et al. Nat Med . 2016;22(3):298-305. doi:10.1038/nm.4045.

Background: HPV infection is implicated in approximately half of global penile squamous cell carcinoma (PSCC) cases. Previous studies on HPV DNA and p16INK4a status in PSCC have yielded inconclusive prognostic findings. This meta-analysis aims to elucidate the prognostic role of HPV in PSCC by pooling data on disease-free survival (DFS), disease-specific survival (DSS), and overall survival (OS). Methods: We systematically searched Medline and Embase up to January 2023 for relevant human studies. Data from eligible publications reporting HPV DNA or p16INK4a status, along with and DFS, DSS, or OS outcomes, were extracted. A random-effects meta-analysis model was used to synthesize data, with study weights based on size and significance. The study protocol was registered with PROSPERO (CRD42019131355). Results: Out of 544 studies screened, 34 publications were included, comprising a pooled sample size of 3,944 patients. p16INK4a-positive status was associated with improved OS (hazard ratio [HR], 0.54; 95% CI, 0.39-0.75; I 2=31%), DFS (HR, 0.52; 95% CI, 0.29-0.94; I 2=20%), and DSS (HR, 0.34; 95% CI, 0.23-0.50; I 2=18%). HPV DNA positivity was significantly associated with improved DFS (HR, 0.63; 95% CI, 0.46-0.87; I 2=13%) and DSS (HR, 0.46; 95% CI, 0.29-0.75; I 2=47%) but not OS (HR, 0.92; 95% CI, 0.74-1.11; I 2=0%). Conclusions: This meta-analysis, comprising the largest number of patients with PSCC to date, shows a notable correlation between p16INK4a immunohistochemistry positivity and survival outcomes. These findings support the understanding that penile cancer cases not associated with HPV tend to behave more aggressively. We support p16INK4a immunohistochemistry testing as part of the initial diagnostic evaluation of patients with PSCC.

Several studies have demonstrated the potential of circulating tumor DNA (ctDNA) for personalization of perioperative systemic treatment in muscle-invasive urothelial carcinoma (UC). Early studies focused on the ability to identify patients with residual disease who may benefit from additional systemic treatment. Further studies have suggested the potential of ctDNA measurement to tailor systemic and local treatments for patients with MIUC. This biomarker may ultimately reduce overtreatment, toxicity, and the financial burden associated with UC care. As ctDNA testing matures, it may offer clinicians a means to truly personalize treatment and thereby improve oncologic outcomes and enhance patients' quality of life. PATIENT SUMMARY: Our mini review looks at studies in which DNA from bladder cancer tumors that is circulating in the blood (called circulating tumor DNA, or ctDNA) is measured. Measurement of ctDNA levels after chemotherapy or immunotherapy can help predict cancer outcomes in patients undergoing bladder removal surgery.

Background:Radiation therapy (RT) for prostate cancer has gastrointestinal and genitourinary toxicities, greater with baseline lower urinary tract symptoms (LUTS) and larger prostate volume (PV). Prostate artery embolization (PAE) improves LUTS and PV before RT. This study evaluates the durability of LUTS improvement from neoadjuvant PAE before prostate RT and oncologic outcomes. Methods:We retrospectively identified patients receiving definitive prostate RT following PAE from a prospective database, including International Prostate Symptom Scores (IPSS), pre- and post-PAE MRI PV, and toxicity per CTCAEv5.0. Primary objective was LUTS by IPSS. Secondary objectives included biochemical recurrence-free survival (bRFS), local recurrence, and distant metastasis. Results:From 9/2017-5/2024, 82 patients underwent PAE before RT, with 30.5 % having unfavorable intermediate risk. RT consisted of conventional fractionation (n = 21), moderate hypofractionation (n = 42), SBRT (n = 11), and EBRT/brachytherapy boost (n = 8); a subset of patients received androgen deprivation therapy. Pelvic lymph nodes were treated in 28 (34 %) patients. Median pre-PAE IPSS was 18 (range 2-34), PV 90 cc (14.2-240), and PSA 8.4 ng/mL (0.02-125.5). Post-PAE, mean IPSS reduction was 10.7 points (-13-30). Mean PV reduction was 30.9 cc (-9-136) or 32 %. PAE converted 52 % of patients contraindicated by size/IPSS for brachytherapy/SBRT. Post-RT, mean IPSS changes at 3, 6, 12, 18 and 24 months were -8.7, -8.5, -9.5, -8.9, and -7.6, respectively (p < 0.001). At 24.2-month median follow-up, 1 local recurrence occurred. Two-year bRFS was 92 % for non-metastatic patients. Conclusion:Urinary improvement is durable after RT in men with large prostates and/or high LUTS burden with neoadjuvant PAE, and no increased risk of recurrence at intermediate-term follow-up. Further investigation is warranted.