Primary Bladder Tumors Research Articles

Adjuvant Nivolumab in High-Risk Muscle-Invasive Urothelial Carcinoma: Expanded Efficacy From CheckMate 274.

Clinical trials frequently include multiple end points that mature at different times. The initial report, typically based on the primary end point, may be published when key planned co-primary or secondary analyses are not yet available. Clinical Trial Updates provide an opportunity to disseminate additional results from studies, published in JCO or elsewhere, for which the primary end point has already been reported.CheckMate 274 is a phase III, randomized, double-blind trial of adjuvant nivolumab versus placebo for muscle-invasive urothelial carcinoma (MIUC) at high risk of recurrence after radical resection. The primary end points of disease-free survival (DFS) in intent-to-treat (ITT) and tumor PD-L1 expression ≥1% populations were met. We report results at an extended median follow-up of 36.1 months in the ITT population. In addition, we report interim overall survival (OS) data for the first time and an exploratory analysis among patients with bladder primary tumors (muscle-invasive bladder cancer [MIBC]). Consistent DFS benefit with nivolumab versus placebo was observed in both the ITT (hazard ratio [HR], 0.71 [95% CI, 0.58 to 0.86]) and PD-L1 ≥1% (HR, 0.52 [95% CI, 0.37 to 0.72]) patients. The HR for OS with nivolumab versus placebo was 0.76 (95% CI, 0.61 to 0.96) in the ITT population and 0.56 (95% CI, 0.36 to 0.86) in the PD-L1 ≥1 population. Continuous benefit in nonurothelial tract recurrence-free survival and distant metastasis-free survival was also observed in both patient populations. The exploratory analysis of patients with MIBC also showed continued efficacy benefits, irrespective of PD-L1 status. No new safety signals were reported. Overall, these results further support adjuvant nivolumab as a standard of care for high-risk MIUC after radical resection.

Bipolar versus Monopolar Transurethral Resection of Bladder Tumors among Patients with Localized Primary Bladder Tumor

Bipolar versus Monopolar Transurethral Resection of Bladder Tumors among Patients with Localized Primary Bladder Tumor

Prognostic value of nucleotide excision repair and translesion DNA synthesis proteins in muscle-infiltrating bladder carcinoma

BackgroundCisplatin (CDDP) remains a key agent in the treatment of muscle-infiltrating bladder carcinoma (MIBC). However, a proportion of MIBC patients do not respond to chemotherapy, which may be caused by the increased repair of CDDP-induced DNA damage. The purpose of this study was to explore the prognostic value of proteins involved in nucleotide excision repair (NER) and translesion DNA synthesis (TLS) in MIBC patients.MethodsThis is a retrospective analysis of 86 MIBC patients. The XPA, XPF, XPG, ERCC1, POLI, POLH and REV3L proteins were stained in primary bladder tumors and their levels were analyzed both in the total cohort and in a subgroup with metastatic urothelial carcinoma (mUC) that received gemcitabine and CDDP as a first-line therapy. Both cohorts were divided by percentage of cancer cells stained positive for each protein into subgroups with high and low expression. In the same manner, the combined expression of NER (XPA + ERCC1 + XPF + XPG) and TLS (POLI + POLH + REV3L), as the whole pathways, was analyzed.ResultsMortality was 89.5% at the median follow-up of 120.2 months. In the total cohort, patients with tumors stained positive for XPA, XPG and POLI had significantly worse overall survival (OS) compared to those with negative staining [hazard ratio (HR) = 0.60, 0.62 and 0.53, respectively]. Both XPG and POLI were independent prognostic factors in multivariate analyses (MVA). In addition, an increase in NER and TLS pathway expression was significantly associated with worse OS in the total cohort (HR = 0.54 and 0.60, respectively). In the mUC subgroup, high POLI expression was associated with significant deterioration of OS (HR = 0.56) in univariate analyses, and its independent prognostic value was shown in MVA.ConclusionsOur study showed significant correlations between the tumor expression of XPG and POLI, as well as NER and TLS as the whole pathways, and inferior OS. Hence, they could constitute prognostic biomarkers and potentially promising therapeutic targets in MIBC. However, a prospective trial is required for further validation, thereby overcoming the limitations of this study.

The Importance of Being Grade 3: A Plea for a Three-tier Hybrid Classification System for Grade in Primary Non–muscle-invasive Bladder Cancer

Grade is an important determinant of progression in non–muscle-invasive bladder cancer. Although the World Health Organization (WHO) 2004/2016 grading system is recommended, other systems such as WHO1973 and WHO1999 are still widely used. Recently, a hybrid (three-tier) system was proposed, separating WHO2004/2016 high grade (HG) into HG/grade 2 (G2) and HG/G3 while maintaining low grade. We assessed the prognostic performance of HG/G3 and HG/G2. Three independent cohorts with 9712 primary (first diagnosis) Ta-T1 bladder tumors were analyzed. Time to progression was analyzed with cumulative incidence functions and Cox regression models. Harrell’s C-index was used to assess discrimination. Time to progression was significantly shorter for HG/G3 than for HG/G2 in multivariable analyses (cohort 1: hazard ratio [HR] = 1.92; cohort 2: HR = 2.51, and cohort 3: HR = 1.69). Corresponding progression risks at 5 yr were 18%, 20%, and 18% for HG/G3 versus 7.3%, 7.5%, and 9.3% for HG/G2, respectively. Cox models using hybrid grade performed better than models with WHO2004/2016 (all cohorts; p < 0.001). For the three cohorts, C-indices for WHO2004/2016 were 0.69, 0.62, and 0.75, while, for hybrid grade, C-indices were 0.74, 0.68, and 0.78, respectively. Subdividing the HG category into HG/G2 and HG/G3 stratifies time to progression and supports the recommendation to adopt the hybrid grading system for Ta/T1 bladder cancers.

Quantitative CT Morphometrics: A Novel Approach for Predicting the Bladder Cancer Grade.

Background and objective Bladder cancer (BC) is a common urothelial neoplasm, with non-muscle invasive formscomprising about 75% of cases and generally having better outcomes than muscle-invasive types. Accurate preoperative grading and staging of BC are essential for appropriate treatment planning. This study investigates the efficacy of computerized tomography (CT) in correlating the morphological features of tumors to predict the histopathological grades of BC. Materials and methods This retrospective cohort involved 100 patients diagnosed with non-muscle invasive BC, who underwent transurethral resection of bladder tumor (TUR-BT) between January 2010 and August 2021. CT imaging, utilizing a 128-slice CT scanner, was employed to measure the tumor height (H) and contact length (CL). The study considered morphometric parameters across axial, coronal, and sagittal planes. Statistical analyses were conducted, comparing radiological findings with histopathological evaluations. Tumor grading was determined according to the 2004/2016 WHO classification. Results Among the 100 patients with primary bladder tumors, 15 were female and 85 were male, with a mean age of 65.28 ± 7.11 years. Furthermore, 58 had high-grade bladder tumors, while 42 had low-grade bladder tumors. Across all planes, high-grade tumors exhibited higher values for the tumor H, CL, and the tumor height-to-contact length (H/CL) ratio compared to low-grade tumors (p<0.05). Notably, the specificity, sensitivity, and diagnostic accuracy of the tumor CL were higher than those of the tumor H and the tumor H/CL ratio. A tumor CL exceeding 19.1mm measured in the axial plane demonstrated 83% sensitivity and specificity for high-grade tumors. Conclusion The measured CL of the tumor in the axial plane on computerized tomography urography has high sensitivity and specificity in detecting high-grade tumors.

Abstract 4248: Patient-derived MTAP-deleted bladder cancer organoid model: A unique platform for drug development

Abstract Introduction: Approximately 30% of advanced bladder cancer (BCa) tumors exhibit MTAP gene deletion, which has been associated with luminal subtype BCa, poor response to chemotherapy, and shorter progression to metastatic disease (De Souza 2023). MTAP deletion has been proposed as a potential biomarker for response to pemetrexed and an emerging class of PRMT5 and MAT2A inhibitors in development for MTAP-deleted tumors. Here, we describe the first patient-derived 3D model of BCa with MTAP deletion and its translational potential as a drug sensitivity platform. Methods: A patient (pt) with metastatic BCa harboring MTAP deletion underwent a pelvic lymph node biopsy. A fresh tumor sample was processed under collagenase/dispase solution for 30 minutes and filtered through a 70-um cell strainer. Cells were cultures in low attachment plates with MammoCult™ Basal Medium (Stem Cell Technologies). After 5 passages and 3D spheroid formation, immunostaining for cytokeratin (CK) 5 and 6, GATA3, CK20, and Ki67 staining were performed to confirm the urothelial origin. The MTAP-del was confirmed by a western blot of the organoid specimen and compared to other BLCa cell lines (UMUC, RT4, J82, and 5637). The viability assays were performed using the CellTiter-Glo® 3D Cell kit. Next-generation sequencing (NGS) of primary BCa tumor revealed deletion of MTAP, CDKN2A, CDKN2B, and mutations in p53, TERT, and KDM6A. Results: The patient organoid sample was positive for the luminal CK5/6 markers and negative for GATA3. Ki67 and CK20 were primarily expressed in the nucleus of the same sample. The organoid retained morphologic and immunohistochemical features of the patient’s primary bladder tumor, showing the same squamous differentiation and similar Ki-67 proliferative index. The organoid displayed no evidence of the MTAP protein by western blot (similar findings with the MTAP-del cell lines UMUC and RT4). The organoid showed sensitivity to pemetrexed [pemetrexed IC50=0.12 uM (other MTAP-del BLCa IC50: 0.1-0.23 uM)] and resistance to gemcitabine and cisplatin [Gem IC50=55 nM (other BLCa IC50: 1-29 nM), Cis IC50=90.5 uM (other BLCa IC50: 2-17 uM). Conclusions: We describe the first patient-derived MTAP-deleted BCa organoid recapitulating the features of the primary tumor. The organoid displayed sensitivity to pemetrexed as described with MTAP-deleted BCa. The organoid represents a unique platform for testing novel therapeutic strategies for MTAP-deleted BCa. Citation Format: Maximilian Schwermann, Benedito Carneiro, Shaolei Lu, Andre De Souza, Matthew Hadfield, Anthony Mega, Galina Lagos, Sari Khaleel, Dragan Golijanin, Sheldon Holder, Praveen Srinivasan, William MacDonald, Andrew George, Lanlan Zhou, Leiqing Zhang, Wafik El-Deiry. Patient-derived MTAP-deleted bladder cancer organoid model: A unique platform for drug development [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4248.

Abstract 862: Multi-omic analysis of allelic expression patterns of imprinted and non-imprinted genes in cancer and their association with drug response

Abstract Malignant cells undergo a broad array of epigenetic changes, including changes in imprinting patterns. In normal cells, imprinted genes have parent of origin-specific monoallelic expression, which is controlled via epigenetic mechanisms. Imprinted gene loci are often complex and frequently include multiple isoforms, which have different individual patterns of parent-of-origin monoallelic or biallelic expression in the normal tissues. Many imprinted genes promote cell proliferation and body growth, and their expression is important during embryonic and postnatal development. Dysregulation of imprinting in tumors has been suggested to contribute to growth and proliferation of cancer cells. Previously we reported that chemotherapy responses of cancer cell lines from a variety of tumors and of patient-derived acute myeloid leukemia samples were associated with copy number, expression, or DNA methylation of selected imprinted genes. In the current project, we examined allele-specific patterns of expression (monoallelic vs. biallelic) of imprinted genes and isoforms in tumors and studied their potential effect on response of cancer cells to drug treatment. We analyzed expression patterns at the whole gene, isoform, and exon levels of 59,283 autosomal protein-coding genes and ncRNA genes, with a special focus on 94 imprinted genes and their isoforms. We developed a computational pipeline to evaluate monoallelic and biallelic expression patterns of each gene in cancer cell lines and in tumor samples based on available matched RNA-seq expression data, whole exome sequencing information, and copy number data. Our initial analysis included 108 cell lines from the Cancer Cell Line Encyclopedia (CCLE), which had been derived from 9 pediatric and adult tumor histologies. We observed variation of allelic expression patterns of imprinted genes and their isoforms in tumor cell lines, including differences across and within cancer histologies. We also observed predominantly monoallelic expression of multiple additional genes. Some of them (PRIM2, BCLAF1, MAP2K3, and SEC22B) had been previously reported as potentially imprinted. Monoallelic expression of other genes identified in our analysis (e.g., GRK2, CBX4, and additional genes) was likely caused by molecular mechanisms other than imprinting. Allelic expression patterns and overall expression levels of isoforms of multiple imprinted and non-imprinted monoallelically expressed genes (e.g., CPA4, MAP2K3, and other genes) were associated with in vitro drug response. We also report our ongoing validation of allelic expression patterns of imprinted and non-imprinted genes, isoforms, and exons in primary bladder and breast tumors and in matched solid normal tissue samples using patient data from the Cancer Genome Atlas (TCGA). These results provide new knowledge about epigenetic dysregulation in cancer. Citation Format: Julia Krushkal, Travis L. Jensen, George Wright, Yingdong Zhao. Multi-omic analysis of allelic expression patterns of imprinted and non-imprinted genes in cancer and their association with drug response [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 862.

Sequencing of erdafitinib (erda) and enfortumab vedotin (EV) in patients (pts) with fibroblast growth factor receptor (FGFR2/3) altered (alt) advanced urothelial cancer (aUC): Analysis of UNITE database.

616 Background: The optimal therapy sequencing in aUC with FGFR2/3 alt is unclear. FGFR inhibition may increase Nectin-4 expression. We hypothesized that outcomes with EV would be more favorable when given after E compared to before E in pts with aUC harboring FGFR2/3 genomic alt. Methods: Pts with FGFR2/3 alts who received EV only (EVo), E then EV (E-&gt;EV), or EV then E (EV-&gt;E) were included. Overall survival (OS) measured from E or EV start (based on agent given first) and progression-free survival (PFS) measured from EV start were assessed with KM method and group comparison by log rank test with Cox proportional hazards regression model. Variables with p ≤0.2 were included in multivariate analysis (MVA). Wilcoxon rank sum and Fisher’s exact test were used to compare continuous and categorical variables, respectively. Observed response rate (ORR) was compared between groups using χ2 test. Results: Among 633 pts from 16 US sites, 487 had NGS data, and 94 (19%) had FGFR2/3 alterations with 24 receiving E-&gt;EV, 15 EV-&gt;E, and 55 EVo. Median age: 72 yrs; 87% Caucasian, 65% primary bladder tumor, 73% pure urothelial histology, 76% BMI &lt;30, 83% ECOG PS 0-1, 60% visceral metastases (mets) with 23% liver mets, 93% prior IO, and 63% prior Plt. Pts treated with E-&gt;EV vs EV-&gt;E had similar baseline characteristics, but at EV start ECOG PS 0-1 was 93% in EV-&gt;E vs 67% in E-&gt;EV (p=0.04). ORR to EV for E-&gt;EV pts was 32% (CI- 12%-51%) vs 67% (CI 54%-91%) for EV-&gt;E pts (p=0.04). ORR for EVo was 49%. Median OS was 21 months (mo) E-&gt;EV, 19 mo EV-&gt;E, and 12 mo EVo; median PFS was 5, 5, 6 mo, respectively. Univariate analysis (UVA) and MVA results are shown in Table. In MVA, longer OS was seen in pts who received both EV and E vs EVo. Conclusions: We showed longersurvival in pts with FGFR2/3 alt aUC who received both EV and E regardless of sequence, which may reflect guarantee-time bias. Additional limitations include retrospective nature, modest sample size, no central scan review, lack of data for pts who received E only, selection and confounding biases. Larger prospective studies are needed to determine optimal sequencing and putative biomarkers. [Table: see text]

Retracted: HPV-16 Expression and Loss of Cell Differentiation in Primary Bladder Tumors.

[This retracts the article DOI: 10.1155/2022/6565620.].

Assessment of aggressive bladder cancer mutations in plasma cell-free DNA.

The spatial and temporal genetic heterogeneity of bladder cancer (BC) makes challenging to find specific drivers of metastatic disease, thus preventing to determine those BC patients at high risk of tumor progression. Our aim was to identify DNA mutations providing aggressive behavior to bladder tumors and analyze them in patients' cell-free DNA (cfDNA) during their follow-up after radical cystectomy (RC) in order to monitor tumor evolution. Six BC patients who underwent RC and presented disease progression during their follow-up were included. Next-generation sequencing was used to determine somatic mutations in several primary tumor and metastatic specimens from each patient. Shared DNA mutations between primary bladder tumor and metastatic sites were identified in cfDNA samples through droplet digital PCR. Besides BC genetic heterogeneity, specific mutations in at least one of these genes -TERT, ATM, RB1, and FGFR3- were found in primary tumors and their metastases in all patients. These mutations were also identified in the patients' cfDNA at different follow-up time points. Additionally, the dynamic changes of these mutations in cfDNA allowed us to determine tumor evolution in response to treatment. The analysis of BC mutations associated with poor prognosis in plasma cfDNA could be a valuable tool to monitor tumor evolution, thus improving the clinical management of BC patients.

Benign urinary bladder masses: rare entities

BackgroundThis study aimed to present the characteristics and outcomes of benign urinary bladder masses, as well as the characteristics of the patients diagnosed with such lesions.MethodsA single-center, cross-sectional, retrospective study was conducted. The study involved patients who underwent transurethral resection of the primary bladder tumor over a four-year period (May 2017–2021) and were subsequently diagnosed with a benign bladder lesion.ResultsOut of 478 patients who underwent transurethral resection of the primary bladder tumor, 26 (5.4%) were diagnosed with a benign bladder lesion. The most common benign bladder lesion was urothelial papilloma (50%, 13 patients). The majority of patients with urothelial papilloma were men (76.9%) and had a history of smoking (61.5%). The mean age was 62 years. Most were diagnosed accidentally (69.2%), while others presented with hematuria (23.1%) or dysuria (7.7%). Most urothelial papillomas had a macroscopic polypoid appearance (61.5%), and most of them were solitary (84.6%), with a mean size amounting to 1 cm. Only one patient experienced a recurrence and developed papillary urothelial neoplasm of low malignant potential (PUNLMP). Cystitis cystica/glandularis and polypoid cystitis were the second most commonly diagnosed benign bladder lesion, each identified in 3 patients. Singular cases of leiomyoma, inflammatory myofibroblastic tumor, chondroma, paraganglioma, villous adenoma, eosinophilic cystitis (pseudotumor), and ectopic prostatic tissue are described.ConclusionBenign bladder lesions constitute a group of various rare entities that can clinically and radiologically mimic urothelial carcinoma, but mostly show a good prognosis and a low incidence of recurrence.

An Evaluation of Monopolar and Bipolar Electrocautery in Transurethral Resection of Urinary Bladder Tumors

Background: Transurethral resection of bladder tumor (TURBT) has a role in the diagnostic evaluation and treatment of bladder cancer, which is traditionally conducted through monopolar electrocautery; however, bipolar electrocautery has gained attention these days. Cautery artifacts are known as the drawbacks of TURBT and can be seen in both monopolar and bipolar electrocautery but with varying severity. Studies comparing bipolar to monopolar TURBT have shown conflicting results. Objectives: This study was carried out to compare the occurrence of cautery artifacts and a number of important clinical outcomes between patients undergoing monopolar and bipolar electrocautery during TURBT. Methods: This prospective study included adult patients with age 18 years old or higher diagnosed with primary bladder tumors with a size ≤4 cm. The patients were randomized into monopolar and bipolar groups (34 patients per group). The occurrence of cautery artifacts, duration of surgery, the incidence of urinary bladder perforation, fall in hemoglobin, need for blood transfusion, transurethral resection syndrome, and postoperative hospital stay were compared between the two groups. Results: In our study, the incidence of cautery artifacts was significantly lower in the bipolar group than in the monopolar group (P-value &lt; 0.0001). The two groups were comparable in terms of the duration of surgery, urinary bladder perforation, fall in hemoglobin, need for blood transfusion, transurethral resection syndrome, and postoperative hospital stay. Conclusions: Bipolar TURBT is superior to monopolar TURBT regarding a reduction in the incidence of cautery artifacts.

En Bloc Versus Conventional Resection of Primary Bladder Tumor (eBLOC): A Prospective, Multicenter, Open-label, Phase 3 Randomized Controlled Trial

BackgroundEn bloc transurethral resection of the bladder (eTURB) might improve the surgical management of non–muscle-invasive bladder cancer (NMIBC) in comparison to conventional TURB (cTURB). ObjectiveTo evaluate whether eTURB is superior to cTURB in resection of NMIBC and specimen retrieval. Design, setting, and participantsThis was a randomized, multicenter trial in patients with up to three cTa–T1 NMIBC tumors of 1–3 cm in size, who were enrolled from January 2019 to January 2022. InterventionParticipants were randomized 1:1 to undergo eTURB (n = 192) or cTURB (n = 192). Outcome measurements and statistical analysisThe primary outcome was the prevalence of detrusor muscle (DM) in the specimen retrieved. Secondary endpoints included bladder perforation, persistent disease at second-look TURB, positive lateral resection margin, positive deep resection margin, operation time, perforation rate, obturator reflex, conversion from eTURB to cTURB, recurrence-free survival, and disease recurrence at 3 mo. Results and limitationsA total of 384 patients were randomized to undergo eTURB or cTURB. A total of 452 tumors were resected and analyzed for the primary outcome. eTURB was superior to cTURB in retrieval of DM (80.7% vs 71.1%; mixed-model p = 0.01). Bladder perforation (5.6% vs 12%; difference −6.4%; 95% confidence interval [CI] −12.2% to −0.6%) and obturator reflex (8.4% vs 16%; difference −7.6%; 95% CI −14.3% to −0.9%) were less frequent in the eTURB arm than in the cTURB arm. Operation time did not differ between the two techniques (26 min, interquartile range [IQR] 20–38 for eTURB vs 25 min, IQR 17–35 for cTURB; difference 1 min, 95% CI –25.9 to 4.99). Second-look TURB was performed in 24 patients in the eTURB arm and 34 in the cTURB arm, with no difference in the rate of residual papillary disease (pTa/pT1: 56% vs 55.9%; difference 0.1%, 95% CI −25.5% to 25.7%). At median follow-up of 13 mo (IQR 7–20), 18.4% of the patients in the eTURB arm and 16.7% in the cTURB arm had experienced bladder cancer recurrence (Cox hazard ratio 0.87, 95% CI 0.49–1.52; p = 0.6). ConclusionsIn patients with clinical NMIBC with up to three tumors of 1–3 cm in size, tumor removal via eTURB resulted in a higher rate of DM in the pathologic specimen in comparison to cTURB. Moreover, eTURB was associated with lower frequency of obturator reflex and bladder perforation than cTURB was. While improving on the quality indicators for NMIBC, the long-term differential oncologic benefits of eTURB remain uncertain. Patient summaryWe compared two techniques for removal of bladder tumors and found that tumor removal in a single piece, called en bloc resection, provides a better-quality specimen for pathology analysis and fewer complications in comparison to the conventional method.This trial is registered at ClinicalTrials.gov as NCT03718754.

The Impact of Histological Variants on Oncological Outcomes in Patients with Muscle Invasive Bladder Cancer Treated with Radical Cystectomy.

Bladder cancer is a heterogeneous entity characterized by a wide range of different morphologies. The aim of this study was to investigate the prognostic effect of bladder tumor with variant histology that is treated with radical cystectomy on oncological outcomes. One hundred eighty-six patients who underwent radical cystectomy between September 2001 and June 2020 were included in the study. The patients were divided into 2 groups variant histology group (n = 54) and transitional cell cancer group (n = 132). Clinicopathologic data were compared between the two groups. The groups were similar in terms of demographic characteristics. In the mul- tivariate analysis of cancer-specific survival in transitional cell cancer against variant histology, high-grade detection of primary transurethral bladder tumor pathology, cystectomy pT, cystectomy positive lymph node, and positive surgical margin in cys- tectomy were determined to be statistically significant. Diagnosis of pT2 and high grade of primary transurethral bladder tumor pathology, cystectomy ≥ pT3, cystec- tomy positive lymph node, and positive surgical margin in cystectomy were statis- tically significant in multivariate analysis of overall survival. Cancer-specific survival time was estimated at 65.1 ± 8.3 months for variant histology and 134.2 ± 10.4 months for transitional cell cancer (P=.004). The estimated overall survival time was 61.9 ± 8.0 months in variant histology and 119.0 ± 9.8 months in transitional cell cancer (P = .014). Pathological features and prognosis of bladder cancer with variant histol- ogies are worse than those of pure urothelial bladder cancer. Overall survival and can- cer-specific survival are shorter in bladder cancer with variant histology than in pure urothelial bladder cancer. Following the diagnosis of variant histology in transurethral bladder tumor, poor prognosis must be considered in the treatment plan.

Radical Cystectomy in the Treatment of Invasive Bladder Cancer: Long-Term Results in 1,054 Patients.

To evaluate our long-term experience with patients treated uniformly with radical cystectomy and pelvic lymph node dissection for invasive bladder cancer and to describe the association of the primary bladder tumor stage and regional lymph node status with clinical outcomes. All patients undergoing radical cystectomy with bilateral pelvic iliac lymphadenectomy, with the intent to cure, for transitional-cell carcinoma of the bladder between July 1971 and December 1997, with or without adjuvant radiation or chemotherapy, were evaluated. The clinical course, pathologic characteristics, and long-term clinical outcomes were evaluated in this group of patients. A total of 1,054 patients (843 men [80%] and 211 women) with a median age of 66 years (range, 22 to 93 years) were uniformly treated. Median follow-up was 10.2 years (range, 0 to 28 years). There were 27 (2.5%) perioperative deaths, with a total of 292 (28%) early complications. Overall recurrence-free survival at 5 and 10 years for the entire cohort was 68% and 66%, respectively. The 5- and 10-year recurrence-free survival for patients with organ-confined, lymph node-negative tumors was 92% and 86% for P0 disease, 91% and 89% for Pis, 79% and 74% for Pa, and 83% and 78% for P1 tumors, respectively. Patients with muscle invasive (P2 and P3a), lymph node-negative tumors had 89% and 87% and 78% and 76% 5- and 10-year recurrence-free survival, respectively. Patients with nonorgan-confined (P3b, P4), lymph node-negative tumors demonstrated a significantly higher probability of recurrence compared with those with organ-confined bladder cancers (P < .001). The 5- and 10-year recurrence-free survival for P3b tumors was 62% and 61%, and for P4 tumors was 50% and 45% , respectively. A total of 246 patients (24%) had lymph node tumor involvement. The 5- and 10-year recurrence-free survival for these patients was 35%, and 34%, respectively, which was significantly lower than for patients without lymph node involvement (P < .001). Patients could also be stratified by the number of lymph nodes involved and by the extent of the primary bladder tumor (p stage). Patients with fewer than five positive lymph nodes, and whose p stage was organ-confined had significantly improved survival rates. Bladder cancer recurred in 311 patients (30%) . The median time to recurrence among those patients in whom the cancer recurred was 12 months (range, 0.04 to 11.1 years). In 234 patients (22%) there was a distant recurrence, and in 77 patients (7%) there was a local (pelvic) recurrence. These data from a large group of patients support the aggressive surgical management of invasive bladder cancer. Excellent long-term survival can be achieved with a low incidence of pelvic recurrence.

Clinical efficacy analysis of patients (pts) with HER-2 expressing metastatic urothelial carcinoma (mUC) treated with enfortumab vedotin (EV).

e16618 Background: EV, an antibody drug conjugate (ADC) targeting NECTIN-4, is an approved salvage treatment for unselected pts with mUC. ADCs targeting the human epidermal growth factor receptor-2 (HER-2) have also shown robust activity in clinical trials for mUC with tumor HER-2 expression. We investigated the interaction between HER-2 expression and clinical outcomes of pts treated with EV, which are currently unknown. Methods: We conducted a retrospective, single institution study analyzing pts with mUC who received EV. Immunohistochemistry (IHC) staining for HER-2 was completed with PATHWAY anti-HER2 (4B5) Antibody (Ventana Medical Systems, Tucson, AZ) using established breast cancer scoring algorithm. Wilcoxon rank sum and Fisher exact tests were used to compare continuous and categorical variables, respectively. Cox proportional hazards regression model was used to evaluate a variable’s ability to predict overall survival (OS). Variables with p-value ≤0.1 were included in the multivariate analysis (MVA). Results: We identified 158 pts with mUC who received EV. Median age at EV start was 70 (IQR 66-76), most pts were Caucasian (144, 91%), male (108, 68%), primary bladder tumors (113, 72%), and pure urothelial histology (95, 60%). 96 pts (61%) received prior platinum therapy and 117 pts (74%) had prior immunotherapy. ECOG scores ≥2 was seen in 54 pts (39%) while 75 pts (54%) had Bellmunt scores ≥2 (54%). Median follow up time was 12.5 months and median OS from EV start was 13 months. 94 pts (60%) had HER2 IHC staining. There was no association between HER2 intensity and any of the clinical variables. On univariate analysis (UVA): HER2 3 vs HER2 ≤2 HR was 0.38 (0.14, 0.98), male vs female HR=1.56 (0.94, 2.58), ECOG ≤1 vs ≥2 HR=0.6 (0.38,0.95), Bellmunt score 0-1 vs 2-3 HR=0.49 (0.3, 0.78), and hemoglobin (Hgb) HR=0.75 (0.67, 0.85). MVA showed HER2 3 vs HER2 ≤2 HR was 0.42 (0.16, 1.12), male vs female HR=2.3 (1.17, 4.42), ECOG ≤1 vs ≥2 HR=0.56 (0.30, 1.05), and Hgb HR=0.77 (0.65, 0.92). Conclusions: MVA of this single-site retrospective cohort did not show any association between HER2 expression and survival outcomes in pts with mUC who received EV. Further studies are needed to continue assessing the role of HER2 as a potential prognostic and predictive biomarker in UC, especially if HER-2 directed therapies become incorporated in the mUC treatment paradigm. [Table: see text]

Biomarkers of response to sacituzumab govitecan (SG) and efficacy after treatment with enfortumab vedotin (EV) in advanced urothelial carcinoma (aUC): Analysis of the UNITE study.

4572 Background: SG is an antibody-drug conjugate (ADC) with accelerated FDA approval for aUC refractory to platinum-based chemotherapy and immune checkpoint inhibitor (ICI). SG activity following treatment with EV, the most commonly used ADC in the post-platinum/ICI setting, and biomarkers of response to SG are not well described. We hypothesized that SG would be active after EV in aUC. Methods: Patients (pts) treated with SG monotherapy who had next-generation sequencing (NGS), were identified in the retrospective UNITE study. Observed response rate (ORR) was determined for evaluable pts with scans after ≥1 SG cycle. All pts were assessed for baseline clinical characteristics, as well as molecular biomarkers including tumor mutational burden, somatic gene alterations (alt) in ≥ 10% of pts and presence of ≥1 DNA damage response (DDR) mutations. ORRs were compared with Chi-squared test. Kaplan Meier method and cox proportional hazard (cph) models were used to assess progression-free survival (PFS) and overall survival (OS) from SG start. Pt characteristics and molecular biomarkers were evaluated in univariate analyses (UVA), followed by evaluation of biomarkers in separate multivariate cph analyses (MVA), while accounting for clinical features. Results: Among 90 pts treated with SG at 9 US sites, 78 had NGS data. Median age at SG start was 68, 65 (72%) men, 73 (81%) Caucasian, 56 (62%) with pure urothelial histology, 60 (67%) primary bladder tumor and 67 (74%) ECOG PS 0/1. Most (n=84, 93%) received SG after EV, and 33 (37%) had ≥4 prior therapies for aUC. ORR with SG was 23% (15/66); 24% in pts with prior CR/PR/SD on EV and 14% after primary PD on EV. Median follow-up from SG start was 8.7 mos, PFS and OS were 3.5 mos and 7.1 mos. In pts with NGS, ORRs to SG were higher in MTAP altered pts (50% vs 19%; p = 0.05). In UVA, low neutrophil to lymphocyte ratio (NLR), high Hgb, no prior smoking history, &lt; 3 prior therapies, as well as BRCA2 and DDR alts were associated with longer OS (p&lt;0.05 for all). In MVA, pts with alt in either TP53 or MDM2 had longer OS. Conclusions: SG has notable activity after EV in heavily pretreated pts with aUC, with ORR consistent with SG phase 2 trial data in post-platinum/ICI only pts. We identified several clinical and genomic biomarkers, including TP53/MDM2 alt, that are potentially associated with improved outcomes with SG treatment. [Table: see text]

Cryoablation inhibits the recurrence and progression of bladder cancer by enhancing tumour‐specific immunity

Recurrence and metastasis of bladder cancer are major factors affecting patient prognosis. Endoscopic cryoablation achieved a better clinical outcome among clinical patients and could be synergistic with ICIs. Thus, this study aimed to evaluate the immunological mechanism of cryoablation for bladder cancer to reveal the therapeutic mechanism. We systematically reviewed the clinical prognosis of patients underwent cryoablation at Huashan Hospital in these first-in-human studies (ChiCTR-INR-17013060). Murine models were constructed to explore cryoablation-induced tumour-specific immunity, which was further confirmed by primary bladder tumour organoids and autologous lymphocytes cocultured system. Cryoablation improved progression-free survival and recurrence-free survival respectively. Assessment of murine models after cryoablation confirmed microenvironment remodelling and tumour-specific T cells expansion. Enhanced antitumour effects were found after coculture of organoids with autologous lymphocytes collected from post-cryoablation. We also demonstrated cryoablation-induced tumour elimination required IFNGR expression on tumour cells. In addition, a long-lasting antitumour memory response is achieved by cryoablation and could be enhanced after combination with ICIs. This study revealed endoscopic cryoablation is an efficient and safe therapy for bladder tumour treatment. The tumour-specific immune responses induced by cryoablation could reduce tumour recurrence and metastasis.

PD09-07 ASSESSING THE UTILITY OF A CELL-FREE TUMOR (ct)DNA ASSAY (MSK-ACCESS) IN NODE POSITIVE (N+) MUSCLE INVASIVE BLADDER CANCER (MIBC) PATIENTS (pts) UNDERGOING NEOADJUVANT CHEMOTHERAPY (NAC)

You have accessJournal of UrologyCME1 Apr 2023PD09-07 ASSESSING THE UTILITY OF A CELL-FREE TUMOR (ct)DNA ASSAY (MSK-ACCESS) IN NODE POSITIVE (N+) MUSCLE INVASIVE BLADDER CANCER (MIBC) PATIENTS (pts) UNDERGOING NEOADJUVANT CHEMOTHERAPY (NAC) Andrew B. Katims, Andrew T. Lenis, Ronak H. Shah, Carissa E. Chu, Neha Ratna, Ashely M. Regazzi, Eugene J. Pietzak, David H. Aggen, Samuel A. Funt, Min Yuen Teo, Jonathan E. Rosenberg, Dean F. Bajorin, Timothy F. Donahue, Bernard H. Bochner, Michael F. Berger, David B. Solit, and Gopa Iyer Andrew B. KatimsAndrew B. Katims More articles by this author , Andrew T. LenisAndrew T. Lenis More articles by this author , Ronak H. ShahRonak H. Shah More articles by this author , Carissa E. ChuCarissa E. Chu More articles by this author , Neha RatnaNeha Ratna More articles by this author , Ashely M. RegazziAshely M. Regazzi More articles by this author , Eugene J. PietzakEugene J. Pietzak More articles by this author , David H. AggenDavid H. Aggen More articles by this author , Samuel A. FuntSamuel A. Funt More articles by this author , Min Yuen TeoMin Yuen Teo More articles by this author , Jonathan E. RosenbergJonathan E. Rosenberg More articles by this author , Dean F. BajorinDean F. Bajorin More articles by this author , Timothy F. DonahueTimothy F. Donahue More articles by this author , Bernard H. BochnerBernard H. Bochner More articles by this author , Michael F. BergerMichael F. Berger More articles by this author , David B. SolitDavid B. Solit More articles by this author , and Gopa IyerGopa Iyer More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000003240.07AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: Circulating ctDNA is associated with disease progression, worse overall survival, and recurrence in pts with bladder cancer. This study correlated targeted exome ctDNA sequencing with pathologic response to NAC and metastatic recurrence in pts with N+ MIBC undergoing radical cystectomy (RC). METHODS: We prospectively identified pts with cT2-3N1-2M0 bladder cancer who underwent NAC prior to RC. Node positivity was determined radiographically and/or by node biopsy. Plasma samples were collected pre-NAC, mid-treatment, after NAC completion, and 3 months after RC. Samples were analyzed using MSK-ACCESS, an ultrasensitive ctDNA platform designed to identify somatic mutations in 129 cancer associated genes. Primary bladder tumors were sequenced using targeted exome sequencing. RESULTS: 31 samples from 9 pts (6 men) were analyzed. Median age was 63 years (IQR 58-69). NAC regimens included gemcitabine and cisplatin alone (78%) or with paclitaxel (22%). Seven (78%) pts had >1 detectable mutation pre-NAC. The most altered genes detected in both tissue and ctDNA included: TERT (88% vs 28%), TP53 (76% vs 40%), ARID1A (43% vs 17%), RB1 (43% vs 15%), KDM6A (43% vs 15%), and ATM (17% vs 17%). Four (45%) pts had complete response (ypT0N0), 1 (11%) had a partial response (ypT1N0), and 4 (33.3%) were non-responders (ypT2N0-3). All non-responders had disease recurrence after RC (median 3 months, range 2-11 months). Of 7 pts with on-treatment MSK-ACCESS, 2 (29%) had detectable ctDNA (1 ypT2N0, 1 ypT0N0). The pt with a PR had detectable ctDNA post-NAC with 1 mutation identified that was not detected at 3 months. All pts with >ypT2N0 had detectable ctDNA post-NAC. Pts with recurrence/non-responders had a significantly higher mutation count 3 months after RC compared to responders, with a median of 7 vs. 0 mutations, respectively. Two pts with CR had detectable ctDNA at 3 months post-RC but have not recurred (Table 1). CONCLUSIONS: Clearance of ctDNA post-NAC correlated with pathologic complete response. Approximately 70% of pts had ctDNA clearance on NAC. All pts with residual disease at RC had detectable ctDNA post-NAC. N+ disease correlated with persistent ctDNA detected at 3 months post-RC. Source of Funding: None © 2023 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 209Issue Supplement 4April 2023Page: e242 Advertisement Copyright & Permissions© 2023 by American Urological Association Education and Research, Inc.MetricsAuthor Information Andrew B. Katims More articles by this author Andrew T. Lenis More articles by this author Ronak H. Shah More articles by this author Carissa E. Chu More articles by this author Neha Ratna More articles by this author Ashely M. Regazzi More articles by this author Eugene J. Pietzak More articles by this author David H. Aggen More articles by this author Samuel A. Funt More articles by this author Min Yuen Teo More articles by this author Jonathan E. Rosenberg More articles by this author Dean F. Bajorin More articles by this author Timothy F. Donahue More articles by this author Bernard H. Bochner More articles by this author Michael F. Berger More articles by this author David B. Solit More articles by this author Gopa Iyer More articles by this author Expand All Advertisement PDF downloadLoading ...

MP32-03 INCIDENCE AND OUTCOMES OF OCCULT LYMPH NODE METASTASIS IN CLINICALLY CT2-4A NO BLADDER CANCER AT RADICAL CYSTECTOMY WITH OR WITHOUT NEOADJUVANT CHEMOTHERAPY

You have accessJournal of UrologyCME1 Apr 2023MP32-03 INCIDENCE AND OUTCOMES OF OCCULT LYMPH NODE METASTASIS IN CLINICALLY CT2-4A NO BLADDER CANCER AT RADICAL CYSTECTOMY WITH OR WITHOUT NEOADJUVANT CHEMOTHERAPY Mahmoud Laymon, Ahmed Elkarta, Amr Elsawy, Osama Ezzat, Ahmed Mosbah, and Hassan Abol-Enein Mahmoud LaymonMahmoud Laymon More articles by this author , Ahmed ElkartaAhmed Elkarta More articles by this author , Amr ElsawyAmr Elsawy More articles by this author , Osama EzzatOsama Ezzat More articles by this author , Ahmed MosbahAhmed Mosbah More articles by this author , and Hassan Abol-EneinHassan Abol-Enein More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000003265.03AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: Radical cystectomy with pelvic lymphadenectomy is the standard treatment of muscle invasive bladder cancer (BC). However, nearly 50% of patients experience tumor recurrence that can be attributed to presence of occult metastasis at the tie of surgery. One of the goals of neoadjuvant chemotherapy (NAC) is to eliminate micro-metastasis before surgery. We aim to compare nodal metastasis at a large cohort of cNoMo patients treated with cystectomy alone and NAC then cystectomy. METHODS: We reviewed the electronic files of 622 consecutive patients diagnosed with cT2-4a NoMo urothelial BC and treated with radical cystectomy between January2004 till December 2014. We also analyzed a recent prospective database of 46 cNoMo patients treated with Cisplatin based NAC then RC between January 2019 till August 2021. The primary end point was the incidence of occult LN metastasis among both groups. The secondary endpoint was to assess recurrence free survival (RFS) in both groups using Kaplan Meier method. RESULTS: Baseline clinical and histopathological characteristics of both groups are shown in Table (1). In the NAC group, 18 patients (39%) had no residual tumor (pTo). Overall, pathological evaluation showed that 140 (21%) of patients had nodal metastasis, eight patients (17.4%) of the NAC group vs 132 (21.2%) of the non-NAC group (p=0.7). Among the patients with cT2 disease, LN metastases were found in 21.5% (23/107) of cases, five patients in NAC (22.7%) group and 18 (21.2%) patients in non NAC group (p=0.8). Regarding, non NAC group, the estimated 1,3and 5 year RFS between pNO vs pN+ve was 90.2%,74.5 and 70.4% vs 83.7, 42.5% and 40% (p<0.0001), respectively. CONCLUSIONS: Presence of occult lymph node metastasis in cNo bladder cancer is not uncommon reaching 21% of cases. Even in clinically organ confined (cT2No) disease, pathologically confirmed nodal metastasis was found in 21.5% of cases. Occult lymph node metastasis was associated with worse RFS. Inspite of the down staging effect of NAC on the primary bladder tumor, nodal metastasis can still be found in 17.4% of patients. These findings should be considered during counselling patients for NAD or bladder sparing treatment. Source of Funding: None © 2023 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 209Issue Supplement 4April 2023Page: e440 Advertisement Copyright & Permissions© 2023 by American Urological Association Education and Research, Inc.MetricsAuthor Information Mahmoud Laymon More articles by this author Ahmed Elkarta More articles by this author Amr Elsawy More articles by this author Osama Ezzat More articles by this author Ahmed Mosbah More articles by this author Hassan Abol-Enein More articles by this author Expand All Advertisement PDF downloadLoading ...