Variant Of Bladder Cancer Research Articles

Survival outcomes of small cell variant bladder cancer: Analysis from nationwide study.

Survival outcomes of small cell variant bladder cancer: Analysis from nationwide study.

Abstract IA018: Metastatic bladder cancer: The expanding role of antibody drug conjugates

Abstract Antibody drug conjugates (ADCs) consist of an antibody, a cytotoxic payload, and a linker between the two. ADCs are becoming increasingly used in metastatic bladder cancer. Enfortumab vedotin (EV) in combination with pembrolizumab recently demonstrated impressive improvements in survival and overall responses compared to chemotherapy in the frontline metastatic setting. Sacituzumab govitecan (SG) and single agent EV are also effective, later line options for patients who have progressed on prior chemotherapy and/or immunotherapy. New ADCs, including those targeting HER2, have also displayed promising results in bladder cancer patients. Trials are exploring the use of ADCs in combination with each other as well as with immunotherapy. Novel ADCs with dual targets, dual payloads, and other augmentations are being developed and may represent new options for patients moving forward. However, these advances raise many questions. How to best manage the differing toxicities seen with ADCs? What is best sequencing of ADCs? What are the common resistance mechanisms to ADCs? How do these resistance mechanisms affect subsequent use of ADCs? And how effective are these agents in bladder cancer variants and divergent histologies? This talk with cover the expanding role of ADCs in metastatic bladder cancer. Citation Format: Nicholas Simon. Metastatic bladder cancer: The expanding role of antibody drug conjugates [abstract]. In: Proceedings of the AACR Special Conference on Bladder Cancer: Transforming the Field; 2024 May 17-20; Charlotte, NC. Philadelphia (PA): AACR; Clin Cancer Res 2024;30(10_Suppl):Abstract nr IA018.

Squamous Cell Carcinoma of the Bladder: Two Case Report

Squamous cell carcinoma (SCC) of the bladder is a rare variant of bladder cancer, accounting for less than 5% of cases. Its occurrence shows a balanced distribution across sexes, although it tends to affect the Black population disproportionately. Clinical presentation is often nonspecific, with hematuria being the predominant symptom. Diagnosis relies on endoscopic resection of the bladder followed by histopathological examination. Due to its rarity, treatment approaches remain a subject of debate. However, radical cystectomy with extensive lymph node dissection is typically favored. In this study, we present a series comprising 2 cases of squamous cell carcinoma. Our objective is to shed light on the epidemiological, clinical, histopathological, and therapeutic aspects associated with squamous cell carcinoma of the bladder. The two cases presented in this study highlight the importance of accurate diagnosis and classification of squamous cell carcinoma of the bladder for optimal treatment planning and patient outcomes.

Systematic Review: Seventy-Seven Cases of Signet Ring Cell Adenocarcinoma of the Bladder

Background: Signet ring cell adenocarcinoma (SRCC) of the bladder is a rare and aggressive histological subtype of bladder cancer. Due to its infrequency, the understanding of its clinical behaviour, treatment strategies, and outcomes remains limited, being primarily derived from isolated case reports and series. Objective: To systematically review and analyse the available literature on SRCC of the bladder, emphasizing its clinical characteristics, diagnostic approaches, treatment modalities, and outcomes. Material and Methods: A comprehensive search was conducted across PubMed, Embase, and Medline following the PRISMA guidelines, including case reports, case series, observational studies, and clinical trials reporting on bladder SRCC. Results: We included 38 articles reporting on 77 patients, primarily males (79.2%), with a median age of 64 years. The most common presenting symptoms were haematuria (64.8%) and lower urinary tract symptoms (46.3%). All the diagnoses were based on histopathological examination of bladder tissue samples and immunohistochemistry. Mixed histological types of bladder cancer were found in 20.7% of cases, most commonly urothelial carcinoma (61.1%). The treatments varied, with 53.2% of patients undergoing radical cystectomy, 24.7% receiving radiotherapy, and 16.9% receiving chemotherapy. The five-year survival rates were 9.4%. Conclusion: Bladder SRCC presents aggressively, with varied treatment strategies; however, radical cystectomy appears to be the optimal means of surgical management for organ-confined disease. The overall survival rate is low, highlighting the need for further research to understand and manage this rare bladder cancer variant. All patients should undergo evaluation to exclude extravesical primaries. This systematic review contributes to a better understanding of this disease and may guide clinical management strategies.

Abstract 6405: Identification of molecular targets in bladder cancer variants using single-cell analysis

Abstract Introduction and objectives: Variant subtypes in bladder cancer, also known as histologic variants, are clinically aggressive tumors associated with poor prognosis. The rarity of these tumors has made molecular characterization elusive using bulk transcriptional profiling. The aim of this study was to use single cell RNA sequencing to identify molecular features associated with variant subtypes that could be potential targets for therapy. Methods: Fresh tissue from bladder cancer patients undergoing surgery at our institution was sequenced using a bead-based single-cell RNA sequencing platform (Seq-Well) to generate an atlas of 9 tumors containing variants (micropapillary, nested, squamous differentiation, pleomorphic giant-cell like, plasmacytoid, small cell) and 3 tumors with pure urothelial carcinoma (UC) histology. Pathologic diagnoses were independently confirmed. Analysis was performed using the Seurat package in R Studio. Immunostaining validation was performed on a separately banked cohort. Bulk RNA sequencing data and clinical data were extracted and analyzed from The Cancer Genome Atlas (TCGA) database. Chimeric Antigen Receptor (CAR) T cells targeting TM4SF1 were generated by lentiviral transduction of primary human T cells and tested against publicly available bladder cancer cell lines. Results: Variant tumors were enriched in TM4SF1, a surface molecule that we demonstrate to be susceptible to CAR T therapy in vitro. Variants also share a cell state characterized by highly specific expression of MUC16 (CA125), which is enriched in metastatic sites, harbors transcriptional hallmarks of epithelial-mesenchymal transition and luminal-basal plasticity, and is associated with poor survival and resistance to chemotherapy. Finally, we find evidence of transcriptional mimicry between variants and similar appearing non-urothelial cells (e.g. plasmacytoid:plasma cell), suggesting common pathways between distinct cell types that could be exploited. Conclusion: We have identified several targetable molecular features within variant bladder cancer subtypes. These findings set a critical starting point for future therapeutic investigation. Funding: California Urology Foundation (HY)Conflicts of interest: noneKeywords: Single cell analysis, bladder cancer, variants, genomics, biomarkers Citation Format: Heiko Yang, Hanbing Song, Paul Allegakoen, Kevin Lu, Elizabeth Yip, Keliana Hui, Kevin Chang, Corynn Kasap, Janae Gayle, Bradley Stohr, Arun Wiita, Chien-Kuang C. Ding, Maxwell V. Meng, Jonathan Chou, Sima P. Porten, Franklin W. Huang. Identification of molecular targets in bladder cancer variants using single-cell analysis [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 6405.

Abstract 4632: Lineage plasticity as a determinant of antibody-drug conjugate target expression in urothelial bladder cancer

Abstract Bladder cancers display a wide spectrum of morphologies that frequently co-exist within individual tumors. Several histologic variants, including plasmacytoid, neuroendocrine, and micropapillary subtypes, are associated with an increased bladder cancer recurrence risk and cancer-specific mortality. The molecular basis and therapeutic implications of this phenotypical plasticity remain poorly understood. Enfortumab vedotin (EV), an antibody-drug conjugate targeting Nectin-4, has also emerged as a new standard-of-care for metastatic bladder cancer patients, but the association between lineage plasticity as manifested by morphologic heterogeneity in bladder cancer, Nectin-4 expression and ADC response remains poorly defined. Previous DNA-based molecular profiling studies of histologic variants revealed that CDH1 mutations were the pathognomonic molecular alteration in plasmacytoid urothelial carcinoma, but no recurrent driver mutations have been found to be unique to the aberrant histology regions of other mixed histology subtypes. Thus, to explore the molecular basis for the lineage plasticity of bladder cancers with aberrant histology and to define the association between lineage plasticity manifested as morphologic heterogeneity and the expression of Nectin-4, HER2 and other potential ADC targets, we performed RNA-seq of pure urothelial carcinomas (n=118, not otherwise specified, UC-NOS) and bladder tumors with divergent differentiation or histologic subtypes (n=199). Our cohort included a subset of tumors in which RNA-seq was performed on microdissected UC-NOS and variant histology regions of the same tumor. Tumors with neuroendocrine, sarcomatoid and squamous histology had the lowest Nectin-4 expression, whereas histologic subtypes that retained a luminal transcriptional profile such as micropapillary, plasmacytoid and nested histology had higher levels of Nectin-4 expression. In mixed histology tumors, Nectin-4 and/or HER2 expression was often restricted to only one of the two histologic components. Gene Set Enrichment Analysis noted enrichment of distinct oncogenic pathway gene sets in different histologic variants. Preliminary investigation into the mechanism(s) of Nectin-4 regulation using bladder cancer cell lines and patient-derived organoids (PDOs) has identified targetable pathways which when inhibited revert lineage plasticity and induce Nectin-4 expression. In sum, lineage plasticity manifested as heterogenous histomorphologies was associated with heterogeneous Nectin-4 expression in some but not all histologic variants of bladder cancer. Ongoing studies using PDOs from bladder cancer patients with mixed histology will seek to identify molecular pathways whose inhibition leads to increased expression of Nectin-4 or other ADC targets such as HER2 and thus increased sensitivity of ADCs targeting these cell surface proteins. Citation Format: Jiaqian Luo, Sizhi P. Gao, Fengshen Kuo, Gamze Gokturk Ozcan, Merve Basar, Florestan Koll, Jacob E. Tallman, Syed M. Alam, Carissa E. Chu, Ziyu Chen, Eugene J. Pietzak, Gopakumar Iyer, Jonathan E. Rosenberg, David B. Solit, Hikmat Al-Ahmadie. Lineage plasticity as a determinant of antibody-drug conjugate target expression in urothelial bladder cancer [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 4632.

Assessment of pathological grade and variants of bladder cancer with a continuous-time random-walk diffusion model.

To evaluate the efficacy of high b-value diffusion-weighted imaging (DWI) with a continuous-time random-walk (CTRW) diffusion model in determining the pathological grade and variant histology (VH) of bladder cancer (BCa). A total of 81 patients (median age, 70 years; range, 35-92 years; 18 females; 66 high grades; 30 with VH) with pathologically confirmed bladder urothelial carcinoma were retrospectively enrolled and underwent bladder MRI on a 3.0T MRI scanner. Multi-b-value DWI was performed using 11 b-values. Three CTRW model parameters were obtained: an anomalous diffusion coefficient (D) and two parameters reflecting temporal (α) and spatial (β) diffusion heterogeneity. The apparent diffusion coefficient (ADC) was calculated using b0 and b800. D, α, β, and ADC were statistically compared between high- and low-grade BCa, and between pure urothelial cancer (pUC) and VH. Comparisons were made using the Mann-Whitney U test between different pathological states. Receiver operating characteristic curve analysis was used to assess performance in differentiating the pathological states of BCa. ADC, D, and α were significantly lower in high-grade BCa compared to low-grade, and in VH compared to pUC (p < 0.001), while β showed no significant differences (p > 0.05). The combination of D and α yielded the best performance for determining BCa grade and VH (area under the curves = 0.913, 0.811), significantly outperforming ADC (area under the curves = 0.823, 0.761). The CTRW model effectively discriminated pathological grades and variants in BCa, highlighting its potential as a noninvasive diagnostic tool.

Long-Term Oncological Outcomes in Patients Diagnosed With Nonmetastatic Plasmacytoid Variant of Bladder Cancer: A 20-Year University of Texas MD Anderson Cancer Center Experience.

The treated natural history of nonmetastatic plasmacytoid variant of bladder cancer (PV-BCa) is poorly understood owing to its rarity. We sought to examine the disease recurrence and metastasis patterns in this select group of patients in order to identify opportunities for intervention. We conducted a natural language processing algorithm-augmented retrospective chart review of 56 consecutive patients who were treated with curative intent for nonmetastatic PV-BCa at our institution between 1998 and 2018. Kaplan-Meier and multivariable Cox regression methods were used for survival analyses. The stage at presentation was: ≤ cT2N0 in 22 (39.3%), cT3N0 in 15 (26.8%), cT4N0 in 13 (23.2%), and ≥ cN1 in 6 patients (10.7%). Forty-nine patients (87.5%) received chemotherapy, and 42 (75%) were able to undergo the planned surgery. Notably, only 4 patients (7.2%) had pT0 stage, while 22 (52.4%) had pN+ disease at the time of surgery. At 36-month follow-up, 28.4% of patients (95% CI: 22.1%-34.5%) were alive and 22.2% (95% CI: 16.1%-28.5%) were free of metastatic disease. The benefit of surgical extirpation was stage specific: successful completion of surgery was associated with improved metastasis-free survival (at 36 months 32.4% vs 0%, log-rank P < .001) in patients with localized or locally advanced disease (≤cT2N0/cT3N0); however, in patients with regionally advanced disease (cT4N0/≥cN1), consolidative surgery following chemotherapy was not associated with improved metastasis-free survival (12.5% vs 10% at 36 months, log-rank P = .49). The median time to metastasis from primary treatment end was 6.5 months (IQR: 2.9-14.7). The predominant site of recurrence/metastasis was the peritoneum (76.1%), either in isolation or along with extraperitoneal lesions. Salvage immunotherapy in these patients significantly reduced the risk of death (HR = 0.11, P = .001). PV-BCa is a disease with high lethality. Despite multimodal treatment, a vast majority of patients develop atypical intraperitoneal metastasis soon after therapy and rapidly succumb to it. Clinical trials evaluating utility of hyperthermic intraperitoneal chemotherapy and/or immunotherapy may be warranted in this high-risk population.

MRI-based radiomics analysis of bladder cancer: prediction of pathological grade and histological variant

To develop magnetic resonance imaging (MRI)-based radiomics models for the prediction of the pathological grade and histological variant of bladder cancer. A total of 227 patients who underwent bladder MRI and had histopathologically confirmed grades and variants were included retrospectively from January 2017 to March 2022. They were assigned to a training set (n=131) and a testing set (n=96) based on the MRI system. MRI-based radiomics features were extracted from manually segmented volumes of interest from high-b-value DWI images and ADC maps. The radiomics models were trained with all possible pipelines in the training set. One optimal model was selected using the fivefold cross-validation method and verified by the testing set according to the pathological results. Univariate and multivariate analyses were performed to identify the significant clinical and imaging factors for developing clinical-radiomics models. The radiomics model for grade prediction had area under the curve (AUC) values of 0.784, 0.786, and 0.733 in the training, cross-validation, and testing sets, respectively. The radiomics model for variant prediction had AUC values of 0.748, 0.757, and 0.789 in the training, cross-validation, and testing sets, respectively. The performance of the clinical-radiomics model was significantly improved compared with the radiomics models alone for the total dataset (AUC for grade: 0.846 versus 0.756; AUC for variant: 0.810 versus 0.757, p<0.05). MRI-based radiomics models could be used to predict the pathological grade and histological variants of bladder cancer with relatively good performance.

Survival outcomes of sarcomatoid versus classic urothelial carcinoma of bladder.

4588 Background: Sarcomatoid urothelial carcinoma (SUC), a rare bladder cancer variant, has both epithelial and mesenchymal differentiation along with frequent TERT C228T promoter mutations and has poorer prognosis. In this study, we compared survival outcomes of SUC with classic urothelial carcinoma (CUC) in patients with T2-T4, N0-N1 bladder cancer after definitive therapy. Methods: All cases meeting our inclusion criteria for SUC and CUC during 2004-2019 were identified from National Cancer Database. Sociodemographic and clinicopathological characteristics were analyzed via descriptive and comparative statistics. Propensity-score matching was performed to adjust for baseline differences between SUC and CUC. Overall survival (OS) was compared using Cox proportional-hazards modelling and visualized through Kaplan-Meier curves. Results: 30072 cases of CUC and 480 of SUC were identified. Propensity-score matching resulted in N = 478 patients in both groups. Matched cohorts had no baseline differences in age, sex, race, comorbidities, insurance status, income, distance to hospital, hospital location, rural versus urban residence, histological grade, and proportion getting regional lymph node surgery. Overall, there were 675 males and 281 females, 435 underwent surgery (Sx), and 521 surgery plus chemotherapy (Sx+Cx). For SUC, median survival with Sx vs Sx+Cx was 29.5 months (95%CI 20.0-50.6) vs 43.1 months (95%CI 25.3-64.4) respectively. For CUC, median survival was 56.1 (95%CI 53.7-58.6) vs 78.0 (95%CI 75.1-81.1) months with Sx vs Sx+Cx respectively. Conclusions: SUC has poorer prognosis than CUC. Perioperative chemotherapy along with surgery was associated with improved survival outcomes compared to surgery alone in patients with SUC. Further studies investigating novel immunotherapy agents are warranted to improve oncologic outcomes. [Table: see text]

154P Can urine cytology predict variants of bladder cancer?

154P Can urine cytology predict variants of bladder cancer?

Long-term Outcomes of Local and Metastatic Small Cell Carcinoma of the Urinary Bladder and Genomic Analysis of Patients Treated With Neoadjuvant Chemotherapy.

Small cell carcinoma of the bladder (SCCB) is a rare variant of bladder cancer with poor outcomes. We evaluated long-term outcomes of nonmetastatic (M0) and metastatic (M1) SCCB and correlated pathologic response with genomic alterations of patients treated with neoadjuvant chemotherapy (NAC). Clinical history and pathology samples from SCCB patients diagnosed at our institution were reviewed. One hundred and ninety-nine SCCB patients were identified. (M0: 147 [74%]; M1: 52 [26%]). Among M0 patients, 108 underwent radical cystectomy (RC) (NAC: 71; RC only: 23; adjuvant chemotherapy: 14); 14 received chemoradiotherapy; the rest received chemotherapy alone or no cancer-directed therapy. RC-only patients had a median follow-up of 9.1 years, and median disease-free survival (DFS) and overall survival (OS) were 1.1 and 1.2 years, respectively. NAC patients had pathologic response (<pT2pN0) and pathologic complete response (pT0pN0) rates of 48% and 38%, respectively, with median follow-up of 7.2 years, and median DFS and OS of 5.6 and 14.5 years, respectively. NAC responders (<ypT2N0) had superior median DFS (14.5 vs. 0.6 years, hazard ratio [HR] 0.24, P< .001) and OS (14.5 vs. 2.5 years, HR 0.31, P = .002). DFS rates for responders and nonresponders were 76% and 27% at 5 years, and 71% and 23% at 10 years, respectively. Local and central nervous system recurrences were infrequent. Median progression-free survival (PFS) and OS for M1 disease were 6.9 and 10.3 months, respectively. Genomic profiling was performed on 47 NAC patients. Loss of ERCC2 function was significantly enriched among those with pathologic complete response to NAC (mutations present in 50% of pathologic complete responders vs. 15% nonresponders, P = .045). M0 SCCB is chemo-sensitive and patients have excellent long-term survival following response to NAC. Patients with M1 disease have poor survival despite systemic therapy. Loss-of-function mutations of ERCC2 were associated with pathologic complete response to NAC.

Unusual histomorphological spectrum of urinary bladder cancers and their treatment modalities revisited: Our experience with series of five cases.

Urinary bladder cancer is the eighth-most frequent carcinoma in men, commonly occurs in elderly male. Major risk factors are smoking, chronic cystitis, urinary stones. The most common histologic variant of bladder cancer is urothelial carcinoma (UC), but certain variants are unusual yet aggressive for which there is no consensus guideline of therapy. Those entities include neuroendocrine tumors both primary and metastatic, squamous cell carcinoma, and sarcomatoid carcinoma. Neuroendocrine tumors comprise carcinoid, small-cell carcinoma, and large-cell carcinoma. The present study is undertaken to highlight certain biological features of these unusual aggressive histological forms of bladder carcinoma and their recent treatment modality to prevent recurrence, metastasis, upgrading of tumor stage, and enable surprisingly complete remission. This piece of hospital-based perspective study was done from June 2018 to May 2020. Both transurethral resection of bladder tumor and cystectomy surgical samples of the symptomatic patients were collected from the urology department of our institute along with demographic data. Then processed, stained in both routine H and E stain and immunohistochemical stains (Immunohistochemistry [IHC]) like PanCK, NSE, synaptophysin, chromogranin, etc. Total number of bladder cancer encountered was 42 cases; of these five rare variants were observed, i.e., one case each of primary and secondary small cell neuroendocrine carcinoma, one large cell carcinoma, one squamous cell carcinoma (SCC), and one case of sarcomatoid carcinoma. Histomorphology with IHC conferred the diagnosis then multimodality therapy (neoadjuvant/radiotherapy/surgery) was installed and followed up. The unconventional forms of UC can be easily diagnosed by histomorphology and can have better survival with the help of the recent multimodal treatment approach.

Prognostic Factors of Survival for High-Grade Neuroendocrine Neoplasia of the Bladder: A SEER Database Analysis.

Background: High-grade neuroendocrine carcinoma (NEC) is a rare and aggressive variant of bladder cancer. Considering its rarity, its therapeutic management is challenging and not standardized. Methods: We analyzed data extracted from the Surveillance, Epidemiology, and End Results (SEER) registry to evaluate prognostic factors for high-grade NEC of the bladder. Results: We extracted data on 1134 patients: 77.6% were small cell NEC, 14.6% were NEC, 5.5% were mixed neuro-endocrine non-neuroendocrine neoplasia, and 2.3% were large cell NEC. The stage at diagnosis was localized for 45% of patients, lymph nodal disease (N+M0) for 9.2% of patients, and metastatic disease for 26.1% of patients. The median overall survival (OS) was 12 months. Multivariate analysis detected that factors associated with worse OS were age being >72 years old (HR 1.94), lymph nodal involvement (HR 2.01), metastatic disease (HR 2.04), and the size of the primary tumor being >44.5 mm (HR 1.80). In the N0M0 populations, the size of the primary tumor being <44.5 mm, age being <72 years old, and major surgery were independently associated with a lower risk of death. In the N+M0 group, the size of the primary lesion was the only factor to retain an association with OS. Conclusions: Our SEER database analysis evidenced prognostic factors for high-grade NEC of the bladder that are of pivotal relevance to guide treatment and the decision-making process.

Diet quality, common genetic polymorphisms, and bladder cancer risk in a New England population-based study.

We examined the interaction between common genetic bladder cancer variants, diet quality, and bladder cancer risk in a population-based case-control study conducted in New England. At the time of enrollment, 806 bladder cancer cases and 974 controls provided a DNA sample and completed a diet history questionnaire. Diet quality was assessed using the 2010 Alternate Healthy Eating Index (AHEI-2010) score. Single nucleotide polymorphisms (SNPs) reported in genome-wide association studies to be associated with bladder cancer risk were combined into a polygenic risk score and also examined individually for interaction with the AHEI-2010. Adjusted odds ratios (OR) and 95% confidence intervals (CI) were calculated using logistic regression. A 1-standard deviation increase in polygenic risk score was associated with higher bladder cancer risk (OR, 1.34; 95% CI 1.21-1.49). Adherence to the AHEI-2010 was not associated with bladder cancer risk (OR, 0.99; 95% CI 0.98-1.00) and the polygenic risk score did not appear to modify the association between the AHEI-2010 and bladder cancer risk. In single-SNP analyses, rs8102137 (bladder cancer risk allele, C) modified the association between the AHEI-2010 total score and bladder cancer risk, with the strongest evidence for the AHEI-2010 long chain fat guideline (OR for TT, 0.92; 95% CI 0.87-0.98; OR for CT, 1.02; 95% CI 0.96-1.08; OR for CC, 1.03; 95% CI 0.93-1.14; p for interaction, 0.02). In conclusion, rs8102137 near the cyclin E1 gene ( CCNE1 ) may be involved in gene-diet interactions for bladder cancer risk.

Clinical and Genomic Characterization of Bladder Carcinomas With Glandular Phenotype.

To compare oncologic outcomes and genomic alteration profiles in patients with bladder and urachal adenocarcinoma, urothelial carcinoma (UC) with glandular differentiation, and UC, not otherwise specified (NOS) undergoing surgical resection, with emphasis on response to systemic therapy. We identified patients with bladder cancer with glandular variants who underwent surgical resection at Memorial Sloan Kettering from 1995 to 2018 (surgical cohort) and/or patients who had tumor sequencing using a targeted next-generation sequencing platform (genomics cohort). Pathologic complete and partial response rates to neoadjuvant chemotherapy (NAC) and recurrence-free and cancer-specific survival were measured. Alteration frequencies between histologic subtypes were compared. Thirty-seven patients with bladder adenocarcinoma, 46 with urachal adenocarcinoma, 84 with UC with glandular differentiation, and 1,049 with UC, NOS comprised the surgical cohort. Despite more advanced disease in patients with bladder and urachal adenocarcinoma, no significant differences in recurrence or cancer-specific survival by histology were observed after adjusting for stage. In patients with UC with glandular differentiation, NAC resulted in partial (≤ pT1N0) and complete (pT0N0) responses in 28% and 17%, respectively. Bladder and urachal adenocarcinoma genomic profiles resembled colorectal adenocarcinoma with frequent TP53, KRAS, and PIK3CA alterations while the genomic profile of UC with glandular differentiation more closely resembled UC, NOS. Limitations include retrospective nature of analysis and small numbers of nonurothelial histology specimens. The genomic profile of bladder adenocarcinomas resembled colorectal adenocarcinomas, whereas UC with glandular differentiation more closely resembled UC, NOS. Differences in outcomes among patients with glandular bladder cancer variants undergoing surgical resection were largely driven by differences in stage. Cisplatin-based NAC demonstrated activity in UC with glandular differentiation, suggesting NAC should be considered for this histologic variant.

PD53-09 ANTIBODY DRUG CONJUGATES AND VARIANT HISTOLOGY MUSCLE-INVASIVE BLADDER CANCER: ARE THE TARGETS PRESENT IN PRIMARY AND/OR METASTATIC TUMORS?

You have accessJournal of UrologyCME1 May 2022PD53-09 ANTIBODY DRUG CONJUGATES AND VARIANT HISTOLOGY MUSCLE-INVASIVE BLADDER CANCER: ARE THE TARGETS PRESENT IN PRIMARY AND/OR METASTATIC TUMORS? Fady Ghali, Martine Roudier, Funda Vakar-Lopez, Jose Garcia, Yan Wang, Gavin Ha, Petros Grivas, John Lee, Evan Yu, Bruce Montgomery, Andrew Hsieh, Jonathan Wright, and Hung-Ming Lam Fady GhaliFady Ghali More articles by this author , Martine RoudierMartine Roudier More articles by this author , Funda Vakar-LopezFunda Vakar-Lopez More articles by this author , Jose GarciaJose Garcia More articles by this author , Yan WangYan Wang More articles by this author , Gavin HaGavin Ha More articles by this author , Petros GrivasPetros Grivas More articles by this author , John LeeJohn Lee More articles by this author , Evan YuEvan Yu More articles by this author , Bruce MontgomeryBruce Montgomery More articles by this author , Andrew HsiehAndrew Hsieh More articles by this author , Jonathan WrightJonathan Wright More articles by this author , and Hung-Ming LamHung-Ming Lam More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000002630.09AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: Nectin-4 and Trop-2 are cell surface targets of novel humanized monoclonal antibody-drug conjugates, Enfortumab-vedotin (EV) and Sacituzumab govitecan (SG), respectively. These agents are FDA-approved for locally advanced/metastatic urothelial cancer (UC), however their wider role in the treatment of variant histology bladder cancer (BC) is unknown. We describe the expression level and sub-cellular localization of Nectin-4 and TROP-2 via immunostaining in histologic variants of BC within primary and matched metastatic samples. METHODS: Immunohistochemistry for Nectin-4 and TROP-2 was performed (using Abcam 192033 and 214488 respectively) on matched primary and metastatic tumor samples from patients with metastatic BC collected via rapid autopsy. Staining was scored by intensity (0-3) and multiplied by % of positive cells resulting in a range of 0-300 H-score. Membranous and cytoplasmic staining were separately evaluated for each sample. RESULTS: A total of 68 samples from 20 patients were collected and analyzed, of which 27 were urothelial carcinoma (UC), 17 plasmacytoid (PUC), 19 Squamous cell carcinoma (SCC), and 5 neuroendocrine (NE); 11 samples were collected from primary tumor sites, 20 from lymph node (LN) and 37 from various metastatic sites; 17 of 20 patients (85%) had received systemic chemotherapy and 35% had received immunotherapy. No patient had received EV or SG. Table 1 demonstrates mean membranous and cytoplasmic H-score levels as well as % positive rates for Nectin-4 and TROP-2. Nectin-4 localized primarily in the cytoplasm rather than the membrane in PUC and SCC for LN and metastatic sites, while primary tumors demonstrated relatively even Nectin-4 distribution between membrane and cytoplasm. TROP-2 was expressed at equivalent levels in both membrane and cytoplasm for both PUC and SCC, and the high expression was conserved from primary to metastases. CONCLUSIONS: Nectin-4 and TROP-2 are highly expressed in UC and variant histology BC, both at primary and metastatic sites, but not in NE histology. Whether differences in membranous vs cytoplasmic localization affects response to EV or SG is unknown. The implications of these findings on treatment response for variant histology BC warrant further study in clinical trials, which we are launching. Source of Funding: N/A © 2022 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 207Issue Supplement 5May 2022Page: e913 Advertisement Copyright & Permissions© 2022 by American Urological Association Education and Research, Inc.MetricsAuthor Information Fady Ghali More articles by this author Martine Roudier More articles by this author Funda Vakar-Lopez More articles by this author Jose Garcia More articles by this author Yan Wang More articles by this author Gavin Ha More articles by this author Petros Grivas More articles by this author John Lee More articles by this author Evan Yu More articles by this author Bruce Montgomery More articles by this author Andrew Hsieh More articles by this author Jonathan Wright More articles by this author Hung-Ming Lam More articles by this author Expand All Advertisement PDF DownloadLoading ...

Sarcomatoid Urothelial Carcinoma: A Population-Based Study of Clinicopathologic Characteristics and Survival Outcomes.

Sarcomatoid urothelial carcinoma (SUC) is a rare and aggressive variant of bladder cancer with limited data regarding epidemiology and survival. In this study, we explored clinicopathologic factors and oncologic outcomes of patients with SUC derived from Survival, Epidemiology and End Results (SEER) database, in comparison to conventional UC (CUC). SEER database was searched for patients with invasive (≥T1) SUC or CUC using the topography codes C67.0 to C67.9 for bladder cancer and the morphologic codes 8120/8122 for CUC/SUC respectively. Demographic/clinicopathologic/treatment/survival data were extracted. Disease-specific survival (DSS) was estimated with the Kaplan-Meier method. Chi-squared tests were used for comparative analysis and Cox proportional hazards model for identifying clinical covariates associated with DSS. A total of 569 patients with SUC and 37,740 with CUC were identified. Overall, there was a male predominant population in both cohorts, although a higher proportion of women were noted in the SUC cohort (32 vs. 25%). Patients with SUC had significantly higher incidence of non-bladder confined disease (T3/4, 37% vs. 22%) and nodal invasion (18% vs. 12%) in comparison to those with CUC (all P < .05). Median DSS was 16 months (95% CI: 12.4-19.6) in the SUC vs. 82 months (95% CI; 75.9-88.1) in the CUC cohort. Presence of SUC histology was independently associated with shorter DSS in the multivariate analysis, when adjusted for other significant clinicopathologic factors. SUC was associated with advanced stage and shorter DSS compared to CUC. Further studies are needed to better understand biological underpinnings behind its aggressive behavior and the role of novel systemic treatments.

Response to neoadjuvant chemotherapy in histologic variants of bladder cancer.

458 Background: Localized muscle invasive bladder carcinoma is mostly treated with neoadjuvant chemotherapy (NAC) before surgery in order to improve the outcome. Urothelial carcinoma (UC) is the most frequent histological type. Histological variants (pure or mixed) occur in 10% of bladder carcinoma. There is a lack of data on NAC efficacy for these histological subtypes. In this study, we evaluated the histologic response to NAC in the variant population of bladder cancer. Methods: Patients from 2 french hospitals (CHU de Nantes and ICM) treated with NAC for bladder cancer from 2010 to August 2021 were included in this retrospective study. We compared response to NAC between UC and histologic variants (pure or mixed) on cystectomy piece. The histological response was defined by the tumor downstaging after NAC (≤pT1Nx). We also collected the pathological complete response (pCR), which was defined by no residual tumor on the cystectomy piece. Results: 87 patients were included. 31 patients harbored a variant pattern: 7 squamous component, 3 adenocarcinoma component, 5 micropapillary component, 2 sarcomatoid component, 4 neuroendocrine carcinoma, 4 nest, 1 lymphoepithelial carcinoma, 2 giant cell, 1 undifferentiated, 1 micropapilallary and adenocarcinoma component and 1 adenosquamous component; 56 were conventional UC. NAC was MVAC in 77% of patient in the variant group, and 82% in the UC group. Others chemotherapy drugs were used as gemzar cisplatine, and platine etoposide. Downstaging was observed in 55% of patients in the variant group (17/31) and in 59% in the UC group (33/56). The difference was not statistically significant (p &lt;0,44). pCR was observed in 39% of patients in the variant group (12/31) and 43% in the UC group (24/56), the difference was not significant (p&lt; 0.44). Conclusions: NAC can be effective in the histologic variant population of bladder carcinoma, nevertheless these data could be confirmed in a larger cohort.

Non-urothelial and urothelial variants of bladder cancer

Non-urothelial bladder cancers make up a rare minority of all genitourinary (GU) tract histologic cancers since urothelial cancer (UC) makes up the most common histologic subtype. Bladder cancer variant histology (BCVH) or urothelial variants also occur rarely though distinction is important given aggressive presentation and natural history. While methods for diagnosis and treatment of typical urothelial cancers (UC) are well-established, there are no clear guidelines with regard to the diagnosis of non-urothelial bladder cancers, which often results in misdiagnosis and treatment delay. This review will focus on the clinicopathologic characteristics of the most common non-urothelial bladder cancers, to be distinguished from bladder cancer variant histology containing a UC component. The role of genomics in non-urothelial bladder cancers is evolving and the use of biomarkers to guide the diagnosis and treatment of these tumors remains a key area of unmet need. Treatment of these cancers will be discussed in a companion review.