Expression of nectin-4 in bladder cancer with variant histology.

2020 ◽  
Vol 38 (6_suppl) ◽  
pp. 546-546
Author(s):  
Jean H. Hoffman-Censits ◽  
Woonyoung Choi ◽  
Kara Lombardo ◽  
Noah M. Hahn ◽  
David James McConkey ◽  
...  
Keyword(s):  
Bladder Cancer ◽  
Staining Intensity ◽  
Antibody Drug Conjugate ◽  
Therapeutic Implications ◽  
Weak Staining ◽  
Variant Histology ◽  
Roche Diagnostics ◽  
Mixed Variant ◽  
Negative Gene ◽  
Normal Urothelium

546 Background: The antibody-drug conjugate enfortumab vedotin is poised to change the bladder cancer (BC) treatment landscape by targeting Nectin-4, near ubiquitously expressed in urothelial cancer (UC). Less is known about this and other targets in BC with pure or mixed variant histology (VH). Methods: Immunohistochemistry (IHC) was performed on a Ventana Discovery Autostainer (Roche Diagnostics) using an ultraView DAB detection kit (Roche Diagnostics) and a Nectin-4 polyclonal antibody (1:100 dilution; Abcam, Cambridge, UK). The intensity and extent of Nectin-4 expression was determined by the histochemical scoring (H-score) used in preclinical testing, defined as the sum of the products of the staining intensity (score of 0–3) x % of cells (0–100) stained at a given intensity. Specimens were assessed by H score as: negative (0–14), weak (15–99), moderate (100–199), and strong (200–300). Results: Forty UC and VH BC were evaluated for Nectin-4 expression by IHC: 15 small cell (SCBC) (8 pure SCBC, 6 mixed SCBC/UC, 1 SCBC/CIS), 8 carcinosarcomas (CS) (7 pure CS, 1 HGUC/sarcomatoid features), and 17 pure HGUCs. Normal urothelium and stroma were negative. Eight of 8 (100%) pure SCBC were negative for Nectin-4. Six of 7 (85.3%) mixed SCBC+HGUC/CIS had weak staining and 1/7 (14.7%) had moderate staining in the urothelial components (comp) while 7/7 (100%) of the SCBC comp were negative. Seven of 7 (100%) pure CS were negative and 1/1 (100%) mixed CS+HGUC showed weak staining in the HGUC comp while the sarcomatoid comp was negative. Expression in UC was: 1/17 (5.9%) strong, 3/17 (17.6%) moderate, 10/17 (58.8%) weak, and 3/17 (17.6%) negative. Gene expression profiling confirmed Nectin-4 was downregulated in VH compared to UC samples, as was ERBB2 and Trop2. Conclusions: There is heterogeneity of expression of Nectin-4 and other targets in BC with VH compared to UC. This may have therapeutic implications, and highlights need for additional research in VH.[Table: see text]

Does “low risk” muscle invasive bladder cancer actually exist?

2015 ◽  
Vol 33 (7_suppl) ◽  
pp. 308-308
Author(s):  
Eugene J. Pietzak ◽  
S. Bruce Malkowicz ◽  
Thomas J. Guzzo
Keyword(s):  
Risk Factors ◽  
Bladder Cancer ◽  
High Risk ◽  
Low Risk ◽  
Risk Patients ◽  
Variant Histology ◽  
Mixed Histology ◽  
Muscle Invasive ◽  
Tumor Upstaging ◽  
Mixed Variant

308 Background: Despite level one evidence demonstrating improved survival with neoadjuvant chemotherapy (NAC), studies suggest that many eligible patients with muscle invasive bladder cancer (MIBC) never receive it prior to radical cystectomy (RC). Our objective was to determine if the absence of known pre-operative risk factors can indeed stratify for low risk of extravesical disease with RC alone. Methods: We identified consecutive NAC-naive patients with clinical stage cT2N0M0 urothelial type bladder cancer treated with RC at our center. cT2 patients with either hydronephrosis, transurethral resection (TUR) specimens containing lymphovascular invasion (LVI), or mixed variant histology were grouped as high risk. Clinicopathologic and survival outcomes were compared to cT2 patients without these adverse features, who were grouped as low risk. Results: Of 251 cT2 patients, 119 (47.4%) were high risk [LVI=31, hydronephrosis=69, mixed histology=54; ≥2 risk factors=70]. High and low risk cohorts did not differ in age, gender, race, BMI, smoking, co-morbidities, prior intravescial therapy, or treatment delay. At time of RC, high risk patients more often had lymph node metastasis (38.6% v. 26.7% p=0.04) & tumor upstaging to pT3/4 (53.7% v. 40.2 p<0.001), with significantly less achieving pT0 (2.5% v. 12.1% p=0.004). There was no difference in adjuvant chemotherapy rates (26.4% v. 25% p=0.8). Two and five year cancer-specific survival (CSS) was 84.8% and 62.3% for low risk patients, but only 59.5% and 42% for high risk patients (p=0.008), with competing risk analysis revealing worse bladder cancer specific mortality (BCSM) (sub HR=2.08 [95%CI=1.36 – 3.2]). Odds Ratio for BCSM was 1.29 (95%CI=0.68-2.5) if one risk factor was present, & 3.2 (95%CI=1.7-5.8) if two risk factors. Only hydronephrosis (2.2 [95%CI=1.2-4.2]) and mixed histology (2.4 [95%CI=1.2-4.8]) were independently associated with worse BCSM on multi-variable analysis. Conclusions: Good cancer control is provided by RC alone to many patients with cT2 MIBC without adverse risk factors, particularly if hydronephrosis & mixed variant histology is absent. However, tumor upstaging and lymph node involvement is not trivial even in low risk patients, which must be included in informed decision making on NAC.

Deletions of Chromosomes 9 and 8p in Histologically Normal Urothelium of Patients with Bladder Cancer

2005 ◽  
Vol 47 (1) ◽  
pp. 58-63 ◽  
Author(s):  
R STOEHR ◽  
S ZIETZ ◽  
M BURGER ◽  
T FILBECK ◽  
S DENZINGER ◽  
...  
Keyword(s):  
Bladder Cancer ◽  
Normal Urothelium

Oncologic Surveillance for Variant Histology Bladder Cancer after Radical Cystectomy

2021 ◽  
Author(s):  
Alberto Martini ◽  
Luca Afferi ◽  
Stefania Zamboni ◽  
Julianne G. Schultz ◽  
Chiara Lonati ◽  
...  
Keyword(s):  
Bladder Cancer ◽  
Radical Cystectomy ◽  
Variant Histology

BIOM-42. IMMUNOHISTOCHEMICAL ASSESSMENT OF MEMBRANOUS SOMATOSTATIN TYPE 2A RECEPTOR (SST2A) EXPRESSION ACROSS HIGH-RISK PEDIATRIC CENTRAL NERVOUS SYSTEM (CNS) TUMORS

2021 ◽  
Vol 23 (Supplement_6) ◽  
pp. vi20-vi20
Author(s):  
Margot Lazow ◽  
Andrew Trout ◽  
Christine Fuller ◽  
Jaime Reuss ◽  
Brian Turpin ◽  
...  
Keyword(s):  
Targeted Therapy ◽  
Somatostatin Receptor ◽  
High Grade Glioma ◽  
Staining Intensity ◽  
Cns Tumors ◽  
Embryonal Tumors ◽  
Therapeutic Implications ◽  
Variable Expression ◽  
Cell Percentage ◽  
Pediatric Cns Tumors

Abstract INTRODUCTION 77Lu-DOTATATE, a radionuclide therapy which binds SST2A, has demonstrated efficacy in neuroendocrine tumors and evidence of CNS penetration, supporting potential expansion within pediatric neuro-oncology. Understanding the prevalence of SST2A expression across pediatric CNS tumors is essential to identify patients who may benefit from somatostatin receptor-targeted therapy and to further elucidate the oncogenic role of SST2A. METHODS SST2A immunohistochemistry (IHC) was performed on tumor specimens and interpreted by two experienced pathologists (blinded), utilizing semi-quantitative scoring of membranous expression within viable tumor. Immunoreactive cell percentage was visually scored as 0 (none), 1 (&lt; 10%), 2 (10-50%), 3 (51-80%), or 4 (&gt;80%). Staining intensity was scored as 0 (none), 1 (weak), 2 (moderate), or 3 (strong). Combined scores for each specimen were calculated by multiplying percent immunoreactivity and staining intensity values (range=0-12). RESULTS A total of 117 tumor samples from 113 patients were analyzed. Significant differences in SST2A IHC scores were observed across histopathologic diagnoses, with consistently high scores in medulloblastoma (mean±SD=7.6±3.6 [n=36]) and meningioma (5.7±3.4 [n=15]), compared to minimal or absent expression in ATRT (0.3±0.6 [n=3]), ETMR (1.0±0 [n=3]), ependymoma (grades I-III; 0.2±0.7 [n=26]), and high-grade glioma (grades III-IV; 0.4±0.7 [n=22]). Pineoblastoma (3.8±1.5 [n=4]) and other embryonal tumors (2.3±3.8 [n=8]) exhibited intermediate, variable expression. Among expressors, there was no association between SST2A IHC score and patient age, sex, presence of metastases, likelihood of relapse, or prior treatment. In a subset of paired primary and recurrent specimens from 3 patients, SST2A IHC scores remained largely unchanged. Among medulloblastomas, SST2A IHC scores were higher in non-SHH (8.6±3.2) than SHH (5.0±3.3) molecular subgroups (p=0.033). CONCLUSIONS High membranous SST2A expression was demonstrated in medulloblastoma, meningioma, and some rarer embryonal tumors with potential diagnostic, biologic, and therapeutic implications. Somatostatin receptor-targeted therapy such as 177Lu-DOTATATE deserves further investigation in these highly SST2A-expressing pediatric CNS tumors.

Genomic characterization of bladder cancer with variant histology.

2021 ◽  
Vol 39 (6_suppl) ◽  
pp. 470-470
Author(s):  
Andrew Thomas Lenis ◽  
Timothy Nguyen Clinton ◽  
Wenhuo Hu ◽  
Nima Almassi ◽  
Peter Reisz ◽  
...  
Keyword(s):  
Bladder Cancer ◽  
Urothelial Carcinoma ◽  
Immune Cell ◽  
Genomic Analysis ◽  
Small Cell ◽  
Prognostic Information ◽  
Immune Cell Population ◽  
Frequent Mutations ◽  
Variant Histology ◽  
Primary Bladder

470 Background: Up to 25% of tumors are of pure variant or mixed urothelial and variant histology. The presence of variant histology may be associated with more advanced stage at presentation and a poorer response to systemic therapy. While histomorphologic assessment provides important prognostic information, genomic analysis of tumors can provide important insight into the biology of disease and inform treatment. In this analysis we performed genomic sequencing of tumors from patients with bladder cancer with variant histology. Methods: Our prospectively generated institutional cohort of molecularly profiled bladder and upper tract tumors contains over 2,000 samples including nearly 300 primary bladder tumor samples from patients with variant histology. Targeted sequencing with MSK-IMPACT was used to identify alterations in cancer-associated genes and to describe trends across variant subtypes. To explore and compare tumor and immune cell heterogeneity, single-cell RNA sequencing (scRNA-seq) was performed on a subset of specimens. Results: Our cohort included patients with pure urothelial carcinoma not otherwise specified (NOS), as well as squamous, small cell, pure adenocarcinoma and urothelial carcinoma with glandular differentiation, micropapillary, nested, and plasmacytoid variants. Compared with urothelial carcinoma NOS, nearly all small cell tumors had mutations in TP53, RB1, and TERT. Squamous tumors had similar mutational frequencies as urothelial carcinoma NOS. Pure adenocarcinoma had frequent mutations in TP53, KRAS, and PIK3CA, resembling colorectal adenocarcinomas, while urothelial carcinoma with glandular differentiation resembled NOS. Micropapillary variant commonly had ERBB2 amplifications. Nested variant was more commonly found to have RHOA mutations and FOXA1 amplifications. Finally, nearly all plasmacytoid variants had pathognomonic alterations in CDH1. To further explore heterogeneity in tumor and immune cell populations, scRNA-seq was performed on four samples from patients with urothelial carcinoma NOS, squamous, micropapillary, and nested variants, showing distinct tumor cell clusters and varying contributions of immune cells from each variant. Conclusions: While the distribution of oncogenic mutations differed among distinct histologic variants, a pathognomonic DNA alteration was not found for most variant histologic subtypes. Within the context of a larger effort to characterize bladder cancer with variant histology, scRNA-seq may reveal differences in immune cell population infiltrates. Further efforts will aim to characterize these cohorts with whole exome sequencing and mutational signatures, and increase the number of samples per histology and representation of variant histologies for scRNA-seq.

The role of enfortumab vedotin and sacituzumab govitecan in treatment of advanced bladder cancer

2021 ◽  
Author(s):  
Kirollos S Hanna ◽  
Samantha Larson ◽  
Jenny Nguyen ◽  
Jenna Boudreau ◽  
Jennifer Bulin ◽  
...  
Keyword(s):  
Bladder Cancer ◽  
Immune Checkpoint ◽  
Checkpoint Inhibitors ◽  
Second Line ◽  
Antibody Drug Conjugate ◽  
Drug Conjugates ◽  
Advanced Bladder Cancer ◽  
Checkpoint Inhibitor Therapy ◽  
Antibody Drug

Abstract Disclaimer In an effort to expedite the publication of articles pandemic, AJHP is posting manuscripts online as soon as possible after acceptance. Accepted manuscripts have been peer-reviewed and copyedited, but are posted online before technical formatting and author proofing. These manuscripts are not the final version of record and will be replaced with the final article (formatted per AJHP style and proofed by the authors) at a later time. Purpose The treatment landscape of advanced bladder cancer continues to evolve with novel therapeutics approved in recent years and many in the pipeline. Here we review the role of the novel agents enfortumab vedotin and sacituzumab govitecan in treatment of advanced disease. Summary Patients with advanced bladder cancer often first receive platinum-based therapy, while immune checkpoint inhibitors offer a maintenance option following cytotoxic chemotherapy or a second-line option. Despite various first- and second-line options, patients with significant comorbidities and treatment-related adverse events will experience disease progression requiring alternative treatment. Enfortumab vedotin and sacituzumab govitecan are novel antibody-drug conjugates approved in patients with advanced bladder cancer following platinum-based and immune checkpoint inhibitor therapy. Following platinum-based therapy and immunotherapy in patients with advanced bladder cancer, enfortumab vedotin, targeting Nectin-4, improves overall survival while sacituzumab govitecan, targeting Trop-2, is associated with a 27% response rate. With these new approaches to disease management, however, it remains critical to understand safety, efficacy, and operational considerations to optimize outcomes. Conclusion When selecting an antibody-drug conjugate to treat patients with bladder cancer, it is important to note the adverse event profile of each agent to optimize outcomes and safety for patients.

Clinical and Genomic Considerations for Variant Histology in Bladder Cancer

2019 ◽  
Vol 21 (3) ◽  
Author(s):  
Justin T. Matulay ◽  
Vikram M. Narayan ◽  
Ashish M. Kamat
Keyword(s):  
Bladder Cancer ◽  
Variant Histology

Plasmacytoid Bladder Cancer: Variant Histology With Aggressive Behavior and a New Mode of Invasion Along Fascial Planes

Urology ◽  
2014 ◽  
Vol 83 (5) ◽  
pp. 1112-1116 ◽  
Author(s):  
Hristos Z. Kaimakliotis ◽  
M. Francesca Monn ◽  
Liang Cheng ◽  
Timothy A. Masterson ◽  
K. Clint Cary ◽  
...  
Keyword(s):  
Bladder Cancer ◽  
Aggressive Behavior ◽  
Variant Histology

scholarly journals Increased concentrations of genotype-interpreted Ca 19-9 in urine of bladder cancer patients mark diffuse atypia of the urothelium

1998 ◽  
Vol 44 (2) ◽  
pp. 197-204 ◽  
Author(s):  
Else Marie Vestergaard ◽  
Hans Wolf ◽  
Torben F Ørntoft
Keyword(s):  
Bladder Cancer ◽  
Cancer Patients ◽  
Reference Group ◽  
Clinical Chemistry ◽  
Healthy Individuals ◽  
Wild Type ◽  
Secretor Status ◽  
Normal Urothelium ◽  
Sialyl Lea ◽  
Apparently Healthy

Abstract We investigated the use of genotype-interpreted measurements of the tumor marker Ca 19-9 in the urine of bladder cancer patients as a marker of the extent of urothelial disease. Ca 19-9 in urine (sialyl-Lea/creatinine ratio) was measured in 81 bladder cancer patients and correlated to T-category, histologic grade, and presence of urothelial dysplasia. As reference group, Ca 19-9 ratio was measured in urine from 21 apparently healthy individuals. The amount of sialyl-Lea expressed is influenced by the Lewis genotype and secretor status. Accordingly, secretor status was determined in urine by a novel ELISA method, and the Lewis genotypes of all of the individuals were determined by PCR cleavage methods. Ca 19-9 concentrations in urine were higher (P &lt;0.01) in bladder cancer patients than in healthy individuals and significantly (P =0.02) higher in cancer patients with concomitant urothelial dysplasia than in those with normal urothelium. For individuals Lewis-genotyped as homozygous wild-type, Ca 19-9 concentrations in urine were higher, both in cancer patients (P = 0.06) and in healthy individuals (P = 0.004), than in the heterozygous individuals. Furthermore, nonsecretor cancer patients had higher (P &lt;0.01) Ca 19-9 concentrations in urine. Attention is drawn to the possibility of a general genotype interpretation of a result in clinical chemistry.

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