281 small cell bladder cancer analysis from spanish institutions

338 Background: Small cell bladder cancer (SCBC), a malignancy indistinguishable from small cell lung cancer (SCLC), is a rare and aggressive subtype of bladder cancer. Response to chemotherapy in SCBC is poor, yet the standard therapy remains cisplatin and etoposide. Novel therapies based on a better understanding of the underlying mechanisms of transformation are needed. The purpose of this study is to identify potential targets and therapeutic options for this disease, using multiplatform tumor profiling. Methods: In total, 19 small cell bladder cancer specimenswere tested via a multiplatform profiling service (Caris Life Sciences, Phoenix, AZ) consisting of gene sequencing (Sanger or next generation sequencing [NGS]), protein expression (immunohistochemistry [IHC]) and gene amplification (CISH or FISH). Results: Loss of RRM1 (22.2%, 4/18), MGMT (83.3%, 15/18), and TS (26.3%, 5/19) by IHC are associated with potential benefit to traditional chemotherapy. High expression of ERCC1, associated with resistance to platinum-based therapy, was 37.5% (3/8). MRP1, a drug pump associated with resistance to various chemotherapies, was present in 100% (5/5) of specimens. PD-L1 (0%, 0/6) was not expressed. EGFR amplification was detected in 25.0% of patients (1/4). NGS aberrations included TP53 (90.0%), cMET (20.0%, 2/10), RB1 (11.1%), FBXW7 (10%, 1/10), PTEN (10%, 1/10). Sanger sequencing also detected KRAS (100%, 1/1) and PIK3CA (33.3%, 1/3) mutations. Conclusions: Multiplatform tumor profiling identified biomarkers which may clarify treatment dilemmas with this rare cancer. MRP1 overexpression and TP53 loss help explain this cancer’s resistance to traditional chemotherapy and its aggressive course. This approach identified potential therapies, some of which are not typically considered, like temozolomide. Immunotherapy may not be as beneficial in SCBC based on absent PD-L1 expression. NGS and Sanger sequencing identified cell surface receptors and downstream molecules that could be candidates for therapeutic strategies.

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Advanced small-cell bladder cancer into a ureterocele: A case report and literature review

Urology Case Reports ◽

10.1016/j.eucr.2019.100986 ◽

2019 ◽

Vol 27 ◽

pp. 100986

Author(s):

Camila R.T. Burity ◽

Fábio.T. Ferreira ◽

André F. Veiga ◽

Ricardo D. Saade

Keyword(s):

Bladder Cancer ◽

Case Report ◽

Literature Review ◽

Small Cell ◽

Cell Bladder Cancer

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Immune Exclusion Is Frequent in Small-Cell Carcinoma of the Bladder

Disease Markers ◽

10.1155/2019/2532518 ◽

2019 ◽

Vol 2019 ◽

pp. 1-6 ◽

Cited By ~ 3

Author(s):

Tim Mandelkow ◽

Niclas C. Blessin ◽

Eva Lueerss ◽

Laura Pott ◽

Ronald Simon ◽

...

Keyword(s):

Bladder Cancer ◽

Cell Carcinoma ◽

Cell Density ◽

Small Cell Carcinoma ◽

Immune Cell ◽

Cell Cancer ◽

Small Cell ◽

Urothelial Carcinomas ◽

Significant Difference ◽

Cell Bladder Cancer

Small-cell cancer of the urinary bladder is a rare but highly aggressive disease. It is currently unclear whether immune checkpoint therapies that have been approved for urothelial carcinomas will also be efficient in small-cell carcinomas. In this study, we analyzed potential predictors of response including PD-L1 expression and the quantity and location of tumor-infiltrating lymphocytes (TILs) in 12 small-cell and 69 “classical” urothelial cancers by immunohistochemistry. The analysis revealed that small-cell carcinomas were characterized by the virtual absence of PD-L1 expression and an “immune-excluded” phenotype with only a few TILs in the center of the tumor (CT). In small-cell carcinomas, the average immune cell density in the CT (CD3: 159±206, CD8: 87±169 cells/mm2) was more than 3 times lower than that in the urothelial carcinomas (CD3: 625±800, p<0.001; CD8: 362±626 cells/mm2, p=0.004) while there was no significant difference in the immune cell density at the invasive margin (IM) (small-cell carcinomas CD3: 899±733, CD8: 404±433 cells/mm2; urothelial carcinomas CD3: 1167±1206, p=0.31; CD8: 582±864 cells/mm2, p=0.27). Positive PD-L1 staining was found in 39% of urothelial cancers, but in only 8% of small-cell bladder cancer cases (p=0.04). Concordant with these data, a sharp decrease of PD-L1 positivity from >80% to 0% positive cells and of TILS in the CT from 466-1063 CD3-positive cells/mm2 to 50-109 CD3-positive cells/mm2 was observed in two cancers with clear-cut progression from “classical” urothelial to small-cell carcinoma. In conclusion, these data demonstrate that small-cell bladder cancer commonly exhibits an immune-excluded phenotype.

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Long term disease free survival with multimodal therapy in small cell bladder cancer

European Journal of Medical Research ◽

10.1186/s40001-016-0234-9 ◽

2016 ◽

Vol 21 (1) ◽

Cited By ~ 1

Author(s):

Isabel Heidegger ◽

Gennadi Tulchiner ◽

Georg Schäfer ◽

Wolfgang Horninger ◽

Renate Pichler

Keyword(s):

Bladder Cancer ◽

Multimodal Therapy ◽

Disease Free Survival ◽

Small Cell ◽

Free Survival ◽

Cell Bladder Cancer ◽

Disease Free

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Correlation between gene expression and prognostic biomarkers in small cell bladder cancer (SCBC).

Journal of Clinical Oncology ◽

10.1200/jco.2018.36.15_suppl.4546 ◽

2018 ◽

Vol 36 (15_suppl) ◽

pp. 4546-4546 ◽

Cited By ~ 1

Author(s):

Vadim S. Koshkin ◽

Andrew Dhawan ◽

Ming Hu ◽

Jordan Reynolds ◽

Paul Elson ◽

...

Keyword(s):

Gene Expression ◽

Bladder Cancer ◽

Small Cell ◽

Prognostic Biomarkers ◽

Cell Bladder Cancer

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Small cell bladder cancer: Treatment patterns and clinical outcomes.

Journal of Clinical Oncology ◽

10.1200/jco.2020.38.15_suppl.e17014 ◽

2020 ◽

Vol 38 (15_suppl) ◽

pp. e17014-e17014

Author(s):

Rishi Robert Sekar ◽

Leonidas Nikolaos Diamantopoulos ◽

Funda Vakar-Lopez, MD ◽

Petros Grivas ◽

Sarah P. Psutka ◽

...

Keyword(s):

Bladder Cancer ◽

Univariate Analysis ◽

Pathologic Complete Response ◽

Multivariable Analysis ◽

Complete Response ◽

Small Cell ◽

Oncologic Outcomes ◽

Rank Test ◽

Definitive Therapy ◽

Cell Bladder Cancer

e17014 Background: Small cell bladder cancer (SCBC) is a rare histologic variant associated with poor oncologic outcomes and propensity for metastasis, however, there remains a paucity of data regarding the role of chemoradiation. We review our institutional experience of patients with small cell bladder cancer (SCBC) treated with radical cystectomy (RC) versus concurrent chemoradiotherapy (CCRT). Methods: We retrospectively reviewed our institutional database for pts with SCBC treated with RC or CCRT and compared them to pts with conventional urothelial carcinoma (CUC) treated with RC. Clinicopathologic data and outcomes were captured and compared between treatment groups. Overall (OS) and recurrence-free survival (RFS) were estimated utilizing the Kaplan Meier method. T test, χ2 test and log-rank test were used for group comparisons. Factors significant in the univariate analysis for OS were included in multivariable Cox models. Results: We identified 38 consecutive pts with SCBC, of whom 24 (63%) had SC predominant ( > 50%) histology. At presentation, 31 (82%) had muscle invasion, 8 (22%) had nodal involvement, and 7 (18%) had distant metastasis. Twenty-eight (73%) pts proceeded to definitive therapy, with RC in 20 (53%) and CCRT in 8 (21%). Among pts treated with CCRT, 4 (50%) had complete response on cystoscopy, 2 (25%) had residual disease with 1 (12.5%) proceeding to salvage cystectomy, and 2 (25%) progressed with metastasis. Among pts treated with RC, 15 (75%) received neoadjuvant chemotherapy (NAC) with platinum/etoposide, of whom 3 (20%) experienced a pathologic complete response (pCR, ypT0N0), 3 (20%) had residual UC but no SCBC, and 9 (60%) had residual SCBC. Median OS was comparable between RC and CCRT groups (30.4 vs. 26.2 months, p = 0.633). Compared to pts with CUC treated with RC (n = 457), those with SCBC treated with RC had similar clinical stage, rates of carcinoma in situ, lymphovascular invasion, and positive surgical margins (all p > 0.05). Median OS and RFS were inferior for SCBC treated with RC (30.4 vs 109.7 months, p = .001; 13.1 vs 86.1 months, p = .002). On multivariable analysis among pts treated with RC, SCBC was significantly associated with shorter OS adjusting for pT and pN stage, performance status, and age. Conclusions: Pts with SCBC undergoing RC had significantly worse oncologic outcomes compared to pts with CUC, however RC and CCRT had comparable outcomes in pts with SCBC. The pCR rate to NAC was unexpectedly low. Larger sample size, assessment of other confounders and longer follow-up are needed for validation.

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Pathogenic variants in PTEN to predict for increased risk of relapse and death in patients with limited stage small cell bladder cancer.

Journal of Clinical Oncology ◽

10.1200/jco.2020.38.6_suppl.526 ◽

2020 ◽

Vol 38 (6_suppl) ◽

pp. 526-526

Author(s):

Earle Frederick Burgess ◽

Nury Steuerwald ◽

James Thomas Symanowski ◽

Chad Livasy ◽

Carol J. Farhangfar ◽

...

Keyword(s):

Bladder Cancer ◽

Tumor Biology ◽

Tumor Resection ◽

Small Cell ◽

Allele Frequencies ◽

Histologic Subtype ◽

Limited Stage ◽

Pathogenic Variants ◽

Increased Risk ◽

Cell Bladder Cancer

526 Background: Small cell bladder cancer (SCBC) is a rare histologic subtype with insufficient genomic characterization. Patients with limited stage (LS) SCBC have a poor prognosis, and no biomarker exists to optimize treatment selection. We sought to identify genomic aberrations in patients with LS-SCBC using a comprehensive next generation sequencing (NGS) platform. Mutations in the PTEN/AKT pathway are important in urothelial tumor biology but have an undefined role in SCBC. Methods: 23 LS-SCBC cases were identified. NGS was performed on diagnostic transurethral bladder tumor resection or cystectomy specimens containing SCBC. Detected variants were filtered by in silico algorithms predicting for a deleterious impact on protein function. Variant allele frequencies (VAF) greater than 2% were permitted in this analysis. Variants in the PTEN gene were assessed for association with relapse-free survival (RFS) and overall survival (OS) using Kaplan-Meier techniques and Cox proportional hazards models. Results: Median follow up for the cohort was 4.02 years. 14/23 (60.9%) patients have died. Six unique deleterious PTEN mutations were observed in 9/23 (39.1%) patients. p.W274C was the most common PTEN variant and was detected in 5 (21.7%) patients. Three variants were detected at > 10% VAF. All 9 patients with a deleterious PTEN variant died. The presence of deleterious PTEN variants [HR = 4.68 [(1.54, 14.27), p = 0.003]] predicted for inferior OS. In the 19 patients with known relapse history, 6/7 (85.7%) with and 3/12 (25%) without any deleterious PTEN mutation relapsed. The presence of deleterious PTEN variants [HR = 9.41 [(2.32, 38.23), p < 0.001]] also predicted for inferior RFS. Conclusions: Pathogenic variants in tumor suppressor PTEN were associated with inferior RFS and OS in this pilot cohort of patients with LS-SCBC, suggesting that disruption of PTEN function may be a critical genomic event underlying the progression of small cell bladder cancer. Our findings also support prior reports that pathogenic gene variants detected at low allele frequencies may be clinically important.

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