scholarly journals FOXA1 Gene Expression for Defining Molecular Subtypes of Muscle-Invasive Bladder Cancer after Radical Cystectomy

2020 ◽  
Vol 9 (4) ◽  
pp. 994 ◽  
Author(s):  
Danijel Sikic ◽  
Markus Eckstein ◽  
Ralph M. Wirtz ◽  
Jonas Jarczyk ◽  
Thomas S. Worst ◽  
...  
Keyword(s):  
Bladder Cancer ◽  
Radical Cystectomy ◽  
Multivariable Analysis ◽  
Disease Free Survival ◽  
Gene Panel ◽  
The Cancer Genome Atlas ◽  
Invasive Bladder Cancer ◽  
Muscle Invasive Bladder Cancer ◽  
Free Survival ◽  
Muscle Invasive

It remains unclear how to implement the recently revealed basal and luminal subtypes of muscle-invasive bladder cancer (MIBC) into daily clinical routine and whether molecular marker panels can be reduced. The mRNA expression of basal (KRT5) and luminal (FOXA1, GATA3, KRT20) markers was measured by reverse transcription quantitative real-time polymerase chain reaction (RT-qPCR) and correlated to clinicopathological features, recurrence-free survival (RFS), disease-free survival (DFS), and overall survival (OS) in 80 patients with MIBC who underwent radical cystectomy. Additionally, the correlation of single markers with the basal and non-basal subtypes defined by a 36-gene panel was examined and then validated in the TCGA (The Cancer Genome Atlas) cohort. High expression of FOXA1 (p = 0.0048) and KRT20 (p = 0.0317) was associated with reduced RFS. In the multivariable analysis, only FOXA1 remained an independent prognostic marker for DFS (p = 0.0333) and RFS (p = 0.0310). FOXA1 expression (AUC = 0.79; p = 0.0007) was closest to the combined marker expression (AUC = 0.79; p = 0.0015) in resembling the non-basal subtype defined by the 36-gene panel. FOXA1 in combination with KRT5 may be used to distinguish the basal and non-basal subtypes of MIBC.

Effectiveness and safety of valrubicin in non–muscle-invasive bladder cancer following reintroduction: Results from a medical chart review study.

2013 ◽  
Vol 31 (6_suppl) ◽  
pp. 296-296
Author(s):  
Michael S. Cookson ◽  
Christine Francis Lihou ◽  
Samira Q. Harper ◽  
Thomas Li ◽  
Surya Chitra ◽  
...  
Keyword(s):  
Bladder Cancer ◽  
Radical Cystectomy ◽  
Concomitant Medication ◽  
Disease Free Survival ◽  
Progression Free Survival ◽  
The United States ◽  
Invasive Bladder Cancer ◽  
Muscle Invasive Bladder Cancer ◽  
Free Survival ◽  
Muscle Invasive

296 Background: Valrubicin was approved in the United States in 1998, removed from the market in 2002 because of manufacturing issues, and reintroduced in 2009. We report secondary outcomes and concomitant medication use from a US multicenter, observational, retrospective study. Methods: Medical records of adult patients with non–muscle-invasive bladder cancer (NMIBC) who used valrubicin were abstracted (March–September 2011). Kaplan-Meier analyses were performed for disease-free survival (DFS), progression-free survival (PFS), worsening-free survival (WFS), cystectomy-free survival (CFS), and time to cystectomy. Results: 113 patients (mean age, 73.7 years) received intravesical valrubicin (median, 6 instillations [range, 2–18]). 107 patients (94.7%) received >3 instillations; 97 (85.8%) completed the full course of therapy (≥6 instillations). DFS was 51.6% (95% CI, 40.9%–61.3%) at 3 months, 30.4% (95% CI, 20.4%–41.1%) at 6 months, and median DFS was 3.5 months (95% CI, 2.5–4.0). PFS was 97.6% (95% CI, 90.9%–99.4%) at 3 months, 87.2% (95% CI, 75.4%–93.5%) at 6 months, and median PFS was 18.2 months (95% CI, 17.2–19.0). WFS was 47.4% (95% CI, 37.2%–57.0%) at 3 months and 28.1% (95% CI, 18.8%–38.2%) at 6 months. CFS was 98.0% (95% CI, 92.2%–99.5%) at 3 months and 93.7% (95% CI, 85.2%–97.4%) at 6 months. Median CFS was not reached; only 13.3% of patients underwent radical cystectomy after starting valrubicin. 56 patients (49.6%) experienced ≥1 local adverse reaction; the most common were hematuria and pollakiuria (both 17.7%), micturition urgency (15.9%), and bladder spasm (14.2%). 55 patients (48.7%) used ≥1 concomitant medication for local adverse reactions; the most commonly used were urinary antispasmodics (21.2%), fluoroquinolones (14.2%), and other urologicals (14.2%). Conclusions: In patients with NMIBC treated with intravesical valrubicin, median DFS and PFS were 3.5 and 18.2 months, respectively, and median CFS was not reached as only 13% of patients underwent radical cystectomy. Valrubicin was well tolerated, and most patients received the full course of 6 instillations. Funding: Research and abstract were supported by Endo Pharmaceuticals Inc.

Feasibility and efficacy of gemcitabine and carboplatin neoadjuvant chemotherapy in muscle-invasive bladder cancer

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. e16100-e16100
Author(s):  
T. Koie ◽  
H. Yamamoto ◽  
A. Okamoto ◽  
S. Hatakeyama ◽  
A. Momose ◽  
...  
Keyword(s):  
Overall Survival ◽  
Bladder Cancer ◽  
Radical Cystectomy ◽  
Objective Response ◽  
Disease Free Survival ◽  
Invasive Bladder Cancer ◽  
Muscle Invasive Bladder Cancer ◽  
Free Survival ◽  
Muscle Invasive ◽  
Disease Free

e16100 Background: The neoadjuvant M-VAC followed by radical cystectomy for muscle-invasive bladder cancer has improved survival compared to radical cystectomy alone. Nevertheless, M-VAC has been associated with severe toxicity. The objective of this retrospective study was to evaluate the objective response rate, the impact on overall survival, disease-free survival, disease-free survival and toxicity adverse events of gemcitabine and carboplatin (GC) neoadjuvant chemotherapy in patients with locally advanced bladder cancer. Methods: We reviewed the clinical and pathological data of 140 patients who underwent radical cystectomy and bilateral pelvic lymphadenectomy for T2N0M0 to T4aN0M0 bladder cancer at our institution between January 2001 and August 2008. Seventy patients were treated with neoadjuvant GC followed by cystectomy between March 2005 and August 2008 (GC group), and 70 patients were treated with cystectomy alone between January 2001 and May 2007 (cystectomy alone group). In the GC group, the patients received 2 courses of GC therapy consisted of 800mg/m2 gemcitabine on days 1, 8, and 15 and carboplatin (AUC 4) on day 2. The primary endpoint was the objective response rate, and the secondary endpoints were overall survival, cancer-specific survival, disease free survival, and toxicity. Results: Fifteen patients (23.8%) had a complete response and 26 patients (41.3%) had a partial response in the GC group. At a mean follow-up period of 26.7 months, the overall survival was 85.0% in the GC group and 47.8% in the cystectomy alone group (p = 0.003). The cancer-specific survival was 78.4% in the GC group and 44.6% in the cystectomy alone group (p = 0.0018). The disease-free survival was 82.9% in the GC group and 35.7% in the cystectomy alone group (p = 0.0001). Hematologic toxicities were the main adverse events. Grade 3/4 neutropenia occurred in 26 patients (37.1%) and thrombocytopenia in 15 (21.4%). There was no grade 3/4 gastrointestinal toxicity and no renal function abnormalities. Conclusions: Although this is not a randomized study, the GC neoadjuvant therapy followed by radical cystectomy is feasible and may be associated with improved survival among patients with muscle-invasive bladder cancer. A randomized trial is warranted. No significant financial relationships to disclose.

Predictors of pathologic response after radical cystectomy for muscle invasive bladder cancer: A population-based analysis.

2018 ◽  
Vol 36 (6_suppl) ◽  
pp. 503-503
Author(s):  
Shane M. Pearce ◽  
Akbar Ashrafi ◽  
Matthew Winter ◽  
Saum Ghodoussipour ◽  
Daniel Zainfeld ◽  
...  
Keyword(s):  
Bladder Cancer ◽  
Radical Cystectomy ◽  
Clinical Stage ◽  
Multivariable Analysis ◽  
Pathologic Response ◽  
Invasive Bladder Cancer ◽  
Muscle Invasive Bladder Cancer ◽  
Academic Center ◽  
Muscle Invasive ◽  
Over Time

503 Background: Neoadjuvant chemotherapy (NAC) improves overall survival (OS) for patients with muscle invasive bladder cancer (MIBC) undergoing radical cystectomy (RC), possibly through an increase in pathologic complete response (CR), defined as a pathologic stage T0 (pT0). We sought to identify predictors of CR for MIBC. Methods: The National Cancer Database from 2004 to 2013 was used to identify patients with cT2-4cN0cM0 urothelial cell carcinoma treated with RC. Patients were grouped based on pathology as CR (pT0), partial response (PR – pTa/Tis/T1) or no response (NR - pT2 or higher). Predictors of NAC and CR were identified with multivariable logistic regression. Cox proportional hazards model was used to compare OS based on cT stage, receipt of NAC and pathologic response. Results: The study population included 10,820 patients and NAC was administered in 16.4%. Use of NAC was associated with higher cT stage (p < 0.01) and increased over time (10% from 2003-2007 vs. 24% from 2011-2013, p < 0.01). Predictors of NAC use on multivariable analysis include younger age, lower comorbidity score, treatment at an academic center, and diagnosis from 2011-2013 (p < 0.01). Overall, CR was achieved in 3.3% without NAC and 16.3% with NAC (p < 0.01). NAC improved 5-year OS for all cT stages, however the survival benefit was only observed among those achieving CR (p < 0.01). Multivariable Cox regression demonstrates that both PR (HR 0. 58, p < 0.01) and CR (OR 0.26, p < 0.01) were independently associated with improved OS among those treated with NAC. Multivariable analysis identified age (OR 0.98, p < 0.01) and increased clinical stage (cT3: OR 0.47, p < 0.01; cT4 OR 0.54, p < 0.01) as negative predictors of CR. Utilization of NAC (OR 4.82 p < 0.01), academic institution, and diagnosis 2011-2013 (OR 1.92, p < 0.01) increased the odds of CR. Conclusions: Use of NAC increased over time and CR occurred in 16% of patients who received NAC. Treatment at an academic center, diagnosis from 2011-2013 and use of NAC were independently associated with CR, while increased age and clinical stage were negative predictors of CR. PR and CR are independently associated with improved OS relative to non-responders.

Development of a genomic-clinical classifier for predicting progression after radical cystectomy in patients with muscle invasive bladder cancer.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 4542-4542
Author(s):  
Anirban Pradip Mitra ◽  
Nicholas Erho ◽  
Lucia L.C. Lam ◽  
Ismael A. Vergara ◽  
Thomas Sierocinski ◽  
...  
Keyword(s):  
Bladder Cancer ◽  
Radical Cystectomy ◽  
Cancer Progression ◽  
External Validation ◽  
Multivariable Analysis ◽  
Invasive Bladder Cancer ◽  
K Nearest Neighbor ◽  
Muscle Invasive Bladder Cancer ◽  
Validation Set ◽  
Muscle Invasive

4542 Background: The mainstay of muscle-invasive bladder cancer treatment is surgical resection with/without multi-agent chemotherapy. Management decisions are based on a small number of clinical and pathologic parameters with poor prognostic and predictive power. There is an urgent need for enhanced biomarkers to guide therapy of this lethal disease. Here we have developed a genomic signature of bladder cancer progression using whole transcriptome profiling technology. Methods: 251 FFPE bladder cancer specimens were obtained from patients undergoing radical cystectomy at the University of Southern California (1998-2004). All patients had pT2-T4a,N0 urothelial carcinoma in the absence of pre-operative chemotherapy. Median follow-up was 5 years. RNA expression levels were measured with 1.4 million feature oligonucleotide microarrays. Patients were divided into a training set (2/3 of cohort) to develop a genomic classifier for risk of progression (defined as any type of bladder cancer recurrence), and a validation set (1/3 of cohort). In parallel, multivariable analysis was used to develop a clinical classifier using typical clinical and pathologic variables. Finally, a genomic-clinical classifier was built combining the genomic classifier with clinical variables using logistic regression. The receiver-operator characteristic (ROC) area under the curve (AUC) metric was used to evaluate each classifier in the validation set. Results: The genomic classifier consisted of 89 features corresponding to 80 genes that were combined in a k-nearest neighbor model (KNN89). KNN89 showed an AUC of 0.77 in ROC analysis on the validation set. The best clinical classifier showed an AUC of 0.72. The genomic-clinical classifier demonstrated an AUC of 0.81. Multivariable analysis incorporating all clinical parameters and KNN89 further revealed that KNN89 was the only significant predictor of bladder cancer progression (p=0.0077). Conclusions: We have developed a combined genomic-clinical classifier that shows improved performance over clinical models alone for prediction of progression after radical cystectomy. External validation of this classifier is ongoing.

scholarly journals Stromal LAG-3+cells infiltration defines poor prognosis subtype muscle-invasive bladder cancer with immunoevasive contexture

2020 ◽  
Vol 8 (1) ◽  
pp. e000651 ◽  
Author(s):  
Han Zeng ◽  
Quan Zhou ◽  
Zewei Wang ◽  
Hongyu Zhang ◽  
Zhaopei Liu ◽  
...  
Keyword(s):  
Bladder Cancer ◽  
T Cells ◽  
Immune Checkpoint ◽  
Cox Regression ◽  
Mrna Level ◽  
Disease Free Survival ◽  
The Cancer Genome Atlas ◽  
Invasive Bladder Cancer ◽  
Muscle Invasive Bladder Cancer ◽  
Muscle Invasive

BackgroundLymphocyte activation gene 3 (LAG-3) is a promising immune checkpoint therapeutic target being evaluated in clinical trials. We assessed the LAG-3+cells distribution, its association with clinical outcomes and immune contexture and its role in the landscape of muscle-invasive bladder cancer (MIBC) treatment.Methods141 patients with MIBC from Zhongshan Hospital were included for survival and adjuvant chemotherapy (ACT) benefit analyses. 32 fresh resected samples of MIBC were collected to detect CD8+T cells functional state. The molecular classification analyses were based on 391 patients with MIBC from The Cancer Genome Atlas. Immunohistochemistry and flow cytometry were performed to characterize various immune cells infiltration.ResultsIn Kaplan-Meier analyses and Cox regression models, stromal LAG-3+cells enrichment was consistently associated with inferior overall survival and disease-free survival, and indicated suboptimal responsiveness to ACT. Patents with high stromal LAG-3+cells possessed increased protumor cells, immunosuppressive cytokines and immune checkpoint expression. The phenotypic analyses of CD8+T cells correlated its dysfunctional state with LAG-3+cells. Besides, LAG-3 mRNA level was linked to luminal and basal subtypes of MIBC. LAG-3-high tumors exhibited limited FGFR3 mutation and signaling signature, and displayed activated immunotherapeutic and EGFR-associated pathway.ConclusionsStromal LAG-3+cells abundance indicated an immunoevasive contexture with dysfunctional CD8+T cells, and represented an independent predictor for adverse survival outcome and ACT resistance in MIBC. LAG-3 expression could potentially be a novel biomarker for FGFR3-targeted and EGFR-targeted therapies and immunotherapy. The crucial role of LAG-3+cells in the therapeutic landscape of MIBC needs further validation retrospectively and prospectively.

scholarly journals Construction of an Immune-Associated Gene-Based Signature in Muscle-Invasive Bladder Cancer

2020 ◽  
Vol 2020 ◽  
pp. 1-13
Author(s):  
Chengquan Shen ◽  
Ting Xu ◽  
Yefeng Sun ◽  
Liping Wang ◽  
Zhijuan Liang ◽  
...  
Keyword(s):  
Bladder Cancer ◽  
Survival Analysis ◽  
Risk Score ◽  
Disease Free Survival ◽  
Differentially Expressed ◽  
Invasive Bladder Cancer ◽  
Prognostic Signature ◽  
Muscle Invasive Bladder Cancer ◽  
Free Survival ◽  
Muscle Invasive

Background. In recent years, immune-associated genes (IAGs) have been documented as having critical roles in the occurrence and progression of muscle-invasive bladder cancer (MIBC). Novel immune-related biomarkers and a robust prognostic signature for MIBC patients are still limited. The study is aimed at developing an IAG-based signature to predict the prognosis of MIBC patients. Methods. In the present study, we identified differentially expressed IAGs in MIBC by using transcriptomics data from The Cancer Genome Atlas (TCGA) database and proteomics data from our samples. We further constructed an IAG-based signature and evaluated its prognostic and predictive value by survival analysis and nomogram. Tumor Immune Estimation Resource (TIMER) was applied to explore the correlation between the IAG-based signature and immune cell infiltration in the microenvironment of MIBC. Results. A total of 22 differentially expressed IAGs were identified, and 2 IAGs (NR2F6 and AHNAK) were used to establish a prognostic signature. Subsequently, survival analysis showed that high-risk scores were significantly correlated with poor overall survival (OS), progression-free survival (PFS), and disease-free survival (DFS) of MIBC patients. A prognostic nomogram was constructed by integrating clinical factors with the IAG-based signature risk score. In addition, the IAG-based signature risk score was positively associated with the infiltration of macrophages and dendritic cells in MIBC. Conclusions. We constructed and verified a novel IAG-based signature, which could predict the prognosis of MIBC and might reflect the status of the immune microenvironment of MIBC. Further studies in more independent clinical cohorts and further experimental exploration of the prognostic IAG-based signature are still needed.

Using radiologic response to predict prognosis in patients with muscle-invasive bladder cancer undergoing carboplatin-based neoadjuvant chemotherapy.

2014 ◽  
Vol 32 (4_suppl) ◽  
pp. 361-361
Author(s):  
Shingo Hatakeyama ◽  
Hayato Yamamoto ◽  
Akiko Okamoto ◽  
Atsushi Imai ◽  
Takahiro Yoneyama ◽  
...  
Keyword(s):  
Bladder Cancer ◽  
Multivariate Analysis ◽  
Neoadjuvant Chemotherapy ◽  
Radical Cystectomy ◽  
Cox Regression ◽  
Disease Free Survival ◽  
Invasive Bladder Cancer ◽  
Muscle Invasive Bladder Cancer ◽  
Contrast Enhanced Ct ◽  
Muscle Invasive

361 Background: Prognosis and tumor responses of carboplatin-based neoadjuvant chemotherapy for muscle invasive bladder cancer (MIBC) are not well documented. To assess the usefulness of carboplatin-based neoadjuvant chemotherapy, we examined the correlation between radiological responses and pathologic down staging on radical cystectomy (RCx) specimens, disease free survival (DFS), and overall survival (OS). Methods: Between March 2005 and June 2013, we performed carboplatin-based neoadjuvant chemotherapy followed by radical cystectomy in 115 patients with T2-4NxM0 MIBC. After diagnostic TUR biopsy, all participants received two courses of Gemcitabine plus Carboplatin therapy. Baseline and post chemotherapy tumor size from contrast enhanced CT were reviewed. The patients were divided in two groups between responders (CR+PR), and non-responders (SD+PD). RCx and bilateral pelvic lymphadenectomy were performed approximately within a month after cessation of chemotherapy. DFS and OS distributions within radiologic response subgroups were estimated with the Kaplan-Meier method and compared using the log-rank test. To evaluate independent predictor for DFS and OS, age, gender, performance status, pathological T and N stage, down-staging, tumor grade, renal function, and radiological responses were applied by Cox-regression multivariate analysis. Results: No significant differences were observed in patient backgrounds between the groups. Radiologic responses were observed in 75 (65%) patients with 69±24% decrease in responder group, whereas tumor response was 2.8±14% in non-responders. The rate of pathological down staging to <pT2 was 37 (49%) in responders, 5 (13%) in non-responders group. Radiologic response was a strong predictor of DFS and OS. A 5-year advantages of DFS and OS in responders vs. non-responders were 88% and 86% vs. 64% and 69%, respectively (P=0.021 and P=0.013). Multivariate analysis showed radiologic response was the independent factor for DFS and OS. Conclusions: Radiological response post carboplatin-based neoadjuvant chemotherapy is associated with OS in patients with MIBC.

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