scholarly journals A Molecular Signature Determines the Prognostic and Therapeutic Subtype of Non-Muscle-Invasive Bladder Cancer Responsive to Intravesical Bacillus Calmette-Guérin Therapy

2021 ◽  
Vol 22 (3) ◽  
pp. 1450
Author(s):  
Seon-Kyu Kim ◽  
Seong-Hwan Park ◽  
Yeong Uk Kim ◽  
Young Joon Byun ◽  
Xuan-Mei Piao ◽  
...  
Keyword(s):  
Bladder Cancer ◽  
Molecular Subtypes ◽  
Molecular Signature ◽  
Invasive Bladder Cancer ◽  
Diagnostic Tools ◽  
Bacillus Calmette Guerin ◽  
Muscle Invasive Bladder Cancer ◽  
Free Survival ◽  
Bcg Therapy ◽  
Muscle Invasive

Non-muscle-invasive bladder cancer (NMIBC) is clinically heterogeneous; thus, many patients fail to respond to treatment and relapse. Here, we identified a molecular signature that is both prognostic and predictive for NMIBC heterogeneity and responses to Bacillus Calmette-Guérin (BCG) therapy. Transcriptomic profiling of 948 NMIBC patients identified a signature-based subtype predictor, MSP888, along with three distinct molecular subtypes: DP.BCG+ (related to progression and response to BCG treatment), REC.BCG+ (related to recurrence and response to BCG treatment), and EP (equivocal prognosis). Patients with the DP.BCG+ subtype showed worse progression-free survival but responded to BCG treatment, whereas those with the REC.BCG+ subtype showed worse recurrence-free survival but responded to BCG treatment. Multivariate analyses revealed that MSP888 showed independent clinical utility for predicting NMIBC prognosis (each p = 0.001 for progression and recurrence, respectively). Comparative analysis of this classifier and previously established molecular subtypes (i.e., Lund taxonomy and UROMOL class) revealed that a great proportion of patients were similar between subtypes; however, the MSP888 predictor better differentiated biological activity or responsiveness to BCG treatment. Our data increase our understanding of the mechanisms underlying the poor prognosis of NMIBC and the effectiveness of BCG therapy, which should improve clinical practice and complement other diagnostic tools.

scholarly journals Non-maintenance intravesical Bacillus Calmette–Guérin induction therapy with eight doses in patients with high- or highest-risk non-muscle invasive bladder cancer: a retrospective non-randomized comparative study

BMC Cancer ◽  
2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Makito Miyake ◽  
◽  
Kota Iida ◽  
Nobutaka Nishimura ◽  
Tatsuki Miyamoto ◽  
...  
Keyword(s):  
Bladder Cancer ◽  
Propensity Score ◽  
Invasive Bladder Cancer ◽  
Rank Test ◽  
Bacillus Calmette Guerin ◽  
Muscle Invasive Bladder Cancer ◽  
Free Survival ◽  
Landmark Analyses ◽  
Muscle Invasive ◽  
Group B

Abstract Background To explore possible solutions to overcome chronic Bacillus Calmette–Guérin (BCG) shortage affecting seriously the management of non-muscle invasive bladder cancer (NMIBC) in Europe and throughout the world, we investigated whether non-maintenance eight-dose induction BCG (iBCG) was comparable to six-dose iBCG plus maintenance BCG (mBCG). Methods This observational study evaluated 2669 patients with high- or highest-risk NMIBC who treated with iBCG with or without mBCG during 2000–2019. The patients were classified into five groups according to treatment pattern: 874 (33%) received non-maintenance six-dose iBCG (Group A), 405 (15%) received six-dose iBCG plus mBCG (Group B), 1189 (44%) received non-maintenance seven−/eight-dose iBCG (Group C), 60 (2.2%) received seven−/eight-dose iBCG plus mBCG, and 141 (5.3%) received only ≤5-dose iBCG. Recurrence-free survival (RFS), progression-free survival, and cancer-specific survival were estimated and compared using Kaplan–Meier analysis and the log-rank test, respectively. Propensity score-based one-to-one matching was performed using a multivariable logistic regression model based on covariates to obtain balanced groups. To eliminate possible immortal bias, 6-, 12-, 18-, and 24-month conditional landmark analyses of RFS were performed. Results RFS comparison confirmed that mBCG yielded significant benefit following six-dose iBCG (Group B) in recurrence risk reduction compared to iBCG alone (groups A and C) before (P < 0.001 and P = 0.0016, respectively) and after propensity score matching (P = 0.001 and P = 0.0074, respectively). Propensity score-matched sequential landmark analyses revealed no significant differences between groups B and C at 12, 18, and 24 months, whereas landmark analyses at 6 and 12 months showed a benefit of mBCG following six-dose iBCG compared to non-maintenance six-dose iBCG (P = 0.0055 and P = 0.032, respectively). There were no significant differences in the risks of progression and cancer-specific death in all comparisons of the matched cohorts. Conclusions Although non-maintenance eight-dose iBCG was inferior to six-dose iBCG plus mBCG, the former might be an alternative remedy in the BCG shortage era. To overcome this challenge, further investigation is warranted to confirm the real clinical value of non-maintenance eight-dose iBCG.

Germline DNA copy number polymorphism to predict the efficacy of BCG therapy for non-muscle invasive bladder cancer.

2020 ◽  
Vol 38 (6_suppl) ◽  
pp. 431-431
Author(s):  
Yoshiaki Yamamoto ◽  
Sho Ozawa ◽  
Masahiro Samoto ◽  
Junichi Mori ◽  
Ryo Inoue ◽  
...  
Keyword(s):  
Bladder Cancer ◽  
Copy Number ◽  
Progression Free Survival ◽  
Japanese Patients ◽  
Intravesical Instillation ◽  
Invasive Bladder Cancer ◽  
Muscle Invasive Bladder Cancer ◽  
Free Survival ◽  
Bcg Therapy ◽  
Muscle Invasive

431 Background: Bacillus Calmette-Guerin (BCG) intravesical instillation is the most effective immunotherapy for non-muscle-invasive bladder cancer (NMIBC), however there are few reliable markers to elucidate the efficacy of BCG therapy. Germline copy number polymorphisms (CNPs) are expected to affect various diseases including human malignancies, but the significance of CNPs in NMIBC treated with BCG therapy remains unclear. FAM81A located on 15q22.2 was reported as one of tumor-associated ETS shared target genes in prostate cancer. PCSK6 located on 15q26.3 was reported to regulate proliferation and tumor progression in several cancers. The purpose of this study is to determine the prognostic value of CNPs for NMIBC treated with BCG therapy. To our knowledge, this is the first report to confirm CNPs as a potential biomarker for assessing the efficacy of immunotherapy. Methods: Array comparative genomic hybridization (CGH) was performed to search for candidate whole genome-wide CNPs related to NMIBC susceptibility. Next, quantitative real-time polymerase chain reaction was carried out to evaluate the effect of BCG therapy for 57 Japanese patients with NMIBC treated with BCG intravesical instillation. Results: Eleven CNPs were associated with NMIBC risk in array CGH. FAM81A and PCSK6 copy number according to those CNPs examined showed significant relationship with disease progression in NMIBC treated with BCG. The means of the relative copy numbers of patients with CNP and those without it were 1.58 and 2.10 for FAM81A ( P < 0.0001), and 1.06 and 1.80 for PCSK6 ( P < 0.0001), respectively. Univariate Cox proportional hazards regression analysis showed that FAM81A ( P = 0.0022), and PCSK6 ( P = 0.0147) copy number had a significant effect on progression-free survival. In multivariate analyses, FAM81A copy number was an independent prognostic factor for progression-free survival ( P = 0.0419, RR = 7.59, 95% CI, 1.07–153.42). The combination of FAM81A or PCSK6 CNP was the most significant prognostic biomarker to predict the efficacy of BCG therapy for NMIBC ( P = 0.0002). Conclusions: Germline DNA CNPs may be a potential new biomarker for estimating the efficacy of BCG therapy in Japanese patients with NMIBC.

scholarly journals Non-muscle Invasive Bladder Cancer Molecular Subtypes Predict Differential Response to Intravesical Bacillus Calmette-Guérin

2021 ◽  
Author(s):  
Florus C. de Jong ◽  
Teemu D. Laajala ◽  
Robert F. Hoedemaeker ◽  
Kimberley R. Jordan ◽  
Angelique C.J. van der Made ◽  
...  
Keyword(s):  
Bladder Cancer ◽  
Radical Cystectomy ◽  
Molecular Subtypes ◽  
Tumor Resection ◽  
Progression Free Survival ◽  
Invasive Bladder Cancer ◽  
Bacillus Calmette Guerin ◽  
Clinical Tool ◽  
Muscle Invasive Bladder Cancer ◽  
Muscle Invasive

SummaryThe recommended treatment for patients with high-risk non-muscle invasive bladder cancer (HR-NMIBC) is tumor resection followed by adjuvant Bacillus Calmette-Guérin (BCG) bladder instillations. However, only 50% of patients benefit from this therapy. In case of progression to advanced disease, patients must undergo a radical cystectomy with significant morbidity and have a poor clinical outcome. Identifying tumors least likely to respond to BCG can translate into alternative treatments, such as early radical cystectomy or novel targeted or immunotherapies. Here we present molecular profiling of 132 BCG-naive, HR-NMIBC patients, and 44 post-BCG recurrences (34 matched), which uncovered three distinct BCG Response Subtypes (BRS1-3). Patients with BRS3 tumors have reduced recurrence and progression-free survival compared to BRS1-2. BRS3 tumors expressed high EMT-basal markers and had an immunosuppresive profile, which was confirmed with spatial proteomics. Tumors which recurred post-BCG were enriched for BRS3. BRS stratification was validated in a second cohort of 151 BCG-naive HR-NMIBC patients and the molecular subtypes outperformed guideline recommended risk stratification based on clinicopathological variables. For clinical application, we validated that a commercially approved assay was able to accurately predict BRS3 tumors (AUROC 0.86). Our findings provide a potential clinical tool for improved identification of HR-NMIBC patients at the highest risk of progression, which can be used to select patients for early radical cystectomy or novel subtype-directed therapies.One Sentence SummaryMolecular subtypes are predictive of response to intravesical Bacillus Calmette-Guérin immunotherapy in non-muscle invasive bladder cancer.

scholarly journals Clinicopathological Criteria Predictive of Recurrence Following Bacillus Calmette-Guérin in Non–Muscle-Invasive Bladder Cancer (Preprint)

2020 ◽  
Author(s):  
Joseph Plasek ◽  
John Weissert ◽  
Tracy Downs ◽  
Kyle Richards ◽  
Kourosh Ravvaz
Keyword(s):  
Bladder Cancer ◽  
High Risk ◽  
Univariate Analysis ◽  
Neutrophil To Lymphocyte Ratio ◽  
Invasive Bladder Cancer ◽  
Bacillus Calmette Guerin ◽  
Muscle Invasive Bladder Cancer ◽  
Lymphocyte Ratio ◽  
Bcg Therapy ◽  
Muscle Invasive

BACKGROUND Bacillus Calmette-Guérin (BCG) is currently the most clinically effective intravesical treatment for non–muscle-invasive bladder cancer (NMIBC), particularly for patients with high-risk NMIBC such as those with carcinoma in-situ (CIS). BCG treatments could be optimized to improve patient safety and conserve supply by predicting BCG efficacy with tumor characteristics or clinicopathological criteria. OBJECTIVE To assess the ability of specific clinicopathological criteria to predict tumor recurrence in patients with NMIBC who received BCG along various treatment timelines. METHODS A total of 1331 patients (Stage Ta, T1, or CIS) who underwent transurethral resection of a bladder tumor (TUR) between 2006 and 2017 were included. Univariate analysis including laboratory tests (e.g. complete blood panels, creatinine levels, Hemoglobin A1c levels) within 180 days post-BCG therapy initiation, medications, and clinical and demographic variables to assess their ability to predict NMIBC recurrence was completed. This was followed by multivariate regression that included the elements of Club Urológico Español de Tratamiento Oncológico (CUETO) and variables that were significant predictors of recurrence in univariate analysis. RESULTS BCG was administered to 183 intermediate- or high-risk patients, and 76 (41.5%) experienced disease recurrence. Abnormal neutrophil-to-lymphocyte ratio measured within 180 days post-induction BCG was a significant predictor (p<0.05) of future cancer recurrence and was a stronger predictor than CUETO or the individual variables included in CUETO via multivariate analysis. CONCLUSIONS Abnormal neutrophil-to-lymphocyte ratio within 180 days following BCG is predictive of recurrence and could be a suggestive for additional or alternative interventions. CLINICALTRIAL N/A

Intravesical rad-IFNα/Syn3 for patients with high-grade, bacillus Calmette-Guérin (BCG) refractory or relapsed non-muscle invasive bladder cancer: A phase II randomized study.

2017 ◽  
Vol 35 (6_suppl) ◽  
pp. 279-279 ◽  
Author(s):  
Stephen A. Boorjian ◽  
Neal D. Shore ◽  
Daniel Canter ◽  
Kenneth Ogan ◽  
Lawrence Ivan Karsh ◽  
...  
Keyword(s):  
Bladder Cancer ◽  
Phase Ii ◽  
Invasive Bladder Cancer ◽  
High Grade ◽  
Recurrence Free Survival ◽  
Bacillus Calmette Guerin ◽  
Efficacy And Safety ◽  
Muscle Invasive Bladder Cancer ◽  
Free Survival ◽  
Muscle Invasive

279 Background: While bacillus Calmette-Guérin (BCG) is the most effective intravesical treatment for reducing recurrence and progression for high-risk non-muscle invasive bladder cancer (NMIBC), many patients are either refractory to treatment or relapse. We assessed the efficacy and safety of rAd-IFNα/Syn 3 (Instiladrin, FKD Finland), a replication deficient recombinant adenovirus gene transfer vector, for patients with high-grade (HG) BCG refractory or relapsed NMIBC. Methods: In this open-label, US multicenter (n=13), parallel-arm Phase II study (NCT01687244), 43 patients with HG BCG refractory or relapsed NMIBC were randomized 1:1 to receive intravesical rAd-IFNα/Syn3 at 1x1011 or 3x1011viral particles/mL. Patients responding at months 3, 6, and 9 were re-treated at months 4, 7, and 10. Most patients (n=21) had a primary tumor classification of carcinoma in situ (CIS); 9 had both CIS and Ta/T1 disease and 10 had Ta/T1 disease alone. The primary endpoint was 12-month HG recurrence-free survival (RFS). All patients receiving at least one dose were included in efficacy and safety analyses. Results: Forty patients received rAd-IFNα/Syn3 (1 x 1011 vp/mL: n=21; 3 x 1011vp/mL: n=19) between November 2012 and April 2015. Fourteen patients (35.0%; 90% CI 22.6%, 49.2%) remained free of HG tumor recurrence 12 months after initial treatment. Comparable 12 month HG RFS was noted between dosage arms, as well as between patients with refractory and relapsed NMIBC. Interestingly, the 12 month HG recurrence-free survival for patients with Ta/T1-only disease was 50% (5/10). rAd-IFNα/Syn3 was well-tolerated, with no Grade 5 adverse events (AEs), one Grade 4 AE (COPD; unrelated to treatment), and no patient discontinuing treatment due to an adverse event. The most frequently reported AEs were micturition urgency (n=16), dysuria and pollakiuria (n=13 each), fatigue (n=9), and nocturia (n=10). Conclusions: rAd-IFNα/Syn3 was well tolerated and demonstrated promising efficacy for patients with HG NMIBC after BCG therapy who are unable or unwilling to undergo radical cystectomy. A phase III trial utilizing this novel agent is ongoing. Clinical trial information: 01687244.

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