Muscle-invasive Bladder Cancer Patients Research Articles

Abstract LB256: New mechanistic insights into cisplatin resistance in muscle-invasive bladder cancer

Abstract The standard of care for eligible patients with muscle-invasive bladder cancer (MIBC) is cisplatin-based neoadjuvant chemotherapy followed by radical cystectomy. However, platinum-based treatments leave up to 70% of MIBC patients with residual disease, and the 5-year survival rate for these individuals is under 30%. Understanding cisplatin resistance mechanisms will improve MIBC treatment by developing more effective therapeutics and precision medicine strategies. We previously identified NPEPPS, an M1 aminopeptidase, as a novel and potentially targetable mediator of platinum drug response. Recently, we have established that NPEPPS controls platinum drug import through its interactions with volume regulated anion channels (VRACs), which have been shown to import cisplatin to cells directly. We have shown that NPEPPS interacts with key VRAC subunit SWELL1 at the cell membrane and that intact SWELL1 is required for NPEPPS-mediated platinum resistance. We further discovered that NPEPPS cannot bind SWELL1 when its enzymatic aminopeptidase function is disrupted genetically or pharmacologically. In vivo studies showed that catalytic-dead NPEPPS-mutant MIBC xenografts were sensitive to cisplatin treatment compared to NPEPPS-wildtype xenografts. Patient cohort data analysis supported the model that the expression of NPEPPS and its relative expression with VRAC proteins are associated with overall survival in treatment-resistant MIBC patients. These findings shed light on how bladder cancer cells resist chemotherapy by disrupting the transport of drugs into cells and suggest new ways to target NPEPPS to enhance the effectiveness of platinum-based therapeutics in treating bladder cancer. Citation Format: Lily Elizabeth R. Feldman, Saswat Mohapatra, Robert Jones, Charlene Tilton, Tahlita Zuiverloon, James Costello, Dan Theodorescu. New mechanistic insights into cisplatin resistance in muscle-invasive bladder cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr LB256.

Identification of a cisplatin resistant-based prognostic immune related gene signature in MIBC

Cisplatin resistance plays a significant role in the dismal prognosis and progression of muscle-invasive bladder cancer (MIBC). However, the strategies to predict prognosis and cisplatin resistance are inefficient, and it remains unclear whether cisplatin resistance is associated with tumor immunity. In this study, we integrated the transcriptional data from cisplatin-resistant cell lines and a TCGA-MIBC cohort to establish cisplatin-resistance-related cluster classification and a cisplatin-resistance-related gene risk score (CRRGRS). Kaplan–Meier survival curves showed that compared with those in low CRRGRS group, MIBC patients belonging to high CRRGRS group had worse prognosis in TCGA-MIBC cohort and external GEO cohorts. Meanwhile, CRRGRS was able to help forecast chemotherapy and immunotherapy response of MIBC patients in the TGCA cohort and IMvigor210 cohort. Moreover, compared with the low CRRGRS group, the high CRRGS group possessed a relatively immunosuppressive “cold tumor” phenotype with a higher tumor immune dysfunction and exclusion (TIDE) score, ESTIMATE score, stromal score and immune score and a lower immunophenoscore (IPS) score. The upregulated expression levels of immune checkpoint genes, including PD-1, PD-L1 and CTLA4, in the high CRRGRS group also further indicated that a relative immunosuppressive tumor microenvironment may exist in MIBC patients belonging to high CRRGRS group. In addition, we integrated CRRGRS and clinical characteristics with prognostic value to develop a nomogram, which could help forecast overall survival of MIBC patients. Furthermore, DIAPH3 was identified as a regulator of proliferation and cisplatin resistance in MIBC. The expression of DIAPH3 was increased in cisplatin-resistant cell lines and chemotherapy-unsensitive people. Further mechanism exploration revealed that DIAPH3 facilitated tumor proliferation and cisplatin resistance by regulating the NF-kB and epithelial-mesenchymal transition (EMT) pathways. In conclusion, the comprehensive investigations of CRRGRS increased the understanding of cisplatin resistance and provided promising insights to restrain tumor growth and overcome chemoresistance by targeting DIAPH3.

Abstract 7641: Prognostic impact of functional germline mutations in muscle-invasive bladder cancer identified by neural network analysis

Abstract Background: An accurate prognostic algorithm based on germline whole exome sequencing (WES) would complement tumor omics as a non-invasive source of biomarkers for guiding cancer patient therapy. In a previous study, we used WES and RNA-seq data from muscle-invasive bladder cancer (MIBC) and normal host cells to train a survival model, wherein we discovered that mutated germline genes accounted for 90% of feature importance. We have since defined a larger cohort to identify key germline biomarkers of overall survival (OS) that may be scalable for application in the clinic. Methods: 169 patients from The Cancer Genome Atlas (TCGA) with MIBC stages T2-T4 that underwent radical cystectomy (RC) w/o neoadjuvant treatment were eligible. OS at 4 years was the primary clinical endpoint as it is associated with death due to metastatic tumor recurrence. Patients were dichotomized to control survivors who were alive at 4+ years, and cases who died within 4 years but no less than 4 months after RC. 49 qualifying survivors were propensity matched against 49 dead patients by stage, adjuvant treatment, gender, race, and age. The remaining 71 dead patients served as a holdout. Only high (e.g. frameshift) and moderate (e.g. indel) impact germline variants were included. Mutations were weighted for allele frequency (penalize common) and genotype (reward homozygous) before grouping at the gene level. A panel of the 21 most differential genes in stratified patients were selected for neural network training using AIQC. The model forced protective/pathogenic genes to interact and produced individual survival probabilities. Gene importance was determined via permutation. Results: OS was accurately predicted for 98.2% of patients: 1 FN, 2 FP, 37 TN, 119 TP. The top 3 permuted genes (and related pathways) were: SORL1 (Aβ), KIF27 (hedgehog), CUL7 (p53). The most differential gene was CUL7: 31% of survivors mutated vs 2% of dead. Conclusion: Neural network analysis identified the promise of germline genetics as an accurate predictor of survival and tumor recurrence in MIBC patients. Upon validation in an external cohort, these biomarkers could be used to inform adjuvant therapy and complement molecular residual disease alongside circulating tumor (ct)-DNA. Citation Format: Guru P. Sonpavde, Amin H. Nassar, Arvind Ravi, Layne Sadler. Prognostic impact of functional germline mutations in muscle-invasive bladder cancer identified by neural network 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 7641.

Abstract 6991: Transcriptomic profiling of human and mouse models highlights YAP pathway hyperactivation as the underlying mechanism of the biological and clinical aggressiveness of Numb-defective bladder cancer

Abstract In this study, we identify a previously uncharacterized role for the tumor suppressor, Numb, in bladder tumorigenesis, defining new predictive biomarkers and potentially actionable targets for the treatment of non-muscle-invasive bladder cancers. We conducted a comprehensive IHC analysis of Numb expression leveraging two retrospective longitudinal cohorts comprising 356 post-cystectomy muscle-invasive bladder cancer (MIBC) patients and 77 high-grade non-muscle-invasive (NMIBC) patients with transurethral resections. We found that Numb expression is frequently deregulated in the tumor compared to the adjacent normal urothelium, with NumbLow status correlating with poorer prognosis both in MIBC, associated with advanced stage at diagnosis, vascular invasion, and worse overall survival, and in NMIBC, where a NumbLow status associates with a higher rate of progression to life-threatening MIBC disease. In a transgenic mouse model with targeted deletion of the Numb gene in the basal layer of the bladder mucosa, we observed that loss of Numb per se is sufficient to drive malignant transformation of the normal urothelium and accelerates tumorigenesis in carcinogen-induced models. Integrative transcriptomic analysis of human and mouse Numb-deficient BC models revealed consistent dysregulation of the YAP1/TAZ1 inhibitory Hippo pathway, identifying YAP1 transcriptional hyperactivation as the most distinguishing trait downstream of NUMB loss. Through genetic and pharmacological functional inhibition studies in relevant mouse and human BC cell line-based models, we provide proof-of-evidence that interfering with YAP pathway activation at multiple upstream levels of the Hippo cascade reverts the aggressive Numb loss-associated tumor phenotypes, in particular growth and invasive/migratory potential, thereby highlighting the YAP pathway as a potential therapeutical vulnerability for the treatment of clinically aggressive Numb-deficient human BC. We also identified a gene signature of early BC depending on loss of Numb that we extensively validated for its potential as a predictor of NMIBC to MIBC progression, arguing for its clinical application as a biomarker for NIMBC patient stratification for targeted anti-YAP signaling treatment to prevent MIBC transition. In summary, our study identifies a previously uncharacterized role of Numb in bladder cancer progression, highlighting its potential as a predictive biomarker of NMIBC to MIBC transition and response to targeted therapies, thereby advancing a framework for precision oncology for NMIBC patients at high risk of progression to life-threatening MIBC disease. Citation Format: Francesco Antonio Tucci, Rosa Pennisi, Maria Grazia Filippone, Roberta Bonfanti, Francesco Romeo, Damiano Rigiracciolo, Stefano Freddi, Francesca Sanguedolce, Giuseppe Renne, Giancarlo Pruneri, Gianluca Vago, Daniela Tosoni, Salvatore Pece. Transcriptomic profiling of human and mouse models highlights YAP pathway hyperactivation as the underlying mechanism of the biological and clinical aggressiveness of Numb-defective 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 6991.

Abstract 5196: Stepwise molecular mechanisms involved in chemoresistance in bladder cancer cells

Abstract Bladder cancer (BC) is one of the most prevalent genitourinary tumors worldwide, with approximately 573,000 new cases reported. Approximately 80% of BC patients are diagnosed with non-muscle-invasive bladder cancer (NMIBC) with a high five-year survival rate, while the remaining 20% are diagnosed with muscle-invasive bladder cancer (MIBC). Although the surgical operation has been utilized to BC, patients with NMIBC frequently experience disease recurrence, of which about 20% progress to MIBC. However, the response rate of MIBC patients to gemcitabine treatment has been shown to be limited to less than 40% efficacy, and only a small number of patients have potential benefits.Chemotherapy resistance is an obstacle to cancer therapy and is considered a major cause of recurrence. Thus, understanding the mechanisms of chemoresistance is critical to improving the prognosis of patients. Here, we have established a stepwise gemcitabine-resistant T24 bladder cancer cell line to understand the molecular mechanisms of chemoresistance within cancer cells. The characteristics of the stepwise chemoresistance cell line were divided into 4 phases (parental, early, intermediate, and late phases). These four phase cells showed increasingly aggressive phenotypes in vitro and in vivo experiments with increasing phases and revealed the molecular properties of the biological process from parent cells to phased gemcitabine-resistant cell line (GRC). Taken together, through the analysis of gene expression profile data, we have characterized gene set of each phase indicating the response to anticancer drug treatment. Specifically, we identified a multigene signature (23-genes including GATA3, APOBEC3G, NT5E, MYC, STC1, FOXD1, SMAD9) and developed a chemoresistance score consisting of that could predict eventual responsiveness to gemcitabine treatment. We suggest that our findings improve prognosis by predicting to acquiring of chemotherapy resistance in bladder cancer patients. Citation Format: Jae-Jun Kim, Gi-Eun Yang, Tae Hwan Shin, Sun-Hee Leem. Stepwise molecular mechanisms involved in chemoresistance in bladder cancer cells [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 5196.

Abstract 6694: Gut microbial drivers of response to bladder-sparing therapy in human muscle-invasive bladder cancer enhance immunotherapy efficacy and limit immunosuppression following fecal microbiome transplantation in vivo

Abstract BACKGROUND: Radiation therapy (RT) is a bladder-sparing option for Muscle-Invasive Bladder Cancer (MIBC), yet encounters a 30% non-response rate, with half of the patients succumbing to metastasis. Preclinical models demonstrate enhanced antitumor responses with RT combined with PD-1/PD-L1 blockade but give limited insight into the determinants of success for such combination therapies (CT). The gut microbiome, pivotal in conditioning local and peripheral immunity, influences PD-1-based immunotherapy efficacy in various cancers. Immune profiling indicates heightened systemic and antitumor immunity in responders with a favorable gut microbiome, enriched in Akkermansia muciniphila, Bifidobacterium, and Faecalibacterium. Oral gavage of immunogenic bacteria further enhances combined RT and anti-PD-L1 therapy. We thus aim to 1) elucidate the role of patients’ microbiome in shaping anti-tumor immune responses to CT, and 2) use its composition as a predictive factor for CT success. METHODS: We performed shotgun metagenomics on microbial DNA from fecal materials of MIBC RT responders (R, n=26) and non-responders (NR, n=11). Fecal homogenates from donors were gavaged into germ-free (GF) mice. Three weeks post-gavage, MB49 tumor cells were subcutaneously delivered to mice, randomized into four groups: control, anti-PD-L1, RT, and RT + anti-PD-L1. Tumors were harvested seven days post-treatment for single-cell RNA-seq and TCR sequencing (10X Genomics), while stool samples were collected weekly for 16S sequencing. RESULTS: Significant gut microbial disparities were observed between R and NR MIBC patients, with particular enrichment in known promoters of anti-PD-L1 response, such as Phocaeicola dorei in R. Transplantation of R microbiome into GF mice resulted in significant increases in predicted survival, tumor growth delay, and counts of effector CD4+ T cell infiltration in the RT+PD-L1 arm. Conversely, NR microbiome transplantation correlated with increased neutrophil and Treg infiltration, abrogating the survival tumor growth delay benefits of the combination arm. Spatial tissue analyses revealed higher neutrophil densities around CD8+ T cells in all NR arms. Single-cell RNA-seq of tumor-infiltrating immune cells unveiled skewed CD4 and CD8 polarization between R and NR in vivo batches. SIGNIFICANCE: To our knowledge, this is the first study to use FMT as a modulator of response in the context of radiation therapy combinations in MIBC. Our results highlight that the gut microbiome alone may condition a favorable immune terrain for combinatorial therapies involving radiation. This offers strong predictive value for personalized therapeutic approaches in selecting patients who will benefit the most from bladder-sparing therapies. Citation Format: Eva Michaud, Sabina Fehric, Cynthia Faubert, Bertrand Routy, Irah King, José Joao Mansure, Wassim Kassouf. Gut microbial drivers of response to bladder-sparing therapy in human muscle-invasive bladder cancer enhance immunotherapy efficacy and limit immunosuppression following fecal microbiome transplantation in vivo [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 6694.

Clinical practice guideline on bladder cancer (Part III)

AbstractBladder cancer (BC) has become a significantly prevalent disease in China, with an incidence rate of 5.80 per 100 000 in 2015, ranking it as the thirteenth most common type of cancer within the nation. This illness presents a serious public health concern, highlighting the imperative need to unify the standards for diagnosis and treatment to improve patient outcomes. The section of the clinical practice guideline in question is dedicated to addressing muscle‐invasive bladder cancer (MIBC) and metastatic BC. The primary treatment strategies for MIBC are well‐defined: preoperative (neoadjuvant) chemotherapy combined with radical cystectomy stands as the conventional treatment protocol. For patients with locally advanced MIBC, integrating systemic and local therapies is advocated to enhance treatment effectiveness. In cases of metastatic BC, the focus shifts to systemic treatment supplemented by supportive care measures. The guideline also succinctly presents the pros and cons of various urinary diversion surgeries, which are critical considerations following radical cystectomy. It provides an in‐depth exploration of the treatment modalities for metastatic urothelial carcinoma of the bladder. Additionally, this part delves into the integrated approach to treatment and the use of radiotherapy in bladder preservation for localized disease. Moreover, it offers a concise overview of the classification, diagnosis, and therapeutic approaches for nonurothelial carcinoma of the bladder. Lastly, this part emphasizes the importance of recommended posttreatment follow‐up for MIBC patients to ensure comprehensive and ongoing care management.

Disitamab Vedotin Alone or in Combination With Immune Checkpoint Inhibitors in Bladder-Sparing Treatment of Muscle-Invasive Bladder Cancer: A Real-World Study

PurposeTo evaluate the efficacy and safety of a novel humanized anti-HER2 antibody, RC48-ADC (Disitamab vedotin, DV), the combination of RC48-ADC with PD-1 inhibitors was used to treat muscle-invasive bladder cancer (MIBC). This combination therapy has potential applications in both bladder preservation and neoadjuvant therapy for MIBC. MethodsPatients with MIBC underwent transurethral resection of bladder tumors followed by RC48-ADC alone or in combination with PD-1 inhibitors. Radiological and endoscopic evaluations were conducted 3 months later. The primary endpoint was objective response rate (ORR), with secondary endpoints including complete response rate (CR), partial response rate (PR), and bladder preservation rate. Treatment safety was assessed according to RECIST v1.1 criteria. ResultsEleven patients were enrolled, with a median follow-up of 19.0 months. Nine patients achieved objective response, including 6 CR and 3 PR cases. The pathological ORR was 81.8%. Eight patients continued combined treatment after 3 months, maintaining a 72.7% bladder preservation rate at 16 months. One elderly patient progressed from ypT2N0M0 to ypT3N0M0 and underwent radical cystectomy but had no recurrence or metastasis 12 months postoperation. All patients reported varying degrees of treatment-related adverse reactions, which were largely manageable. ConclusionThe combination of RC48-ADC and PD-1 inhibitors proves to be a viable and safe option for bladder-sparing therapy, particularly for T2-stage MIBC patients who are ineligible for surgery and chemotherapy. This approach offers a promising new direction for bladder preservation or neoadjuvant therapy in MIBC patients.

Integration of CD4+ T cells and molecular subtype predicts benefit from PD-L1 blockade in muscle-invasive bladder cancer.

Muscle-invasive bladder cancer (MIBC) is a disease characterized by molecular and clinical heterogeneity, posing challenges in selecting the most appropriate treatment in clinical settings. Considering the significant role of CD4+ T cells, there is an emerging need to integrate CD4+ T cells with molecular subtypes to refine classification. We conducted a comprehensive study involving 895 MIBC patients from four independent cohorts. The Zhongshan Hospital (ZSHS) and The Cancer Genome Atlas (TCGA) cohorts were included to investigate chemotherapeutic response. The IMvigor210 cohort was included to assess the immunotherapeutic response. NCT03179943 was used to evaluate the clinical response to a combination of immune checkpoint blockade (ICB) and chemotherapy. Additionally, we evaluated genomic characteristics and the immune microenvironment to gain deeper insights into the distinctive features of each subtype. We unveiled four immune-molecular subtypes, each exhibiting distinct clinical outcomes and molecular characteristics. These subtypes include luminal CD4+ Thigh , which demonstrated benefits from both immunotherapy and chemotherapy; luminal CD4+ Tlow , characterized by the highest level of fibroblast growth factor receptor 3 (FGFR3) mutation, thus indicating potential responsiveness to FGFR inhibitors; basal CD4+ Thigh , which could benefit from a combination of ICB and chemotherapy; and basal CD4+ Tlow , characterized by an immune suppression microenvironment and likely to benefit from transforming growth factor-β (TGF-β) inhibition. This immune-molecular classification offers new possibilities for optimizing therapeutic interventions in MIBC.

Effect of Clinical Complete Remission Following Neoadjuvant Pembrolizumab or Chemotherapy in Bladder-Preservation Strategy in Patients with Muscle-Invasive Bladder Cancer Declining Definitive Local Therapy.

This study aimed to evaluate the outcomes and identify the predictive factors of a bladder-preservation approach incorporating maximal transurethral resection of bladder tumor (TURBT) coupled with either pembrolizumab or chemotherapy for patients diagnosed with muscle-invasive bladder cancer (MIBC) who opted against definitive local therapy. We conducted a retrospective analysis on 53 MIBC (cT2-T3N0M0) patients who initially planned for neoadjuvant pembrolizumab or chemotherapy after maximal TURBT but later declined radical cystectomy and radiotherapy. Post-therapy clinical restaging and conservative bladder-preservation measures were employed. Clinical complete remission was defined as negative findings on cystoscopy with biopsy confirming the absence of malignancy if performed, negative urine cytology, and unremarkable cross-sectional imaging (either CT scan or MRI) following neoadjuvant therapy. Twenty-three patients received pembrolizumab, while thirty received chemotherapy. Our findings revealed that twenty-three (43.4%) patients achieved clinical complete response after neoadjuvant therapy. The complete remission rate was marginally higher in pembrolizumab group in comparison to chemotherapy group (52.1% vs. 36.7%, p = 0.26). After a median follow-up of 37.6 months, patients in the pembrolizumab group demonstrated a longer PFS (median, not reached vs. 20.2 months, p = 0.078) and OS (median, not reached vs. 26.8 months, p = 0.027) relative to those in chemotherapy group. Those achieving clinical complete remission post-neoadjuvant therapy also exhibited prolonged PFS (median, not reached vs. 10.2 months, p < 0.001) and OS (median, not reached vs. 24.4 months, p = 0.004). In the multivariate analysis, clinical complete remission subsequent to neoadjuvant therapy was independently associated with superior PFS and OS. In conclusion, bladder preservation emerges as a viable therapeutic strategy for a carefully selected cohort of MIBC patients without definitive local therapy, especially those achieving clinical complete remission following neoadjuvant treatment. For patients unfit for chemotherapy, pembrolizumab offers a promising alternative treatment option.

A CT-based deep learning model predicts overall survival in patients with muscle invasive bladder cancer after radical cystectomy: a multicenter retrospective cohort study.

Muscle invasive bladder cancer (MIBC) has a poor prognosis even after radical cystectomy (RC). Postoperative survival stratification based on radiomics and deep learning algorithms may be useful for treatment decision-making and follow-up management. This study was aimed to develop and validate a deep learning (DL) model based on preoperative CT for predicting post-cystectomy overall survival in patients with MIBC. MIBC patients who underwent RC were retrospectively included from four centers, and divided into the training, internal validation and external validation sets. A deep learning model incorporated the convolutional block attention module (CBAM) was built for predicting overall survival using preoperative CT images. We assessed the prognostic accuracy of the DL model and compared it with classic handcrafted radiomics model and clinical model. Then, a deep learning radiomics nomogram (DLRN) was developed by combining clinicopathological factors, radiomics score (Rad-score) and deep learning score (DL-score). Model performance was assessed by C-index, KM curve, and time-dependent ROC curve. A total of 405 patients with MIBC were included in this study. The DL-score achieved a much higher C-index than Rad-score and clinical model (0.690 vs. 0.652 vs. 0.618 in the internal validation set, and 0.658 vs. 0.601 vs. 0.610 in the external validation set). After adjusting for clinicopathologic variables, the DL-score was identified as a significantly independent risk factor for OS by the multivariate Cox regression analysis in all sets (all P<0.01). The DLRN further improved the performance, with a C-index of 0.713 (95%CI: 0.627-0.798) in the internal validation set and 0.685 (95%CI: 0.586-0.765) in external validation set, respectively. A DL model based on preoperative CT can predict survival outcome of patients with MIBC, which may help in risk stratification and guide treatment decision-making and follow-up management.

Challenges and technical aspects in the management of muscle invasive bladder cancer as retrograde radical cystectomy with ileal conduit.

To evaluate long-term outcomes in patients homogenously treated with radical cystectomy and ileal conduit for muscle invasive bladder cancer. The retrospective study was conducted at the Urology Department of Pakistan Kidney and Liver Institute and Research Centre, Lahore, Pakistan, and comprised data from December 25, 2017, to January 16, 2023, related to patients who underwent radical cystectomy with ileal conduit with or without neo-adjuvant and adjuvant radiation, chemotherapy, or immunotherapy for papillary urothelial carcinom of the bladder. Clinical trajectory, histopathological characteristics and long-term clinical outcomes were noted. Data was analysed using SPSS 20. In our study of 40 patients with muscle invasive bladder cancer, males predominated (32, 80%), with a median age of 57.4 years (IQR: 29-80). Diagnosis was early in 5 (12.5%) patients with varying haematuria durations, while 34 (85%) patients had a smoking history. Comorbidities included hypertension in 17 (42.5%) patients, diabetes in 1 (2.5%) patient, both hypertension and diabetes in 9 (22.5%) patients and a combination of hypertension, diabetes, and ischaemic heart disease in 3 (7.5%) patients. Transurethral resection was performed once in 13 (32.5%) patients and multiple times in 27 (67.5%) patients. Additionally, 5 (12.5%) patients received immunotherapy, 11 (27.5%) patients underwent non-adjuvant radiation, and 14 (35%) patients received non-adjuvant chemotherapy. Papillary urothelial carcinoma was the predominant histological subtype among 37 (92.5%) patients. Patients receiving chemotherapy had significantly better overall survival (p=0.02). No significant differences were noted in recurrence or survival by therapy modality (p>0.05). These findings highlight the significance of early diagnosis, tailored treatments, and comorbidity management in muscle invasive bladder cancer patients. Age stratification revealed significant survival differences across groups (χ²=10.923, df=3, p= 0.012). Analysis by complications did not show age-related survival variations (χ² =3.978, df = 3, p=0.264). Achieving excellent long-term survival in MIBC patients requires a multidisciplinary approach, emphasizing early diagnosis, tailored treatment, and adherence to guidelines and protocols.

Neutralizing GDF-15 in muscle-invasive bladder cancer (MIBC): A neoadjuvant immunotherapy trial of visugromab (CTL-002) in combination with the anti-PD1 antibody nivolumab (GDFather-Neo).

TPS712 Background: Neoadjuvant chemotherapy (NACT) is a well-established treatment modality in MIBC but suffers from limited activity and significant toxicity. Neoadjuvant immunotherapy (I/O) demonstrated clinical safety and efficacy in various solid tumors including MIBC, with potentially less toxicity. Results from previous studies of single-agent I/O indicated a proportion of pathologic complete responses (ypT0N0) similar to that reported with NACT. Therefore, improving ypT0N0 responses remains a major task for treatment of MIBC. Increasing evidence emerged that Growth and Differentiation Factor 15 (GDF-15) plays a critical local immunosuppressive role. Apart from blocking immune-cell entry into tissues GDF-15 also has major impact on the formation of the immune synapse. Many tumors overexpress GDF-15 and have hijacked this mechanism to block I/O therapy success. Various translational research efforts indicated that GDF-15 may play a significant role for immunosuppression and T-cell exclusion in urothelial carcinoma (UC). Visugromab (CTL-002) is a GDF-15 neutralizing IgG4 monoclonal antibody that demonstrated in Phase 1 a favorable safety profile and promising clinical activity with durable and deep responses in PD-1/PD-L1 relapsed/refractory metastatic solid tumors in combination with the anti-PD1 antibody Nivolumab (Nivo)*. The Neo-GDFather trial is intended to investigate the combination of Visugromab with Nivo vs. Nivo monotherapy as neoadjuvant therapy for MIBC in patients (pts) who are ineligible for or elect not to undergo NACT. Primary endpoints are the complete pathologic response rate and radiologic response. Methods: Multi-center, parallel-cohorts and single-blinded Phase 2 study of neoadjuvant therapy in pts planned for radical cystectomy (RC). A total number of 30 subjects with stage T2-T4N0M0 MIBC will be enrolled and assigned 1:1 to receive either Nivo + Visugromab or Nivo + Placebo after stratification for CPS PD-L1 expression and cT-stage. Other inclusion criteria comprise an ECOG performance status 0-1 and a pure/predominant UC histology. No statistical assumptions were undertaken at this stage.Treatment consists of three 4-week cycles [i.v., Q4Wk], and RC is planned 4-8 weeks after last dose of study drug. After RC, pts will follow standard recommendations of EAU guidelines. Primary endpoints are the proportion of ypT0N0 response and radiologic response rate. Secondary endpoints comprise additional efficacy parameter, surgical and medical safety, PK and PD assessments. Translational research includes evaluation of immunologic parameters in the tumor, other immune-correlates and molecular profiles, as well as evaluation of treatment-emergent cytokine and chemokine profiles in peripheral blood. * Melero et al., #2501 ASCO Annual Meeting 2023 Oral Abstract Session. Clinical trial information: Not yet available.

Predictive roles of NETs and IgG in neoadjuvant chemotherapy for muscle-invasive bladder cancer.

659 Background: Cisplatin-based chemotherapy is the recommended therapy for muscle-invasive bladder cancer (MIBC), in the neoadjuvant setting. However, the efficacy of MIBC for chemotherapy is only about 40%. Therefore, predictors of therapy response are urgently needed. Neutrophils form neutrophil extracellular traps (NETs), a network structure, and growing evidence indicated that it could be a prognostic and predictive marker in cancer. Besides, NETs and IgG could reflect the immune response, even may induce immune tolerance. In MIBC, the predictive role of NETs or IgG in chemotherapy resistance is unclear. Methods: This study included 54 patients with MIBC undergoing neoadjuvant chemotherapy. Immunohistochemical staining with NETs was performed on tumor primary lesions before chemotherapy, and the staining intensity was scored. Serum IgG levels in the pre-treatment baseline and 1 month after chemotherapy were also measured for these patients. Results: Citrullinated histone H3 (H3Cit) as a hallmark of NETs, was an independent predictor of chemotherapy resistance as determined by the multivariate logistic regression analyses [OR=5.94, 95% CI 1.20–45.50, P=0.045]. Additionally, in patients with favorable chemotherapy response, serum IgG levels significantly decreased after 1 month of treatment (P=0.0018), while in those with poor response, there was no significant change. Conclusions: The baseline levels of NETs and the change of IgG after 1-month treatment demonstrated predictive capabilities during neoadjuvant chemotherapy, possibly reflecting the immune status. MIBC patients with high NETs and IgG levels were resistant to neoadjuvant chemotherapy, providing new insights into the treatment of MIBC. However, these results require further validation through larger sample studies. Further validation of our findings could provide a theoretical basis regarding NETs inhibitors or IgG antibodies combined with chemotherapy strategy.

Effects of perioperative chemotherapy on prognosis in muscle invasive bladder cancer treated with radical cystectomy.

592 Background: We aimed to evaluate the effect of the number of neoadjuvant chemotherapy (NAC) cycles and the adding adjuvant chemotherapy (AC) after NAC in muscle-invasive bladder cancer (MIBC) on overall survival (OS). Methods: This multicenter retrospective study included 2674 patients with MIBC who underwent radical cystectomy (RC) from 36 institutions within the Japanese Urological Oncology Group. Among them, we selected 1687 patients with cT2-4NxM0 who were treated with RC alone or RC plus perioperative chemotherapy. We compared the effect of the number of NAC cycles (2 vs. ≥3 cycles) and the addition of AC on OS. Cox proportional-hazards regression was used to assess the association of treatment received with OS. Results: Of 1687 patients, 946 were treated with NAC with a median of 3 cycles. Use of NAC significantly prolonged OS compared to the RC alone. The pathological complete response rate was not significantly different between the 2 cycles (22.9%) and ≥3 cycles (27.5%, P = 0.112) groups. OS was not significantly different between the groups (P = 0.559). Multivariable Cox regression analysis showed that pathological high-risk (ypT2–4, pT3–4, or pN+) or cisplatin ineligibility were significantly associated with poor OS, but not the number of NAC cycles (P = 0.238). We identified 942 pathologically high-risk patients after RC who were eligible for AC. We observed no significant OS improvement with addition of AC after NAC as intensive perioperative chemotherapy. The primary limitation is selection bias from confounding by clinical indication. Conclusions: The impact of 3 or more NAC cycles and the addition of AC on OS in MIBC patients treated with RC may be limited.

Assessing the Impact of Percutaneous Nephrostomy Presence on Neoadjuvant Treatment Quality in Patients With Muscle Invasive Bladder Cancer

IntroductionSymptomatic hydronephrosis associated with muscle invasive bladder cancer (MIBC) necessitates percutaneous nephrostomy (PCN) insertion before neoadjuvant chemotherapy (NAC). This study assesses the impact of PCN presence on standard intended NAC quality, its related complications and outcome after radical cystectomy (RC). Materials and MethodsThe study comprises a retrospective, multicenter cohort of 193 consecutive RCs performed between 2016 and 2019. Eighty (42%) of these patients received NAC and were divided in 2 comparison groups by presence (n = 26; 33%) or absence (n = 54; 67%) of PCN. Endpoints included completion of adequate NAC treatment (cisplatin-based chemotherapy for at least 4 courses), complications during NAC, post-RC complications and hospital stay. ResultsOverall, patients with PCN (45/193; 23%) featured a higher referral rate to NAC (58% vs. 36%, P = .01), worse glomerular filtration rates (P < .001) and more adverse events (P = .04), in comparison to non-PCN patients. In the NAC cohort, PCN patients had less adequate treatment rates (54% vs. 85%, P = .005), and more infections (35% vs, 7%; P = .008) and hospitalizations (58% vs. 13%; P < .001) during chemotherapy. Post-RC outcome was similar for both comparison groups. PCN was an independent risk factor for inadequate NAC (OR = 3.9, P = .04), and infections (OR = 11.3, P = .01) and hospitalizations (OR = 7.5, P = .004) during NAC. ConclusionsPCN in MIBC patients is a significant risk factor for inadequate NAC and adverse events during treatment. This finding may quire the rationale of NAC, potentially leading to consideration of NAC avoidance and upfront RC in PCN patients. Further survival studies with long follow-up are needed for elucidating this issue.

Comparative survival analysis of bladder preservation therapy versus radical cystectomy in muscle-invasive bladder cancer.

Bladder preservation therapy is an alternative to radical cystectomy in patients with muscle-invasive bladder cancer (MIBC). The purpose of this study is to compare survival outcomes between bladder preservation therapy and radical cystectomy in MIBC patients using an Asian nationwide cancer registry database. From the Taiwan Cancer Registry database and the Taiwan National Health Insurance Research Database, we identified bladder cancer patients from 2008 to 2018. The patients with urothelial carcinoma and clinical stage T2-T4aN0-1 M0 were included. Propensity score matching by age, gender, clinical stage, cT classification, and Charlson Comorbidity Index score was used between those receiving bladder preservation therapy or radical cystectomy. Overall survival (OS), cancer-specific survival (CSS), and disease-free survival (DFS) were compared using the Kaplan-Meier method. Multivariate Cox regression models were used to determine the predictive factors of OS, CSS, and DFS. Following the propensity score matching, 393 MIBC patients were analyzed, 131 (33.3%) receiving bladder preservation therapy and 262 (66.7%) receiving radical cystectomy. After 5 years of the follow-up period the overall duration was with a median of 15.6 months. The treatment groups did not differ significantly in OS, CSS, and DFS (p = 0.2681, 0.7208, and 0.3616, respectively). In multivariable Cox regression models, bladder preservation therapy remained non-inferior to radical cystectomy in OS (adjusted hazard ratio [aHR] 1.08; 95% confidence interval [CI], 0.77-1.50; p = 0.6689), CSS (aHR, 1.06; 95% CI, 0.72-1.57; p = 0.7728), and DFS (aHR, 0.76; 95% CI, 0.46-1.27; p = 0.2929). Additionally, among patients ≥80 years, the use of bladder preservation therapy compared with radical cystectomy resulted in an equivalent OS, CSS and DSS. In Asian populations, bladder preservation therapy yielded similar survival outcomes as radical cystectomy in MIBC patients. Based on the results, it is evident that a multidisciplinary approach and shared decision-making are recommended for bladder cancer treatment.

Comparative Outcomes of Radical Cystectomy in Muscle-Invasive Bladder Cancer: A Systematic Review and Meta-Analysis.

Muscle-invasive bladder cancerposes a significant clinical challenge that necessitates effective therapeutic interventions. Radical cystectomy is a primary treatment option, but a comprehensive understanding of its outcomes is crucial for informed clinical decision-making.This systematic review and meta-analysis aimed to investigate and summarize the outcomes associated with radical cystectomy as a primary treatment for muscle-invasive bladder cancer with a focus on survival rates, complications, and quality of life.A systematic search across databases-PubMed, Google Scholar, and others-covered studies from 2017 onwards. Included were studies reporting survival rates, complications, and quality of life post-radical cystectomy in muscle-invasive bladder cancer patients, including randomized controlled trials, cohort, and observational studies. Multidimensional analysis revealed promising findings regarding the efficacy of radical cystectomy in muscle-invasive bladder cancer. Survival outcomes, including overall survival and disease-specific mortality, have demonstrated significant improvements, particularly in recent randomized controlled trials and cohort studies. Complications associated with the surgical procedure, such as positive surgical margins and lymph node yields, were generally acceptable. Quality of life outcomes post-radical cystectomy exhibited positive trends, although variations were noted in the emotional and social domains. This review underscores radical cystectomy's role in enhancing overall survival and reducing disease-specific mortality in muscle-invasive bladder cancer. Despite reported complications, recent studies support its acceptable risk profile. Detailed examination of various factors contributes to a comprehensive understanding of the procedure. These findings emphasize the importance of individualized treatment approaches in the management of muscle-invasive bladder cancer, considering both oncological efficacy and perioperative outcomes.Radical cystectomy remains fundamental in urological oncology, with ongoing advancements refining its significance.

Circulating Basophils as a Prognostic Marker for Response to Bacillus Calmette-Guérin

PurposeTo predict recurrence and progression in non–muscle-invasive bladder cancer (NMIBC) patients receiving bacillus Calmette-Guérin (BCG), we evaluated circulating basophils as a biomarker that could be detected from the complete blood count. Patients and MethodsWe use a pooled cohort of patients from the Centre Hospitalier Universitaire de Québec-Université Laval (2016-2020) and the Vancouver General Hospital (2010-2018) where a complete blood count was available before transurethral resection of bladder tumor (TURBT) of a high-grade NMIBC and subsequent BCG. Descriptive statistics described the cohort based on the dichotomous presence or absence of basophils on the complete blood count. Kaplan-Meier estimates and a log-rank test compared recurrence-free survival (RFS) and progression-free survival (PFS), with multivariable cox regression analysis used to estimate proportional hazard ratios. ResultsThe study cohort included 261 patients, with a median follow-up of 31.5 months (interquartile range 18.1-45.0 months). The median age was 74.0 years and 16.8% were female. Circulating basophils were detectable in 49 (18.9%) patients. Both RFS and PFS were significantly lower in patients with detectable basophils. Multivariable analysis demonstrated detectable basophils were an independent predictor of both recurrence (HR = 1.85; 95% confidence interval [CI] 1.20-2.85; P = .01) and progression (HR = 2.29; 95% CI 1.14-4.60; P = .02). ConclusionOur results confirm that baseline levels of circulating basophils are an immunological biomarker to predict recurrence and progression of NMIBC.

Vesical imaging reporting and data system (VI-RADS) could predict the survival of bladder-cancer patients who received radical cystectomy

Vesical Imaging Reporting and Data System (VI-RADS) shows good potential in determining muscle-invasive bladder cancer (MIBC) patients. However, whether VI-RADS could predict the prognosis of radical cystectomy (RC) patients has not been reported. Our purpose is to determine whether VI-RADS contributed to predict oncologic outcomes. In this retrospective study, we analysed the information of bladder cancer patients who admitted to our centre from June 2012 to June 2022. All patients who underwent multiparametric magnetic resonance imaging (mpMRI) and underwent RC were included. VI-RADS scoring was performed by two radiologists blinded to the clinical data. Patients’ clinical features, pathology data, and imaging information were recorded. Kaplan–Meier method was used to estimate patients' overall survival (OS) and progression-free survival (PFS). Log-rank test was used to assess statistical differences. COX regression analysis was used to estimate risk factors. Ultimately, we included 219 patients, with 188 males and 31 females. The median age was 66 (IQR = 61–74.5) years. The VI-RADS scores were as follows: VI-RADS 1, 4 (1.8%); VI-RADS 2, 68 (31.1%); VI-RADS 3, 40 (18.3%); VI-RADS 4, 69 (31.5%); and VI-RADS 5, 38 (17.4%). Patients with VI-RADS ≥ 3 had poorer OS and PFS than those with VI-RADS < 3. The AUC of VI-RADS predicting 3-year OS was 0.804, with sensitivity of 0.824 and negative predictive value of 0.942. Multivariate COX analysis showed that VI-RADS ≥ 3 was risk factors for OS (HR = 3.517, P = 0.003) and PFS (HR = 4.175, P < 0.001). In the MIBC subgroup, patients with VI-RADS ≥ 4 had poorer OS and PFS. In the non-muscle invasive bladder cancer (NMIBC) subgroup, the prognosis of patients with VI-RADS ≥ 3 remained poorer. VI-RADS scores could effectively predict the survival of patients after RC.