Metastatic Bladder Cancer Patients Research Articles

Contemporary survival in metastatic bladder cancer patients: A population-based study.

The overall survival (OS) improvement after the advent of several novel systemic therapies, designed for treatment of metastatic urothelial carcinoma of the urinary bladder (mUCUB), is not conclusively studied in either contemporary UCUB patients and/or non-UCUB patients. Within the Surveillance, Epidemiology, and End Results database, contemporary (2017-2020) and historical (2000-2016) systemic therapy-exposed metastatic UCUB and, subsequently, non-UCUB patients were identified. Separate Kaplan-Meier and multivariable Cox regression (CRM) analyses first addressed OS in mUCUB and, subsequently, in metastatic non-UCUB (mn-UCUB). Of 3443 systemic therapy-exposed patients, 2725 (79%) harbored mUCUB versus 709 (21%) harbored mn-UCUB. Of 2725 mUCUB patients, 582 (21%) were contemporary (2017-2020) versus 2143 (79%) were historical (2000-2016). In mUCUB, median OS was 11 months in contemporary versus 8 months in historical patients (Δ = 3 months; p < .0001). After multivariable CRM, contemporary membership status (2017-2020) independently predicted lower overall mortality (OM; hazard ratio [HR] = 0.68, 95% confidence interval [CI] = 0.60-0.76; p < .001). Of 709 mn-UCUB patients, 167 (24%) were contemporary (2017-2020) and 542 (76%) were historical (2000-2016). In mn-UCUB, median OS was 8 months in contemporary versus 7 months in historical patients (Δ = 1 month; p = .034). After multivariable CRM, contemporary membership status (2017-2020) was associated with HR of 0.81 (95% CI = 0.66-1.01; p = .06). In conclusion, contemporary systemic therapy-exposed metastatic patients exhibited better OS in UCUB. However, the magnitude of survival benefit was threefold higher in mUCUB and approximated the survival benefits recorded in prospective randomized trials of novel systemic therapies.

Abstract A003: Characterization of circulating tumor cells from patients with metastatic bladder cancer

Abstract Assessing the molecular profile of bladder tumors from patients with metastatic disease is crucial for implementing personalized treatment. Current standards are based on highly invasive biopsies. Alternatively, liquid biopsies of tumor cells, proteins, and nucleic acids allows longitudinal profiling in a less invasive manner. Circulating tumor cells (CTCs) isolated from blood are a key analyte of liquid biopsy. In this study, we developed a protein and transcriptomic co-analysis workflow for bladder cancer CTCs utilizing the graphene oxide (GO) microfluidic chip conjugated with antibodies against both EpCAM and EGFR to isolate CTCs from blood of patients with metastatic bladder cancer. Following CTC capture, protein and mRNA were analyzed using immunofluorescent staining and ion-torrent whole transcriptome sequencing. This is the first time that whole transcriptome sequencing was used in a downstream application for the GO microfluidic platform. We found that elevated CTC counts were significantly associated with patient disease status at the time of blood draw and that greater than 2 CTCs per mL were associated with shorter overall survival. Invasive markers, including EGFR, HER-2, CD31, and ADAM15, were detected in subpopulations of CTCs. Targeted whole transcriptome sequencing showed distinct expression profiles from patients with metastatic burden at the time of blood draw. In these patients, we found significant upregulation of several metastasis-related and chemotherapy-resistant genes demonstrating the capability of identifying tumor-related RNA signatures from circulating CTCs using immune-affinity GO chip-based assays. In addition, this workflow highlights the prognostic potential of CTCs in metastatic bladder cancer patients. Citation Format: Zeqi Niu, Molly Kozminski, Kathleen C. Day, Luke Broses, Marian L. Henderson, Sophia Merajver, Aaron Udager, Phillip L. Palmbos, Sunitha Nagrath, Mark L. Day. Characterization of circulating tumor cells from patients with metastatic bladder cancer [abstract]. In: Proceedings of the AACR Special Conference on Bladder Cancer: Transforming the Field; 2024 May 17-20; Charlotte, NC. Philadelphia (PA): AACR; Clin Cancer Res 2024;30(10_Suppl):Abstract nr A003.

Abstract 4632: Lineage plasticity as a determinant of antibody-drug conjugate target expression in urothelial bladder cancer

Abstract Bladder cancers display a wide spectrum of morphologies that frequently co-exist within individual tumors. Several histologic variants, including plasmacytoid, neuroendocrine, and micropapillary subtypes, are associated with an increased bladder cancer recurrence risk and cancer-specific mortality. The molecular basis and therapeutic implications of this phenotypical plasticity remain poorly understood. Enfortumab vedotin (EV), an antibody-drug conjugate targeting Nectin-4, has also emerged as a new standard-of-care for metastatic bladder cancer patients, but the association between lineage plasticity as manifested by morphologic heterogeneity in bladder cancer, Nectin-4 expression and ADC response remains poorly defined. Previous DNA-based molecular profiling studies of histologic variants revealed that CDH1 mutations were the pathognomonic molecular alteration in plasmacytoid urothelial carcinoma, but no recurrent driver mutations have been found to be unique to the aberrant histology regions of other mixed histology subtypes. Thus, to explore the molecular basis for the lineage plasticity of bladder cancers with aberrant histology and to define the association between lineage plasticity manifested as morphologic heterogeneity and the expression of Nectin-4, HER2 and other potential ADC targets, we performed RNA-seq of pure urothelial carcinomas (n=118, not otherwise specified, UC-NOS) and bladder tumors with divergent differentiation or histologic subtypes (n=199). Our cohort included a subset of tumors in which RNA-seq was performed on microdissected UC-NOS and variant histology regions of the same tumor. Tumors with neuroendocrine, sarcomatoid and squamous histology had the lowest Nectin-4 expression, whereas histologic subtypes that retained a luminal transcriptional profile such as micropapillary, plasmacytoid and nested histology had higher levels of Nectin-4 expression. In mixed histology tumors, Nectin-4 and/or HER2 expression was often restricted to only one of the two histologic components. Gene Set Enrichment Analysis noted enrichment of distinct oncogenic pathway gene sets in different histologic variants. Preliminary investigation into the mechanism(s) of Nectin-4 regulation using bladder cancer cell lines and patient-derived organoids (PDOs) has identified targetable pathways which when inhibited revert lineage plasticity and induce Nectin-4 expression. In sum, lineage plasticity manifested as heterogenous histomorphologies was associated with heterogeneous Nectin-4 expression in some but not all histologic variants of bladder cancer. Ongoing studies using PDOs from bladder cancer patients with mixed histology will seek to identify molecular pathways whose inhibition leads to increased expression of Nectin-4 or other ADC targets such as HER2 and thus increased sensitivity of ADCs targeting these cell surface proteins. Citation Format: Jiaqian Luo, Sizhi P. Gao, Fengshen Kuo, Gamze Gokturk Ozcan, Merve Basar, Florestan Koll, Jacob E. Tallman, Syed M. Alam, Carissa E. Chu, Ziyu Chen, Eugene J. Pietzak, Gopakumar Iyer, Jonathan E. Rosenberg, David B. Solit, Hikmat Al-Ahmadie. Lineage plasticity as a determinant of antibody-drug conjugate target expression in urothelial 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 4632.

EIF4A3-mediated biogenesis of circSTX6 promotes bladder cancer metastasis and cisplatin resistance

BackgroundCisplatin (CDDP)-based chemotherapy is a standard first-line treatment for metastatic bladder cancer (BCa) patients, and chemoresistance remains a major challenge in clinical practice. Circular RNAs (circRNAs) have emerged as essential regulators in carcinogenesis and cancer progression. However, the role of circRNAs in mediating CDDP chemosensitivity has yet to be well elucidated in BCa.MethodsCircSTX6 (hsa_circ_0007905) was identified by mining the public circRNA datasets and verified by Sanger sequencing, agarose gel electrophoresis, RNase R treatment and qRT-PCR assays. Then, function experiments were performed to evaluate the effects of circSTX6 on BCa metastasis. Luciferase reporter assay, RNA pull-down, RNA immunoprecipitation (RIP), RNA stability assay, Fluorescence in situ hybridization (FISH) and Immunofluorescence (IF) were conducted to evaluate the interaction among circSTX6, miR-515-3p, PABPC1 and SUZ12. Animal experiments were performed to explore the function of circSTX6 in tumor metastasis and CDDP sensitivity.ResultsWe identified that circSTX6 was significantly upregulated in clinical samples and cells of BCa. Functionally, circSTX6 promoted cell migration and invasion both in vitro and in vivo. Mechanistically, circSTX6 could act as a miR-515-3p sponge and abolish its effect on SUZ12. Moreover, circSTX6 was confirmed to increase the stability of SUZ12 mRNA by interacting with a mRNA stabilizer PABPC1 and subsequently promote the expression of SUZ12. Importantly, silencing of circSTX6 improved the chemosensitivity of CDDP-resistant bladder cancer cells to CDDP. Furthermore, in vivo analysis supported that knockdown of circSTX6 attenuated CDDP resistance in BCa tumors.ConclusionThese studies demonstrate that circSTX6 plays a pivotal role in BCa metastasis and chemoresistance, and has potential to serve as a therapeutic target for treatment of BCa.

Predictive nomograms for risk and prognostic factors in metastatic bladder cancer: a population-based study.

Given the poor prognosis of patients with metastatic bladder cancer (MBC), the development of an effective diagnostic and prognostic model is significant in cancer management and for guidance in clinical practice. We acquired data of 23,180 bladder cancer patients from Surveillance Epidemiology and End Results (SEER) database registered from 2010 to 2019. The optimal cut-off value for patient age and tumor size was determined by x-tile software. Independent risk factors for MBC were identified by univariate and multivariate logistic regression analyses and prognosis factors were identified by univariate and multivariate cox regression analyses, and risk and prognostic nomograms were constructed. The accuracy of the nomograms was verified by receiver operating characteristic (ROC) curves, calibration curves, and its clinical utility was determined by decision curve analysis (DCA) curves and clinical impact curves (CIC). Kaplan-Meier (K-M) survival curves further confirmed the clinical validity of the prognostic model. Through logistic regression analyses, we derived that age, histological type, tumor size, T stage, and N stage were independent risk factors for metastasis in bladder cancer patients. By cox regression analyses, age, chemotherapy, histological type, bone, lung and liver metastases were identified as risk factors influencing prognosis of MBC patients. Area under the curve (AUC) of the risk nomogram was 0.80, the AUC values of 1/2/3 years were 0.74/0.71/0.71 in the training group and 0.81/0.77/0.77 in the validation group. Based on calibration curves, DCA curves, CIC and K-M curves, the nomograms were validated with excellent predictive performance and clinical utility for MBC. The nomograms we constructed have perfect predictive accuracy and clinical practicality for MBC patients, enabling clinicians to provide treatment advice and clinical guidance to patients.

Nonlinear multilevel joint model for individual lesion kinetics and survival to characterize intra-individual heterogeneity in patients with advanced cancer.

In advanced cancer patients, tumor burden is calculated using the sum of the longest diameters (SLD) of the target lesions, a measure that lumps all lesions together and ignores intra-patient heterogeneity. Here, we used a rich dataset of 342 metastatic bladder cancer patients treated with a novel immunotherapy agent to develop a Bayesian multilevel joint model that can quantify heterogeneity in lesion dynamics and measure their impact on survival. Using a nonlinear model of tumor growth inhibition, we estimated that dynamics differed greatly among lesions, and inter-lesion variability accounted for 21% and 28% of the total variance in tumor shrinkage and treatment effect duration, respectively. Next, we investigated the impact of individual lesion dynamics on survival. Lesions located in the liver and in the bladder had twice as much impact on the instantaneous risk of death compared to those located in the lung or the lymph nodes. Finally, we evaluated the utility of individual lesion follow-up for dynamic predictions. Consistent with results at the population level, the individual lesion model outperformed a model relying only on SLD, especially at early landmark times and in patients with liver or bladder target lesions. Our results show that an individual lesion model can characterize the heterogeneity in tumor dynamics and its impact on survival in advanced cancerpatients.

Serum soluble MAdCAM-1: A new biomarker for cancer immunotherapy.

4548 Background: Antibiotics (ATB) deviate the gut taxonomic microbiota composition and have a deleterious impact on survival in ICI-treated pts. ATB downregulate the ileal mucosal addressin cell adhesion molecule-1 (MAdCAM-1), leading to the recirculation of immunosuppressive enterotropic T cells into the tumor and ICI resistance. Here, we aimed to assess the prognostic impact of MAdCAM-1 in ICI-treated mRCC pts. Methods: The GETUG-AFU 26 NIVOREN phase II trial (NCT 0301335) is a multicentric study that assessed the activity and safety of Nivolumab in pts with clear cell mRCC after anti-angiogenic therapy. We measured serum soluble MAdCAM-1 (sMAdCAM-1) levels (correlating ileal MAdCAM-1 transcripts) using Human Luminex Discovery Assay in the available plasma. Progression-free survival (PFS), overall survival (OS) and clinical benefit rate (CBR) were assessed using sMAdCAM-1 median as a cut off value (high if &gt;median and low if &lt;median). Multivariate Cox analysis adjusted for established risk factors: ATB, gender, age, international Metastatic RCC Database Consortium (IMDC) score, number of previous lines, hypoalbuminemia, and brain, bone and liver metastasis. Two independent cohorts of metastatic lung and bladder cancer patients validated the data. Results: Overall, 212 pts were included. Median age was 64 years (22-87), and pts were mostly male (82%). ATB users had lower levels of sMadCAM-1. Low sMadCAM-1 pts had diminished OS compared to high sMadCAM-1 pts [HR 2.97 (95%CI 1.99-4.44), p&lt;.0001]: 13.3 (95%CI 9.8-14.9; 72/106) versus 25.3 (95%CI 24.1-NR; 36/106) months. Also, low sMadCAM-1 pts had diminished PFS [HR 1.92 (1.43-2.57), p&lt;.0001]: 2.6 (95%CI 2.4-2.8; 99/106) versus 5.2 (95%CI 4.6-5.7; 86/106) months. Interestingly, sMAdCAM-1 was independently associated with OS [HR 2.40 (1.52-3.80), p=0.0002] and PFS [HR 1.55 (1.13-2.13), p=0.0071] in multivariate analysis. Low sMadCAM-1 pts had lower CBR (37% versus 63%, p=0.0004). Serum sMAdCAM-1 also predicted OS in 381 ICI-treated patients with lung and bladder cancer. Conclusions: Low sMAdCAM-1 is associated with ATB intake, ATB-independent gut dysbiosis and worse outcomes, in ICI-treated pts with metastatic lung, bladder and RCC cancer. ELISA determination of sMAdCAM-1 might guide the selection of patients amenable to microbiota-centered interventions, such as Akkermansia sp., and fecal microbiota transplantation. Clinical trial information: NCT0301335 .

Consolidative Radiotherapy for Metastatic Urothelial Bladder Cancer Patients with No Progression and with No More than Five Residual Metastatic Lesions Following First-Line Systemic Therapy: A Retrospective Analysis.

Patients who received first-line therapy for the treatment of metastatic urothelial bladder cancer (mUBC) and who were progression-free following treatment with no more than five residual metastases were retrospectively identified through the database of four Comprehensive Cancer Centers, between January 2005 and December 2018. Among them, patients who received subsequent definitive radiotherapy (of EQD2Gy > 45Gy) to the bladder and residual metastases were included in the consolidative group (irradiated (IR) group), and the other patients were included in the observation group (NIR group). Progression-free survival (PFS) and overall survival (OS) were determined from the start of the first-line chemotherapy using the Kaplan-Meier method. To prevent immortal time bias, a Cox model with time-dependent covariates and 6-month landmark analyses were performed to examine OS and PFS. A total of 91 patients with at least stable disease following first-line therapy and with no more than five residual metastases were analyzed: 51 in the IR group and 40 in the NIR group. Metachronous metastatic disease was more frequent in the NIR group (19% vs. 5%, p = 0.02); the median number of metastases in the IR group vs. in the NIR group was 2 (1-9) vs. 3 (1-5) (p = 0.04) at metastatic presentation, and 1 (0-5) vs. 2 (0-5) (p = 0.18) after completion of chemotherapy (residual lesions), respectively. Two grade 3 toxicities (3.9%) and no grade 4 toxicity were reported in the IR group related to radiotherapy. With a median follow up of 85.9 months (95% IC (36.7; 101.6)), median OS and PFS were 21.7 months (95% IC (17.1; 29.7)) and 11.1 months (95% IC (9.9; 14.1)) for the whole cohort, respectively. In multivariable analysis, consolidative radiotherapy conferred a benefit in both PFS (HR = 0.49, p = 0.007) and OS (HR = 0.47, p = 0.015) in the whole population; in the landmark analysis at 6 months, radiotherapy was associated with improved OS (HR = 0.48, p = 0.026), with a trend for PFS (HR = 0.57, p = 0.082). Consolidative radiotherapy for mUBC patients who have not progressed after first-line therapy and with limited residual disease seems to confer both OS and PFS benefits. The role of consolidative radiotherapy in the context of avelumab maintenance should be addressed prospectively.

The ratio of adaptive to innate immune cells differs between genders and associates with improved prognosis and response to immunotherapy.

Immunotherapy has revolutionised cancer treatment. However, not all cancer patients benefit, and current stratification strategies based primarily on PD1 status and mutation burden are far from perfect. We hypothesised that high activation of an innate response relative to the adaptive response may prevent proper tumour neoantigen identification and decrease the specific anticancer response, both in the presence and absence of immunotherapy. To investigate this, we obtained transcriptomic data from three large publicly available cancer datasets, the Cancer Genome Atlas (TCGA), the Hartwig Medical Foundation (HMF), and a recently published cohort of metastatic bladder cancer patients treated with immunotherapy. To analyse immune infiltration into bulk tumours, we developed an RNAseq-based model based on previously published definitions to estimate the overall level of infiltrating innate and adaptive immune cells from bulk tumour RNAseq data. From these, the adaptive-to-innate immune ratio (A/I ratio) was defined. A meta-analysis of 32 cancer types from TCGA overall showed improved overall survival in patients with an A/I ratio above median (Hazard ratio (HR) females 0.73, HR males 0.86, P < 0.05). Of particular interest, we found that the association was different for males and females for eight cancer types, demonstrating a gender bias in the relative balance of the infiltration of innate and adaptive immune cells. For patients with metastatic disease, we found that responders to immunotherapy had a significantly higher A/I ratio than non-responders in HMF (P = 0.036) and a significantly higher ratio in complete responders in a separate metastatic bladder cancer dataset (P = 0.022). Overall, the adaptive-to-innate immune ratio seems to define separate states of immune activation, likely linked to fundamental immunological reactions to cancer. This ratio was associated with improved prognosis and improved response to immunotherapy, demonstrating potential relevance to patient stratification. Furthermore, by demonstrating a significant difference between males and females that associates with response, we highlight an important gender bias which likely has direct clinical relevance.

Survival trends in chemotherapy exposed metastatic bladder cancer patients and chemotherapy effect across different age, sex, and race/ethnicity.

To test for survival differences in metastatic urothelial carcinoma of the urinary bladder (mUCUB) patients, according to years of diagnosis, age, sex, and race/ethnicity over time and for the effect of chemotherapy on overall mortality (OM). Within the Surveillance, Epidemiology, and End Results (2000-2016), we identified 6860 mUCUB patients. Of those, 3,249 were exposed to chemotherapy. Kaplan-Meier plots and Cox regression models focused on OM. First, we tested the effect of years of diagnosis (historical [2000-2005] vs. intermediate [2006-2011] vs. contemporary [2012-2016]) in chemotherapy exposed mUCUB patients. Second, we tested the effect of chemotherapy in all mUCUB patients. In chemotherapy exposed mUCUB patients according to historical vs. intermediate vs. contemporary years, median overall survival was 11 vs. 13 vs. 14 months respectively, which translated into hazard ratios (HR) of 0.86 (P = 0.005) and 0.75 (P < 0.001) in intermediate and contemporary vs. historical, respectively. Subgroup analyses in <70 years old, males and Caucasians were in agreement regarding statistically significant differences between historical vs. intermediate vs. contemporary, respectively. In multivariable Cox regression models fitted in the entire mUCUB cohort, chemotherapy exposure reduced OM (HR: 0.46; P < 0.001). Virtually the same results were recorded in age, sex, and race/ethnicity subgroups analyses. Contemporary chemotherapy exposed mUCUB patients exhibited better survival than their historical and intermediate counterparts. Chemotherapy reduced mortality by half, across all patient types.

Abstract CT035: Safety, preliminary efficacy and pharmacodynamic (PD) analysis of maveropepimut-S, intermittent low-dose cyclophosphamide and pembrolizumab in patients with advanced, metastatic bladder cancer

Abstract Background: Maveropepimut-S (MVP-S) is a novel immunotherapeutic that educates a specific CD8 T cell response to the cancer antigen, survivin, to orchestrate immune-mediated elimination of survivin-expressing cancer cells. Specifically, MVP-S is a lipid-in-oil formulation of the DPX delivery platform, incorporating five survivin-specific immunogenic peptides, the innate immune stimulant, polydIdC, and a CD4 T cell helper peptide. In prior clinical studies, MVP-S and intermittent low-dose cyclophosphamide (CPA) elicited confirmed clinical responses (both partial and complete by RECISTv1.1) and induced a robust, durable survivin-specific CD8 T cell response. Moreover, the combination with pembrolizumab appeared to be well tolerated in solid tumors and lymphomas. The purpose of this phase 2 study is to explore whether this combination may be safe and effective in advanced, metastatic bladder cancer patients, both naïve to, and previously treated with, immune checkpoint inhibitors. Results: Seventeen (17) subjects were treated with the combination of MVP-S, CPA and pembrolizumab. Subjects received an average of 3 prior lines of therapy with 13/17 (76.4%) having previously received an anti-PD1/L1. Seven subjects progressed on or after anti-PD1/L1 as last line of therapy prior to entering the trial. The combination was well-tolerated, with majority of AEs being grade 1 or grade 2. Five (5) out of 17 subjects showed response: 3 subjects with PR (unconfirmed) and 2 with CR (confirmed). Three of these, including the 2 CRs, had progressed on anti-PD-1/L1. Long-term clinical benefit has been observed in several subjects (one patient is still on treatment after 17 months) and coincides with an increase in detectable survivin-specific T cells in peripheral blood. Conclusion: Preliminary data suggest that MVP-S/CPA and pembrolizumab is a well-tolerated combination and shows encouraging preliminary clinical activity in the treatment of advanced or metastatic bladder cancer patients, including patients who have progressed on prior anti-PD-1/L1 therapy. Citation Format: Olivier Rixe, Vincent Castonguay, Henry Conter, Eva Chalas, Pratibha Desai, Christian Squillante, Lisa A. MacDonald, Rebekah Conlon, Yogesh Bramhecha, Heather Hirsch, Jeremy R. Graff, Stephan Fiset. Safety, preliminary efficacy and pharmacodynamic (PD) analysis of maveropepimut-S, intermittent low-dose cyclophosphamide and pembrolizumab in patients with advanced, metastatic bladder cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr CT035.

Abstract 2724: High relative ratio of adaptive to innate tumor infiltrating immune cells predicts for immunotherapy response and associates with improved prognosis

Abstract Immunotherapy has revolutionized cancer treatment. However, not all cancer patients benefit, and current stratification strategies based primarily on PD1 status and mutation burden is far from perfect. We hypothesized that high activation of an innate response relative to the adaptive response may prevent proper tumor neoantigen identification and decrease the specific anticancer response, both in the presence and absence of immunotherapy. To investigate this, we defined signatures of innate and adaptive immune response from bulk tumor RNAseq data, and compared the relative activation of both immune compartments. We acquired publicly available transcriptomic data from both primary and metastatic cancer cohorts from the Cancer Genome Atlas (TCGA), the Hartwig Medical Foundation (HMF), and from a recently published cohort of metastatic bladder cancer patients treated with immunotherapy. To analyse adaptive and innate immune infiltration into bulk tumors, we developed a model to estimate the overall level of innate and adaptive immune cells, based on previously published definitions. From these, we defined the overall adaptive-to-innate immune ratio (AIR) score as the ratio of average gene expression of genes associated with the adaptive and innate immune system, respectively. Pan-cancer analysis of primary tumor samples from TCGA showed improved progression free survival in patients with an AIR score above median (P &amp;lt; 0.0001), and that patients without a progression event had overall a significantly higher AIR score (P &amp;lt; 2*10-16). Interestingly, we found that the association was different for males and females for several cancer types, indicating a potential a gender bias in activation of the immune response (female P &amp;lt; 2*10-16, male P = 1.1*10-14). For patients with metastatic disease, we found that responders to immunotherapy have a significantly higher AIR score than non-responders in HMF (female P = 0.0037, male P = 2.5*10-5) and a significantly higher score in complete responders in a separate metastatic bladder cancer dataset where response was primarily observed in male patients (P = 0.015). Furthermore, histological analysis revealed that tumors which had a significantly higher AIR score, were highly infiltrated by immune cells (P = 0.00047), providing orthogonal support that the AIR score associates with an anti-tumor immune response. Overall, the adaptive-to-innate immune ratio seems to define separate states of immune activation, likely linked to fundamental immunological reactions to cancer. Our score associates with both improved prognosis and improved response to immunotherapy, demonstrating potential use in patient stratification. Furthermore, by demonstrating a significant difference between males and females that associates with response, we highlight an important gender bias which likely has direct clinical relevance. Citation Format: Johanne Ahrenfeldt, Andreas B. Østergaard, Ditte S. Christensen, Judit Kisistók, Mateo Sokač, Nicolai J. Birkbak. High relative ratio of adaptive to innate tumor infiltrating immune cells predicts for immunotherapy response and associates with improved prognosis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2724.

Life expectancy in metastatic urothelial bladder cancer patients according to race/ethnicity.

to compare observed overall survival vs age-adjusted lifetable (LT) derived life expectancy (LE) in metastatic urothelial bladder cancer (MBCa) patients according to race/ethnicity. We identified Caucasian, African American, Hispanic/Latino and Asian metastatic urothelial bladder cancer patients from 2004 to 2011 within the Surveillance, Epidemiology and End Results database. Social Security Administration tables were used to compute 5year LE. LT-derived LE was compared to observed overall survival OS. Additionally, we relied on Poisson regression plots to display cancer-specific mortality (CSM) relative to other-cause mortality (OCM) for each race/ethnicity. Overall, 2286 MBCa patients were identified. Of those, 1800 (79%) were Caucasian vs 212 (9.3%) African American vs 189 (8.3%) Hispanic/Latino vs 85 (3.7%) Asians. The median age at diagnosis was 71years for Asians vs 70 for Caucasians vs 67 for Hispanic/Latinos vs 67 for African Americans. African Americans showed the biggest difference between observed OS and LT-predicted LE at five years (-83.8%), followed by Hispanic/Latinos (-81%), Caucasians (-77%) and Asian patients (-69%). In Poisson regression plots, Hispanic/Latinos displayed the highest cancer-specific mortality rate (88%), while African/Americans showed the highest other cause mortality rate (12%). Conversely, Asian patients displayed the lowest CSM rate (83%) and second lowest OCM rate (7%). African Americans showed the least favorable survival profile in MBCa, despite being youngest at diagnosis. Contrarily, Asians displayed the best survival profile in MBCa, despite being oldest at diagnosis.

MP03-10 LIFE EXPECTANCY IN METASTATIC UROTHELIAL BLADDER CANCER PATIENTS ACCORDING TO RACE/ETHNICITY

You have accessJournal of UrologyCME1 May 2022MP03-10 LIFE EXPECTANCY IN METASTATIC UROTHELIAL BLADDER CANCER PATIENTS ACCORDING TO RACE/ETHNICITY Francesco Chierigo, Christoph Würnschimmel, Rocco Simone Flammia, Benedikt Horlemann, Gabriele Sorce, Benedikt Hoeh, Zhe Tian, Fred Saad, Markus Graefen, Michele Gallucci, Alberto Briganti, Francesco Montorsi, Felix K.H. Chun, Shahrokh F. Shariat, Guglielmo Mantica, Maro Borghesi, Nazareno Suardi, Carlo Terrone, and Pierre I. Karakiewicz Francesco ChierigoFrancesco Chierigo More articles by this author , Christoph WürnschimmelChristoph Würnschimmel More articles by this author , Rocco Simone FlammiaRocco Simone Flammia More articles by this author , Benedikt HorlemannBenedikt Horlemann More articles by this author , Gabriele SorceGabriele Sorce More articles by this author , Benedikt HoehBenedikt Hoeh More articles by this author , Zhe TianZhe Tian More articles by this author , Fred SaadFred Saad More articles by this author , Markus GraefenMarkus Graefen More articles by this author , Michele GallucciMichele Gallucci More articles by this author , Alberto BrigantiAlberto Briganti More articles by this author , Francesco MontorsiFrancesco Montorsi More articles by this author , Felix K.H. ChunFelix K.H. Chun More articles by this author , Shahrokh F. ShariatShahrokh F. Shariat More articles by this author , Guglielmo ManticaGuglielmo Mantica More articles by this author , Maro BorghesiMaro Borghesi More articles by this author , Nazareno SuardiNazareno Suardi More articles by this author , Carlo TerroneCarlo Terrone More articles by this author , and Pierre I. KarakiewiczPierre I. Karakiewicz More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000002515.10AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: To compare observed overall survival vs age-adjusted life-table (LT) derived life expectancy (LE) in metastatic urothelial bladder cancer (MBCa) patients according to race/ethnicity. METHODS: We identified Caucasian, African American, Hipanic/Latino and Asian metastatic urothelial bladder cancer patients from 2004 to 2011 within the Surveillance, Epidemiology and End Results database to. Social Security Administration tables were used to compute five-year LE. LT-derived LE was compared with observed overall survival OS. Additionally, we relied on Poisson regression plots to display cancer-specific mortality (CSM) relative to other-cause mortality (OCM) for each race/ethnicity. RESULTS: Overall, 2,286 MBCa patients were identified. Of those, 1,800 (79%) were Caucasian vs 212 (9.3%) African American vs 189 (8.3%) Hispanic/Latino vs 85 (3.7%) Asians. The median age at diagnosis was 71 years for Asians vs 70 for Caucasians vs 67 for Hispanic/Latinos vs 67 for African Americans. African Americans showed the biggest difference between observed OS and LT-predicted LE at five years (-83.8%), followed by Hispanic/Latinos (-81%), Caucasians (-77%) and Asian patients (-69%). In Poisson regression plots, Hispanic/Latinos displayed the highest cancer-specific mortality rate (88%), while African/Americans showed the highest other cause mortality rate (12%). Conversely, Asian patients displayed the lowest CSM rate (83%) and second-lowest OCM rate (7%). CONCLUSIONS: African Americans showed the least favorable survival profile in MBCa, despite being youngest at diagnosis. Contrarily, Asians displayed the best survival profile in MBCa, despite being oldest at diagnosis. Source of Funding: no funding © 2022 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 207Issue Supplement 5May 2022Page: e23 Advertisement Copyright & Permissions© 2022 by American Urological Association Education and Research, Inc.MetricsAuthor Information Francesco Chierigo More articles by this author Christoph Würnschimmel More articles by this author Rocco Simone Flammia More articles by this author Benedikt Horlemann More articles by this author Gabriele Sorce More articles by this author Benedikt Hoeh More articles by this author Zhe Tian More articles by this author Fred Saad More articles by this author Markus Graefen More articles by this author Michele Gallucci More articles by this author Alberto Briganti More articles by this author Francesco Montorsi More articles by this author Felix K.H. Chun More articles by this author Shahrokh F. Shariat More articles by this author Guglielmo Mantica More articles by this author Maro Borghesi More articles by this author Nazareno Suardi More articles by this author Carlo Terrone More articles by this author Pierre I. Karakiewicz More articles by this author Expand All Advertisement PDF DownloadLoading ...

Hospital variation in treatment patterns and oncological outcomes for patients with muscle-invasive and metastatic bladder cancer in the Netherlands.

Population-based studies on treatment patterns in oncology and corresponding clinical outcomes can help identify strategies towards optimal value for patients. This study was performed to describe the variation in treatment patterns and major oncological outcomes for muscle-invasive or metastatic bladder cancer (MIBC/mBC) patients in the Netherlands. Patients diagnosed with cT2-4aN0-3M0-1 disease between 2008 and 2016 in seven large teaching hospitals in the Netherlands were included. Baseline characteristics, disease stage, intended and definitive treatment, and oncological outcomes were collected. Patients were categorized based on cTNM-stage: (1) cT2-4aN0M0, (2) cT2-4aN1-3M0 and (3) cT4b and/or M1. The total study population comprised 1853 patients, of which 1303 patients were diagnosed with cT2-4aN0M0 disease. Overall, curative treatment was intended in 81% (range 74-85%, P value = 0.132). Radical cystectomy (RC) and curative radiotherapy (RTx) ranged between hospitals from 42 to 66% and 13 to 27%, respectively (P value < 0.001). For 334 patients staged cT4b and/or M1, frequencies for palliative therapy and best supportive care (no anti-cancer therapy) ranged between hospitals from 20 to 54% and 44 to 71%, respectively (P value < 0.001). There was no association between hospital site and overall survival (OS) in a univariable and multivariable Cox regression for survival analysis (after adjusting for age and cT-stage), for all three cTNM-groups. Neoadjuvant or induction chemotherapy (NAIC) utilization rates before RC ranged from 8 to 38% (P value < 0.001). There is large inter-hospital variation in treatment intent in MIBC/mBC patients. This variation does not seem to translate to differences in overall survival rates. There is an ongoing trend of increased use of RC. Utilisation of NAIC is relatively low considering European guideline recommendations.

PARP inhibitors chemopotentiate and synergize with cisplatin to inhibit bladder cancer cell survival and tumor growth

BackgroundManagement of bladder cancer (BLCA) has not changed significantly in the past few decades, with platinum agent chemotherapy being used in most cases. Chemotherapy reduces tumor recurrence after resection, but debilitating toxicities render a large percentage of patients ineligible. Recently approved immunotherapy can improve outcomes in only a third of metastatic BLCA patients. Therefore, more options for therapy are needed. In this study, we explored the efficacy of PARP inhibitors (PARPi) as single agents or as combinations with platinum therapy.MethodsWe treated BLCA cells with PARPi (olaparib, niraparib, rucaparib, veliparib, or talazoparib) alone or as the combination of cisplatin with PARPi. We then measured their survival, proliferation, apoptosis, as well as their ability to form colonies. BLCA xenografts in male SCID mice were treated similarly, followed by the assessment of their growth, proliferation, and apoptosis.ResultsPARPi niraparib and talazoparib were effective in reducing BLCA cell survival as single agents. Combinations of Cisplatin with talazoparib and niraparib effectively reduced the survival of BLCA cells, while veliparib was not effective even at high concentrations. In vivo, the combinations of cisplatin with niraparib, rucaparib, or talazoparib reduced BLCA xenograft growth significantly.ConclusionsWe provide evidence that PARPi can be effective against BLCA as single agents or as combinatorial therapy with cisplatin.

TROP2 Expression Across Molecular Subtypes of Urothelial Carcinoma and Enfortumab Vedotin-resistant Cells

Sacituzumab govitecan (SG) is an antibody-drug conjugate (ADC) targeting TROP2, which has recently been approved for treatment-refractory metastatic urothelial cancer (UC). However, the variability of TROP2 expression across different bladder cancer (BC) subtypes, as well as after enfortumab vedotin (EV) exposure, remains unknown. Using gene expression data from four clinical cohorts with >1400 patient samples of muscle-invasive BC and a BC tissue microarray, we found that TROP2 mRNA and protein are highly expressed across basal, luminal, and stroma-rich subtypes, but depleted in the neuroendocrine subtype. In addition, TROP2 mRNA levels are correlated with NECTIN4 mRNA but are more highly expressed than NECTIN4 mRNA in patient cohorts and BC cell lines. Moreover, CRISPR/Cas9-mediated knockdown of TROP2 demonstrates that its expression is one factor governing SG sensitivity. After prolonged EV exposure, cells can downregulate NECTIN4, leading to EV resistance, but retain TROP2 expression and remain sensitive to SG, suggesting nonoverlapping resistance mechanisms to these ADCs. While our findings warrant further validation, they have significant implications for biomarker development, patient selection, and treatment sequencing in the clinic as well as clinical trial design and stratification for metastatic BC patients. Patient summaryIn this report, we investigated the expression levels of the drug target TROP2 across different molecular subtypes of bladder cancer in multiple patient cohorts and cell lines. We found high levels of TROP2 in most subtypes except in the neuroendocrine subtype. Overall, TROP2 gene expression is higher than NECTIN4 gene expression, and cells resistant to enfortumab vedotin (EV), a NECTIN4-targeting antibody-drug conjugate, remain sensitive to sacituzumab govitecan (SG). Our findings suggest that SG may be effective across most bladder cancer subtypes, including the bladder cancers previously treated with EV.

Safety lead-in of phase II SBRT and durvalumab with or without tremelimumab for unresectable and cisplatin-ineligible, locally advanced or metastatic bladder cancer.

517 Background: Many patients with muscle-invasive bladder cancer are not ideal candidates for chemotherapy or radical cystectomy. Moreover, local progression may further impair quality of life. Bladder preservation with maximal transurethral resection of bladder tumor (TURBT) and stereotactic body radiotherapy (SBRT) is a viable treatment option for such patients, offering durable local control while potentiating the effect of immunotherapy. Herein, we report on the safety profile of SBRT in combination with durvalumab (anti-PDL1) and tremelimumab (anti-CTLA4) in the safety lead-in cohort of an institutional Phase II trial for cisplatin-ineligible, unresectable locally advanced or metastatic bladder cancer patients. Methods: Patients with locally advanced or metastatic urothelial carcinoma, who were unwilling or unable to undergo radical cystectomy and/or systemic chemotherapy were eligible. Patients received maximal TURBT, followed by durvalumab 1500mg IV every 4 weeks and bladder SBRT 33Gy in 5 fractions between the first 2 cycles. After 6 such patients did not experience a dose limiting toxicity, tremelimumab 75mg IV was added for cycles 1-2. Patients were followed with CT Chest/Abdomen/Pelvis and cystoscopy every 3 months. Treatment-related adverse events (TRAEs) were assessed per CTCAE 5.0 and progression was assessed per RECIST 1.1. Results: Between January 2019 and May 2020, 10 patients received TURBT followed by SBRT and durvalumab (Age 73-96, 3 Female, 7 ECOG 1, 3 ECOG 0). Five patients had localized disease and 5 had nodal or distant metastases. Median cycles of durvalumab was 12.5 (2-13), and 4 patients received 2 cycles of tremelimumab. At a median follow-up of 16.8mo (6.4-30mo), there were 2 Grade 3+ immunotherapy-related TRAEs (1 Grade 3 lipase elevation self-resolved, 2 Grade 3 myositis treated with steroids). The most common TRAEs of any grade included pancreatic enzyme elevation (3 patients), rash (3 patients), and urinary symptoms related to RT (3 patients). Disease control rate 70% and local control was 90%. There were 3 non-treatment related deaths. Conclusions: Bladder SBRT with durvalumab and tremelimumab was well tolerated and demonstrated promising local control in the safety lead-in cohort. Clinical trial information: NCT03601455.

Gemcitabine and carboplatin versus gemcitabine and paclitaxel chemotherapy in cisplatin ineligible advanced-stage urothelial cancers: A prospective randomized control study.

500 Background: Cisplatin ineligibility in metastatic urinary bladder cancer patients poses a major therapeutic challenge. The reported incidence was approximately 20-30% of metastatic urinary bladder cancer. In the absence of insurance, "the immunotherapy" can be economically draining at the current cost. Moreover, there are patients in whom immunotherapy might not be feasible due to comorbid conditions. Therefore, there persists a need to optimize chemotherapy options for gemcitabine combination with either Paclitaxel or Carboplatin are recommended chemotherapy options. However, limited prospective studies are comparing the two options. Methods: This was a non-funded, prospective, randomized, single-center study among treatment naïve cisplatin-ineligible metastatic urothelial cancer from a tertiary care institute from India. The study enrollment duration was 18 months. Patients were randomized in one of the two treatment arms. The "Arm A" received (Gemcitabine and Carboplatin) and "Arm B" received the (Gemcitabine and Paclitaxel) combination chemotherapy, respectively. The two treatment arms were compared prospectively for disease control, survival, and adverse events in an Intention to treat analysis. Results: A total of 32 eligible participants were randomized in the study. "Arm A" vs. "Arm B" had an 18.7% vs. 25% drops out rate, respectively. The ORR was 40% vs. 88.4%; median PFS and OS were 3.7 vs. 3.8 months and 7.3 vs. 14.0 months, respectively. The serious adverse events were nonoverlapping. Hospitalization was needed for the care of adverse events among 37.5% vs. 12.5% patients, respectively. Conclusions: Both groups reported that similar PFS. However, better ORR, OS (though not statically significant), and lower hospitalizations for adverse event management favor the Gemcitabine with paclitaxel combination over Gemcitabine with Carboplatin. Clinical trial information: CTRI/2020/02/023402.

Comparing the outcome of doublet therapy (gemcitabine and cisplatin) with triplet therapy (gemcitabine, cisplatin and nab paclitaxel) in locally advanced or metastatic gall bladder carcinoma patients: An open-label randomized control trial.

TPS497 Background: There are various studies evaluating the role of dual agent chemotherapy like gemcitabine and cisplatin in locally advanced or metastatic gall bladder cancer (1). This has been the standard of treatment up till now. Also there has been a single arm phase II trial of gemcitabine, cisplatin and nab-paclitaxel (triplet therapy) by Shroff et al (2) reporting an impressive data with RR (response rate) of 45 %, median PFS (progression free survival) of 11.8 months (5% CI; 6.0-15.6) and median OS (overall survival) was 19.2 months. This data was promising when compared to historical data of dual agents like gemcitabine and cisplatin. So it would be informative to conduct an RCT comparing doublet chemotherapy in locally advanced or metastatic GBC with triplet regimen chemotherapy. Methods: It is an open label randomized control study conducted in Indraprastha Apollo hospital New Delhi, India in newly diagnosed locally advanced or metastatic gall bladder cancer patients proven histologically and on imaging. The sample size calculated using the appropriate formula is, 27 in each arm that is total of 54 patients, but 60 patients will be enrolled in the study keeping in view 10% drop out rate. For simple randomization, we will use online computer generated random number table and then patients will be assigned in two groups, arms A and B. Arm A receiving two drugs gemcitabine 1,000mg/m2 i.v and cisplatin 25mg/m2 i.v on Day 1 and Day 8 of 21-day cycle and arm B receiving three drugs gemcitabine, 1,000 mg/m2, cisplatin, 25 mg/m2, and nab-paclitaxel, 125 mg/m2, on days 1 and 8 of 21-day cycle. Primary end point was response rates based on radiological response as per RECIST or PRECIST. Secondary end points were to determine median progression free survival and median overall survival and to evaluate the toxicities according to NCI-CTC v 4.0.Then response [on basis of RECIST or PRECIST criteria] will be seen after 3 and 6 cycles of chemotherapy are completed and at follow up of every 6 months for 2 years period for assessment of primary and secondary end points of the study. Statistical analysis for correlation between clinical and laboratory features and treatment outcomes will be done using the SPSS software. Till now we have enrolled 1 patient in each arm. CTRI/2021/09/036362.