Muscle-invasive Urothelial Bladder Cancer Patients Research Articles

MP14-15 MACROPHAGES AND REGULATORY T-CELLS AS PROGNOSTIC FACTORS IN PATIENTS WITH UROTHELIAL MUSCLE-INVASIVE BLADDER CANCER

You have accessJournal of UrologyCME1 Apr 2023MP14-15 MACROPHAGES AND REGULATORY T-CELLS AS PROGNOSTIC FACTORS IN PATIENTS WITH UROTHELIAL MUSCLE-INVASIVE BLADDER CANCER Florestan Koll, Severine Banek, Luis Kluth, Jens Köllermann, Andreas Weigert, Felix Chun, Peter Wild, and Henning Reis Florestan KollFlorestan Koll More articles by this author , Severine BanekSeverine Banek More articles by this author , Luis KluthLuis Kluth More articles by this author , Jens KöllermannJens Köllermann More articles by this author , Andreas WeigertAndreas Weigert More articles by this author , Felix ChunFelix Chun More articles by this author , Peter WildPeter Wild More articles by this author , and Henning ReisHenning Reis More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000003234.15AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: The prognosis of muscle-invasive urothelial bladder cancer (MIBC) is poor and response rates to systemic therapy are insufficient. Infiltration of tumors by immune cells has been described to be associated with response rates to immune- and chemotherapy and patient’s outcome. However, tumor-associated macrophages (TAMs) are abundant in many tumors and can promote cancer progression. In this study we evaluate different subsets of immune cells in the tumor microenvironment (TME) as predictors of prognosis in MIBC and survival rates with adjuvant chemotherapy. METHODS: We used multiplex immunohistochemistry (IHC) to quantify and characterize immune, tumor and stroma cells: double negative T-cells (CD3+CD4-CD8-); T-helper cells (CD4+); cytotoxic T-cells (CD8+); PD-1 positive T-cells; macrophages (CD163+); regulatory T-cells (Tregs; FoxP3+)); fibroblasts (Vimentin+); immune cells (CD45+); tumor cells (panCK+); PD-L1 positive tumor cells; proliferating immune cells (CD45+Ki67+); proliferating tumor cells (panCK+Ki67+). Analysis was performed in 101 MIBC patients receiving radical cystectomy. Uni- and multivariate Cox regression were used to identify cell types that predict prognosis. Patients were divided into three clusters for their macrophage and Treg infiltration. RESULTS: High Treg infiltration was associated with better overall survival (OS) (HR 0.1, 95% CI 0.01-0.7; p=0.03) and high macrophage infiltration was associated with decreased OS (HR 10.9, 95% CI 2.8-40.5; p=0.0004) in the multivariate Cox-regression model adjusting for tumor stage, lymph node status and application of adjuvant chemotherapy. The cluster with high Treg concentration was also enriched for other immune cells and cells showed high PD1 and PD-L1 expression. Patients in the cluster with high macrophage concentration had the worst OS also when adjuvant chemotherapy was given. We validated the findings using standardized IHC for CD163 as a macrophage marker using a digital analysis software in 141 patients. CONCLUSIONS: In MIBC high macrophage concentration is an independent predictor of poor prognosis. High levels of Tregs are associated with other immune cells in the TME which might lead to better survival rates. Using routine IHC for TAMs (CD163) should be prospectively validated to confirm findings and to evaluate the predictive value for response to systemic therapies. Source of Funding: Deutsche Krebshilfe (German Cancer Aid). Wilhelm-Sander Foundation. Hessen State Ministry for Higher Education, Research and the Arts © 2023 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 209Issue Supplement 4April 2023Page: e188 Advertisement Copyright & Permissions© 2023 by American Urological Association Education and Research, Inc.MetricsAuthor Information Florestan Koll More articles by this author Severine Banek More articles by this author Luis Kluth More articles by this author Jens Köllermann More articles by this author Andreas Weigert More articles by this author Felix Chun More articles by this author Peter Wild More articles by this author Henning Reis More articles by this author Expand All Advertisement PDF downloadLoading ...

Immune Cell-Associated Protein Expression Helps to Predict Survival in Muscle-Invasive Urothelial Bladder Cancer Patients after Radical Cystectomy and Optional Adjuvant Chemotherapy.

Simple SummaryAdjuvant chemotherapy following radical cystectomy is a common therapy for muscle invasive bladder cancer (MIBC) patients. No applicable biomarkers exist to predict which patients will benefit from chemotherapy. Three immune cell markers, the chemokine CC motif ligand 2 (CCL2), the pan macrophage marker CD68, and the M2 macrophage marker CD163, were examined using immunohistochemistry to determine their predictive value for chemotherapy responses in different nodal stage and tumor stage subgroups. The presence of tumor-infiltrating immune cells, characterized by the markers CD68, CD163, and CCL2, was associated with a superior prognosis, and chemotherapy may not add an advantage for prognosis. However, a depleted immune microenvironment, here represented as a reduction or loss of macrophages, helped to predict the benefit of chemotherapy in N1 + 2 stage patients. Altogether, it is meaningful to consider the abundance of immune cells, such as macrophages, to better predict the response to chemotherapy for bladder cancer (BCa) patients after radical treatment.Bladder cancer (BCa) is the tenth most commonly diagnosed malignant cancer worldwide. Although adjuvant chemotherapy following radical cystectomy is a common therapy for muscle invasive bladder cancer patients, no applicable biomarkers exist to predict which patients will benefit from chemotherapy. In this study, we examined three immune cell markers, the chemokine CC motif ligand 2 (CCL2), the pan macrophage marker cluster of differentiation 68 (CD68) and the M2 macrophage marker cluster of differentiation 163 (CD163), using immunohistochemistry to determine their predictive value for the chemotherapy response in different nodal stage (pN0 vs. pN1 + 2) and tumor stage subgroups (pT2 vs. pT3 + 4). The prognosis was studied in terms of the overall survival (OS), disease-specific survival (DSS), and recurrence-free-survival (RFS) in 168 muscle invasive BCa patients. Chemotherapy was associated with a poorer prognosis in patients with a higher expression of the immune markers CCL2 (RFS), CD68 (DSS and RFS), and CD163 (DSS and RFS) in the N0 group and with poorer survival in patients with a higher expression of the immune markers CCL2 (OS, DSS, and RFS), CD68 (OS, DSS, and RFS), and CD163 (OS, DSS, and RFS) in the pT2 group when compared with treatments without chemotherapy. In contrast, chemotherapy was associated with a better prognosis in patients with a low expression of the immune markers CCL2 (DSS and RFS), CD68 (OS, DSS, and RFS), and CD163 (OS) in the N1 + 2 group. In addition, chemotherapy was associated with improved survival in patients with a low expression of the immune marker CD68 (OS and DSS) and there was a trend for a better prognosis in patients with a low expression of CD163 (OS) in the pT3 + 4 group compared to patients not treated with chemotherapy. Interestingly, CD68 appeared to be the most applicable immune marker to stratify patients by the outcome of chemotherapy in the nodal stage and tumor stage groups. Overall, we suggest that, in addition to the clinical factors of tumor stage and nodal stage, it is also meaningful to consider the abundance of immune cells, such as macrophages, to better predict the response to chemotherapy for BCa patients after radical treatment.

Mutations of METTL3 predict response to neoadjuvant chemotherapy in muscle-invasive bladder cancer

Neoadjuvant chemotherapy (NAC) followed by radical cystectomy is the current gold standard treatment for muscle-invasive urothelial bladder cancer (MIBC). Nonetheless, some MIBC patients showed limited pathological response after NAC. Herein, we used whole-exome sequencing (WES) to identify genetic mutations in MIBC that can predict NAC response. Forty MIBC patients were enrolled in this study, in which 33 were successfully examined by WES and Sanger sequencing in the discovery cohort (n=13) and the validation cohort (n=20), respectively. ANNOVAR software was used to identify the potential mutations based on the data of WES. In addition, tumor-specific somatic mutations including single nucleotide variants and indels were called with the muTECT and Strelka software. The mutational analysis of specific genes was carried out based on the data from cBioPortal for Cancer Genomics. In the discovery cohort, the mutation frequencies of TP53, MED16, DRC7, CEND1, ATAD5, SETD8, and PIK3CA were significantly higher in 13 MIBC patients. Specifically, the presence of somatic mutations of APC, ATM, CDH9, CTNNB1, METTL3, NBEAL1, PTPRH, RNASEL, and FBXW7 in NAC responder signifies that these mutations were potential predictors of pathological response to NAC. Furthermore, somatic mutations of CCDC141, PIK3CA, CHD5, GPR149, MUC20, TSC1, and USP54 were exclusively identified in NAC nonresponders, suggesting that these mutations may participate in the process of NAC resistance. In the validation cohort, the somatic mutations of CDH9, METTL3, and PTPRH were significantly enriched in NAC responders while the somatic mutation of CCDC141 was significantly enriched in NAC nonresponders. Furthermore, survival analysis revealed that the patients expressing mutated METTL3 have a longer overall survival and disease- or progression-free survival than the patients acquiring wild-type METTL3. The somatic mutation of METTL3 can be a potential predictive biomarker of NAC response in MIBC patients. MIBC patients bearing mutated METTL3 display a pathological response to NAC and have a significantly longer overall survival or disease/progression-free survival as compared to the patients bearing wild-type METTL3. Thus, the somatic mutation of METTL3 is a potential biomarker for predicting response to NAC in MIBC patients, assisting doctors in making the clinical decision.

DUTRENEO Trial: A randomized phase II trial of DUrvalumab and TREmelimumab versus chemotherapy as a NEOadjuvant approach to muscle-invasive urothelial bladder cancer (MIBC) patients (pts) prospectively selected by an interferon (INF)-gamma immune signature.

5012 Background: Cisplatin-based neoadjuvant chemotherapy (CT) followed by radical cystectomy (RC) is a standard treatment for MIBC. PD-1/L1 inhibitors as single agent induce pathological complete responses (pCR) in this setting. Predictors of response are still ill defined. DUTRENEO trial aimed to prospectively explore the activity of anti-PDL1 + anti-CTLA4 vs CT in pts selected according to a tumor pro-inflammatory IFN-gamma signature (tumor immune score, TIS). Methods: Cisplatin-eligible pts with urothelial MIBC (cT2-T4a, N≤1, M0) candidates to RC were classified as “hot” or “cold” according to a tumor TIS determined by Nanostring technology. Patients with "hot" tumors were randomized to DU 1500 mg + TRE 75 mg every 4 weeks x 3 cycles or standard cisplatin-based CT (GEMCIS or MVACdd). Pts in the “cold” arm received standard CT. Primary endpoint was to achieve ≥8 pCR in the DU+TRE arm. PDL1 expression was assessed using immunohistochemistry. Results: 61 pts were recruited in 10 sites between oct-2018 and dec-2019. Pts randomized in the “hot” arms received standard CT (n = 22) or DU+TRE (n = 23) and had a pCR rate of 8/22 pts (36.4%) vs 8/23 pts (34.8%), respectively [OR = 0.923 (0.26 – 3.24)]. In the “cold” arm, 16 pts received CT obtaining a pCR rate of 68.8% (11/16 pts). There were more PDL1 low tumors in the "cold" TIS arm (10/12, 83.3%). pCR rate by PDL1 status is shown in the table. One pt in the DU+TRE arm refused RC. Full treatment was delivered to 81.3% of CT "cold" vs 59.1% of CT "hot" vs 73.9% in the DU+TRE arm pts. Grade 3-4 toxicities were more frequent in the CT arms. Conclusions: The combination of DU+TRE is safe and active in MIBC patients in the neoadjuvant setting. Nevertheless prospective stratification by a pro-inflammatory IFN-gamma signature failed to select patients more likely to benefit from IO vs CT in this context. Further studies are required to guide treatment selection. Clinical trial information: NCT03472274 . [Table: see text]

Cytotoxic T-cell-related gene expression signature predicts improved survival in muscle-invasive urothelial bladder cancer patients after radical cystectomy and adjuvant chemotherapy

BackgroundAssessment of the immune status of muscle-invasive bladder cancer (MIBC) has previously shown to be prognostically relevant after treatment with curative intent. We conducted this study to develop a clinically...

Neoadjuvant cisplatin-based chemotherapy in patients with ureteral obstruction secondary to muscle invasive bladder cancer.

523 Background: Neoadjuvant cisplatin-based chemotherapy (NAC) followed by cystectomy is the standard of care for muscle-invasive urothelial bladder cancer (MIBC). 15-35% of MIBC patients present with ureteral obstruction. Poor renal function increases cisplatin toxicity. It is unknown whether patients with ureteral obstruction which has been relieved (whether by nephrostomy tube or nephroureteral stent) have the same risk of toxicity as patients without ureteral obstruction. Methods: We retrospectively reviewed an institutional database of all patients undergoing NAC for MIBC with either dose dense MVAC (ddMVAC) or gemcitabine and cisplatin (GC) from January 2004 through May 2017. Patients without ureteral obstruction prior to initiation of NAC (Group A) were compared to those who had ureteral obstruction which was relieved prior to undergoing NAC (Group B). Continuous variables were compared using the Wilcoxon rank-sum test and categorical variables were compared using Fisher’s exact test. The primary outcome was premature discontinuation of NAC, which was defined as failure to complete all planned cycles. Logistic regression was used to test for differences between the groups in this outcome adjusting for age, ECOG performance status, and baseline glomerular filtration rate (GFR). Results: 160 patients in Group A and 59 patients in Group B were identified. Baseline age, Charlson Comorbidity Index, race, smoking status, and ECOG performance status were similar. Patients in Group B had lower GFR (99.2% vs 78.8% p <0.001) and were more likely to be female (21.9% vs 27.3% p <0.025) and to receive ddMVAC (65.0% vs. 83.1% p =0.012). There was no significant difference between groups in rates of premature NAC discontinuation (15.8% vs 22.0% p = 0.284) or grade ≥3 adverse events (23.4% vs 30.5% p = 0.285). Adjusted analysis showed no significant difference between the groups in frequency of premature NAC discontinuation (OR 1.96, 95% CI 0.84-4.57 p=0.12). Conclusions: We detected no difference in frequency of premature discontinuation of NAC in patients with relieved malignant ureteral obstruction relative to patients without obstruction. NAC for MIBC is likely safe in this population.

Blood transfusions during neoadjuvant chemotherapy for muscle-invasive urinary bladder cancer may have a negative impact on overall survival

Objective: To evaluate the extent and plausible effects of blood transfusions given during cisplatin-based neoadjuvant chemotherapy (NAC) on overall survival in patients with muscle-invasive urothelial bladder cancer (MIBC) undergoing NAC and radical cystectomy (RC).Background: Several studies have demonstrated a decreased survival for MIBC patients receiving allogenic peri- and postoperative blood transfusions in conjunction with RC. No studies have previously investigated the effects of blood transfusions during NAC.Materials and methods: 120 patients with MIBC (cT2-T4aN0M0) undergoing NAC and RC between 2008 and 2014 at four Swedish cystectomy centers were retrospectively evaluated. Clinicopathological data were obtained, including data of allogenic blood administration. Survival data was analyzed by Kaplan–Meier plotting and Cox regression.Results: One third of the cohort received blood transfusions during the period of NAC. In univariate analysis, blood transfusions during NAC, nodal stage and advanced tumor stage (pT >2) were negative prognostic factors for survival. In multivariate analysis, only pNx and pT >2 remained significant negative prognostic factors. In a subgroup analysis consisting of patients with localized tumors without dissemination (n = 96), patients that received transfusions during NAC showed an 18.5% absolute risk increase of death at five years of observation, although without statistical significance (p = .197).Conclusions: This is the first time that the extent and plausible effects of allogenic blood transfusions during NAC is examined in MIBC. Data suggest that there may be an association between blood transfusion and poor pathological and oncological outcome. Firm conclusions are difficult to draw due to few study participants and the retrospective nature of the study.

448 - Cytotoxic T cell related gene expression signature predicts improved outcome in muscle-invasive urothelial bladder cancer patients following radical cystectomy and adjuvant chemotherapy

448 - Cytotoxic T cell related gene expression signature predicts improved outcome in muscle-invasive urothelial bladder cancer patients following radical cystectomy and adjuvant chemotherapy

Sentinel node detection in muscle-invasive urothelial bladder cancer is feasible after neoadjuvant chemotherapy in all pT stages, a prospective multicenter report

PurposeTo determine whether sentinel node detection (SNd) in muscle-invasive urothelial bladder cancer (MIBC) can be performed in patients undergoing neoadjuvant chemotherapy (NAC) and determine whether SNd is feasible in all pT stages, including pT0.BackgroundPrevious published series of SNd in MIBC have not included patients undergoing NAC, and systematic reports of pT0 patients w/wo NAC were absent. Translational immunological tumor research on MIBC focusing on SNd, in the era of NAC, requires technical feasibility. Additionally, SNd in MIBC requests further evaluations as a method for nodal staging.Materials and methodsNinety-nine patients with suspected urothelial MIBC were prospectively selected from six urological centers. After TUR-B and primary staging, 65 MIBC patients qualified for radical cystectomy. Precystectomy staging was cT2a-T4aN0M0, including 47 NAC patients and 18 chemo-naïve patients. All 65 patients underwent intraoperative SNd by peritumoral injection of 80 Mbq Technetium and Geiger probe detection. Postcystectomy staging was pT0-T4aN0-N2M0. SNs were defined by two calculations, SNdef1 and SNdef2.ResultsTotally 1063 lymph nodes were removed (total SNs; 222–227). NAC patients with pT0 (n = 24) displayed a true positive detection in 91.7 % by either SNdef, with a median of 3.0 SNs. NACpT >0 patients had a true positive detection in 87 % (SNdef1) and 91.3 % (SNdef2). In a univariate analysis, patient group neither NAC nor tumor downstaging influenced detection rates, regardless of SN definition. In total eight patients, 4/22 metastatic nodes were SNs while 18/22 were non-SNs.ConclusionsSentinel node detection in MIBC is feasible also in NAC patients, regardless of pT stage. SNd played no role in nodal staging.