Primary Muscle-invasive Bladder Cancer Research Articles

Nomogram for the Pathological Complete Response After Neoadjuvant Chemotherapy in Muscle-Invasive Bladder Cancer Patients.

No validated instrument currently exists to predict neoadjuvant chemotherapy (NAC) response in muscle-invasive bladder cancer (MIBC) patients. We aim to develop and validate a nomogram based on clinicopathological factors for predicting who would benefit most from NAC. Between January 2016 and April 2023, 361 consecutive MIBC patients treated with NAC were enrolled in the study. Two hundred sixty patients at the Hu Nan institution comprised the development cohort. The validation cohort (91 patients) was from the Xiang Hua center. Patient clinicopathologic information was documented. Using regression coefficients, a predictive model was constructed using multivariate logistic regression. The likelihood ratio test with Akaike's information criterion was then used as the ending rule for backward stepwise selection. This predictive model's efficacy was evaluated for discrimination, calibration, and clinical utility. Predictors of this model included the origin of MIBC, pathological tumor type, clinical tumor stage, and tumor size. In the validation cohort, the model demonstrated good discrimination with an AUROC of 0.7221 (P < 0.001) and calibration (Unreliability test, P = 0.580). In addition, decision curve analysis revealed that the model was clinically beneficial. This study indicated that primary MIBC, pure UC pathological type, lower clinical tumor stage, and maximum tumor diameter <3 cm were significant predictors of ypCR in MIBC patients after NAC. This nomogram may contribute to the preciousadministration of NAC and the avoidance of chemotherapy toxicity and delayed RC.

Total extra-peritoneal approach to radical cystectomy with ureterostomy: A novel technique for the elderly and frail

ObjectivesRadical cystectomy with urinary diversion is the gold standard treatment for bladder cancer (high-risk/muscle invasive). The transperitoneal approach is associated with significant gastrointestinal complications like ileus. In the elderly and frail with a single functional kidney, we describe an extraperitoneal technique of radical cystectomy, with a ureterostomy, to be performed without general anesthesia. Materials and methodsThe elderly, frail, and high-risk candidates for general anesthesia, with a prior history of nephroureterectomy with a second primary muscle-invasive bladder cancer, were chosen. All patients underwent the described procedure under combined spinal and epidural anesthesia. The posterior dissection was retrograde, caudal to cranial, with the peritoneum being opened only for resection of the dome. A cutaneous ureterostomy was fashioned on the side of the functional kidney. Peri-operative parameters were assessed for early recovery in this high-risk group. ResultsThe mean age was 82 years (range: 73–91), with Charleson Comorbidity Index 5, and were all deemed unfit for neoadjuvant chemotherapy. With a median duration of 127.5 minutes, an average blood loss of 225ml, and no patient requiring general anesthesia; early ambulation, early return of bowel function, and a lesser hospital stay (7 days) with minimal morbidity were achieved. Negative surgical margins were achieved in all cases, with a mean harvest of 29 lymph nodes. Only 1 patient developed stomal stenosis. The cause-specific survival (CSS) is 100% at 2 years. ConclusionsThe highlighting features are the early return of bowel function (flatus passage on day 1) and the avoidance of the cardio-pulmonary complications of general anesthesia. The extraperitoneal cystectomy offers a promising alternative in this select group and warrants further studies to extrapolate this technique for bilateral urinary drainage.

Markers in Identifying Pathological Complete Response Status in Muscle Invasive Bladder Cancer Patients Who Achieved Clinical Complete Response After Neoadjuvant Chemotherapy

BackgroundPrior research has demonstrated a discrepancy between pathologic and clinical staging in individuals with muscle-invasive bladder cancer (MIBC) following neoadjuvant chemotherapy (NAC). These findings were the major reasons for the under-usage of the bladder preservation strategy. Hence, we aim to explore the reliable markers in identifying pathological complete response (ypCR) status in MIBC patients who achieved clinical complete response (cCR) after NAC. MethodsBetween January 2016 and April 2023, 161 consecutive MIBC patients treated with NAC and achieved cCR were enrolled in the study. Patient clinicopathologic information was documented. Multivariate binary logistic regression was used for determining adjusted odds ratios (OR) and 95% confidence intervals (CI). It considered statistically significant when a P < .05. ResultsOf the 161 MIBC patients with cCR after NAC, 64.0% (103/161) achieved ypCR after RC. The independent factors for ypCR status were the origin of MIBC (secondary vs. Primary) with odds ratios (OR) of 0.433 (P = .027), the pathological type (pure vs. mixed) with OR of 3.556 (P = .003), concurrent carcinoma in situ (yes vs. no) with OR of 0.360 (P = .016), and lymphovascular invasion (yes vs. no) with OR of 0.271 (P = .007). ConclusionThis study demonstrated that primary MIBC, pure UC pathological type, absence of concurrent CIS, and LVI were significant predictors of ypCR in MIBC patients who achieved cCR after NAC and before surgery. These findings may contribute to the decision-making process of bladder preservation strategy in selected patients.

PD36-10 SURVIVAL DIFFERENCES BETWEEN PRIMARY VERSUS SECONDARY MUSCLE-INVASIVE BLADDER CANCER PATIENTS TREATED WITH RADICAL CYSTECTOMY

You have accessJournal of UrologyCME1 Apr 2023PD36-10 SURVIVAL DIFFERENCES BETWEEN PRIMARY VERSUS SECONDARY MUSCLE-INVASIVE BLADDER CANCER PATIENTS TREATED WITH RADICAL CYSTECTOMY Cristina Cano Garcia, Severine Banek, Mike Wenzel, Benedikt Hoeh, Clara Humke, Clarissa Wittler, Jens Köllermann, Pierre I. Karakiewicz, Philipp Mandel, Felix K.H. Chun, and Luis A. Kluth Cristina Cano GarciaCristina Cano Garcia More articles by this author , Severine BanekSeverine Banek More articles by this author , Mike WenzelMike Wenzel More articles by this author , Benedikt HoehBenedikt Hoeh More articles by this author , Clara HumkeClara Humke More articles by this author , Clarissa WittlerClarissa Wittler More articles by this author , Jens KöllermannJens Köllermann More articles by this author , Pierre I. KarakiewiczPierre I. Karakiewicz More articles by this author , Philipp MandelPhilipp Mandel More articles by this author , Felix K.H. ChunFelix K.H. Chun More articles by this author , and Luis A. KluthLuis A. Kluth More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000003334.10AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: Differentiation exists between primary muscle-invasive bladder cancer (MIBC) patients and prior history of non-muscle invasive bladder cancer (NMIBC) with progression to secondary MIBC. However, data comparing survival of primary vs. secondary MIBC treated with radical cystectomy (RC) are reporting conflicting results. Therefore, we aim to test the survival difference between primary vs. secondary MIBC treated with RC within our tertiary-case database. METHODS: We relied on an institutional tertiary-care database to identify non-metastatic primary and secondary MIBC patients who underwent RC between 2010 and 2021. Specifically, the definition of MIBC consisted of muscle invasion presented in the histological specimen from transurethral resection of the bladder. Kaplan Meier curves depicted two-year overall survival (OS) and recurrence-free survival (RFS). Multivariable cox regression models tested independent predictor status of primary vs. secondary MIBC in analyses addressing OS and RFS. Co-variables consisted of age, sex, pT stage, pN stage, R status, and histology (pure urothelial vs. mixed), as well as intravesical therapy, neoadjuvant chemotherapy and adjuvant chemotherapy. RESULTS: Of 107 MIBC patients treated with RC, 82 (77%) exhibited primary and 25 (23%) secondary MIBC. Median follow-up was 12.8 months. Higher rates of pN0 (60 vs. 40%, p=0.01) were recorded in primary compared to secondary MIBC patients. At two-year follow-up, no statistically significant OS difference was observed between primary vs. secondary MIBC patients (55.3 vs. 46.0%, p=0.45). Similarly, in multivariable cox regression models, secondary MIBC did not predict lower OS compared to primary MIBC (Hazard Ratio (HR): 1.30, 95% confidence interval (CI): 0.59-2.88, p=0.51). At two-year follow-up, no PFS difference was observed between primary vs. secondary MIBC patients (43.2 vs. 41.2%, p=0.81). Similarly, in multivariable cox regression model, secondary MIBC did not predict lower RFS compared to primary MIBC (HR: 1.16, 95% CI: 0.52-2.60, p=0.72). CONCLUSIONS: In this tertiary-based institution study comparing, secondary MIBS patients exhibited lower OS than their primary MIBC counterparts. However, no statistically significant OS were observed between these two examined groups. Moreover, no RFS differences were observed between primary vs. secondary MIBC patients. Nonetheless, ongoing patient surveillance is required to identify early MIBC progression in patients with NMIBC. Source of Funding: None © 2023 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 209Issue Supplement 4April 2023Page: e984 Advertisement Copyright & Permissions© 2023 by American Urological Association Education and Research, Inc.MetricsAuthor Information Cristina Cano Garcia More articles by this author Severine Banek More articles by this author Mike Wenzel More articles by this author Benedikt Hoeh More articles by this author Clara Humke More articles by this author Clarissa Wittler More articles by this author Jens Köllermann More articles by this author Pierre I. Karakiewicz More articles by this author Philipp Mandel More articles by this author Felix K.H. Chun More articles by this author Luis A. Kluth More articles by this author Expand All Advertisement PDF downloadLoading ...

The Impact of Primary Versus Secondary Muscle-invasive Bladder Cancer at Diagnosis on the Response to Neoadjuvant Chemotherapy

BackgroundThere might be differential sensitivity to neoadjuvant chemotherapy (NAC) in patients with primary muscle-invasive bladder cancer (MIBC) in comparison to patients with secondary MIBC after a history of non–muscle-invasive disease. ObjectiveTo investigate pathologic response rates and survival associated with primary versus secondary MIBC among patients treated with cisplatin-based NAC for cT2–4N0M0 MIBC. Design, setting, and participantsOncologic outcomes were compared for 350 patients with primary MIBC and 64 with secondary MIBC treated with NAC and radical cystectomy between 1992 and 2021 at 11 academic centers. Genomic analyses were performed for 476 patients from the Memorial Sloan Kettering/The Cancer Genome Atlas cohort. Outcome measurements and statistical analysisThe outcome measures were pathologic objective response (pOR; ≤ypT1 N0), pathologic complete response (pCR; ypT0 N0), overall mortality, and cancer-specific mortality. Results and limitationsThe primary MIBC group had higher pOR (51% vs 34%; p = 0.02) and pCR (33% vs 17%; p = 0.01) rates in comparison to the secondary MIBC group. On multivariable logistic regression analysis, primary MIBC was independently associated with both pOR (odds ratio [OR] 0.49, 95% confidence interval [CI] 0.26–0.87; p = 0.02) and pCR (OR 0.41, 95% CI 0.19–0.82; p = 0.02). However, on multivariable Cox regression analysis, primary MIBC was not associated with overall mortality (hazard ratio 1.70, 95% CI 0.84–3.44; p = 0.14) or cancer-specific mortality (hazard ratio 1.50, 95% CI 0.66–3.40; p = 0.3). Genomic analyses revealed a significantly higher ERCC2 mutation rate in primary MIBC than in secondary MIBC (12.4% vs 1.3%; p < 0.001). ConclusionsPatients with primary MIBC have better pathologic response rates to NAC in comparison to patients with secondary MIBC. Chemoresistance might be related to the different genomic profile of primary versus secondary MIBC. Patient summaryWe investigated the treatment response to neoadjuvant chemotherapy (NAC; chemotherapy received before the primary course of treatment) and survival for patients with a primary diagnosis of muscle-invasive bladder cancer (MIBC) in comparison to patients with a history of non–muscle-invasive bladder cancer that progressed to MIBC. Patients with primary MIBC had a better response to NAC but this did not translate to better survival after accounting for other tumor characteristics.

Primary versus secondary muscle-invasive bladder cancer: survival after curative treatment

Purpose To assess if cancer-specific survival (CSS) following curative intent treatment (CIT) for muscle-invasive bladder cancer (MIBC) differs between patients presenting with MIBC (primary) and patients presenting with non-muscle-invasive bladder cancer who progress to MIBC (secondary). Methods This study uses data from the Cancer Registry of Norway on patients initially diagnosed with bladder cancer in 2008–2012 and treated with radical cystectomy (RC) or radiotherapy (RT). To ensure a clinically relevant population, we selected patients with a pre-treatment histology confirming muscle-invasion. Survival models were applied to evaluate differences in observed and adjusted CSS by type of MIBC and stratified by type of CIT. Adjustment was made for age group, sex, previous cancer, diagnostic hospital’s academic status and geographical region, and type of CIT. Results We identified 650 eligible patients: 589 (91%) primary MIBC and 61 (9%) secondary MIBC. A total of 556 (86%) patients underwent RC and 94 (14%) RT. The 5-year CSS for primary MIBC was 56% and 59% for secondary MIBC (p = 0.68). The type of MIBC did not impact the risk of bladder cancer death (HR = 0.85, CI = 0.55–1.33, p = 0.48), nor when stratified for CIT (RC: HR = 0.93, CI = 0.57–1.53, p = 0.78); RT: HR = 0.71, CI = 0.24–2.16, p = 0.55). Conclusion This first nation-wide population-based study comparing CSS between primary and secondary MIBC showed no significant difference in survival regardless of type of CIT. Continued surveillance of patients with non-muscle-invasive bladder cancer is necessary to detect early progression to MIBC. Future studies should include molecular and genetic characteristics in addition to detailed clinicopathologic information.

MP03-15 PRIMARY VERSUS SECONDARY MUSCLE INVASIVE BLADDER CANCER: COMPARING THE PATHOLOGIC AND ONCOLOGIC OUTCOMES BETWEEN BOTH FORMS OF MUSCLE INVASIVE DISEASE WHEN TREATED WITH STANDARD OF CARE

You have accessJournal of UrologyCME1 May 2022MP03-15 PRIMARY VERSUS SECONDARY MUSCLE INVASIVE BLADDER CANCER: COMPARING THE PATHOLOGIC AND ONCOLOGIC OUTCOMES BETWEEN BOTH FORMS OF MUSCLE INVASIVE DISEASE WHEN TREATED WITH STANDARD OF CARE Tarik Benidir, Zaeem Lone, Ao Zhang, Carlos Munoz-Lopez, Pranay Hegde, Kevin Fung, Jesse Fajnzylber, Eric Klein, Mohammed Eltemamy, Jihad Kaouk, Georges Pascal-Haber, Nima Almassi, Christopher Weight, and Byron Lee Tarik BenidirTarik Benidir More articles by this author , Zaeem LoneZaeem Lone More articles by this author , Ao ZhangAo Zhang More articles by this author , Carlos Munoz-LopezCarlos Munoz-Lopez More articles by this author , Pranay HegdePranay Hegde More articles by this author , Kevin FungKevin Fung More articles by this author , Jesse FajnzylberJesse Fajnzylber More articles by this author , Eric KleinEric Klein More articles by this author , Mohammed EltemamyMohammed Eltemamy More articles by this author , Jihad KaoukJihad Kaouk More articles by this author , Georges Pascal-HaberGeorges Pascal-Haber More articles by this author , Nima AlmassiNima Almassi More articles by this author , Christopher WeightChristopher Weight More articles by this author , and Byron LeeByron Lee More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000002515.15AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: Primary muscle invasive bladder cancer (P-MIBC) is the most common presentation at initial consultation; however, a subset of patients progress to MIBC following initial management for non-muscle invasive bladder cancer (NMIBC). The latter has been coined secondary MIBC (S-MIBC) and may exhibit decreased sensitivity to cisplatin-based chemotherapy. We aimed to explore response to neoadjuvant chemotherapy (NAC) and oncologic outcomes between P-MIBC and S-MIBC patients receiving radical cystectomy at a high-volume tertiary care center. METHODS: We performed a retrospective review of radical cystectomy (RC) patients from 2010 to 2019 who were cT2-T4/N0 and treated with a cisplatin-based NAC regimen. Patients were defined as S-MIBC if they had history of NMBIC, were treated with at least one course of induction BCG, and progressed to MIBC. Our primary outcomes of interest were down-staging rates, which was defined as <pT2/N0, and complete pathologic response (pT0/N0). Secondary outcomes of interest were cancer specific survival (CSS), overall survival (OS), and recurrence free survival (RFS). Categorical variables were compared with the Pearson-Chi Square test. Survival outcomes were assessed using the Kaplan-Meier method with log rank. Multivariate Cox Proportional Hazards models were utilized to identify predictors of survival outcomes. RESULTS: 333 patients were included (48 S-MIBC vs. 285 P-MIBC). Following NAC and RC, there were no differences in down-staging rates between both groups (S-MIBC: 54% vs. P-MIBC: 51%, p=0.67). There was no difference in complete pathologic response rates between the two groups (S-MIBC: 33% vs. P-MIBC: 28%, p=0.41). There were no differences in CSS (p=0.97), OS (p=0.94), or RFS (p=0.83). On Cox Proportional Hazards regression, only ³ pT2 and N+ disease predicted poorer CSS, OS, and RFS. CONCLUSIONS: S-MIBC is an uncommon presentation as compared to P-MIBC. In our patient population, there were no differences between P-MIBC and S-MIBC with respect to cisplatin sensitivity and oncologic outcomes. Future studies should focus on molecular biomarkers that can predict NAC response in these patients. Source of Funding: N/A © 2022 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 207Issue Supplement 5May 2022Page: e26 Advertisement Copyright & Permissions© 2022 by American Urological Association Education and Research, Inc.MetricsAuthor Information Tarik Benidir More articles by this author Zaeem Lone More articles by this author Ao Zhang More articles by this author Carlos Munoz-Lopez More articles by this author Pranay Hegde More articles by this author Kevin Fung More articles by this author Jesse Fajnzylber More articles by this author Eric Klein More articles by this author Mohammed Eltemamy More articles by this author Jihad Kaouk More articles by this author Georges Pascal-Haber More articles by this author Nima Almassi More articles by this author Christopher Weight More articles by this author Byron Lee More articles by this author Expand All Advertisement PDF DownloadLoading ...

Evaluating the impact of 18F-FDG-PET-CT on risk stratification and treatment adaptation for patients with muscle-invasive bladder cancer (EFFORT-MIBC): a phase II prospective trial

BackgroundThe outcome of patients with muscle-invasive bladder cancer (MIBC) remains poor, despite aggressive treatments. Inadequate primary staging, classically performed by computed tomography (CT)-imaging, could lead to inappropriate treatment and might contribute to these poor results. Although not (yet) adapted by international guidelines, several reports have indicated the superiority of 18F-fluorodeoxyglucose-positron emission tomography-CT (18F-FDG-PET-CT) compared to CT in the detection of lymph node and distant metastases. Thereby the presence of extra-vesical disease on 18F-FDG-PET-CT has been correlated with a worse overall survival. This supports the hypothesis that 18F-FDG-PET-CT is useful in stratifying MIBC patients and that adapting the treatment plan accordingly might result in improved outcome.MethodsEFFORT-MIBC is a multicentric prospective phase II trial aiming to include 156 patients. Eligible patients are patients with histopathology-proven MIBC or ≥ T3 on conventional imaging treated with MIBC radical treatment, without extra-pelvic metastases on conventional imaging (thoracic CT and abdominopelvic CT/ magnetic resonance imaging (MRI)). All patients will undergo radical local therapy and if eligible neo-adjuvant chemotherapy. An 18F-FDG-PET-CT will be performed in addition to and at the timing of the conventional imaging. In case of presence of extra-pelvic metastasis on 18F-FDG-PET-CT, appropriate intensification of treatment with metastasis-directed therapy (MDT) (in case of ≤3 metastases) or systemic immunotherapy (> 3 metastases) will be provided. The primary outcome is the 2-year overall survival rate. Secondary endpoints are progression-free survival, distant metastasis-free survival, disease-specific survival and quality of life. Furthermore, the added diagnostic value of 18F-FDG-PET-CT compared to conventional imaging will be evaluated and biomarkers in tumor specimen, urine and blood will be correlated with primary and secondary endpoints.DiscussionThis is a prospective phase II trial evaluating the impact of 18F-FDG-PET-CT in stratifying patients with primary MIBC and tailoring the treatment accordingly. We hypothesize that the information on the pelvic nodes can be used to guide local treatment and that the presence of extra-pelvic metastases enables MDT or necessitates the early initiation of immunotherapy leading to an improved outcome.Trial registrationThe Ethics Committee of the Ghent University Hospital (BC-07456) approved this study on 11/5/2020. The trial was registered on ClinicalTrials.gov (NCT04724928) on 21/1/2021.

P0783 - Comparison of clinicopathological characteristics between primary muscle-invasive bladder cancer and secondary muscle invasive bladder recurrence subsequent to upper tract urothelial carcinoma

P0783 - Comparison of clinicopathological characteristics between primary muscle-invasive bladder cancer and secondary muscle invasive bladder recurrence subsequent to upper tract urothelial carcinoma

P0830 - Luminal primary muscle-invasive bladder cancer patients are less likely to benefit from platinum-based neoadjuvant chemotherapy

P0830 - Luminal primary muscle-invasive bladder cancer patients are less likely to benefit from platinum-based neoadjuvant chemotherapy

Comparison of the prognosis of primary vs. progressive muscle invasive bladder cancer after radical cystectomy: Results from a large multicenter study

PurposeTo assess whether progressive and primary muscle invasive bladder cancer (MIBC) have different prognosis after radical cystectomy or not. To date only a few data are available on this topic with conflicting results. Further studies on large cohort are needed to clarify these outcomes that may influence bladder cancer management for these patients. Material and methodsA multicentre retrospective study was conducted on patient treated for MIBC at 5 centres between 2005 and 2015 by radical cystectomy. Patients’ outcomes were compared between patients with primary MIBC vs. progressive MIBC subsequent to a history of non-muscle invasive bladder cancer (NMIBC). ResultsA total of 1197 patients were included. Median (IQ) age was 65 (58–72) years and median follow-up was 65 months. Baseline characteristics were similar between the groups as well as the Tumour pT stage, N status and positive surgical margins. Patients with progressive MIBC had worse overall survival (OS) (hazard ratio [HR] 1.36, [95%CI 1.10–1.76]; P = 0.004), cancer specific survival (CSS) (HR 1.41 [1.13–1.78]; P = 0.002), and recurrence-free survival (RFS) (HR 1.21 [1.01–1.49]; P = 0.05). Pathological stage ≥pT3, positive surgical margins, and positive lymph nodes status (pN+) were also found as predictors of OS, CSS, and RFS. ConclusionsOur results suggest that patient having a progressive BC have a worse prognosis in terms of OS, PFS, and CSS than patient with primary disease. These 2 groups may require different management and patients with high risk NMIBC should be assessed properly to avoid progression and be offered early cystectomy.

Abstract PR08: The genomic landscape of metastatic urothelial carcinoma from circulating tumor DNA

Abstract The recent expansion of treatment options for patients with metastatic urothelial carcinoma (mUC) has emphasized the need for molecular biomarkers in this setting. However, knowledge of the somatic genome landscape in mUC is limited; large-scale sequencing efforts have relied on primary tumor tissue from muscle-invasive bladder cancer (MIBC), revealing a molecularly heterogeneous disease characterized in particular by high somatic mutation rates. Putative prognostic and predictive biomarkers described from primary tissue need validation in metastatic tumors. Given the challenge of obtaining metastatic tissue, we sought to utilize circulating tumor DNA (ctDNA) to characterize the somatic landscape in mUC. We collected 162 whole-blood samples from 90 mUC patients. Targeted next-generation sequencing was performed on cell-free DNA (cfDNA) and matched leukocyte DNA utilizing a custom 50-gene panel. Somatic alteration frequencies in our metastatic cohort were compared to those reported for primary MIBC by TCGA (Cell 2017, n=412), with data obtained via cBioPortal. Our cohort of 90 mUC patients included 14% with upper tract disease. The median cfDNA sequencing depth was 986x, with ctDNA detectable in at least one blood collection for 81% (73/90) of mUC patients. In 10/73 patients, the estimated tumor mutation burden was ≥30 mutations per Mb. TP53 was the most frequently mutated gene (46/73 ctDNA-positive patients). Chromatin modifiers were also frequently altered: ARID1A 27%, and 25% for KDM6A and KMT2D. Genes mutated in the PI3K pathway included PIK3CA (22%), PTEN (5.5%), and PIK3R1 (1.4%). FGFR3 mutations were identified in 8.2% of patients. ERBB2 mutations were present in 12.3% of patients, and amplification was detected in eight patients. Thus, the metastatic somatic landscape closely resembles primary disease; however, comparison to TCGA dataset revealed mutations in TP53 and FGFR1 were enriched for in the metastatic setting (TP53: 63.0% vs. 48.1%, p = 0.022; FGFR1: 5.5% vs. 1.5%, p = 0.049; two-sided Fisher's exact test). Profiling of ctDNA from a large mUC cohort suggests a relatively similar somatic landscape to primary MIBC. However, alterations in key driver genes are potentially over- or underrepresented in metastatic disease, which has prognostic implications. In mUC, ctDNA profiling is a powerful alternative to metastatic tissue biopsy. This abstract is also being presented as Poster B19. Citation Format: Gillian R. Vandekerkhove, Matti Annala, Jean-Michel Lavoie, Nora Sundahl, Simon Walz, Takeshi Sano, Andrew Murtha, Tilman Todenhöfer, Piet Ost, Kim N. Chi, Peter C. Black, Bernhard Eigl, Alexander W. Wyatt. The genomic landscape of metastatic urothelial carcinoma from circulating tumor DNA [abstract]. In: Proceedings of the AACR Special Conference on Bladder Cancer: Transforming the Field; 2019 May 18-21; Denver, CO. Philadelphia (PA): AACR; Clin Cancer Res 2020;26(15_Suppl):Abstract nr PR08.

The prognostic value of the urokinase-plasminogen activator system (uPA) in bladder cancer patients treated with radical cystectomy (RC)

PurposeUrokinase-plasminogen activator (uPA), its receptor (uPAR), and the plasmin-activator inhibitor type 1 (PAI-1) have been associated with oncologic outcomes in various malignancies and could help identify bladder cancer (BC) patients treated with radical cystectomy (RC) who are likely to benefit from intensification of therapy to prevent disease progression. Our aim was to assess the value of uPA, uPAR, and PAI-1 for prognosticating survival outcomes of patients treated with RC for BC. Materials and methodsTumor specimens from 272 consecutive patients treated with RC for advanced BC were assessed with immunohistochemical staining for uPA, uPAR, and PAI-1. Overexpression was assessed by pathological image analysis. Kaplan-Meier estimates and multivariable Cox-regression were used to analyze survival. Harrell's C-index was used to assess for clinical impact of the uPA system. ResultsuPA, uPAR, and PAI-1 were overexpressed in 48.2%, 51.1%, and 52.2% of patients, respectively. uPA overexpression was associated with lymphovascular invasion (P = 0.034) and nodal status (P = 0.013); PAI-1 overexpression was associated with primary muscle-invasive BC (P = 0.015) and lymphovascular invasion (P = 0.024). uPA, uPAR, and the number of overexpressed markers were all 3 significantly associated with shorter overall recurrence-free-, distant recurrence-free-, and cancer-specific survival. In multivariable analyses, uPA overexpression remained associated with shorter recurrence-free survival (hazard ratio [HR] = 1.79; P = 0.036) in the entire cohort, in patients without lymph node metastasis (HR = 1.98; P = 0.018) and those with nonorgan-confined disease (HR = 1.98; P = 0.022). uPAR overexpression was associated with shorter recurrence-free survival in patients without lymph node metastasis (HR = 2.01; P = 0.021) and those with organ-confined disease (HR = 4.11; P = 0.037). ConclusionMembers of the uPA system are associated with features of biologically aggressive BC and oncologic outcomes. However, their value beyond currently available information remains limited.

Efficacy of neoadjuvant chemotherapy followed by resection in primary and secondary muscle-invasive bladder cancer (MIBC).

497 Background: Neoadjuvant chemotherapy followed by cystectomy in MIBC is associated with improved survival compared to cystectomy alone. Recent retrospective studies indicated that secondary MIBC (non-MIBC progressed to MIBC) had worse outcome with cisplatin based neoadjuvant chemotherapy when compared to primary MIBC. To further evaluate this observation, we queried our database to assess the differential response and determine if prior use of intravesical therapy diminishes the effect of cisplatin based neoadjuvant chemotherapy. Methods: A total of 387 patients diagnosed with T2-4 or N0-3 and M0 from 2000-2018 and underwent cystectomy were retrospectively chart reviewed for demographics, treatment and outcomes at University of Iowa Holden Comprehensive Cancer Center. Cox regression models were utilized to assess differences in recurrence-free survival (RFS) and overall survival (OS). Time was calculated from cystectomy to recurrence or death due to any cause for RFS and OS, respectively. Results: Of the 387 patients, 324 patients had primary MIBC and 63 had secondary MIBC. Median follow up was 25.8 months. Intravesical therapy was administered to 98% (62/63) of secondary MIBC patients. Neoadjuvant chemotherapy was administered to 38% (122/324) of primary MIBC patients and 21% (13/63) of secondary MIBC patients. NAC had no difference in response rates (CR and PR) for primary vs secondary MIBC (p=0.73). Additionally, there was no difference between the primary and secondary MIBC with regards to RFS (p=0.54) and OS (p=0.12) on univariate analysis. The effect of neoadjuvant chemotherapy did not differ based on prior use of intravesical therapy in terms of RFS (p=0.61) or OS (p=0.40). Additionally, neoadjuvant chemotherapy irrespective of prior use of intravesical therapy was not associated with RFS (p=0.66) or OS (p=0.15). Conclusions: Prior intravesical therapy was not associated with differential efficacy of neoadjuvant chemotherapy in secondary MIBC when compared to primary MIBC.

Amplification of 7p12 Is Associated with Pathologic Nonresponse to Neoadjuvant Chemotherapy in Muscle-Invasive Bladder Cancer

Pathologic downstaging (pDS) to neoadjuvant chemotherapy (NAC) is one of the most important predictors of survival in muscle-invasive bladder cancer (MIBC). The use of NAC is limited as pDS is only achieved in 30% to 40% of cases and predictive biomarkers are still lacking. We performed a comprehensive immunomolecular biomarker analysis to characterize the role of immune cells and inhibitory checkpoints, genome-wide frequencies of copy number alterations, mutational signatures in whole exome, and tumor mutational burden in predicting NAC response. Our retrospective study included 23 primary MIBC patients who underwent NAC, followed by radical cystectomy. pDS to NAC was a significant prognostic factor for better recurrence-free survival (P<0.001), with a median time to recurrence of 41.2 versus 5.5 months in nonresponders. DNA damage repair alterations were noticed in 38.1% (n = 8), confirming a positive correlation with high tumor mutational burden (P=0.007). Chromosomal 7p12 amplification, including the genes HUS1, EGFR, ABCA13, and IKZF1, predicted nonresponse in patients with a sensitivity, a negative predictive value, and a specificity of 71.4%, 87.5%, and 100%, respectively. Total count of CD3+ T cells/mm2 tumor was a significant predictor of NAC response. In conclusion, 7p12 amplification may predict nonresponse to NAC and worse survival in MIBC. Multicenter, prospective trials with sufficient statistical power may further fortify these findings.

Systematic screening of protein-coding gene expression identified HMMR as a potential independent indicator of unfavorable survival in patients with papillary muscle-invasive bladder cancer

Papillary and non-papillary are two histological patterns of bladder carcinogenesis and are considered as dual-track oncogenic pathways, which have different genetic alterations. The TCGA-bladder cancer (BLCA) database contains clinicopathological, genomic and survival data from over 400 muscle-invasive bladder cancer patients. In this study, using data from this database, we performed a systematic screening of gene expression to identify the protein-coding gene that might have prognostic value in papillary and non-papillary muscle-invasive bladder cancer (MIBC). The data of patients with primary MIBC in TCGA-BLCA was acquired from the UCSC Xena project (http://xena.ucsc.edu) for re-analysis. By setting |log2 fold change|≥2 and adjusted p value <0.01 as the screening criteria, we found 751 significantly dysregulated genes, including 183 overexpressed and 568 downregulated genes. HMMR was identified as a potential prognostic marker with unique expression. Multivariate analysis showed that its expression was an independent prognostic indicator of shorter progression-free survival (PFS) (HR: 1.400, 95%CI: 1.021–1.920, p = 0.037) in the papillary subtype. ENST00000393915.8 and ENST00000358715.3, two transcripts that contain all 18 exons and encode the full length of HMMR, were significantly upregulated in cancer tissues compared with normal bladder tissues. None of the 17 CpG sites in its DNA locus was relevant to HMMR expression. 26/403 (6.5%) MIBC cases had HMMR gene-level amplification, which was associated with upregulated HMMR expression compared with the copy-neutral and deletion groups. Gene set enrichment analysis (GSEA) in papillary MIBC found that the high HMMR expression group was associated with upregulated genes enriched in multiple gene sets with well-established role in BC development, including G2M checkpoint, E2 F Targets, Myc Targets V1, Myc Targets V2 and Glycolysis. Based on these findings, we infer that HMMR expression might be a specific prognostic marker in terms of PFS in papillary MIBC. DNA amplification might be an important mechanism of its elevation.

Prognostic significance of history of nonmuscle invasive bladder cancer in patients with muscle invasive bladder cancer treated with neoadjuvant chemotherapy followed by surgery.

375 Background: Efficacy of cisplatin-based neoadjuvant chemotherapy (NAC) followed by radical cystectomy (RC) for T2-4aN1M0 muscle-invasive bladder cancer (MIBC) was proved by randomize controlled trials. Recent retrospective studies suggested that MIBC patients who had a history of non-muscle invasive bladder cancer (NMIBC) had lower pathologic complete response and worse overall survival rate to NAC and RC. This study aimed to compare clinical outcomes between MIBC that progressed from NMIBC (secondary MIBC) and primary MIBC. Methods: A retrospective analysis of patients with urothelial carcinoma (cT2-4aN0-1M0) who received neoadjuvant chemotherapy from January 2011 and December 2017 in Asan Medical Center was conducted. Clinicopathologic outcomes were compared between 187 patients with primary MIBC and 38 patients with secondary MIBC. Results: Baseline characteristics are well balanced between the groups. Downstaging rate ( &lt; ypT2 and no N upstaging) are 46.7% for secondary MIBC group, 55.6% for primary MIBC group (p = 0.390), and positive pathologic metastatic nodes (ypN1+) are observed in 23.3% for secondary MIBC group, 18.3% for primary MIBC group (p = 0.523). There were no differences in overall survival (OS) (3 year OS 69.3% for secondary MIBC, 70.3% for primary MIBC, p = 0.420), disease-free survival (DFS) (3 year DFS 57.7% vs 56.6%, p = 0.880) between the groups. History of NMIBC is not independent prognostic factor for OS on multivariable analysis. Conclusions: Patients with secondary MIBC treated with NAC showed no differences in NAC response, pathologic downstaging rate, OS, DFS compared to patients with primary MIBC. Prospective or larger cohort study are required in the future. Genomic analysis is ongoing to identify genetic differences between two groups.

Genomic Differences Between “Primary” and “Secondary” Muscle-invasive Bladder Cancer as a Basis for Disparate Outcomes to Cisplatin-based Neoadjuvant Chemotherapy

BackgroundCisplatin-based neoadjuvant chemotherapy (NAC) followed by radical cystectomy (RC) is the standard of care for patients with muscle-invasive bladder cancer (MIBC). It is unknown whether this treatment strategy is appropriate for patients who progress to MIBC after treatment for prior noninvasive disease (secondary MIBC). ObjectiveTo determine whether clinical and genomic differences exist between primary and secondary MIBC treated with NAC and RC. Design, setting, and participantsClinicopathologic outcomes were compared between 245 patients with clinical T2-4aN0M0-stage primary MIBC and 43 with secondary MIBC treated with NAC and RC at Memorial Sloan Kettering Cancer Center (MSKCC) from 2001 to 2015. Genomic differences were assessed in a retrospective cohort of 385 prechemotherapy specimens sequenced by whole-exome or targeted exon capture by the Cancer Genome Atlas or at MSKCC. Findings were confirmed in an independent validation cohort of 94 MIBC patients undergoing prospective targeted exon sequencing at MSKCC. Outcome measurements and statistical analysisPathologic response rates, recurrence-free survival (RFS), bladder cancer-specific survival (CSS), and overall survival (OS) were measured. Differences in somatic genomic alteration rates were compared using Fisher's exact test and the Benjamini-Hochberg false discovery rate method. Results and limitationsPatients with secondary MIBC had lower pathologic response rates following NAC than those with primary MIBC (univariable: 26% vs 45%, multivariable: odds ratio=0.4 [95% confidence interval=0.18−0.84] p=0.02) and significantly worse RFS, CSS, and OS. Patients with secondary MIBC treated with NAC had worse CSS compared with cystectomy alone (p=0.002). In a separate genomic analysis, we detected significantly more likely deleterious somatic ERCC2 missense mutations in primary MIBC tumors in both the discovery (10.9% [36/330] vs 1.8% [1/55], p=0.04) and the validation (15.7% [12/70] vs 0% [0/24], p=0.03) cohort. ConclusionsPatients with secondary MIBC treated with NAC had worse clinical outcomes than similarly treated patients with primary MIBC. ERCC2 mutations predicted to result in increased cisplatin sensitivity were enriched in primary versus secondary MIBC. Prospective validation is still needed, but given the lack of clinical benefit with cisplatin-based NAC in patients with secondary MIBC, upfront RC or enrollment in clinical trials should be considered. Patient summaryA retrospective cohort study of patients with “primary” and “secondary” muscle-invasive bladder cancer (MIBC) treated with chemotherapy before surgical removal of the bladder identified lower response rates and shorter survival in patients with secondary MIBC. Tumor genetic sequencing of separate discovery and validation cohorts revealed that chemotherapy-sensitizing DNA damage repair gene mutations occur predominantly in primary MIBC tumors and may underlie the greater sensitivity of primary MIBC to chemotherapy. Prospective validation is still needed, but patients with secondary MIBC may derive greater benefit from upfront surgery or enrollment in clinical trials rather than from standard chemotherapy.

Oncological Outcome of Primary and Secondary Muscle-Invasive Bladder Cancer: A Systematic Review and Meta-analysis

Conflicting results of survival outcomes for primary and secondary muscle-invasive bladder cancer (MIBC) have been reported in previous studies. Primary MIBC is defined as presentation of muscle-invasive disease at initial diagnosis while secondary MIBC presumes that non-muscle invasive disease later progressed to MIBC. Due to the varying reports, we conducted a systematic review and meta-analysis to compare survival outcomes between the two groups. Relevant studies were retrieved from Medline, Embase, the Cochrane Library, and Scopus using a comprehensive search approach. Cancer-specific survival (CSS) was the outcome measure. A total of 14 studies involving 4,075 cases were included. Patients with secondary MIBC were significantly correlated with worse CSS in model I (pooled HR: 1.29, 95% CI: 1.07–1.56, P = 0.008). The results of sensitivity analyses indicated that the omission of any single study each time did not have a significant impact on the combined risk estimates. Egger’s test suggested no publication bias among these studies. The European Organization for Research and Treatment of Cancer (EORTC) risk score offers the possibility of stratifying the secondary MIBC patients into different risk groups. In high-risk NMIBC, timely radical cystectomy should be considered. Further study is required to assess the multimodal therapy in both high-risk NMIBC and secondary MIBC patients as well as to evaluate genetic and molecular drivers of tumor induction, promotion, and progression.

History of Non-Muscle-Invasive Bladder Cancer May Have a Worse Prognostic Impact in cT2-4aN0M0 Bladder Cancer Patients Treated With Radical Cystectomy.

To investigate whether a history of non-muscle-invasive bladder cancer (NMIBC) plays a prognostic role in patients with muscle-invasive bladder cancer (MIBC) treated with radical cystectomy in the era when neoadjuvant chemotherapy was established as standard therapy for MIBC. A total of 282 patients who were diagnosed with cT2-T4aN0M0 bladder cancer treated with open radical cystectomy at our institutions were included. Initially diagnosed MIBC without a history of NMIBC was defined as primary MIBC group (n= 231), and MIBC that progressed from NMIBC was defined as progressive MIBC (n= 51). The rate of cT3/4a tumors was significantly higher in the primary MIBC group than in the progressive MIBC group (P= .004). Five-year recurrence-free survival and cancer-specific survival (CSS) rates for the primary MIBC group versus progressive MIBC group were 68.2% versus 55.9% (P= .039) and 76.1% versus 61.6% (P= .005), respectively. Progressive MIBC (hazard ratio, 2.170; P= .008) was independently associated with cancer death. In the primary MIBC group, the 5-year CSS rate in patients treated with neoadjuvant chemotherapy was 85.4%, which was significantly higher than that in patients without (71.5%, P= .023). In the progressive MIBC group, no significant differences were observed in CSS between patients treated with and without neoadjuvant chemotherapy. MIBC that progressed from NMIBC had a significantly worse clinical outcome than MIBC without a history of NMIBC and may not respond as well to neoadjuvant chemotherapy. These results are informative, even for NMIBC patients treated with conservative intravesical therapy.