Secondary Muscle-invasive Bladder Cancer Research Articles

Comparison of the survival outcomes between primary and secondary muscle-invasive bladder cancer: a propensity score-matched study.

Studies have classified muscle-invasive bladder cancer (MIBC) into primary (initially muscle-invasive, PMIBC) and secondary subtypes (initially non-muscle-invasive but progresses, SMIBC), for which controversial survival outcomes were demonstrated. This study aimed to compare the survival outcomes between PMIBC and SMIBC patients in China. Patients diagnosed with PMIBC or SMIBC at West China Hospital from January 2009 to June 2019 were retrospectively included. Kruskal-Wallis and Fisher tests were employed to compare clinicopathological characteristics. Kaplan-Meier curves and Cox competing proportional risk model were used to compare survival outcomes. Propensity score matching (PSM) was employed to reduce the bias and subgroup analysis was used to confirm the outcomes. A total of 405 MIBC patients were enrolled, including 286 PMIBC and 119 SMIBC, with a mean follow-up of 27.54 and 53.30 months, respectively. The SMIBC group had a higher proportion of older patients (17.65% [21/119] vs. 9.09% [26/286]), chronic disease (32.77% [39/119] vs . 22.38% [64/286]), and neoadjuvant chemotherapy (19.33% [23/119] vs . 8.04% [23/286]). Before matching, SMIBC had a lower risk of overall mortality (OM) (hazard ratios [HR] 0.60, 95% confidence interval [CI] 0.41-0.85, P = 0.005) and cancer-specific mortality (CSM) (HR 0.64, 95% CI 0.44-0.94, P = 0.022) after the initial diagnosis. However, higher risks of OM (HR 1.47, 95% CI 1.02-2.10, P = 0.038) and CSM (HR 1.58, 95% CI 1.09-2.29, P = 0.016) were observed for SMIBC once it became muscle-invasive. After PSM, the baseline characteristics of 146 patients (73 for each group) were well matched, and SMIBC was confirmed to have an increased CSM risk (HR 1.83, 95% CI 1.09-3.06, P = 0.021) than PMIBC after muscle invasion. Compared with PMIBC, SMIBC had worse survival outcomes once it became muscle-invasive. Specific attention should be paid to non-muscle-invasive bladder cancer with a high progression risk.

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 ...

146P Comparison of the survival outcomes between primary and secondary muscle-invasive bladder cancer: A propensity score-matched Chinese cohort

146P Comparison of the survival outcomes between primary and secondary muscle-invasive bladder cancer: A propensity score-matched Chinese cohort

Comparing Pathologic and Survival Outcomes Between Primary and Secondary Muscle Invasive Bladder Cancer When Treated by Radical Cystectomy With or Without Neoadjuvant Chemotherapy

OBJECTIVETo compare pathologic and survival outcomes between primary muscle invasive (pMIBC) and secondary muscle invasive (sMIBC) bladder cancer patients who were treated with or without cisplatin-based neoadjuvant chemotherapy (NAC) followed by radical cystectomy (RC). METHODSWe reviewed cT2-T4/N0 MIBC patients at our institution between 2010-2019. pMIBC was defined as presenting with > cT2 disease on initial or restaging TURBT with no prior history of bladder cancer. sMIBC was defined as prior history of NMIBC that was treated with at least one induction course of BCG that progressed to MIBC. Outcomes analyzed included pathologic downstaging rates defined as <pT2/N0, pathologic complete response rates (pT0/N0), and survival outcomes (RFS, CSS, OS). Survival outcomes were analyzed using the Kaplan-Meier Method or Gray's test with log rank. Cox Proportional Hazards and semiparametric hazards models proposed by Fine and Gray were constructed to identify predictors of oncologic outcomes. RESULTS333 patients were included in the analysis (sMIBC: 48 vs pMIBC: 285). There were no differences in pathologic downstaging (sMIBC: 54% vs pMIBC: 51%, P = .67) or pathologic complete response (sMIBC: 33% vs pMIBC: 28, P = .46). Survival analysis showed no differences when patients were treated with NAC+RC in oncologic outcomes. On regression analysis, only >pT2 and N+ disease were predictors of poorer CSS and OS. Separate analysis of sMIBC patients whom underwent RC only (N = 61), demonstrated inferior oncologic outcomes to other cohorts (P < .01). CONCLUSIONThere were no differences in pathologic response or survival between pMIBC and sMIBC patients when managed with NAC and RC.

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.

Comparative Outcomes of Primary Versus Recurrent High-risk Non–muscle-invasive and Primary Versus Secondary Muscle-invasive Bladder Cancer After Radical Cystectomy: Results from a Retrospective Multicenter Study

BackgroundRadical cystectomy (RC) is indicated in primary or secondary muscle-invasive bladder cancer (primMIBC, secMIBC) and in primary or recurrent high- or very high-risk non–muscle-invasive bladder cancer (primHR-NMIBC, recHR-NMIBC). The optimal timing for RC along the disease spectrum of nonmetastatic urothelial carcinoma remains unclear. ObjectiveTo compare outcomes after RC between patients with primHR-NMIBC, recHR-NMIBC, primMIBC, and secMIBC. Design, setting, and participantsThis retrospective, multicenter study included patients with clinically nonmetastatic bladder cancer (BC) treated with RC. Outcome measurements and statistical analysisWe assessed oncological outcomes for patients who underwent RC according to the natural history of their BC. primHR-NMIBC and primMIBC were defined as no prior history of BC, and recHR-NMIBC and secMIBC as previously treated NMIBC that recurred or progressed to MIBC, respectively. Log-rank analysis was used to compare survival outcomes, and univariable and multivariable Cox and logistic regression analyses were used to identify predictors for survival. Results and limitationsAmong the 908 patients included, 211 (23%) had primHR-NMIBC, 125 (14%) had recHR-NMIBC, 404 (44%) had primMIBC, and 168 (19%) had secMIBC. Lymph node involvement and pathological upstaging were more frequent in the secMIBC group than in the other groups (p < 0.001). The median follow-up was 37 mo. The 5-year recurrence-free survival (RFS), cancer-specific survival (CSS), and overall survival (OS) were 77.9%, 83.2%, and 72.7% in primHR-NMIBC, 60.0%, 59%, and 48.9% in recHR-NMIBC, 60.9%, 64.5%, and 54.8% in primMIBC, and 41.3%, 46.5%, and 39% in secMIBC, respectively, with statistically significant differences across all survival outcomes except between recHR-NMIBC and primMIBC. On multivariable Cox regression, recHR-NMIBC was independently associated with shorter RFS (hazard ratio [HR] 1.64; p = 0.03), CSS (HR 1.79; p = 0.01), and OS (HR 1.45; p = 0.03), and secMIBC was associated with shorter CSS (HR 1.77; p = 0.01) and OS (HR 1.57; p = 0.006). Limitations include the biases inherent to the retrospective study design. ConclusionsPatients with recHR-NMIBC and primHR-MIBC had similar survival outcomes, while those with sec-MIBC had the worst outcomes. Therefore, early radical intervention may be indicated in selected patients, and potentially neoadjuvant systemic therapies in some patients with recHR-NMIBC. Patient summaryWe compared cancer outcomes in different bladder cancer scenarios in a large, multinational series of patients who underwent removal of the bladder with curative intent. We found that patients who experienced recurrence of non–muscle-invasive bladder cancer (NMIBC) had similar survival outcomes to those with initial muscle-invasive bladder cancer (MIBC), while patients who experienced progression of NMIBC to MIBC had the worst outcomes. Selected patients with non–muscle-invasive disease may benefit from early radical surgery or from perioperative chemotherapy or immunotherapy.

Pathological Downstaging and Survival Outcomes Associated with Neoadjuvant Chemotherapy for Variant Histology Muscle Invasive Bladder Cancer.

Patients with muscle invasive bladder cancer (MIBC) of variant histology have a poor prognosis. It is unclear if neoadjuvant chemotherapy prior to radical cystectomy is associated with pathological downstaging or improved overall survival (OS) for patients with variant histology. Our objective was to assess for associations between receipt of neoadjuvant chemotherapy, pathological downstaging and OS for patients with variant histology MIBC. Patients were identified in the National Cancer Database from 2004 to 2017 with MIBC, without metastases, who underwent radical cystectomy. Patients were stratified by histological subgroup, and receipt or nonreceipt of neoadjuvant chemotherapy. Pathological downstaging was defined as pT0N0 or pT ≤1N0, and OS from the time of diagnosis to date of death or censoring at last followup. Multivariable logistic regression analysis determined associations between neoadjuvant chemotherapy and pathological downstaging. Multivariable Cox regression analysis determined associations between neoadjuvant chemotherapy and OS. A total of 31,218 patients were included in the final study population (urothelial carcinoma [UC]: 27,779; sarcomatoid UC: 501; micropapillary UC: 418; squamous cell carcinoma: 1,141; neuroendocrine carcinoma: 629; adenocarcinoma: 750). Neoadjuvant chemotherapy was associated with pathological downstaging to pT0N0 in all histological subgroups (UC: OR 5.1 [4.6-5.6]; sarcomatoid UC: OR 13.8 [5.5-39.0]; micropapillary UC: OR 9.7 [2.8-46.8]; squamous cell carcinoma: OR 7.4 [2.1-24.5]; neuroendocrine: OR 4.7 [2.6-9.2]; adenocarcinoma: OR 23.3 [8.0-74.2]). Neoadjuvant chemotherapy was associated with improved OS for UC (HR 0.8 [0.77-0.84]), sarcomatoid UC (HR 0.64 [0.44-0.91]) and neuroendocrine carcinoma (HR 0.55 [0.43-0.70]). Neoadjuvant chemotherapy was associated with pathological downstaging for all MIBC histological variants, with improved OS for patients with UC, sarcomatoid variant UC and neuroendocrine carcinoma.

Differential Prognosis and Response of Denovo vs. Secondary Muscle-Invasive Bladder Cancer: An Updated Systematic Review and Meta-Analysis

Simple SummaryBladder cancer is one of the leading causes of death worldwide. About 75% of patients initially present with non-muscle-invasive disease, while the rest presents with primary muscle-invasive disease. Up to a third of non-muscle-invasive bladder cancers progresses into secondary muscle-invasive bladder cancer. Little is known about clinical outcomes after upfront neoadjuvant cisplatin-based chemotherapy and subsequent radical cystectomy for secondary muscle-invasive bladder cancer compared to primary muscle-invasive bladder cancer. Here, we systematically reviewed the current literature evaluate oncological outcomes between primary and secondary muscle-invasive bladder cancer.To evaluate oncological outcomes of primary versus secondary muscle-invasive bladder cancer treated with radical cystectomy. Medline, Embase, Scopus and Cochrane Library were searched for eligible studies. Hazard ratios for overall survival (OS), cancer specific survival (CSS) and progression free survival (PFS) were calculated using survival data extracted from Kaplan-Meier curves. A total of 16 studies with 5270 patients were included. Pooled analysis showed similar 5-year and 10-year OS (HR 1, p = 0.96 and HR 1, p = 0.14) and CSS (HR 1.02, p = 0.85 and HR 0.99, p = 0.93) between primMIBC and secMIBC. Subgroup analyses according to starting point of follow-up and second-look transurethral resection revealed similar results. Subgroup analyses of studies in which neoadjuvant chemotherapy was administered demonstrated significantly worse 5-year CSS (HR 1.5, p = 0.04) but not 10-year CSS (HR 1.36, p = 0.13) in patients with secMIBC. Patients with secMIBC had significantly worse PFS at 5-year (HR 1.41, p = 0.002) but not at 10-year follow-up (HR 1.25, p = 0.34). This review found comparable oncologic outcomes between primMIBC and secMIBC patients treated with RC regarding OS and CSS. Subgroup analysis showed worse 5-year CSS but not 10-year CSS for neoadjuvant chemotherapy in the secMIBC group. Prospective clinical trials incorporating molecular markers, that allow precise risk stratification of secMIBC and further research uncovering underlying molecular and clinical drivers of the heterogeneous group of secMIBC is needed.

Influence of Primary or Secondary Muscle Invasive Bladder Cancer on Oncologic Outcomes After Radical Cystectomy

Influence of Primary or Secondary Muscle Invasive Bladder Cancer on Oncologic Outcomes After Radical Cystectomy

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.

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.

MP58-02 GENOMIC DIFFERENCES BETWEEN “PRIMARY” AND “SECONDARY” MUSCLE INVASIVE BLADDER CANCER: IMPLICATIONS FOR NEOADJUVANT CHEMOTHERAPY

You have accessJournal of UrologyBladder Cancer: Invasive V1 Apr 2017MP58-02 GENOMIC DIFFERENCES BETWEEN “PRIMARY” AND “SECONDARY” MUSCLE INVASIVE BLADDER CANCER: IMPLICATIONS FOR NEOADJUVANT CHEMOTHERAPY Eugene Pietzak, Aditya Bagrodia, Hikmat Al-Ahmadie, Harry Herr, Emily Zabor, David Barron, Qiang Li, Francois Audenet, Samuel Funt, Ahmet Zehir, Maria Arcila, Priscilla Baez, Michael Berger, Nikolaus Schultz, David Solit, Dean Bajorin, Jonathan Rosenberg, Eugene Cha, Bernard Bochner, and Gopa Iyer Eugene PietzakEugene Pietzak More articles by this author , Aditya BagrodiaAditya Bagrodia More articles by this author , Hikmat Al-AhmadieHikmat Al-Ahmadie More articles by this author , Harry HerrHarry Herr More articles by this author , Emily ZaborEmily Zabor More articles by this author , David BarronDavid Barron More articles by this author , Qiang LiQiang Li More articles by this author , Francois AudenetFrancois Audenet More articles by this author , Samuel FuntSamuel Funt More articles by this author , Ahmet ZehirAhmet Zehir More articles by this author , Maria ArcilaMaria Arcila More articles by this author , Priscilla BaezPriscilla Baez More articles by this author , Michael BergerMichael Berger More articles by this author , Nikolaus SchultzNikolaus Schultz More articles by this author , David SolitDavid Solit More articles by this author , Dean BajorinDean Bajorin More articles by this author , Jonathan RosenbergJonathan Rosenberg More articles by this author , Eugene ChaEugene Cha More articles by this author , Bernard BochnerBernard Bochner More articles by this author , and Gopa IyerGopa Iyer More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2017.02.1797AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES We recently reported that patients with secondary muscle-invasive bladder cancer (MIBC) have substantially worse outcomes with neoadjuvant chemotherapy compared to primary MIBC (Pietzak, et al. AUA 2016). We subsequently used next-generation sequencing to investigate genetic differences between primary and secondary MIBC specimens. METHODS We examined MIBC specimens from the Cancer Genome Atlas (TCGA) (n=131), our institutional genomic research database (n=569), and a prospective clinical sequencing protocol (n=214) to identify 342 chemotherapy-naive urothelial MIBC specimens (270 primary and 72 secondary) that underwent whole-exome or targeted exon-capture sequencing. Primary and secondary MIBC specimens were compared for genomic alterations in 341 known cancer genes. Primary MIBC was defined as clinical stage ≥T2 on either initial or re-staging TUR on first bladder tumor diagnosis. Patients with a history of NMIBC (Tis, Ta, or T1 with uninvolved detrusor muscle in specimen) confirmed by a second cystoscopy prior to the eventual diagnosis of clinical stage ≥T2 were considered to have secondary MIBC. RESULTS We compared 270 primary and 72 secondary MIBC specimens for differences in genomic alterations in 341 cancer-associated genes. We identified significantly different rates of ERCC2, APC, and FGFR3 alterations. FGFR3-activating mutations (S249C, Y373C) occurred more frequently in secondary MIBC specimens (18% [13/72] vs. 9% [24/270], p=0.03). APC mutations were only seen in primary MIBC specimens (5% [14/270] vs. 0% [0/72], p=0.047). Surprisingly, ERCC2 missense mutations, which are associated with extreme sensitivity to cisplatin chemotherapy, only occurred in primary MIBC specimens (12% [32/270] vs. 0% [0/72], p<0.001). After adjusting for multiple comparisons using the Benjamini-Hochberg false discovery rate method, only ERCC2 mutations remained significant (adjusted p =0.016). CONCLUSIONS ERCC2 is involved in repair of cisplatin-induced DNA damage, and mutations in ERCC2 are associated with clinical responses to cisplatin. ERCC2 mutations occurred exclusively in primary MIBC patients and may account for their improved outcomes with neoadjuvant chemotherapy compared to secondary MIBC patients. © 2017FiguresReferencesRelatedDetails Volume 197Issue 4SApril 2017Page: e772-e773 Advertisement Copyright & Permissions© 2017MetricsAuthor Information Eugene Pietzak More articles by this author Aditya Bagrodia More articles by this author Hikmat Al-Ahmadie More articles by this author Harry Herr More articles by this author Emily Zabor More articles by this author David Barron More articles by this author Qiang Li More articles by this author Francois Audenet More articles by this author Samuel Funt More articles by this author Ahmet Zehir More articles by this author Maria Arcila More articles by this author Priscilla Baez More articles by this author Michael Berger More articles by this author Nikolaus Schultz More articles by this author David Solit More articles by this author Dean Bajorin More articles by this author Jonathan Rosenberg More articles by this author Eugene Cha More articles by this author Bernard Bochner More articles by this author Gopa Iyer More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...

Differences in somatic DNA damage repair (DDR) gene alterations between primary and secondary muscle invasive bladder cancer (MIBC).

4519Background: Alterations in DDR genes, including the nucleotide excision repair gene ERCC2, have been shown to be associated with response to systemic chemotherapy in MIBC (Van Allen, 2014). We ...

646 Oncological outcome of primary and secondary muscle-invasive bladder cancer: Is there a difference? A meta-analysis

646 Oncological outcome of primary and secondary muscle-invasive bladder cancer: Is there a difference? A meta-analysis

EORTC Progression Score Identifies Patients at High Risk of Cancer-Specific Mortality After Radical Cystectomy for Secondary Muscle-Invasive Bladder Cancer

BackgroundThe aim of this study was to develop a risk stratification of patients with muscle-invasive bladder cancer (MIBC) after radical cystectomy (RC). For this purpose, we compared the cancer-specific mortality (CSM) of patients with primary MIBC and patients with secondary MIBC in different risk groups according to the European Organisation for Research and Treatment of Cancer (EORTC) progression score. Patients and MethodsThe records of 521 consecutive patients treated with RC for clinical MIBC according to transurethral resection of bladder cancer (TURBT) diagnosis were reviewed. Of the 521 patients, 399 (76.6%) had primary MIBC (study group 1 [SG1]) and 122 (23.4%) had secondary MIBC (study group 2 [SG2]). Patients in SG2 were stratified into risk groups according to the results of the first and last TURBT in non-MIBC using the EORTC progression score. ResultsCSM for patients with primary and secondary MIBC did not differ significantly. Patients in SG2 with the highest risk for tumor stage progression at time of the first and last TURBT in non-MIBC showed a significantly higher CSM after RC compared with patients with low-to-intermediate risk and compared with patients in SG1. In multivariable analyses, stage pT 3/4 (hazard ratio [HR], 2.12; P < .001), lymphovascular invasion (LVI) (HR, 3.47; P < .001), female sex (HR, 1.35; P = .048), and time from diagnosis of MIBC to RC > 90 days (HR, 2.07; P < .001) were significantly associated with higher CSM. ConclusionRisk stratification by the EORTC progression score can help to identify those patients with the highest risk of CSM after progression to MIBC and thus enable us to offer these patients a multimodal treatment. Our results need to be verified in large prospective studies.

Oncological Outcome of Primary versus Secondary Muscle-Invasive Bladder Cancer Is Comparable after Radical Cystectomy

Background: High-risk non-muscle-invasive bladder cancer (NMIBC) progressing to muscle-invasive bladder cancer (MIBC) is associated with adverse tumour biology. It is unclear, however, whether outcome of NMIBC progressing to MIBC is adverse compared to primary MIBC and whether NMIBC of higher risk of progression to MIBC is adverse compared to NMIBC of lower risk. Objective: Our objective was to assess cancer-specific survival (CSS) following radical cystectomy (RC) for primary MIBC and for NMIBC progressing to MIBC in dependence of EORTC risk score. Materials and Methods: Clinical and histopathological characteristics and CSS of 150 patients were assessed. Secondary MIBCs were stratified by EORTC risk score at the last transurethral resection of bladder tumour for NMIBC. Results: CSS did not differ significantly between primary and secondary MIBC (p = 0.521). Secondary MIBC with high EORTC score had significantly shorter CSS compared to secondary MIBC with intermediate EORTC score (p = 0.029). In multivariable analysis, pathological tumour stage (HR = 3.77; p = 0.020) and lymph node stage (HR = 2.34; p = 0.022) were significantly correlated with CSS. Conclusion: While the outcome of secondary MIBC is not generally adverse compared to primary MIBC, the EORTC risk score not only reflects high risk of progression of NMIBC to MIBC, but also worse outcome following RC for secondary MIBC. Timely RC should thus be debated in high-risk NMIBC.

The natural history of secondary muscle-invasive bladder cancer

BackgroundThe management of patients with high-grade non muscle invasive bladder cancer (NMIBC) brings diagnostic and therapeutic challenges. In the current study, we sought to study the natural history of progression to "secondary" muscle-invasive bladder cancer (MIBC)-cancer that developed during follow up of patients presenting with non-muscle invasive bladder cancer (NMIBC).MethodsBetween 1998 and 2008, 760 patients were treated for bladder cancer. Primary MIBC (>=T2) tumors (present upon presentation) were diagnosed in 114 patients. All patients with high-grade NMIBC were treated with intravesical BCG. Mean follow-up was 44 months.ResultsForty patients (6.1%) developed secondary MIBC after a mean period of 21 months from initial diagnosis of bladder cancer. The 2- and 5-year disease-specific survival rates were better for patients with secondary MIBC (90% and 56% compared to 69% and 42% for patients with primary disease, p=0.03). The Kaplan-Meier curves of the two groups were parallel but displaced by approximately 2 years.ConclusionIn the current series, MIBC progression occurred among initially presenting patients with NMIBC in 6.1%. In most patients, the initial diagnosis of NMIBC is correct and muscle invasion occurs after a mean period of about 2 years. This supports a non-radical approach in patients with high-grade T1, Ta or Tis. Meticulous follow-up with liberal biopsy of any suspicious lesion may provide early diagnosis of invasive disease.