Frequency and Nature of Genomic Alterations in ERBB2-Altered Urothelial Bladder Cancer.

BACKGROUND: Human epidermal growth factor-2 (HER2) overexpression is an oncogenic driver in many solid tumors, including urothelial bladder cancer (UBC). In addition, activating mutations in the ERBB2 gene have been shown to play an oncogenic role similar to ERBB2 amplification. OBJECTIVE: To describe and compare the frequency and nature of genomic alterations (GA) of ERBB2-altered (mutations, amplification) and ERBB2 wild-type UBC. PATIENTS AND METHODS: Using a hybrid capture-based comprehensive profiling assay, 9518 UBC cases were grouped by ERBB2 alteration and evaluated for all classes of genomic alterations (GA), tumor mutational burden (TMB), microsatellite instability (MSI), genome-wide loss of heterozygosity (gLOH), and genomic mutational signature. PD-L1 expression was measured by immunohistochemistry (Dako 22C3). Categorical statistical comparisons were performed using Fisher's exact tests. RESULTS: A total of 602 (6.3%) UBC cases featured ERBB2 extracellular domain short variant (SV) GA (ECDmut+), 253 (2.7%) cases featured ERBB2 kinase domain SV GA (KDmut+), 866 (9.1%) cases had ERBB2 amplification (amp+), and 7797 (81.9%) cases were ERBB2 wild-type (wt). European genetic ancestry of ECDmut+ was higher than ERBB2wt. Numerous significant associations were observed when comparing GA by group. Notably among these, CDKN2A/MTAP loss were more frequent in ERBB2wt versus ECDmut+ and amp+. ERBB3 GA were more frequent in ECDmut+ and KDmut+ than ERBB2wt. TERT GA were more frequent in ECDmut+, KDmut+, and amp+ versus ERBB2wt. TOP2A amplification was significantly more common in ECDmut+ and amp+ versus ERBB2wt, and TP53 SV GA were significantly higher in ERBB2 amp+ versus ERBB2wt. Mean TMB levels were significantly higher in ECDmut+, KDmut+, and amp+ than in ERBB2wt. Apolipoprotein B mRNA-editing enzyme, catalytic polypeptides (APOBEC) signature was more frequent in ECDmut+, KDmut+, and amp+ versus ERBB2wt. No significant differences were observed in PD-L1 status between groups, while gLOH-high status was more common in amp+ versus ERBB2wt. MSI-high status was more frequent in KDmut+ versus ERBB2wt, and in ERBB2wt than in amp+. CONCLUSIONS: We noted important differences in co-occurring GA in ERBB2-altered (ECDmut+, KDmut+, amp+) versus ERBB2wt UBC, as well as higher mean TMB and higher APOBEC mutational signature in the ERBB2-altered groups. Our results can help refine future clinical trial designs and elucidate possible response and resistance mechanisms for ERBB2-altered UBC.

Standardization of the evaluation and surveillance of patients with BCG unresponsive high grade non-muscle invasive bladder cancer clinical trials.

There are multiple ongoing and planned clinical trials that are evaluating novel therapies to treat patients with BCG-unresponsive high grade nonmuscle invasive bladder cancer (NMIBC). Importantly, there is considerable variation in surveillance strategies between these clinical trials, specifically with regards to the use of advanced imaging, enhanced cystoscopy, and mandatory biopsies, which could impact landmark efficacy assessments of investigational agents. To present guideline recommendations for the standardization of cystoscopic evaluation, surveillance, and efficacy assessments for patients with BCG-unresponsive NMIBC participating in clinical trials. On September 29, 2023 at the annual meeting of the International Bladder Cancer Network, a breakout session was convened, during which representatives from various disciplines discussed potential guidance statements with opportunity for discussion and comment. A set of statements regarding use of white light and enhanced cystoscopy were developed to help guide a pragmatic approach to surveillance and efficacy assessments of patients in clinical trials. The use of "for cause" and "mandatory" biopsies was also addressed. A standard approach to evaluation of patients within the context of clinical trials is necessary to accurately assess the efficacy of novel agents, especially within single arm trials that lack an appropriate comparator. Additionally, the utilization and timing of mandatory biopsies is critical, as these biopsies may impact both disease evaluations and the determination of duration of response.

Influence of lamina propria invasion extension on T1 high-grade non-muscle-invasive bladder cancer in patients undergoing BCG or radical cystectomy.

OBJECTIVE: To evaluate the prognostic value of T1 substaging in patients treated with bacillus Calmette-Guérin (BCG) or immediate radical cystectomy (iRC). MATERIALS AND METHODS: We performed an institutional review board-approved retrospective study analysing non-muscle-invasive bladder cancer (NMIBC) patients with pT1 disease treated with either BCG or iRC between 2000 and 2020. Lamina propria (LP) invasion characteristics were extracted from the pathology report. The Kaplan-Meier method was used to calculate overall survival (OS), cancer-specific survival (CSS) and metastasis-free survival (MFS). Multivariable Cox models were used to determine the association between progression-free survival (PFS) and characteristics in the BCG cohort. A logistic regression model explored the relationship between T1 substaging and upstaging to >pT2 at iRC. RESULTS: A total of 411 T1 high-grade patients were identified. LP invasion characteristics were as follows: not specified: 115 (28%); focal/superficial (F/S): 147 (35.8%); and extensive/multifocal (E/M): 149 (36.2%). Overall, 303 patients (73.7%) received BCG, and 108 patients (26.3%) underwent iRC. The median (interquartile range) follow-up was 53 (32-96) months. Patients with E/M LP invasion were significantly more likely to undergo iRC (34% vs. 19%; P = 0.003). Patients with E/M LP invasion showed poorer MFS and CSS compared to those with F/S LP invasion when treated with BCG but not when treated with iRC. Among BCG-treated patients, progression occurred in 41 patients and E/M LP invasion was independently associated with progression after BCG (hazard ratio 5.3, 95% confidence interval [CI] 2.2-13.1; P < 0.001). T1 substaging was not associated with upstaging at RC (odds ratio 3.15, 95% CI 0.82-12.12; P = 0.095). CONCLUSIONS: Extensive/multifocal LP invasion was associated with poor PFS, MFS and CSS in patients treated with BCG. T1 substaging provides valuable prognostic information and should be reported in pathology reports.

Association of Age with Non-muscle-invasive Bladder Cancer: Unearthing a Biological Basis for Epidemiological Disparities?

BACKGROUND: Age disparity in patients with non-muscle-invasive bladder cancer (NMIBC) exists. Whether this is due to differences in adequate cancer care or tumour biology is unclear. OBJECTIVE: To investigate age disparities in NMIBC using the Surveillance, Epidemiology, and End Results (SEER)-Medicare and UROMOL datasets. DESIGN, SETTING, AND PARTICIPANTS: The SEER-Medicare data were used to identify patients with clinical stage Ta, Tis, and T1 NMIBC between 2005 and 2017 (n = 32 225). Using the UROMOL cohort (n = 834), age disparities across transcriptomic, genomic, and spatial proteomic domains were assessed. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: For the SEER-Medicare data, multivariable competing-risk regression was used to examine the association between age and recurrence, progression, and bladder cancer-specific mortality (BCSM). For the UROMOL cohort, multivariable general linear model and multinomial logistic regression were performed to evaluate the association between age and tumour biology. RESULTS AND LIMITATIONS: An analysis of the SEER-Medicare cohort revealed 5-yr recurrence rates of 55.2%, 57.4%, and 58.9%; 5-yr progression rates of 25.6%, 29.2%, and 36.9%; and 5-yr BCSM rates of 3.9%, 5.8%, and 11.8% in patients aged 66-70, 71-80, and ≥81 yr, respectively. After multivariable adjustment, age ≥81 yr was associated with a higher risk of recurrence (hazard ratio [HR] 1.07, 95% confidence interval [CI] 1.03-1.12; p = 0.001), progression (HR 1.32, p < 0.001), and BCSM (HR 2.58, p < 0.001). UROMOL2021 transcriptomic class 2a was most frequently observed in patients with advanced age (34.0% in ≥76 yr vs 21.6% in ≤65 yr; p = 0.004), a finding confirmed on multivariable analysis (risk ratio [RR] 3.86, p = 0.002). UROMOL2021 genomic class 3 was observed more frequently in patients aged ≥76 yr (4.9% vs 24.2%; p = 0.001). Limitations include the definitions used for recurrence and progression, which may lead to under- or overestimation of true rates. CONCLUSIONS: Among SEER-Medicare patients with NMIBC, advanced age is associated with inferior oncological outcomes. These results reflect age-related molecular biological differences observed across transcriptomic and genomic domains, providing further evidence that innate tumour biology contributes to observed disparities in NMIBC outcomes. PATIENT SUMMARY: Older patients with non-muscle-invasive bladder cancer have worse oncological outcomes than younger patients. Some of this age disparity may be due to differences in tumour biology.

Characterizing the Genomic Landscape of the Micropapillary Subtype of Urothelial Carcinoma of the Bladder Harboring Activating Extracellular Mutations of ERBB2.

The micropapillary subtype of urothelial carcinoma (MPUC) of the bladder is a very aggressive histological variant of urothelial bladder cancer (UBC). A high frequency of MPUC contains activating mutations in the extracellular domain (ECD) of ERBB2. We sought to further characterize ERBB2 ECD-mutated MPUC to identify additional genomic alterations that have been associated with tumor progression and therapeutic response. In total, 5,485 cases of archived formalin-fixed, paraffin-embedded UBC underwent comprehensive genomic profiling to identify ERBB2 ECD-mutated MPUC and evaluate the frequencies of genomic co-alterations. We identified 219 cases of UBC with ERBB2 ECD mutations (74% S310F and 26% S310Y), of which 63 (28.8%) were MPUC. Genomic analysis revealed that TERT, TP53, and ARID1A were the most common co-altered genes in ERBB2-mutant MPUC (82.5%, 58.7%, and 39.7%, respectively) and did not differ from ERBB2-mutant non-MPUC (86.5%, 51.9%, and 35.3%). The main differences between ERBB2 ECD-mutated MPUC compared with non-MPUC were KMT2D, RB1, and MTAP alterations. KMT2D and RB1 are tumor-suppressor genes. KMT2D frequency was significantly decreased in ERBB2 ECD-mutated MPUC (6.3%) in contrast to non-MPUC (27.6%; P < .001). RB1 mutations were more frequent in ERBB2 ECD-mutated MPUC (33.3%) than in non-MPUC (17.3%; P = .012). Finally, MTAP loss, an emerging biomarker for new synthetic lethality-based anticancer drugs, was less frequent in ERBB2 ECD-mutated MPUC (11.1%) than in non-MPUC (26.9%; P = .018). Characterizing the genomic landscape of MPUC may not only improve our fundamental knowledge about this aggressive morphological variant of UBC but also has the potential to identify possible prognostic and predictive biomarkers that may drive tumor progression and dictate treatment response to therapeutic approaches.

Circulating tumor DNA as a Predictive and Prognostic Biomarker in the Perioperative Treatment of Muscle-invasive Bladder Cancer: A Systematic Review.

CONTEXT: Predictive and prognostic biomarkers in the perioperative treatment of muscle-invasive bladder cancer (MIBC) are an unmet need. Circulating tumor DNA (ctDNA) holds promise as a biomarker in this setting. OBJECTIVE: To review the evidence of ctDNA as a prognostic and predictive biomarker in the perioperative treatment of MIBC. EVIDENCE ACQUISITION: We systematically reviewed the literature using PubMed, MEDLINE, and Embase databases according to the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) statement. We included prospective studies investigating neoadjuvant and/or adjuvant chemotherapy and/or immunotherapy for MIBC (T2-T4a, any N, and M0) treated with radical cystectomy. We reported ctDNA results to monitor and/or predict disease status, relapse, and progression. The research retrieved 223 records. Six papers were considered for this review based on prespecified inclusion criteria. EVIDENCE SYNTHESIS: Our review confirms the prognostic role of ctDNA after cystectomy and shows a potential predictive benefit in using neoadjuvant chemotherapy and preoperative immunotherapy. Circulating tumor DNA was used to monitor recurrence, and changes in ctDNA status anticipated radiological progression with a median difference of time from 101 to 932 d. A subgroup analysis of the phase 3 Imvigor010 trial showed that only ctDNA-positive patients treated with atezolizumab had an improvement in disease-free survival (DFS; hazard ratio [HR] = 3.36, 95% confidence interval [CI]: 2.44-4.62). Clearance of ctDNA after two cycles of adjuvant atezolizumab was associated with improved outcomes (DFS HR = 0.26, 95% CI: 0.12-0.56, p = 0.0014; overall survival HR = 0.14, 95% CI: 0.03-0.59). CONCLUSIONS: Circulating tumor DNA is a prognostic factor after cystectomy and may be used to monitor recurrence. In the adjuvant immunotherapy setting, ctDNA might select patients who benefit the most from this strategy. PATIENT SUMMARY: In the perioperative treatment of muscle-invasive bladder cancer, circulating tumor DNA (ctDNA) positivity correlates with the outcomes after cystectomy and might select patients who may benefit from neoadjuvant chemotherapy and/or immunotherapy. Changes in ctDNA status anticipated radiological progression.

Long-Term Oncological Outcomes in Patients Diagnosed With Nonmetastatic Plasmacytoid Variant of Bladder Cancer: A 20-Year University of Texas MD Anderson Cancer Center Experience.

PURPOSE: The treated natural history of nonmetastatic plasmacytoid variant of bladder cancer (PV-BCa) is poorly understood owing to its rarity. We sought to examine the disease recurrence and metastasis patterns in this select group of patients in order to identify opportunities for intervention. MATERIALS AND METHODS: We conducted a natural language processing algorithm-augmented retrospective chart review of 56 consecutive patients who were treated with curative intent for nonmetastatic PV-BCa at our institution between 1998 and 2018. Kaplan-Meier and multivariable Cox regression methods were used for survival analyses. RESULTS: The stage at presentation was: ≤ cT2N0 in 22 (39.3%), cT3N0 in 15 (26.8%), cT4N0 in 13 (23.2%), and ≥ cN1 in 6 patients (10.7%). Forty-nine patients (87.5%) received chemotherapy, and 42 (75%) were able to undergo the planned surgery. Notably, only 4 patients (7.2%) had pT0 stage, while 22 (52.4%) had pN+ disease at the time of surgery. At 36-month follow-up, 28.4% of patients (95% CI: 22.1%-34.5%) were alive and 22.2% (95% CI: 16.1%-28.5%) were free of metastatic disease. The benefit of surgical extirpation was stage specific: successful completion of surgery was associated with improved metastasis-free survival (at 36 months 32.4% vs 0%, log-rank P < .001) in patients with localized or locally advanced disease (≤cT2N0/cT3N0); however, in patients with regionally advanced disease (cT4N0/≥cN1), consolidative surgery following chemotherapy was not associated with improved metastasis-free survival (12.5% vs 10% at 36 months, log-rank P = .49). The median time to metastasis from primary treatment end was 6.5 months (IQR: 2.9-14.7). The predominant site of recurrence/metastasis was the peritoneum (76.1%), either in isolation or along with extraperitoneal lesions. Salvage immunotherapy in these patients significantly reduced the risk of death (HR = 0.11, P = .001). CONCLUSIONS: PV-BCa is a disease with high lethality. Despite multimodal treatment, a vast majority of patients develop atypical intraperitoneal metastasis soon after therapy and rapidly succumb to it. Clinical trials evaluating utility of hyperthermic intraperitoneal chemotherapy and/or immunotherapy may be warranted in this high-risk population.

Impact of age >70 years on oncological outcomes in patients with non-muscle-invasive bladder cancer treated with Bacillus Calmette-Guérin.

OBJECTIVE: To evaluate the impact of age on oncological outcomes in a large contemporary cohort of patients with non-muscle-invasive bladder cancer (NMIBC) treated with adequate Bacillus Calmette-Guérin (BCG). PATIENTS AND METHODS: We performed an Institutional Review Board-approved retrospective study analysing patients with NMIBC treated with adequate BCG at our institution from 2000 to 2020. Adequate BCG was defined as per United States Food and Drug Administration (FDA) guidelines as being receipt of at least five of six induction BCG instillations with a minimum of two additional doses (of planned maintenance or of re-induction) of BCG instillations within a span of 6 months. The study's primary outcome was to determine if age >70 years was associated with progression to MIBC cancer or distant metastasis. The cumulative incidence method and the competing-risk regression analyses were used to investigate the association of advanced age (>70 years) with progression, high-grade (HG) recurrence and cancer-specific mortality (CSM). RESULTS: Overall, data from 632 patients were analysed: 355 patients (56.2%) were aged ≤70 years and 277 (43.8%) were >70 years. Age >70 years did not adversely affect either cumulative incidence of progression or HG recurrence (P = 0.067 and P = 0.644, respectively). On competing-risk regression analyses, age >70 years did not emerge as an independent predictor of progression or HG recurrence (sub-standardised hazard ratio [SHR] 1.57, 95% confidence interval [CI] 0.87-2.81, P = 0.134; and SHR 1.05, 95% CI 0.77-1.44, P = 0.749). Not unexpectedly, patients in the older group did have higher overall mortality (P < 0.001) but not CSM (P = 0.057). CONCLUSION: Age >70 years was not associated with adverse oncological outcomes in a large contemporary cohort of patients receiving adequate intravesical BCG for NMIBC. BCG should not be withheld from older patients seeking for bladder sparing options.

Interruptions in bladder cancer care during the COVID-19 public health emergency.

BACKGROUND: Academic and community urology centers participating in a pragmatic clinical trial in non-muscle-invasive bladder cancer completed monthly surveys assessing restrictions in aspects of bladder cancer care due to the COVID-19 Public Health Emergency. Our objective was to describe pandemic-related restrictions on bladder cancer care. METHODS: We invited 32 sites participating in a multicenter pragmatic bladder cancer trial to complete monthly surveys distributed through REDCap beginning in May 2020. These surveys queried sites on whether they were experiencing restrictions in the use of elective surgery, transurethral resection of bladder tumors (TURBT), radical cystectomy, office cystoscopy, and intravesical bacillus Calmette-Guerin (BCG) availability. Responses were collated with descriptive statistics. RESULTS: Of 32 eligible sites, 21 sites had at least a 50% monthly response rate over the study period and were included in the analysis. Elective surgery was paused at 76% of sites in May 2020, 48% of sites in January 2021, and 52% of sites in January 2022. Over those same periods, coinciding with COVID-19 incidence waves, TURBT was restricted at 10%, 14%, and 14% of sites, respectively, radical cystectomy was restricted at 10%, 14%, and 19% of sites, respectively, and cystoscopy was restricted at 33%, 0%, and 10% of sites, respectively. CONCLUSIONS: Bladder cancer care was minimally restricted compared with more pronounced restrictions seen in general elective surgeries during the COVID-19 pandemic.

Contemporary Role of Lymph Node Dissection in Genitourinary Cancers: Where Are We in 2023?

CONTEXT: Lymphadenectomy during surgery for genitourinary malignancies has varying benefits. OBJECTIVE: To review contemporary evidence on lymph node dissection in genitourinary cancers. EVIDENCE ACQUISITION: We performed a collaborative review to summarize current evidence supporting lymph node dissection in urothelial, prostate, kidney, penile, and testis cancers. We present the evidence on patient selection and recommended dissection templates, and highlight knowledge gaps and ongoing areas of investigation. EVIDENCE SYNTHESIS: Lymph node dissection remains the reference standard for lymph node staging. Pathologic nodal stage informs prognosis and guides adjuvant treatment. Appropriate template and patient selection are paramount to optimize outcomes and capitalize on the selective therapeutic benefits. CONCLUSIONS: Accurate staging with lymphadenectomy is contingent on appropriate template selection. The cumulative benefit will depend on judicious patient selection. PATIENT SUMMARY: We performed a collaborative review by a diverse group of experts in urology. We reviewed current evidence on lymph node dissection.

Definitions, End Points, and Clinical Trial Designs for Bladder Cancer: Recommendations From the Society for Immunotherapy of Cancer and the International Bladder Cancer Group.

PURPOSE: There is a significant unmet need for new and efficacious therapies in urothelial cancer (UC). To provide recommendations on appropriate clinical trial designs across disease settings in UC, the Society for Immunotherapy of Cancer (SITC) and the International Bladder Cancer Group (IBCG) convened a multidisciplinary, international consensus panel. METHODS: Through open communication and scientific debate in small- and whole-group settings, surveying, and responses to clinical questionnaires, the consensus panel developed recommendations on optimal definitions of the disease state, end points, trial design, evaluations, sample size calculations, and pathology considerations for definitive studies in low- and intermediate-risk nonmuscle-invasive bladder cancer (NMIBC), high-risk NMIBC, muscle-invasive bladder cancer in the neoadjuvant and adjuvant settings, and metastatic UC. The expert panel also solicited input on the recommendations through presentations and public discussion during an open session at the 2021 Bladder Cancer Advocacy Network (BCAN) Think Tank (held virtually). RESULTS: The consensus panel developed a set of stage-specific bladder cancer clinical trial design recommendations, which are summarized in the table that accompanies this text. CONCLUSION: These recommendations developed by the SITC-IBCG Bladder Cancer Clinical Trial Design consensus panel will encourage uniformity among studies and facilitate drug development in this disease.

Bacillus Calmette-Guérin vaccination as defense against SARS-CoV-2 (BADAS): a randomized controlled trial to protect healthcare workers in the USA by enhanced trained immune responses.

BACKGROUND: A large epidemic, such as that observed with SARS-CoV-2, seriously challenges available hospital capacity, and this would be augmented by infection of healthcare workers (HCW). Bacillus Calmette-Guérin (BCG) is a vaccine against tuberculosis, with protective non-specific effects against other respiratory tract infections in vitro and in vivo. Preliminary analyses suggest that regions of the world with existing BCG vaccination programs have lower incidence and mortality from COVID-19. We hypothesize that BCG vaccination can reduce SARS-CoV-2 infection and disease severity. METHODS: This will be a placebo-controlled adaptive multi-center randomized controlled trial. A total of 1800 individuals considered to be at high risk, including those with comorbidities (hypertension, diabetes, obesity, reactive airway disease, smokers), racial and ethnic minorities, elderly, teachers, police, restaurant wait-staff, delivery personnel, health care workers who are defined as personnel working in a healthcare setting, at a hospital, medical center or clinic (veterinary, dental, ophthalmology), and first responders (paramedics, firefighters, or law enforcement), will be randomly assigned to two treatment groups. The treatment groups will receive intradermal administration of BCG vaccine or placebo (saline) with groups at a 1:1 ratio. Individuals will be tracked for evidence of SARS-CoV-2 infection and severity as well as obtaining whole blood to track immunological markers, and a sub-study will include cognitive function and brain imaging. The majority of individuals will be followed for 6 months, with an option to extend for another 6 months, and the cognitive sub-study duration is 2 years. We will plot Kaplan-Meier curves that will be plotted comparing groups and hazard ratios and p-values reported using Cox proportional hazard models. DISCUSSION: It is expected this trial will allow evaluation of the effects of BCG vaccination at a population level in high-risk healthcare individuals through a mitigated clinical course of SARS-CoV-2 infection and inform policy making during the ongoing epidemic. TRIAL REGISTRATION: ClinicalTrials.gov NCT04348370. Registered on April 16, 2020.

Comparative Effectiveness Analysis of Treatment Strategies for Surgically Resectable Neuroendocrine Carcinoma of the Urinary Tract.

BACKGROUND: Neoadjuvant chemotherapy (neoCTX) has been recommended as the optimal strategy in surgically resectable neuroendocrine carcinoma (NEC) of the urinary tract (NEC-URO). OBJECTIVE: To determine the systemic therapy regimen and timing, which are most active against NEC-URO. DESIGN, SETTING, AND PARTICIPANTS: We used our institutional historical clinical and pathological database to study 203 patients (cT2, 74%; cT3/4a, 22%; and cTx, 4%) with surgically resectable NEC-URO between November 1985 and May 2020. A total of 141 patients received neoCTX and 62 underwent initial radical surgery, 24 of whom received adjuvant CTX (adjCTX). INTERVENTION: Neoadjuvant CTX with etoposide/cisplatin (EP), an alternating doublet of ifosfamide/doxorubicin (IA) and EP, dose-dense methotrexate/vinblastine/doxorubicin/cisplatin (MVAC), gemcitabine/cisplatin (GC), or others. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Overall survival (OS), downstaging rate, and pathological complete response using a multivariable model adjusting for tumor- and patient-related factors. RESULTS AND LIMITATIONS: Downstaging rate was significantly improved with neoCTX versus initial surgery (49.6% vs 14.5%, p < 0.0001), stage cT2N0 versus cT3/4N0 (44% vs 25%, p = 0.01), or presence of carcinoma in situ (47% vs 28%, p = 0.01). Downstaging was greatest with IA/EP (65%) versus EP (39%), MVAC/GC (27%), or others (36%, p = 0.04). After adjusting for age and Eastern Cooperative Oncology Group performance status, IA/EP was still associated with improved downstaging (odds ratio = 3.7 [1.3-10.2], p = 0.01). At a median follow-up of 59.7 mo, 5-yr OS rates for neoCTX followed by surgery, surgery alone, and surgery followed by adjCTX were 57%, 22%, and 30%, respectively. An NEC regimen (IA/EP or EP) versus a urothelial regimen (MVAC/GC or others) was associated with improved survival (145.4 vs 42.5 mo, hazard ratio = 0.49, 95% confidence interval: 0.25-0.94). CONCLUSIONS: Neoadjuvant CTX remains the standard-of-care treatment for NEC-URO with an advantage for NEC regimens over traditional urothelial regimens. IA/EP improves pathological downstaging at the time of surgery compared with EP, but is reserved for younger and higher function patients. PATIENT SUMMARY: In this report, we looked at the outcomes from invasive neuroendocrine carcinoma of the urinary tract in a large US population. We found that the outcomes varied with treatment strategy. We conclude that the best outcomes are seen in patients treated with chemotherapy prior to surgery and regimens tailored to histology and tolerance.

Oncological Outcomes for Patients with European Association of Urology Very High-risk Non-muscle-Invasive Bladder Cancer Treated with Bacillus Calmette-Guérin or Early Radical Cystectomy.

BACKGROUND: European Urology Association (EAU) guidelines recommend immediate radical cystectomy (early RC) for patients with very high-risk (VHR) non-muscle invasive bladder cancer (NMIBC), with bacillus Calmette-Guérin (BCG) recommended only for those who refuse or are unfit for RC. OBJECTIVE: To describe oncological outcomes following BCG or early RC in a contemporary cohort of patients with VHR NMIBC (EAU criteria). DESIGN, SETTING, AND PARTICIPANTS: Patients diagnosed with VHR NMIBC between 2000 and 2020 were identified from our institutional NMIBC registry. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The primary outcomes were overall survival (OS) and cancer-specific mortality (CSM). Secondary outcomes were the progression rate and high-grade recurrence (HGR) rate for patients receiving BCG. RESULTS AND LIMITATIONS: We identified 235 patients with VHR NMIBC, of whom 157 (67%) received BCG and 78 (33%) underwent early RC. The median follow-up was 52.8 mo. OS and CSM rates were 80.2% and 5.3% in the BCG group, and 88.1% and 4.9% in the early RC group, respectively with no significant difference in OS (p = 0.6) or CSM (p = 0.8) between the two groups. Among the patients treated with BCG, 5-yr HGR and progression rates were 41.9% and 17.4%, respectively; 39 patients (25%) underwent delayed RC after BCG. No significant difference in CSM emerged when comparing patients treated with delayed RC (after BCG) with those undergoing early RC (p = 0.86). CONCLUSIONS: Our findings suggest that intravesical BCG can be offered to patients as a resonable alternative to early RC for selected patients with VHR NMIBC. PATIENT SUMMARY: We evaluated outcomes for patients with very high-risk non-muscle-invasive bladder cancer (NMIBC) treated with BCG (bacillus Calmette-Guérin) versus early surgical removal of the bladder and found no differences in survival. We conclude that BCG could be offered to selected patients with this type of bladder cancer as a reasonable alternative to early bladder removal.