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Background Erdafitinib, a pan-fibroblast growth factor receptor (FGFR) tyrosine kinase inhibitor, was shown to be clinically active and tolerable in patients with advanced urothelial carcinoma and prespecified FGFR alterations in the primary analysis of the BLC2001 study at median 11 months of follow-up. We aimed to assess the long-term efficacy and safety of the selected regimen of erdafitinib determined in the initial part of the study. Methods The open-label, non-comparator, phase 2, BLC2001 study was done at 126 medical centres in 14 countries across Asia, Europe, and North America. Eligible patients were aged 18 years or older with locally advanced and unresectable or metastatic urothelial carcinoma, at least one prespecified FGFR alteration, an Eastern Cooperative Oncology Group performance status of 0–2, and progressive disease after receiving at least one systemic chemotherapy or within 12 months of neoadjuvant or adjuvant chemotherapy or were ineligible for cisplatin. The selected regimen determined in the initial part of the study was continuous once daily 8 mg/day oral erdafitinib in 28-day cycles, with provision for pharmacodynamically guided uptitration to 9 mg/day (8 mg/day UpT). The primary endpoint was investigator-assessed confirmed objective response rate according to Response Evaluation Criteria In Solid Tumors version 1.1. Efficacy and safety were analysed in all treated patients who received at least one dose of erdafitinib. This is the final analysis of this study. This study is registered with ClinicalTrials.gov, NCT02365597. Findings Between May 25, 2015, and Aug 9, 2018, 2328 patients were screened, of whom 212 were enrolled and 101 were treated with the selected erdafitinib 8 mg/day UpT regimen. The data cutoff date for this analysis was Aug 9, 2019. Median efficacy follow-up was 24·0 months (IQR 22·7–26·6). The investigator-assessed objective response rate for patients treated with the selected erdafitinib regimen was 40 (40%; 95% CI 30–49) of 101 patients. The safety profile remained similar to that in the primary analysis, with no new safety signals reported with longer follow-up. Grade 3–4 treatment-emergent adverse events of any causality occurred in 72 (71%) of 101 patients. The most common grade 3–4 treatment-emergent adverse events of any cause were stomatitis (in 14 [14%] of 101 patients) and hyponatraemia (in 11 [11%]). There were no treatment-related deaths. Interpretation With longer follow-up, treatment with the selected regimen of erdafitinib showed consistent activity and a manageable safety profile in patients with locally advanced or metastatic urothelial carcinoma and prespecified FGFR alterations.

Objectives To investigate the gene mutational profile of urachal carcinoma in correlation with its clinicopathologic features. Methods We analyzed genetic mutations in 30 cases of urachal carcinoma by next-generation sequencing (NGS) test. Histologic slides and clinical data were reviewed. Results The patients included 21 men and 9 women, with a mean age of 53 years (range, 24-75 years). The urachal carcinomas included mucinous (11), enteric (10), signet ring cell (8), and high-grade neuroendocrine (1) subtypes. Targeted NGS analysis demonstrated genetic mutations in all the urachal tumors (mean, 2; range, 1-4). TP53 was the most mutated gene (25), followed by KRAS (9) and GNAS (8) genes. TP53 mutations were more common in the signet ring cell subtype (7/8), and GNAS mutations were present only in the mucinous (5/11) and signet ring cell subtypes (3/8) but not in the enteric subtype (0/10). KRAS mutations were significantly associated with cancer stage IV (P = .02) and younger patient age (P = .046). Furthermore, the presence of KRAS mutations in urachal carcinoma portended a poorer overall survival (P = .006). Conclusions Urachal carcinoma demonstrates frequent gene mutations that are associated with distinct clinicopathologic features. Gene mutation may underlie the development and progression of this aggressive disease.

In our study the Bladder Cancer Molecular Taxonomy Group collaborated to extend a first consensus report, addressing the need for a consensus molecular classification for muscle-invasive bladder cancer (MIBC) that would support basic research and clinical trials. We provide such a consensus classification and offer a single-sample classifier (http://cit.ligue-cancer.net:3838/apps/consensusMIBC_web).

Emerging data suggests improved outcomes in patients receiving neoadjuvant chemotherapy (NAC) prior to radical nephroureterectomy (RNU) for high-risk upper tract urothelial carcinoma. In one of the largest single-center experiences to date, we provide an updated analysis of outcomes of patients receiving NAC followed by RNU.A retrospective review of patients with high-risk UTUC who received NAC followed by surgery between 2004 to 2017 was conducted. 126 patients were evaluated as part of the analysis. Kaplan-Meier method was used to estimate survival probabilities. Multivariable Cox modeling was used to evaluate for association with outcomes, and the cumulative incidence factor was used for competing risk analysis.Median OS time was 106 months. 14.3% of patients had a pathologic complete response and 60% were down-staged to ypT0-1 ypN0. The estimated 5 and 10-year DSS rates were 89.8% and 80.6%, respectively. The estimated 5 and 10-year metastasis-free survival rates were 81% and 75.4%, respectively. The estimated 5 and 10-year OS rates were 73.7% and 35.9 %, respectively. Recurrences mainly occurred in lymph nodes and lung at a median time of 15.5 months (IQR 8.9-27). The estimated 5 and 10-year cumulative incidence factor for death from UTUC was 9.5% and 16.1%, respectively. Limitations include retrospective nature and challenge of accurate pre-surgical staging.NAC prior to RNU in high-risk UTUC shows durable 5 and 10-year OS and DSS rates in a large single-institution series, confirming prior findings in prospective trials and retrospective studies.

Methylthioadenosine phosphorylase, an essential enzyme for the adenine salvage pathway, is often deficient (MTAPdef) in tumors with 9p21 loss and hypothetically renders tumors susceptible to synthetic lethality by antifolates targeting de novo purine synthesis. Here we report our single arm phase II trial (NCT02693717) that assesses pemetrexed in MTAPdef urothelial carcinoma (UC) with the primary endpoint of overall response rate (ORR). Three of 7 enrolled MTAPdef patients show response to pemetrexed (ORR 43%). Furthermore, a historic cohort shows 4 of 4 MTAPdef patients respond to pemetrexed as compared to 1 of 10 MTAP-proficient patients. In vitro and in vivo preclinical data using UC cell lines demonstrate increased sensitivity to pemetrexed by inducing DNA damage, and distorting nucleotide pools. In addition, MTAP-knockdown increases sensitivity to pemetrexed. Furthermore, in a lung adenocarcinoma retrospective cohort (N = 72) from the published BATTLE2 clinical trial (NCT01248247), MTAPdef associates with an improved response rate to pemetrexed. Our data demonstrate a synthetic lethal interaction between MTAPdef and de novo purine inhibition, which represents a promising therapeutic strategy for larger prospective trials.

Background: Muscle-invasive bladder cancer (MIBC) is a molecularly diverse disease with heterogeneous clinical outcomes. Several molecular classifications have been proposed, but the diversity of their subtype sets impedes their clinical application. Objective: To achieve an international consensus on MIBC molecular subtypes that reconciles the published classification schemes. Design, setting, and participants: We used 1750 MIBC transcriptomic profiles from 16 published datasets and two additional cohorts. Outcome measurements and statistical analysis: We performed a network-based analysis of six independent MIBC classification systems to identify a consensus set of molecular classes. Association with survival was assessed using multivariable Cox models. Results and limitations: We report the results of an international effort to reach a consensus on MIBC molecular subtypes. We identified a consensus set of six molecular classes: luminal papillary (24%), luminal nonspecified (8%), luminal unstable (15%), stroma-rich (15%), basal/squamous (35%), and neuroendocrine-like (3%). These consensus classes differ regarding underlying oncogenic mechanisms, infiltration by immune and stromal cells, and histological and clinical characteristics, including outcomes. We provide a single-sample classifier that assigns a consensus class label to a tumor sample's transcriptome. Limitations of the work are retrospective clinical data collection and a lack of complete information regarding patient treatment. Conclusions: This consensus system offers a robust framework that will enable testing and validation of predictive biomarkers in future prospective clinical trials. Patient summary: Bladder cancers are heterogeneous at the molecular level, and scientists have proposed several classifications into sets of molecular classes. While these classifications may be useful to stratify patients for prognosis or response to treatment, a consensus classification would facilitate the clinical use of molecular classes. Conducted by multidisciplinary expert teams in the field, this study proposes such a consensus and provides a tool for applying the consensus classification in the clinical setting. An international consortium of bladder cancer expert teams establishes a consensus reconciling the diverse molecular classifications of muscle-invasive bladder cancer. This work offers a robust framework that will enable testing and validating predictive biomarkers in future prospective clinical trials.

Plasmacytoid urothelial carcinoma (PUC) of the bladder is a rare histologic variant. We retrospectively analyzed a large series of bladder PUC from a single institution.The patients consisted of 44 men and five women with a mean age of 62 years (range, 45-86 years).PUC was pure in 23 cases and mixed with other histologic types in 26 cases. All PUCs diffusely invaded the bladder wall. Most PUCs lacked immunoreactivity for the retinoblastoma (RB) gene protein (12/32) and E-cadherin (8/30). Of the 44 patients with follow-up information, 25 died of PUC at a mean of 23 months, whereas 19 patients were alive at a mean of 22 months.Our findings support that bladder PUC is a highly aggressive disease. The lack of E-cadherin expression in PUCs may underlie the distinct discohesive histologic appearance, and abnormal function of the RB gene may be implicated in the development of PUC.

Epithelial-mesenchymal transition (EMT) is a physiological process that plays important roles in tumor metastasis, "stemness," and drug resistance. EMT is typically characterized by the loss of the epithelial marker E-cadherin and increased expression of EMT-associated transcriptional repressors, including ZEB1 and ZEB2. The miR-200 family and miR-205 prevent EMT through suppression of ZEB1/2. p53 has been implicated in the regulation of miR-200c, but the mechanisms controlling miR-205 expression remain elusive. Here we report that the p53 family member and p63 isoform, ΔNp63α, promotes miR-205 transcription and controls EMT in human bladder cancer cells. ΔNp63α, E-cadherin and miR-205 were coexpressed in a panel of bladder cancer cell lines (n = 28) and a cohort of primary bladder tumors (n = 98). Stable knockdown of ΔNp63α in the "epithelial" bladder cancer cell line UM-UC6 decreased the expression of miR-205 and induced the expression of ZEB1/2, effects that were reversed by expression of exogenous miR-205. Conversely, overexpression of ΔNp63α in the "mesenchymal" bladder cancer cell line UM-UC3 induced miR-205 and suppressed ZEB1/2. ΔNp63α knockdown reduced the expression of the primary and mature forms of miR-205 and the miR-205 "host" gene (miR-205HG) and decreased binding of RNA Pol II to the miR-205HG promoter, inhibiting miR-205HG transcription. Finally, high miR-205 expression was associated with adverse clinical outcomes in bladder cancer patients. Together, our data demonstrate that ΔNp63α-mediated expression of miR-205 contributes to the regulation of EMT in bladder cancer cells and identify miR-205 as a molecular marker of the lethal subset of human bladder cancers.

We identified a subset of patients with bladder cancer (transitional cell carcinoma) and regional nodal metastasis to the retroperitoneal lymph nodes without detectable systemic dissemination. While the majority of these patients respond initially to chemotherapy, most have disease relapse at the same site within a year. We report the results of a phase II study exploring the potential benefit of retroperitoneal lymph node dissection in patients with transitional cell carcinoma of the bladder in whom disease has shown a significant response to chemotherapy.A total of 11 patients with biopsy proven metastatic transitional cell carcinoma in the retroperitoneal lymph nodes and no evidence of visceral metastatic disease in whom disease showed a significant response to chemotherapy underwent complete bilateral retroperitoneal lymph node dissection. The end point of study was disease specific survival, calculated from the time of retroperitoneal lymph node dissection to death from transitional cell carcinoma of the bladder.Four patients underwent delayed retroperitoneal lymph node dissection. Seven patients underwent concurrent cystectomy, and pelvic and retroperitoneal lymph node dissection. There was no perioperative mortality. Nine patients had evidence of residual disease in the retroperitoneal nodes. Seven patients have recurrence outside of the original surgical field with a median time to recurrence of 7 months and 6 died at a median time to death of 8 months (range 5 to 14). One patient with retrocrural recurrence attained a complete response to salvage chemotherapy and remained disease-free 57 months after retroperitoneal lymph node dissection. For all 11 patients median disease specific and recurrence-free survival rates were 14 and 7 months, respectively. Four-year disease specific and recurrence-free survival rates were 36% and 27%, respectively. We stratified the patients based on the number of involved lymph nodes at retroperitoneal lymph node dissection and noted that viable tumor in no more than 2 lymph nodes correlated with greater disease specific and recurrence-free survival (p = 0.006 and 0.01, respectively).Retroperitoneal lymph node dissection can be safely performed for metastatic transitional cell carcinoma. Retroperitoneal lymph node dissection has curative potential, particularly in patients with viable tumor in no more than 2 lymph nodes after chemotherapy.