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Phase I clinical trials are important in developing novel therapies for patients with metastatic urothelial carcinoma (mUC), and prognostic scores may improve patient selection for enrollment in these studies. We evaluated urothelial carcinoma specific (Bellmunt, Bajorin) and phase I specific (Royal Marsden Hospital (RMH), MD Anderson Cancer Center (MDACC)) prognostic scores in a cohort of 57 trial participants (TPs) enrolling in phase 1 clinical trials. The RMH and MDACC phase I prognostic scores accurately predicted survival in patients with mUC and outperformed the urothelial carcinoma-specific scores at time of enrollment on phase I clinical trials. Our findings suggest that the RMH and MDACC prognostic scores could optimize selection of patients with mUC for phase I clinical trials. Introduction: Enrolling patients with metastatic urothelial carcinoma (mUC) in phase I trials provides an opportunity to identify biological drug activity. Developing prognostic scores may aid in patient selection for phase 1 trials. Patients and Methods: :We analyzed records of patients with mUC who participated in targeted therapy and immunotherapy phase I clinical trials at MD Anderson Cancer Center (MDACC). The Bellmunt and Bajorin scores were calculated as bladder cancer-specific prognostic scores. The Royal Marsden Hospital (RMH) and MDACC scores were calculated as phase I prognostic scores. Hazard ratios (HR) were calculated using the Cox proportional hazard model. The prognostic value of the Bellmunt, Bajorin, RMH, and MDACC scores were assessed using the Likelihood ratio (LR) χ² test and the c-index. Results: Between 2015 and 2019, 43 patients were enrolled in phase I trials and 12 were enrolled in > I trial leading to a total of 57 trial participants (TPs). Ninty-seven percent of TPs received prior platinum therapy and 60% received a prior checkpoint inhibitor. Median overall survival (OS) and progression-free survival (PFS) were significantly shorter with increasing Bajorin, RMH, or MDACC scores, but not with increasing Bellmunt score. The RMH (c-index = 0.658, LR χ² = 11.8, P = .008) and MDACC scores (c-index = 0.66, LR χ² = 12.76, P = .01) outperformed the Bajorin score (cindex = 0.522, LR χ² = 1.22, P = .5) and the Bellmunt score (c-index = 0.537, LR χ² = 0.36, P = .9) in predicting overall survivalover. The Bajorin, RMH, and MDACC scores, but not the Bellmunt score, were also predictive of progressionfree survival (PFS)prog. The RMH and MDACC scores again outperformed the Bajorin scoreand the Bellmunt score for predicting PFS. Conclusion: The RMH and MDACC phase I prognostic scores accurately predicted survival in patients with mUC and outperformed the bladder cancer-specific scores at time of enrollment on phase 1 clinical trials. The RMH and MDACC scores could optimize selection of patients with mUC for phase I clinical trials. [ABSTRACT FROM AUTHOR]

Small cell (SC) urothelial cancer (UC) is a rare aggressive subtype with limited treatments and scarce knowledge about its biology. It frequently (60-70%) co-exists with different histologic forms, mainly urothelial carcinoma (UC), in the largest described series. Yet, it is currently unknown whether co-existent histologic components are found in metastatic SCUC tumors.;Given the presence of targeted therapies in UC, understanding the contribution of these mixed morphologies may help improve treatment strategies. In this study, we aimed to describe the morphologies of metastatic SCUC biopsies from localized disease (LD) to metastatic disease (MD). Data was extracted from a historical cohort of 409 patients with SCUC treated at MDACC between 1985 and 2020. Out of 124 patients who developed metastases after treatment for localized disease, 61 had a metastatic site biopsy. We assessed morphology in specimens reviewed by MDACC pathologists at three timepoints in patient trajectory: at LD or at transurethral resection (TUR), at definitive surgery (when available), and at MD. In morphological annotation, 'predominant SCUC' was defined as >50% of SC components in a biospecimen while 'minority SCUC' refers to less than 50% of SC. Patients were mostly male (52/61, 85.2%) and Caucasian (57/61, 93.4%), with a median age of 68.3 years [ICR: 60.3-70]. Fourty one (41/61, 67.2%) patients had a smoking history. At definitive treatment, 51/61 (83.6%) had radical or partial cystectomy, 30/61 (49.2%) received neoadjuvant chemotherapy and 16/61 (26.2%) received adjuvant treatment. The morphologies seen at TUR were 'SCUC only' in 13/61 patients (21.3%), 'predominant SCUC' in 30/61;(49.2%) and 'minority SCUC' in 18/61;(29.5%). In mixed tumors at TUR, UC was the most frequent co-existent morphology in 37/48 (77.1%). At surgery, 10/13 (76.9%) of patients with;'SCUC only' at TUR had other non-SC morphologies. At MD, most biopsies reflected 'SCUC only'; final distribution at MD was 'SCUC only' in 38/61 (62.3%), followed by 'predominant SCUC' in 11/61 (18%) and 'non-SCUC' in 12/61 (19.7%).;At;MD, most 'predominant SCUC' morphologies at TUR (21/30, 70%) had 'SCUC only', most 'SCUC only' (11/13,;84.6%) stayed the same, while;'minority SCUC' did not follow a specific pattern.;These shifts in SC predominance between LD and MD might reflect;the effect of chemotherapy;and limitations in tumor sampling when comparing tissues between TUR, resection and metastasis. In patients with 'SCUC only' prior to receiving neoadjuvant chemotherapy, around 77% were found to have non-SC components at the time of surgery. Yet, upon development of MD, most biopsies demonstrate 'SCUC only' morphology. This likely represents the more rapid proliferation and early metastatic potential observed with SCUC. Understanding the impact of various co-existent histological subtypes may help us understand whether targeted therapies play a role in the management of this disease. The challenges include the inability to assess tumor heterogeneity of SCUC in biospecimens at LD and MD. [ABSTRACT FROM AUTHOR]