Prognostic Model for Predicting Survival of Patients With Metastatic Urothelial Cancer Treated With Cisplatin-Based Chemotherapy

A prognostic model that predicts overall survival (OS) for metastatic urothelial cancer (MetUC) patients treated with cisplatin-based chemotherapy was developed, validated, and compared with a commonly used Memorial Sloan-Kettering Cancer Center (MSKCC) risk-score model. Data from 7 protocols that enrolled 308 patients with MetUC were pooled. An external multi-institutional dataset was used to validate the model. The primary measurement of predictive discrimination was Harrell's c-index, computed with 95% confidence interval (CI). The final model included four pretreatment variables to predict OS: visceral metastases, albumin, performance status, and hemoglobin. The Harrell's c-index was 0.67 for the four-variable model and 0.64 for the MSKCC risk-score model, with a prediction improvement for OS (the U statistic and its standard deviation were used to calculate the two-sided P = .002). In the validation cohort, the c-indices for the four-variable and the MSKCC risk-score models were 0.63 (95% CI = 0.56 to 0.69) and 0.58 (95% CI = 0.52 to 0.65), respectively, with superiority of the four-variable model compared with the MSKCC risk-score model for OS (the U statistic and its standard deviation were used to calculate the two-sided P = .02)

Abstract 3931: BRD4, BRD3, NSD3, and ZNF532 fusions in histologies beyond NUT carcinomas: Investigation of a large pan-cancer cohort

Abstract Background: NUT rearrangements drive NUT carcinomas (NCs), which are rare, poorly differentiated tumors with a survival from diagnosis of ~6-7 months. Common NUT fusion partners (NCFPs) include BRD4, BRD3, NSD3, and ZNF532, which are associated with epigenetic changes leading to tumor growth. Recent clinical trials have aimed to address NCs, but little is known about fusions involving NCFPs in other histologies. We characterized NCFPs in a large, pan-cancer cohort. Methods: The MSK-IMPACT (DNA sequencing; n=71,423) and MSK-Fusion (RNA sequencing; n=10,897) clinical cohorts were mined to identify patients (pts) with all forms of structural variants (SVs) involving NCFPs, detected between April, 2015 and June, 2022. The targeted NGS panels included BRD4 and NSD3 only; detection of BRD3 and ZNF532 SVs was possible for fusions with a partner present on either panel. SVs were manually reviewed to identify in-frame fusions with oncogenic potential if critical domains present in NC fusions were conserved. Pts were followed through July 2022 and manual chart review enabled assessment of treatment history and clinical outcomes. Results: SVs involving NCFP genes were detected in 182 (BRD4=110, NSD3=61, BRD3=8 and ZNF532=3) pts (0.002%). Putative NCFP fusions not involving any of the NUT gene family members comprised a total of 20 fusions with likely oncogenic potential including 11 with BRD4 (55%), 5 with NSD3 (25%), 3 with ZNF532 (15%), and 1 with BRD3 (5%). BRD4::NOTCH3 and ZNF532::MALT1 were the most enriched fusions, present in 3 samples each. The most common histologies were breast (3 ductal; 1 lobular), lung (2 squamous cell carcinoma, 1 adenocarcinoma and 1 mixed histology), and colon and esophageal adenocarcinoma (2 samples each). Median age at diagnosis was 62. 11 (55%) pts were female and 9 (45%) were male. 13 (65%) pts ultimately were diagnosed with stage IV disease and had a median overall survival from stage IV diagnosis of 2.5 years (95% CI: 1.41, NR). DNA sequencing in 19/20 tumors revealed a mean tumor mutational burden (TMB) of 5.0 mut/Mb including 15 with low TMB (10). No tumor showed microsatellite instability (MSI-high). TP53 mutations were the most common co-alteration, found in 11 (58%) cases. 18/20 pts received systemic therapy; 18 (90%) received cytotoxic chemotherapy and/or mAb therapy, including 13 (65%) who received a platinum. 8 pts (40%) received immunotherapy (IO), and 4 (20%) received small molecule inhibitors. No pts received BET inhibitors. Among pts who received IO, median time to treatment discontinuation was 64 days (95% CI: 20, NR). Conclusion: Tumor sequencing from a large cohort reveals potential oncogenic fusions involving BRD4, BRD3, NSD3, and ZNF532 across multiple histologies. Further biological characterization of their oncogenicity and potential targetability is warranted. Citation Format: Ian R. Nykaza, Christopher A. Febres-Aldana, Sabrina T. Lin, Ryma Benayed, Kerry Mullaney, Emiliano Cocco, Alexia Iasonos, Marc Ladanyi, Alexander E. Drilon, Yonina R. Murciano-Goroff. BRD4, BRD3, NSD3, and ZNF532 fusions in histologies beyond NUT carcinomas: Investigation of a large pan-cancer cohort. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3931

Small cell neuroendocrine carcinoma of the cervix: Analysis of prognostic factors and patterns of metastasis

Objectives: To describe characteristics and outcomes of patients with small cell neuroendocrine carcinoma of the cervix (SCNCC) and determine the staging system most predictive of outcome-the two-tier (limited-stage [LS] vs. extensive-stage [ES]) or International Federation of Gynecology and Obstetrics (FIGO) staging system. Methods: Patients with SCNCC evaluated at our institution from 1/1/1990-6/30/2021 were included. Medical records were reviewed for variables of interest. Appropriate statistical tests were performed to determine associations. Survival curves were created using the Kaplan-Meier method. Concordance probability estimates (CPEs) were calculated to evaluate the prediction probability of the staging systems. Results: Of 63 patients, 41 had LS and 22 ES SCNCC. Patients with ES disease were significantly older than those with LS disease (median, 54 and 37 years, respectively; p \u3c 0.001). Smoking status, race, and history of HPV were not associated with stage or outcomes. Forty-eight patients had metastatic disease (24 [50%] at initial diagnosis). The most common first sites of metastasis were lung (n = 20/48, 42%), lymph nodes (n = 19/48, 40%), and liver (n = 13/48, 27%). Nine patients had brain metastasis (8 symptomatic at recurrence; 1 asymptomatic at initial diagnosis). Both staging systems were associated with progression-free and overall survival. Adjusted CPE found the FIGO staging system was more predictive of outcomes than the two-tier staging system. Conclusions: Providers should have a low threshold to obtain brain imaging for patients with SCNCC, especially in the presence of visceral metastases. FIGO staging should be used to classify SCNCC. Further research is necessary to understand prognostic factors of this rare disease