Comparative Genomic Characterization of Small Cell Carcinoma of the Bladder Compared With Urothelial Carcinoma and Small Cell Lung Carcinoma.

Abstract

Small cell bladder cancer (SCBC) is a rare histologic variant of bladder cancer with an aggressive disease course and poor outcomes. Given its uncommon nature, there is a paucity of high-quality data characterizing genomic drivers of this disease, and most patients are treated with approaches mirroring small cell lung cancer (SCLC). Leveraging the Tempus Lens deidentified clinically annotated genomic data set, we sought to evaluate the mutational landscape of SCBC relative to urothelial carcinoma (UC) and SCLC. Somatic pathogenic genomic alterations in patients with SCBC, UC, and SCLC of any stage who underwent blood- or tissue-based genomic profiling through the Tempus assay were cataloged. Baseline clinical and demographic features were compared across histologic groups. Alterations were collated and summarized using descriptive statistics. Pairwise comparisons were performed to assess differences in mutation frequency across pathologic cohorts. In total, 149 SCBC, 4,350 UC, and 1,697 SCLC patients were included in the study. The most common genomic alterations in SCBC were in <i>TP53</i> (87%), <i>TERT</i> (75%), and <i>RB1</i> (70%). Among SCBC patients with <i>TP53</i> mutations, <i>RB1</i> comutations were observed in 77% of patients. Compared with UC, SCBC patients were significantly enriched for <i>TP53</i>, <i>RB1</i>, <i>KMT2D</i>, and <i>KDM6A</i> mutations. Compared with SCLC, SCBC patients were enriched for <i>TERT</i>, <i>ARID1A</i>, and <i>CREBBP</i> mutations, among others (<i>P</i> < .05). Multiple clinically targetable mutations were observed in SCBC, including <i>PIK3CA</i> (19%), <i>ERBB2/3</i> (13%), and <i>ALK</i> (10%). Limitations of this study include its retrospective nature. This study represents one of the most extensive efforts to characterize SCBC to date, providing a novel understanding of the genomic alterations underlying the disease and revealing actionable mutations that could serve as potential targets for improved clinical outcomes.