Tumor Landscapes in Urothelial Carcinoma With or Without Squamous Differentiation

A retrospective study from Nishita Tripathi, MD, and colleagues, presented in Poster Session B, Urothelial Carcinoma, at the 2022 American Society of Clinical Oncology (ASCO) Genitourinary Cancers Symposium, compared genomic profiles of locally advanced or metastatic urothelial carcinomas with squamous differentiation (UCS) to standard urothelial carcinoma (UC). They noted that alterations of the KMT2D gene were significantly more frequent in the UCS cohort, and supplied that, “it is interesting to note that both KMT2D and CUL4A (higher frequency in UCS) are involved in epigenetic regulation.”

The trial included patients with advanced UCS and UC undergoing tumor-based genomic profiling. Genes with alterations in less than 5% of patients, patients with secondary variants of UC, and patients with variants of unknown significance were all excluded from the analysis.

A total of 87 patients were included in the study, 31 of which had UCS and 56 had UC. KMT2D genes with alterations were significantly enriched in the UCS group versus the UC group (15/31 vs, 0/56; false discovery rate [FDR] <0.001, p <0.001). Additionally, CUL4A alterations were numerically higher for UCS compared to UC (4/31 vs. 1/56, FDR= 0.444; p = 0.03). Interestingly, the investigators observed that the “frequency of genomic aberrations per patient were not significantly different in the groups.”

While the authors acknowledged that their “hypothesis-generating data” was limited by small sample size, selection, and confounding biases, they felt it warranted external validation. Ultimately, they suggested that “identification of underlying molecular targets and biomarkers can guide further drug development in this population.”