Bladder urothelial carcinoma (BLCA) is pathologically categorized as non-muscle-invasive (NMIBC) and muscle-invasive (MIBC) bladder cancers. But its clinical heterogeneity has been suggested that biologically relevant subtypes may exist within and between NMIBC and MIBC. Here we identified that BLCA could be subgrouped into four major classes with distinct molecular characteristics regardless of previously known clinicopathological factors, using a series of unsupervised learning approaches. The predictor to discriminate distinct molecular subgroups of BLCA was constructed in a training cohort and validated in six independent cohorts with a total of 1,992 samples. The predictor showed a prognostic significance of the four subtype of BLCA, especially aggressive clinical behavior of the class 3 subtype. Interestingly, class 3 subtype has distinct biological features associated with potential responsiveness to immunotherapy, such as high somatic mutation rates and alterations of genes involved in DNA damage response and repair (DDR). Analyses of anti-PD-L1-treated BLCA patient tumor samples suggested that class 3 subtype was correlated with response to immune checkpoint inhibitors. Our findings have the potential to lead to the improvement of the current molecular classification system of BLCA and the achievement of better clinical outcomes for high-risk patients with BLCA treated with immunotherapy.

Note: This abstract was not presented at the meeting.

Citation Format: In-Sun Chu, Bic-Na Song, Sun-Hee Leem. Identification of bladder cancer subtypes with different sensitivities to immunotherapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1687.