Improved risk stratification and predictive biomarkers of treatment response are needed for non-muscle-invasive bladder cancer (NMIBC). Here we assessed the clinical utility of targeted RNA and DNA molecular profiling in NMIBC.
Gene expression in NMIBC samples was profiled by NanoString nCounter, a RNA quantification platform, from two independent cohorts (n = 28, n = 50); targeted panel sequencing was performed in a subgroup (n = 50). Gene signatures were externally validated using two RNAseq datasets of NMIBC tumors (n = 438, n=73). Established molecular subtype classifiers and novel gene expression signatures were assessed for associations with clinicopathologic characteristics, somatic tumor mutations, and treatment outcomes.
Molecular subtypes distinguished between low-grade Ta tumors with FGFR3 mutations and overexpression (UROMOL-class 1) and tumors with more aggressive clinicopathologic characteristics (UROMOL-classes 2 and 3), which were significantly enriched with TERT promoter mutations. However, UROMOL subclasses were not associated with recurrence after bacillus Calmette-Guerin (BCG) immunotherapy in two independent cohorts. In contrast, a novel expression signature of an inflamed tumor microenvironment (TME) was associated with improved recurrence-free survival after BCG. Expression of immune checkpoint genes (PD-L1/PD-1/CTLA-4) was associated with an inflamed TME, but not with higher recurrence rates after BCG. FGFR3 mutations and overexpression were both associated with low immune signatures.
Assessment of the immune TME, rather than molecular subtypes, is a promising predictive biomarker of BCG response. Modulating the TME in an immunologically "cold" tumor warrants further investigation. Integrated transcriptomic and exome sequencing should improve treatment selection in NMIBC.
Clinical cancer research : an official journal of the American Association for Cancer Research. 2021 Jun 11 [Epub ahead of print]
Jeffrey S Damrauer, Kyle R Roell, Markia A Smith, Xuezheng Sun, Erin L Kirk, Katherine A Hoadley, Halei C Benefield, Gopakumar Iyer, David B Solit, Matthew I Milowsky, William Y Kim, Matthew E Nielsen, Sara E Wobker, Guido Dalbagni, Hikmat A Al-Ahmadie, Andrew F Olshan, Bernard H Bochner, Helena Furberg, Melissa A Troester, Eugene J Pietzak
Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill., Department of Epidemiology, University of North Carolina at Chapel Hill., Department of Genetics, Computational Medicine Program, Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill., Department of Epidemiology, Gillings School of Global Public Health, University of North Carolina at Chapel Hill., Medicine, Memorial Sloan Kettering Cancer Center., Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center., Medicine, University of North Carolina at Chapel Hill., Medicine, Genetics, Pharmacology, and Urology, University of North Carolina at Chapel Hill., Surgery/Urology, University of North Carolina at Chapel Hill School of Medicine., Pathology and Laboratory Medicine, University of North Carolina at Chapel Hill., Surgery, Memorial Sloan Kettering Cancer Center., Pathology, Memorial Sloan Kettering Cancer Center., Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center., Department of Surgery, Memorial Sloan Kettering Cancer Center .