Title: Identification of a Novel Inflamed Tumor Microenvironment Signature as a Predictive Biomarker of Bacillus Calmette-Guérin Immunotherapy in Non-Muscle-Invasive Bladder Cancer.

Authors: Damrauer, Jeffrey S; Roell, Kyle R; Smith, Markia A; Sun, Xuezheng; Kirk, Erin L; Hoadley, Katherine A; Benefield, Halei C; Iyer, Gopakumar; Solit, David B; Milowsky, Matthew I; Kim, William Y; Nielsen, Matthew E; Wobker, Sara E; Dalbagni, Guido; Al-Ahmadie, Hikmat A; Olshan, Andrew F; Bochner, Bernard H; Furberg, Helena; Troester, Melissa A; Pietzak, Eugene J

Published In Clin Cancer Res, (2021 Aug 15)

Abstract: PURPOSE: 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. EXPERIMENTAL DESIGN: Gene expression in NMIBC samples was profiled by NanoString nCounter, an 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 RNA sequencing 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. RESULTS: 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-Guérin (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. CONCLUSIONS: 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.

PubMed ID: 34117034

MeSH Terms: Adjuvants, Immunologic/therapeutic use*; Aged; BCG Vaccine/therapeutic use*; Female; Humans; Inflammation; Male; Middle Aged; Mutation; Neoplasm Invasiveness; Transcriptome*; Treatment Outcome; Tumor Microenvironment*; Urinary Bladder Neoplasms/drug therapy*; Urinary Bladder Neoplasms/genetics*; Urinary Bladder Neoplasms/pathology