Citation
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., et al. (2021). Identification of a Novel Inflamed Tumor Microenvironment Signature as a Predictive Biomarker of Bacillus Calmette-Guerin Immunotherapy in Non-Muscle Invasive Bladder Cancer. Clinical Cancer Research, 27(16), 4599-4609. PMCID: PMC8416390Abstract
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, 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.
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-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.
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.
URL
http://dx.doi.org/10.1158/1078-0432.Ccr-21-0205Reference Type
Journal ArticleYear Published
2021Journal Title
Clinical Cancer ResearchAuthor(s)
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.