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

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. (Online ahead of print). 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.

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, 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-21-0205

Reference Type

Journal Article

Article Type

Regular

Year Published

Online ahead of print

Journal Title

Clinical Cancer Research

Author(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.

Continent/Country

United States of America

State

Nonspecific