Identification of a novel inflamed tumor microenvironment signature as a predictive biomarker of bacillus Calmette-Guérin immunotherapy in non-muscle-invasive bladder cancer Journal Article
| Authors: | Damrauer, J. S.; Roell, K. R.; Smith, M. A.; Sun, X.; Kirk, E. L.; Hoadley, K. A.; Benefield, H. C.; Iyer, G.; Solit, D. B.; Milowsky, M. I.; Kim, W. Y.; Nielsen, M. E.; Wobker, S. E.; Dalbagni, G.; Al-Ahmadie, H. A.; Olshan, A. F.; Bochner, B. H.; Furberg, H.; Troester, M. A.; Pietzak, E. J. |
| Article Title: | Identification of a novel inflamed tumor microenvironment signature as a predictive biomarker of bacillus Calmette-Guérin immunotherapy in non-muscle-invasive bladder cancer |
| 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. © 2021 The Authors; Published by the American Association for Cancer Research |
| Keywords: | adult; treatment outcome; treatment response; aged; middle aged; gene mutation; major clinical study; promoter region; sequence analysis; clinical feature; cancer recurrence; recurrence risk; cancer grading; medical decision making; gene overexpression; bcg vaccine; cancer immunotherapy; gene expression; tumor volume; cohort analysis; transcriptomics; fibroblast growth factor receptor 3; tumor marker; prediction; rna; dna; cystectomy; cytotoxic t lymphocyte antigen 4; transurethral resection; mitomycin; recurrence free survival; programmed death 1 ligand 1; programmed death 1 receptor; tumor microenvironment; rna analysis; classifier; non muscle invasive bladder cancer; human; male; female; article; whole exome sequencing |
| Journal Title: | Clinical Cancer Research |
| Volume: | 27 |
| Issue: | 16 |
| ISSN: | 1078-0432 |
| Publisher: | American Association for Cancer Research |
| Date Published: | 2021-08-15 |
| Start Page: | 4599 |
| End Page: | 4609 |
| Language: | English |
| DOI: | 10.1158/1078-0432.Ccr-21-0205 |
| PUBMED: | 34117034 |
| PROVIDER: | scopus |
| PMCID: | PMC8416390 |
| DOI/URL: | |
| Notes: | Article -- Export Date: 1 September 2021 -- Source: Scopus |
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