Impact of Immune and Stromal Infiltration on Outcomes Following Bladder-Sparing Trimodality Therapy for Muscle-Invasive Bladder Cancer.
Aged
Biomarkers
Chemoradiotherapy, Adjuvant
Chemotherapy, Adjuvant
Cystectomy
/ methods
Female
Humans
Interferon-gamma
/ genetics
Lymphocyte Activation
/ genetics
Lymphocytes, Tumor-Infiltrating
/ immunology
Male
Middle Aged
Neoadjuvant Therapy
Neoplasm Invasiveness
Organ Sparing Treatments
Prognosis
Retrospective Studies
Stromal Cells
/ physiology
Survival Rate
T-Lymphocytes
/ immunology
Transcriptome
Treatment Outcome
Urinary Bladder
/ pathology
Urinary Bladder Neoplasms
/ genetics
Biomarker
Bladder cancer
Bladder preservation
Bladder-sparing
Chemoradiation
Gene expression profiling
Immune
Muscle-invasive bladder cancer
Radiation
Stromal
Trimodality therapy
Journal
European urology
ISSN: 1873-7560
Titre abrégé: Eur Urol
Pays: Switzerland
ID NLM: 7512719
Informations de publication
Date de publication:
07 2019
07 2019
Historique:
received:
30
07
2018
accepted:
07
01
2019
pubmed:
5
2
2019
medline:
8
10
2020
entrez:
5
2
2019
Statut:
ppublish
Résumé
Bladder-sparing trimodality therapy (TMT) is an alternative to radical cystectomy (RC) for muscle-invasive bladder cancer (MIBC), and biomarkers to inform therapy selection are needed. To evaluate the prognostic value of immune and stromal signatures in MIBC treated with TMT. We used a clinical-grade platform to perform transcriptome-wide gene expression profiling of primary tumors from 136 MIBC patients treated with TMT at a single institution. We observed 60 overall survival events at 5yr, and median follow-up time for patients without an event was 5.0yr (interquartile range 3.1, 5.0). Expression data from another cohort of 223 MIBC patients treated with neoadjuvant chemotherapy (NAC) and RC were also analyzed. Molecular subtype, immune, and stromal signatures were evaluated for associations with disease-specific survival (DSS) and overall survival (OS) in TMT patients, and in patients treated with NAC and RC. Gene expression profiling of TMT cases identified luminal (N=40), luminal-infiltrated (N=26), basal (N=54), and claudin-low (N=16) subtypes. Signatures of T-cell activation and interferon gamma signaling were associated with improved DSS in the TMT cohort (hazard ratio 0.30 [0.14-0.65], p=0.002 for T cells), but not in the NAC and RC cohort. Conversely, a stromal signature was associated with worse DSS in the NAC and RC cohort (p=0.006), but not in the TMT cohort. This study is limited by its retrospective nature. Higher immune infiltration in MIBC is associated with improved DSS after TMT, whereas higher stromal infiltration is associated with shorter DSS after NAC and RC. Additional studies should be conducted to determine whether gene expression profiling can predict treatment response. We used gene expression profiling to study the association between tumor microenvironment and outcomes following bladder preservation therapy for invasive bladder cancer. We found that outcomes varied with immune and stromal signatures within the tumor. We conclude that gene expression profiling has potential to guide treatment decisions in bladder cancer.
Sections du résumé
BACKGROUND
Bladder-sparing trimodality therapy (TMT) is an alternative to radical cystectomy (RC) for muscle-invasive bladder cancer (MIBC), and biomarkers to inform therapy selection are needed.
OBJECTIVE
To evaluate the prognostic value of immune and stromal signatures in MIBC treated with TMT.
DESIGN, SETTING, AND PARTICIPANTS
We used a clinical-grade platform to perform transcriptome-wide gene expression profiling of primary tumors from 136 MIBC patients treated with TMT at a single institution. We observed 60 overall survival events at 5yr, and median follow-up time for patients without an event was 5.0yr (interquartile range 3.1, 5.0). Expression data from another cohort of 223 MIBC patients treated with neoadjuvant chemotherapy (NAC) and RC were also analyzed.
OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS
Molecular subtype, immune, and stromal signatures were evaluated for associations with disease-specific survival (DSS) and overall survival (OS) in TMT patients, and in patients treated with NAC and RC.
RESULTS AND LIMITATIONS
Gene expression profiling of TMT cases identified luminal (N=40), luminal-infiltrated (N=26), basal (N=54), and claudin-low (N=16) subtypes. Signatures of T-cell activation and interferon gamma signaling were associated with improved DSS in the TMT cohort (hazard ratio 0.30 [0.14-0.65], p=0.002 for T cells), but not in the NAC and RC cohort. Conversely, a stromal signature was associated with worse DSS in the NAC and RC cohort (p=0.006), but not in the TMT cohort. This study is limited by its retrospective nature.
CONCLUSIONS
Higher immune infiltration in MIBC is associated with improved DSS after TMT, whereas higher stromal infiltration is associated with shorter DSS after NAC and RC. Additional studies should be conducted to determine whether gene expression profiling can predict treatment response.
PATIENT SUMMARY
We used gene expression profiling to study the association between tumor microenvironment and outcomes following bladder preservation therapy for invasive bladder cancer. We found that outcomes varied with immune and stromal signatures within the tumor. We conclude that gene expression profiling has potential to guide treatment decisions in bladder cancer.
Identifiants
pubmed: 30712971
pii: S0302-2838(19)30012-0
doi: 10.1016/j.eururo.2019.01.011
pmc: PMC6571058
mid: NIHMS1520464
pii:
doi:
Substances chimiques
Biomarkers
0
Interferon-gamma
82115-62-6
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
59-68Subventions
Organisme : NCI NIH HHS
ID : C06 CA059267
Pays : United States
Organisme : NCI NIH HHS
ID : K08 CA219504
Pays : United States
Commentaires et corrections
Type : CommentIn
Type : CommentIn
Type : CommentIn
Type : CommentIn
Type : CommentIn
Informations de copyright
Copyright © 2019 European Association of Urology. Published by Elsevier B.V. All rights reserved.
Références
Science. 2006 Sep 29;313(5795):1960-4
pubmed: 17008531
BJU Int. 2010 Sep;106(6):753-5
pubmed: 20707796
Br J Cancer. 2011 Jun 28;105(1):93-103
pubmed: 21629244
J Immunol. 2011 Nov 15;187(10):5336-45
pubmed: 22013119
Clin Cancer Res. 2012 Jun 15;18(12):3377-86
pubmed: 22553347
Eur Urol. 2013 Jan;63(1):45-57
pubmed: 22917985
Front Oncol. 2014 Jan 21;4:1
pubmed: 24478982
Proc Natl Acad Sci U S A. 2014 Feb 25;111(8):3110-5
pubmed: 24520177
Cancer Cell. 2014 Feb 10;25(2):152-65
pubmed: 24525232
J Clin Oncol. 2014 Dec 1;32(34):3801-9
pubmed: 25366678
Cell Syst. 2015 Dec 23;1(6):417-425
pubmed: 26771021
Cell. 2016 May 19;165(5):1092-1105
pubmed: 27133165
Cancer Immunol Res. 2016 Jul;4(7):563-8
pubmed: 27197067
Nat Immunol. 2016 Sep 20;17(10):1142-9
pubmed: 27648547
Int J Radiat Oncol Biol Phys. 2016 Dec 1;96(5):1028-1036
pubmed: 27727064
Eur Urol. 2017 Jun;71(6):952-960
pubmed: 28081860
Int J Radiat Oncol Biol Phys. 2017 Apr 1;97(5):1002-1020
pubmed: 28332983
Eur Urol. 2017 Sep;72(3):354-365
pubmed: 28365159
Eur Urol. 2017 Oct;72(4):544-554
pubmed: 28390739
Clin Cancer Res. 2017 Aug 15;23(16):4761-4768
pubmed: 28400426
J Clin Oncol. 2017 Jul 10;35(20):2299-2305
pubmed: 28410011
J Urol. 2017 Sep;198(3):552-559
pubmed: 28456635
PLoS Med. 2017 May 26;14(5):e1002309
pubmed: 28552987
Clin Cancer Res. 2018 Jan 15;24(2):259-265
pubmed: 28751442
Cell. 2017 Oct 19;171(3):540-556.e25
pubmed: 28988769
Nat Rev Urol. 2018 Feb;15(2):92-111
pubmed: 29133939
Nature. 2018 Feb 22;554(7693):544-548
pubmed: 29443960
Sci Rep. 2018 Feb 27;8(1):3737
pubmed: 29487377
Lancet Oncol. 2018 Dec;19(12):e683-e695
pubmed: 30507435
Bladder Cancer. 2015 Apr 30;1(1):15-27
pubmed: 30561443