Impact of Immune and Stromal Infiltration on Outcomes Following Bladder-Sparing Trimodality Therapy for Muscle-Invasive Bladder Cancer

Abstract

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.

Keywords: Biomarker; Bladder cancer; Bladder preservation; Bladder-sparing; Chemoradiation; Gene expression profiling; Immune; Muscle-invasive bladder cancer; Radiation; Stromal; Trimodality therapy.

Fig. 1 –

Gene expression subtypes and clinical outcomes in a TMT cohort. (A) Heat map showing genomic subtype classifier (GSC) subtype for each tumor in the TMT cohort (n = 136) and gene expression levels across several gene sets. Classification using the TCGA subtypes is also shown for each tumor. (B and C) Kaplan-Meier curves for disease-specific survival (DSS) and overall survival (OS) among GSC subtypes in the TMT cohort. Log-rank p values and the number of patients at risk are shown. ECM = extracellular matrix; infil. = infiltrated; TCGA = The Cancer Genome Atlas; TMT = trimodality therapy.

Fig. 2 –

A T-cell–inflamed gene expression signature is associated with outcomes in the TMT cohort but not in the NAC cohort. (A) Heat map showing expression of the T-cell– inflamed gene expression signature [18] across tumors from the TMT cohort. Kaplan-Meier curves for disease-specific survival (DSS) and overall survival (OS) by T-cell– inflamed expression scores in (B and C) the TMT cohort and (D and E) the NAC cohort. Log-rank p values and the number of patients at risk are shown. (F) Notched box plots showing the T-cell–inflamed scores across GSC subtypes in the TMT cohort. GSC = genomic subtyping classifier; Lum. = luminal; NAC = neoadjuvant chemotherapy; TMT = trimodality therapy.

Fig. 3 –

An interferon-gamma (IFNg) gene expression signature is associated with outcomes in the TMT cohort but not in the NAC cohort. (A) Heat map showing expression of a subset of genes from an IFNg gene expression signature [19] across tumors from the TMT cohort. Kaplan-Meier curves for disease-specific survival (DSS) and overall survival (OS) by IFNg expression scores in (B and C) the TMT cohort and (D and E) the NAC cohort. Log-rank p values and the number of patients at risk are shown. (F) Notched box plots showing the IFNg expression scores across GSC subtypes in the TMT cohort. GSC = genomic subtyping classifier; NAC = neoadjuvant chemotherapy; TMT = trimodality therapy.

Fig. 4 –

A stromal gene expression signature is associated with outcomes in the NAC cohort but not in the TMT cohort. (A) Heat map showing expression of genes in the stromal gene expression signature across tumors from the TMT cohort. Notched box plots showing the stromal signature scores across GSC subtypes in the (B) TMT and (C) NAC cohorts. Kaplan-Meier curves for disease-specific survival (DSS) and overall survival (OS) by stromal signature scores in (D and E) the TMT cohort and (F and G) the NAC cohort. Log-rank p values and the number of patients at risk are shown. GSC = genomic subtyping classifier; infiltr. = infiltrated; NAC = neoadjuvant chemotherapy; TMT = trimodality therapy.