Elsevier

European Urology

Volume 76, Issue 1, July 2019, Pages 59-68
European Urology

Platinum Priority – Bladder Cancer – Editor's Choice
Editorial by Ananya Choudhury and Peter J. Hoskin on pp. 69–70 of this issue
Impact of Immune and Stromal Infiltration on Outcomes Following Bladder-Sparing Trimodality Therapy for Muscle-Invasive Bladder Cancer

https://doi.org/10.1016/j.eururo.2019.01.011Get rights and content

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 5 yr, and median follow-up time for patients without an event was 5.0 yr (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.

Introduction

Although radical cystectomy (RC) with or without neoadjuvant chemotherapy (NAC) is a common treatment for muscle-invasive bladder cancer (MIBC), bladder-sparing trimodality therapy (TMT) with maximal transurethral resection of bladder tumor (TURBT) followed by concurrent chemoradiotherapy is an acceptable alternative for select patients [1], [2], [3]. A randomized trial comparing TMT and RC for MIBC failed to complete accrual [4], but multiple series demonstrate that long-term disease control and quality-of-life outcomes for TMT compare favorably with RC [5], [6], [7], [8], [9]. Both TMT and RC are recommended as acceptable treatment options for MIBC in multiple national and international consensus guidelines [1], [2], [3]. However, TMT remains underutilized, in part due to difficulty in identifying appropriate patients. Therefore, there is an urgent need for reliable predictive biomarkers to guide treatment selection for MIBC patients.

Transcriptional profiling of MIBC has identified molecular subtypes characterized by distinct gene expression patterns [10], [11], [12], [13]. Although subtype characteristics and nomenclature vary across published cohorts, bladder tumors can broadly be categorized based on luminal versus basal gene expression patterns. Recent integrated analyses indicate that patterns of genomic alterations vary across subtypes [14], with important prognostic and predictive implications [10], [15]. In patients undergoing RC without NAC, luminal subtype was associated with improved overall survival (OS) compared with basal subtype [15]. Interestingly, patients with basal tumors experienced a significant benefit in OS from the addition of NAC, whereas patients with luminal tumors had similar outcomes with or without NAC, suggesting that molecular subtype may serve as a predictive biomarker to guide the use of NAC [15]. However, it is not known whether molecular subtype predicts response to radiotherapy.

Radiation triggers an immune response against tumor cells through several mechanisms, including antigen release, promotion of chemokine secretion, and recruitment of immune effector cells [16]. Given the association between radiation and immune activation, we hypothesized that the presence of a tumor immune infiltrate may be associated with an improved response to TMT. In addition, fibroblasts in the tumor microenvironment have been associated with a T-cell exclusion phenotype in bladder tumors, with an impact on response to systemic therapy [17]. Thus, radiotherapy responses may also vary with the extent of tumor stromal infiltration. Recent studies demonstrated that tumor gene expression profiling can quantify immune activity, including CD8(+) T-cell infiltration [18] and interferon (IFN)-gamma signaling [19]. Here, we report results from clinical-grade whole transcriptome gene expression profiling of a large cohort of MIBC patients managed with TMT. We classified the cohort using molecular subtypes, and tested the association of immune and stromal gene signatures with clinically relevant endpoints.

Section snippets

Patients and clinical samples

This is a retrospective analysis of tumor samples from a previously reported cohort of 475 patients with cT2-T4aN0M0 MIBC treated with TMT at a single institution [6]. Institutional review board approval was obtained for this study. High-quality transcriptomic data were available from 136 cases and were included in the final analyses (see below). We observed 60 OS events (death by any cause) and 32 disease-specific survival (DSS) events at 5-yr follow-up; the median follow-up time for patients

Transcriptomic analysis identifies four gene expression subtypes in the TMT cohort

Whole transcriptome expression profiles were available from pretreatment TURBT specimens from 136 MIBC patients treated with TMT and from a previously published cohort of 223 MIBC patients treated with NAC and RC [15]. Clinical characteristics of both cohorts are summarized in Table 1 and are described in detail in prior publications [6], [15]. There were several differences between the TMT and NAC cohorts, including a higher median age, a larger proportion of males, and lower T stages for TMT

Discussion

Recent studies in MIBC have identified molecular subtypes with distinct biological features and clinical behaviors [13], [15], [25], but most studies focus on patients treated with RC. In contrast, little is known about the impact of genomic features on outcomes following TMT. As randomized data comparing RC versus TMT are not available, selection of therapy for MIBC relies on clinical factors and patient/provider preference. There is thus a critical need for biomarkers to refine therapy

Conclusions

Transcriptional profiling of tumors from patients with MIBC revealed significant associations between immune and stromal signatures, and cancer-specific outcomes. Among MIBC patients treated with TMT, decreased tumor immune infiltration was associated with shorter DSS, whereas there was no association between stromal infiltration and DSS. Conversely, among MIBC patients treated with NAC followed by RC, there was no association between immune infiltration and DSS, whereas increased tumor stromal

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