Muscle invasive bladder cancer (MIBC) demonstrates neoadjuvant cisplatin-based chemotherapy (NAC) related changes in molecular subtype and immune infiltration.

Abstract

Listen

Translate article

443 Background: Defining the role of MIBC molecular subtypes and immune expression in determining clinical outcomes is an area of active investigation. However, changes in these transcriptomic profiles pre- and post-NAC have not been well characterized. Methods: This retrospective study reviewed 53 pts with MIBC treated with NAC, of whom 12 pts without complete pathological response had both pre- and post-NAC samples of sufficient quality. Post-NAC staging was > = pT2 in 11 pts and pT1 in 1 pt. We performed RNA expression analysis of matched pre-NAC transurethral resection of bladder tumor specimens and post-treatment radical cystectomy primary bladder tumor specimens. We used a customized NanoString panel incorporating previously reported immune signatures (Ayers, JCI 2017; O’Donnell, ASCO 2017) and additional genes to assign basal ( CD14, CD44, PDGFC, KRT14, KRT5) and luminal ( GATA3, PPARG, SHH, CD24, FOXA1, WNT7B, ERBB2) molecular subtypes. Results: We first classified the bladder cancer cohort of The Cancer Genome Atlas into basal and luminal subtypes using the BASE47 signature (Damrauer, PNAS 2014) and the NanoString panel and there was good agreement (Rand Index = 0.72). We then assigned subtypes using the NanoString panel on matched pre- and post-NAC samples and found marked subtype shift (Table). We identified two robust clusters of samples according to immune expression with a 3-fold change of immune expression between them (FDR = 0.0008). We found that 4 pts switched from the low to the high cluster, while 2 switched from the high to the low cluster after NAC (Table). Conclusions: MIBC molecular subtype membership is dynamic and is influenced by NAC. NAC can induce both enhanced and suppressed immune activity. These findings have implications on future studies exploring the predictive value of RNA expression patterns for bladder cancer therapies as well as post-NAC immunotherapy. [Table: see text]