Abstract
BackgroundTranscriptome expression studies identified distinct muscle invasive bladder cancer (MIBC) subtypes closely related with breast cancer subclasses. Here we developed a sensitive quantification method for MIBC subclassification (luminal, basal, p53-like). In addition, the subtype specific expression of drug targets has been investigated.MethodsAbsolute quantification (nCounter) of a 64-gene panel was performed on MIBC patients (n=47) treated exclusively with radical cystectomy (RC). In conjunction of 170 MIBCs from 3 independent cohorts, a minimal set of consensus genes has been established. Survival of the consensus subtypes has been assessed by multivariate analysis. Relevant drug targets were tested for their subtype specificity in a clustering independent assessment.ResultsA reduced 36-gene panel stably clustered into 3 subtypes throughout the cohorts (luminal, basal, infiltrated). Patients treated by RC only, showed worst 8-year disease specific survival (DSS) for the luminal subtype in contrast to the infiltrated subtype (17% vs. 73%, p=0.011). In multivariate analyses, the risk stratification based on luminal versus not-luminal MIBC proved to be an independent predictor for DSS superior to the TNM system in patients with RC. Drug targets (e.g. ERBB2, FGFR, AR, PDGFRB) showed a distinct subtype attribution. The subtypes based on this nCounter screening could further be validated by the TCGA cohort.ConclusionThis MIBC subtype screening predicted survival and allowed an analysis of subtype specific drug targets, thus being a powerful tool for the translation of personalized MIBC treatment concepts.
Highlights
Even though bladder cancer accounts to the top ten most common malignancies, personalized therapy concepts have not yet found their advent into clinical routine
The risk stratification based on luminal versus not-luminal muscle invasive bladder cancer (MIBC) proved to be an independent predictor for disease specific survival (DSS) superior to the TNM system in patients with radical cystectomy (RC)
The molecular subclassification based on basal, luminal and p53-like gene signatures resulted in a consensus gene panel of 36 stable clustering genes for the Mannheim, Chungbuk, MDA and Lund cohort (Venn diagrams, Supplementary Figure 2)
Summary
Even though bladder cancer accounts to the top ten most common malignancies, personalized therapy concepts have not yet found their advent into clinical routine. No targeted frontline therapies are established besides the recent approval of PD-1/PD-L1 inhibitors as a 2nd-line treatment against metastatic MIBC [1]. Patients with pT3-pT4 pN+ muscle invasive bladder cancer (MIBC) have a 5-year overall survival (OS) rate of only 35% [2]. MIBC accounts for 20-40% of tumor incidence [3]. Many clinical studies try to reevaluate the role of perioperative therapy concepts but are confronted to two major problems: clinical understaging and uncertain pathologic assessments especially after transurethral resection of the bladder (TURB) [5]. Transcriptome expression studies identified distinct muscle invasive bladder cancer (MIBC) subtypes closely related with breast cancer subclasses. The subtype specific expression of drug targets has been investigated
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