Molecular subtypes applied to a population-based modern cystectomy series do not predict cancer-specific survival

Objectives: To investigate the preoperative prognostic value of molecular subtypes in relation to clinical information, histopathological findings, and molecular markers for patients with bladder cancer treated with radical cystectomy. Patients and methods: After standard preoperative staging, a population-based cohort of 519 patients underwent radical cystectomy between 2006 and 2011. Following pathological review of all transurethral resection of bladder tumor specimens, tissue microarrays were constructed, and RNA was extracted from formalin-fixed tissue blocks. Immunohistochemistry (IHC) was performed using markers suggested to be relevant for prognosis (ZEB2, CCND1, CD3, CD68, CDH3, HER3, KRT14, CDKN2A(p16), TP63, FGFR3, EPCAM, GATA3, FOXA1, ERBB2, and EGFR). IHC- and gene-expression-based molecular classification was also conducted. Univariate and multivariate Cox proportional hazards regression were used for survival analyses. Results: Clinical T3 stage (Hazard Ratio [HR] 1.6, Confidence Interval [CI] 1.1–2.3), hydronephrosis (HR 1.7, CI 1.2–2.3), lymphovascular invasion (LVI) (HR 2.6, CI 1.9–3.6), extensive necrosis (HR 1.6, CI 1.1–2.5), and CD68/CD3-ratio >1 (HR 1.3, CI 1.1–1.5) in the transurethral resection of bladder tumor specimen was associated with worse cancer-specific survival (CSS) and progression-free survival (data not shown). In multivariate analysis, higher clinical T stage (HR 1.3, CI 1.1–1.7; P = 0.007) and presence of LVI (HR 2.4, CI 1.7–3.5; P = 1.8 × 10 ^{− 6} ) were associated with worse CSS, whereas only LVI was associated with progression-free survival. Molecular subtypes (assessed by Lund taxonomy and the Consensus molecular subtypes of muscle-invasive bladder cancer) and published single IHC markers were not associated with survival. Conclusions: In the present large population-based cystectomy series, LVI and clinical stage were independently associated with CSS. However, molecular subtypes determined by global gene expression showed no such association with CSS according to either the Consensus molecular subtypes of muscle-invasive bladder cancer or Lund taxonomy.