Assistant Professor Department of Urology, Ludwig-Maximilians-University, Munich
Introduction: Molecular bladder cancer (BC) subtypes define distinct biological entities and were shown to predict treatment response in neoadjuvant and adjuvant setting. The extent of intratumoral heterogeneity (ITH) might affect subtyping of individual patients. This study intended to comprehensively asses ITH in a cohort of muscle-invasive BC. Methods: 251 patients undergoing radical cystectomy were screened. Three cores of the tumor center (TC) and 3 cores of the invasive tumor front (TF) of each patient were assembled in a tissue-microarray. Molecular subtypes were determined employing 12 pre-evaluated immunohistochemical markers (FGFR3, CCND1, RB1, CDKN2A, KRT5, KRT14, FOXA1, GATA3, TUBB2B, EPCAM, CDH1, Vimentin). A total of 18,072 spots were evaluated of which 15,002 spots were assessed based on intensity, distribution or the combination. Allocation to one of 5 different molecular subtypes: Urothelial-like (Uro); Genomically Unstable (GU); Small-cell/Neuroendocrine-like (Sc/NE-like); Basal/SCC-like (Basal); Mesenchymal-like (Mes) was conducted for each patient for the complete tumor, individual cores, TF, and TC separately. Primary objective: ITH between TF and TC (n=208 patients). Secondary objective: Multi-region ITH (n=191 patients). Analysis of the composition of ITH-cases, correlation with clinicopathological parameters, and prognosis. Results: Subtyping of the complete cohort revealed Uro: 37.1%, GU: 34.3%, Sc/NE-like: 8.8%, Basal/SCC-like: 18.7%, and Mesenchymal-like: 1.2%. ITH between TF and TC was seen in 12.5% (n=26/208) and ITH defined by at least two different subtypes of any location in 24.6% (n=47/191). ITH was more frequent in locally confined (pT2) vs. advanced (pT=3) BC stages (38.7% vs. 21.9%, p=0.046). pT4 BC presented with significantly more basal subtypes compared to pT2 BC (26.2% vs. 11.5%, p=0.049). There was no correlation of ITH with prognosis or molecular subtypes. Conclusions: Several molecular subtypes can be found in nearly every fourth case of muscle-invasive BC. ITH must be given due consideration for individualized, subtype-based therapeutic approaches. SOURCE OF Funding: university internal funds, no external funding
