Abstract 459: Comprehensive molecular characterization of treatment naive muscle invasive bladder cancer
Authors: Taber Ann , Lamy Philippe , Nodentoft Iver , Christensen Emil , Prip Frederik F. , Lindskrog Sia V. , Birkenkamp-Demtröder Karin , Agerbæk Mads , Jensen Jørgen B. , Dyrskjøt Lars 
Published: August 2019

Abstract
Background: The interplay between carcinoma cells and their microenvironment plays an important part in cancer development, progression, metastasis and treatment efficacy. In bladder cancer, however, little is currently known about how the tumor microenvironment affects disease outcome and treatment. To study this, we analyzed tumor tissue from a clinically well characterized cohort of 608 patients with muscle invasive bladder cancer (MIBC).
Methods: Multiplex Immunofluorescence (IF) was used to assess the tumor microenvironment in 608 patients with MIBC. Digital pathology was used to quantify the immune context (CD8, CD3, FOXP3) within carcinoma cells and in the adjacent stroma. Immune cell densities were correlated to clinical characteristics, survival outcome and chemotherapy response (n=187). To explore chemotherapy response mechanisms further, a total of 107 patients with metastatic disease are also being characterized by multi-omics analysis (exome-, transcriptome-, and methylome-analysis). Patients receiving chemotherapy were included based on the following criteria: 1) treatment naive primary tumors, 2) received a minimum of 4 cycles of cisplatin based chemotherapy, 3) ECOG Performance Status &lt;2, 4) Response evaluated according to the RECIST criteria (version 1.1).
Results: In total, 384 of 608 patients had metastatic disease. Analysis of the immune cell compositions revealed a immune profile consisting of high levels of CTLs and T helper cells, and a low level of Tregs significantly associated with a better outcome (p&lt;0.0001). For patients receiving chemotherapy for metastatic disease, we observed no significant differences in the treatment naive primary tumors when correlating individual or combined immune cell types (CTLs, T helper cells, Tregs) to treatment response. Preliminary analysis of exome seq data showed a tendency towards a higher mutation burden in complete responders (p=0.047), however response was not associated with DDR mutations nor mutational signatures in this patient cohort. Furthermore, gene expression subtypes did not predict treatment response.
Conclusions: Results from the multiplex IF showed that immune profiles (CTLs, T helper cells, Tregs) correlated with recurrence and survival outcome. However, they did not predict chemotherapy response. A full and integrated molecular characterization of our clinically well annotated metastatic subgroup (n=107) will be presented at the AACR 2019 meeting.
Citation Format: Ann Taber, Philippe Lamy, Iver Nodentoft, Emil Christensen, Frederik F. Prip, Sia V. Lindskrog, Karin Birkenkamp-Demtröder, Mads Agerbæk, Jørgen B. Jensen, Lars Dyrskjøt. Comprehensive molecular characterization of treatment naive muscle invasive bladder cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 459.