Role of Gut Microbiome in Neoadjuvant Chemotherapy Response in Urothelial Carcinoma: A Multi-Institutional Prospective Cohort Evaluation

Treatment with neoadjuvant chemotherapy (NAC) in muscle invasive bladder cancer (MIBC) is associated with clinical benefit in urothelial carcinoma. While extensive research evaluating role of tumor mutational expression profiles and clinicopathologic factors into chemoresponse has been published, the role of gut microbiome (GM) in bladder cancer in chemoresponse has not been thoroughly evaluated. A working knowledge of the microbiome and its effect on all forms of cancer therapy in BC is critical. Here we examine gut microbiome of bladder cancer patients undergoing NAC. Overall, there was no significant difference in alpha and beta diversity by responder status. However, analysis of fecal microbiome samples showed that a higher abundance of Bacteroides within both institutional cohorts during NAC was associated with residual disease at the time of radical cystectomy regardless of chemotherapy regimen. Group community analysis revealed presence of favorable microbial subtypes in complete responders. Finally, fecal microbial composition outperformed clinical variables in prediction of complete response (AUC 0.88 vs AUC 0.50), however, no single microbial species could be regarded as a fully consistent biomarker. Microbiome-based community signature as compared to single microbial species is more likely to be associated as the link between bacterial composition and NAC response. ### Competing Interest Statement The authors have declared no competing interest. * NGS : Next-Generation Sequencing BC : Bladder Cancer CTR : Controls rRNA : Ribosomal RNA OTU : Operational Taxonomic Unit QIIME : Quantitative Insights into Microbial Ecology PCoA : Principal Coordinate Analysis LEfSe : Linear discriminant analysis Effect Size CLR : Centered Log Ratios NR : Non-Responder CR : Complete Response CTRL : Controls MIBC : Muscle-Invasive Bladder Cancer NMIBC : Non-Muscle Invasive Bladder Cancer FDR : False Discovery Rate ctDNA : Circulating tumor DNA NAC : Neoadjuvant chemotherapy GM : Gut microbiome