423 Background: Standard therapy for high-risk non-muscle invasive bladder cancer (NMIBC) is intravesical BCG. Despite its established efficacy, up to 50% of patients may recur. The development of predictive biomarkers for BCG immunotherapy would enhance treatment algorithms and potentially uncover mechanisms of resistance. Recent data have characterized the presence of a commensal urine microbiome, but its role in BCG-treated NMIBC patients remains unexplored. We assessed the composition of the urine microbiome in NMIBC patients and evaluated associations with response to therapy. Methods: Patients with a newly diagnosed bladder tumor were enrolled prior to TURBT on an institutional review board-approved study at a single institution. Adjuvant BCG instillation was administrated to high-risk patients according to the surgical histology. Urine samples for microbiome assessment were collected by catheterization to eliminate urethral contamination before the TURBT and up to 8 additional timepoints. 16S sequencing and analysis was performed on baseline specimens prior to BCG. Results: Among 31 patients enrolled, 10 (32%) recurred and 21 (68%) had no recurrence with a median follow up of 6 months. Median age was 69 years (range 46-87), and 9 (29%) patients were female and 22 patients (71%) were male. The most abundant phyla observed were Actinobacteria, Bacteroidetes, Firmicutes, Proteobacteria, and Tenericutes. Together these accounted for > 99% of the phyla detected in the cohort. Global analysis of distances by operational taxonomic units (OTUs) indicated a significant difference between patients with and without recurrence (Bonferroni-corrected P = 0.017). The abundance of Proteobacteria was higher in patients with recurrence (P = 0.035), with stronger differences observed for specific classes such as Gammaproteobacteria (P = 0.0025). Firmicutes such as Lactobacillales were more abundant in patients without recurrence (P = 0.049). Conclusions: In this study we detected variation in the composition of the urine microbiome in NMIBC patients, which may predict response to BCG immunotherapy. Further studies to confirm these results are ongoing.

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Bacillus Calmette-Guerin (BCG) is an intravesical immunotherapy that is standard of care to prevent recurrence of non-muscle invasive bladder cancer. Even with adequate BCG treatment, recurrences occur in up to 50% of patients within 5 years. The identification of a commensal urinary microbiome has been recently reported, but it has not been studied in the context of bladder cancer treatment. We hypothesized that variation in the urine microbiome is associated with response to BCG immunotherapy. A clinical study was initiated that enrolled patients with a newly diagnosed bladder tumor to evaluate urinary biomarkers. Urine samples were collected via catheterization to minimize contamination at baseline and up to 8 additional time points. Samples were centrifuged and DNA was extracted. The microbial composition for each sample determined by the 16S rRNA gene sequencing-based method and analyzed by Operational Taxonomic Units (OTUs). Interferon gamma and interleukin-2 levels were measured using the Invitrogen ProcartaPlex immunoassay. Thirty-one patients were enrolled with a median age of 69 years, including 9 females and 22 males. All patients were treated with BCG and 10 patients were diagnosed with recurrent disease at a median follow up of 6 months. In baseline samples, a significant difference in microbial composition was observed by distance matrix computation between patients with and without recurrence (Bonferroni-corrected P=0.017). Actinobacteria, Bacteroidetes, Firmicutes, Proteobacteria, and Tenericutes accounted for >99% of the phyla detected across all samples. Proteobacteria had a significantly higher abundance in patients who developed recurrence (P=0.035). In particular, the Enterobacteriacae family was significantly more abundant among patients with recurrence (P=0.001). Lactobacillales was lower in abundance in patients with recurrence versus those without recurrence (P=0.049). A subset of 13 patients, including 6 with recurrence, were analyzed for changes in urine gamma interferon and interleukin-2 levels after BCG induction (week 6), and no difference was observed between patients with and without recurrence (P=0.79 and P=0.96, respectively). Characterizing the commensal urine microbiome in bladder cancer patients is feasible, and variation in composition may predict response to BCG therapy. Further studies are ongoing to validate these findings and determine longitudinal patterns over time. Citation Format: Randy F. Sweis, Shay Golan, Nimrod Barashi, Elle Hill, Ciro Andolfi, Ryan Werntz, Jeffrey Bloodworth, Thomas Gajewski, Gary D. Steinberg. The commensal urinary microbiome as a predictor of response to Bacillus Calmette-Guerin (BCG) immunotherapy in non-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 2836.