Introduction: Patients with BCG-unresponsive non-muscle invasive bladder cancer (NMIBC) are commonly treated with intravesical gemcitabine and docetaxel chemotherapy (GEMDOCE). However, studies evaluating biomarkers of GEMDOCE response in BCG-unresponsive NMIBC have been limited. Docetaxel is a microtubule-stabilizing agent that induces cell cycle arrest and apoptosis through mitotic catastrophe. We evaluated whether early and late cell cycle signatures were associated with GEMDOCE response in BCG-unresponsive NMIBC tumors. Methods: We performed a retrospective study of patients with BCG-unresponsive NMIBC who underwent intravesical GEMDOCE. Monthly maintenance therapy was given for 52% of patients with a 3-month complete response. RNAseq and DNA panel sequencing were performed on FFPE tissues from pre-treatment TURBT samples. Gene set variation analysis (GSVA) was performed to calculate gene set enrichment scores with cell cycle and immune signatures. Cluster analysis was performed to assess whether cell-cycle signatures and other gene signatures were associated with response and recurrence-free survival. Results: A total of 30 patients with BCG-unresponsive NMIBC were included, of whom 63% (19) experienced disease recurrence. Cluster analysis with cell cycle signatures yielded 2 clusters with high expression of either late (cluster 1) or early (cluster 2) cell cycle signatures (Figure 1). Tumors enriched with late cell cycle signatures showed significant recurrence-free survival benefit compared to tumors with high expression of early cell cycle signatures (Figure 2). TP53 alterations were enriched in cluster 1 which demonstrated a clinical benefit from GEMDOCE. In contrast to prior work from our lab on BCG-treated tumors, response in GEMDOCE-treated tumors was not associated with immune signatures. Conclusions: These early data suggest that there may be molecular signatures that stratify patients with BCG-unresponsive NMIBC treated with GEMDOCE. Further expansion of these cohorts in both BCG-naïve and BCG-unresponsive cohorts is ongoing. SOURCE OF Funding: NA
