IBCN 2023: Molecular Signatures Predict GEMDOCE Responses for BCG-Unresponsive Non-Muscle Invasive Bladder Cancer

Intravesical combination chemotherapy (gemcitabine and docetaxel [GEMDOCE]) is commonly used to treat patients with BCG-unresponsive non-muscle invasive bladder cancer (NMIBC). However, potential biomarkers of GEMDOCE response in BCG unresponsive NMIBC has not been fully evaluated. Microtubule targeting agent, Docetaxel, and DNA damaging agent, Gemcitabine have shown therapeutic effects by inducing chromosomal instability, cell cycle arrest, and apoptosis. Therefore, they explored whether these gene signatures were associated with GEMDOCE response in patients with BCG-unresponsive NMIBC tumors.

Whole transcriptome RNAseq and DNA panel sequencing were performed on a cohort of patients with BCG-unresponsive NMIBC who underwent intravesical GEMDOCE. Cluster analysis and gene set variant analysis (GSVA) were used to assess whether gene set signatures were associated with therapeutic response and recurrence-free survival.

Cluster analysis with early and late cell cycle signatures (CCND1, WEE1, CCNA2, CCNB1, CCNE1, etc) generated two main clusters that expressed high levels of late (cluster 1) or early (cluster 2) cell cycle signatures. Cluster 1, which was associated with enrichment of late cell cycle gene signatures showed significant recurrence-free survival benefit compared to cluster 2 (enriched with high level of early cell cycle gene signatures).

Additionally, cluster 1 was enriched with the expression of chromosome instability gene signatures such as chromosome segregation (AURKA, CENPA, PLK1, etc) and DNA damage response (p53, ATR, BRCA1/2, etc). TP53 alterations tended to be enriched in cluster 1.

In summary, these data suggest that cell cycle and chromosome instability gene signatures may stratify response to GEMDOCE in patients with BCG-unresponsive tumors. Future studies with larger cohorts will be required to validate the clinical relevance of these observations.

Presented by: Woonyoung Choi, Johns Hopkins School of Medicine

Written by: Stephen B. Williams, MD, MBA, MS @SWilliams_MD on Twitter during the International Bladder Cancer Network (IBCN) Annual Meeting, September 29-30, 2023, Montreal, Canada