(UroToday.com) The American Urologic Association (AUA) 2025 Annual Meeting, held in Las Vegas, NV, was host to a non-invasive bladder cancer interactive poster session. Dr. Kendrick Yim presented a study evaluating genomic drivers of sensitivity to intravesical gemcitabine + docetaxel in patients with BCG-unresponsive non-muscle invasive bladder cancer (NMIBC).
Sequential intravesical gemcitabine + docetaxel is an effective therapy in patients with BCG-unresponsive NMIBC, with an observed two-year high-grade recurrence-free survival (HG-RFS) of 50%.1 Genomic profiling of these tumors is challenging due to scant tumor tissue collected at the time of recurrence. Thus, the genomic landscape and whether distinct mutations are associated with gemcitabine + docetaxel response remain unknown. The objective of this study was to define the mutational features of BCG-unresponsive NMIBC and nominate genomic drivers of response and resistance to gemcitabine + docetaxel.
Dr. Yim and colleagues identified BCG-unresponsive NMIBC patients from Brigham and Women’s Hospital who received gemcitabine + docetaxel and performed whole exome sequencing of these tumors (n=23). The TCGA pipeline was used to account for mutation calls. Copy number events were inferred using ABSOLUTE and phylogenetic trajectories using PhylogicNDT. They used the SigMA algorithm to identify mutational processes present in tumors.
The clonal evolution of BCG unresponsive tumors responsive/resistant to gemcitabine + docetaxel is illustrated below. Responsive tumors have mutations implicated in homologous recombination. Non-responders harbor mutations associated with a worse prognosis in bladder cancer.
Key takeaways from this analysis were as follows:
- BCG-unresponsive NMIBC harbor mutational features that biologically explain response to gemcitabine + docetaxel
- Mutations in CREBBP and STAG2 lead to genomic instability as well as clonal BAP1 mutations, which may sensitize tumors to gemcitabine + docetaxel, resulting in long-term responses to intravesical chemotherapy.
- Future efforts should focus on determining the presence of CREBBP and STAG2 prior to gemcitabine + docetaxel to improve intravesical treatment response in NMIBC
Presented by: Kendrick Yim, MD, Resident Physician, Department of Urology, Brigham and Women's Hospital/Harvard Medical School, Boston, MA
Written by: Rashid K. Sayyid, MD, MSc – Robotic Urologic Oncology Fellow at The University of Southern California, @rksayyid on Twitter during the 2025 American Urological Association (AUA) annual meeting held in Las Vegas, NV, Saturday, April 26 - Tuesday, April 29, 2025
References:
- Steinberg RL, Thomas LJ, Brooks N, et al. Multi-Institution Evaluation of Sequential Gemcitabine and Docetaxel as Rescue Therapy for Nonmuscle Invasive Bladder Cancer. J Urol. 2020; 203(5): 902-909.