(UroToday.com) Only ~40% of muscle invasive bladder cancer patients show an objective response to neoadjuvant chemotherapy. While genomic alterations and transcriptomic classifiers have predicted response to chemotherapy in retrospective studies, proteomic analysis of MIBC has not yet been performed. In this study, Dr. Contreras-Sanz et al profiled the proteome of MIBC in the context of NAC to identify potential biomarkers and understand the biology driving chemotherapy response. 107 MIBC patients’ pre-treatment samples were profiled. Residual tumor (≥pT1N0-3) in the RC specimen was present in 62% of patients following NAC, and was available for 55 of those patients (51%). Multiregional sampling was conducted in 37/107 pre-NAC and 15/55 post-NAC samples. Benign urothelium was used as control.
SP3-Clinical Tissue Proteomics (SP3-CTP) and bioinformatic analysis using formalin-fixed paraffin-embedded tissue (FFPE) were performed. 9769 proteins were quantified across all samples. Unsupervised clustering of pre-NAC tissue established four clusters with distinct survival outcomes, but no difference in pT stage after NAC. CC1 showed high metabolic activity and had a luminal profile; CC2, with high nuclear activity; CC3 with high immune infiltration, and basal characteristics; and CC4, with high immune infiltration and increased lipid metabolism. CC3 showed worse overall survival (p<0.01) and aligned with the RNA-based basal subtype. Multivariable analysis adjusting for prognostic variables identified novel favorable (MAPK9 and MTIF) and unfavorable (DVL2 and NES) biomarkers. Matched analysis of pre-and post-NAC tissue identified markers indicative of NAC resistance (AZGP1 and ORM1). Multiregional analysis showed distinct proteomic tumor profiles in selected pre- and post-NAC matched samples.
Presented by: Alberto Contreras-Sanz, PhD, Vancouver Prostate Centre, Vancouver, British Columbia
Written by: Roger Li, MD, Urologic Oncologist, Moffitt Cancer Center, during the International Bladder Cancer Network Annual Meeting, September 28-October 1, 2022, Barcelona, Spain