Impact of Molecular Subtyping and Immune Infiltration on Pathological Response and Outcome Following Neoadjuvant Pembrolizumab in Muscle-invasive Bladder Cancer
Background: The PURE-01 study (NCT02736266) evaluated the use of pembrolizumab before radical cystectomy (RC) in muscle-invasive bladder cancer (MIBC). Objective: To evaluate the ability of molecular signatures to predict the pathological complete response (CR: ypT0N0) and progression-free survival (PFS) after pembrolizumab and RC. Design, setting, and participants: We analyzed the expression data from patients with T2–4aN0M0 MIBC enrolled in the PURE-01 study (N = 84) and from patients of a retrospective multicenter cohort treated with cisplatin-based neoadjuvant chemotherapy (NAC; N = 140). Intervention: Neoadjuvant pembrolizumab or NAC and RC. Outcome measurements and statistical analysis: Immune signatures and molecular subtyping (The Cancer Genome Atlas, consensus model, and genomic subtyping classifier [GSC]) were evaluated in relation to CR and PFS. Multivariable logistic regression analyses for CR were used, adjusting for gender and clinical T stage. Results and limitations: The Immune190 signature was significant for CR on multivariable logistic regression analyses (p = 0.02) in PURE-01, but not in the NAC cohort (p = 0.7). Hallmark signatures for interferon gamma (IFNγ; p = 0.004) and IFNα response (p = 0.006) were also associated with CR for PURE-01, but not for NAC (IFNγ: p = 0.9 and IFNα: p = 0.8). In PURE-01, 93% of patients with the highest Immune190 scores (>1st quartile) had 2-yr PFS versus 79% of those with lower scores; no difference was observed in NAC patients, as well as for the other hallmarks in both groups. The neuroendocrine-like subtype had the worst 2-yr PFS in all three subtyping models (33%) and the GSC claudin-low subtype had the best, with no recurrences in 2 yr. Basal subtypes (across classifications) with higher Immune190 scores showed 100% 2-yr PFS after pembrolizumab therapy (p = 0.04, compared with basal-Immune190 low). Statistical analyses are limited by the small number of events and short follow-up. Conclusions: Higher RNA-based immune signature scores were significantly associated with CR and numerically improved PFS outcomes after pembrolizumab, but not after NAC. These data emphasize that RNA profiling is a potential tool for personalizing neoadjuvant therapy selection. Patient summary: We used gene expression profiling to evaluate the association between immune gene expression and response to neoadjuvant immunotherapy, compared with standard chemotherapy, in patients with muscle-invasive bladder cancer (MIBC). We found a significant association between immune gene expression and response to pembrolizumab, but not chemotherapy. We conclude that gene expression profiling has the potential to guide personalized neoadjuvant therapy in MIBC. By using gene expression profiling of transurethral bladder tumor resection samples from patients with muscle-invasive bladder cancer (MIBC), we reported a significant association between pre-existing immune gene expression and response to neoadjuvant pembrolizumab, but not to neoadjuvant chemotherapy. Different outcomes were also obtained according to the molecular subtype. Gene expression profiling has the potential to guide personalized neoadjuvant therapy in MIBC.
|Biomarkers, Gene signature, Muscle-invasive bladder cancer, Neoadjuvant immunotherapy, Pembrolizumab|
|European Urology : Official Journal of the European Association of Urology|
|Organisation||Department of Urology|
Necchi, A, Raggi, D. (Daniele), Gallina, A. (Andrea), Ross, J.S. (Jeffrey S.), Farè, E. (Elena), Giannatempo, P. (Patrizia), … Gibb, E.A. (Ewan A.). (2020). Impact of Molecular Subtyping and Immune Infiltration on Pathological Response and Outcome Following Neoadjuvant Pembrolizumab in Muscle-invasive Bladder Cancer. European Urology : Official Journal of the European Association of Urology. doi:10.1016/j.eururo.2020.02.028