Relapse-Free Survival and PD-L1 Expression in First High- and Low-Grade Relapsed Luminal, Basal and Double-Negative P53-Mutant Non-Muscular Invasive Bladder Cancer Depending on Previous Chemo- and Immunotherapy

Abstract

The goal of this study was to assess how PD-L1 expression in tissue specimens of patients with main molecular subtypes of NMIBC (luminal, basal and double-negative p53-mutant) associates with relapsed-free survival in dependence on the tumor grade and prior treatment of primary bladder cancer. PD-L1 expressions on the membrane of neoplastic and CD8+ immune cells were assessed in tumor specimens (n = 240) of primary and relapsed luminal, basal and double-negative p53-mutant NMIBC. Association between relapse-free survival and PD-L1 expression was estimated for high- and low-grade relapsed NMIBC according to previous treatment and their molecular profile, using the Kaplan–Meier method, and assessed by using the log-rank test. Potential confounders were adjusted by Cox regression models. In a group of patients who underwent only TUR without intravesical therapy, there were significant differences in relapse time between high- and low-grade tumors in basal and luminal molecular subtypes; for basal relapsed carcinoma, RFS was shorter in cases where tumors were less malignant. Both intravesical mitomycin and Bacillus Calmette–Guerin (BCG) therapy significantly extended the time of recurrence of low-grade luminal and basal bladder malignancies with no intergroup differences in double-negative NMIBC. PD-L1 expression status was associated with RFS for luminal relapsed NMIBCs in the group without previous frontline intervention, and with RFS in the group of patients with luminal relapsed bladder cancer previously utilized BCG. Obtained results may be considered as a promising approach for further clinical implementation.

Prognostic Role of FGFR3 Expression Status and Tumor-Related MicroRNAs Level in Association with PD-L1 Expression in Primary Luminal Non-Muscular Invasive Bladder Carcinoma

“…Based on the recent studies, we narrowed our current research focus on three molecular pathways—immune checkpoint axis PD1/PD-L1, fibroblast growth factor receptor 3 expression status, and tumor-dependent miRs. The prognostic role of PD-L1 for bladder cancer progression and the treatment success of immune checkpoint inhibitors have been rigorously evaluated in many studies [ 7 , 8 , 9 , 10 , 11 , 12 ]. In our previous study, we demonstrated that PD-L1 expression level correlated with RFS in relapsed aggressive non-muscular invasive bladder carcinoma of the luminal molecular subtype (GATA3-expressing NMIBC) [ 12 , 25 ].…”

“…The prognostic role of PD-L1 for bladder cancer progression and the treatment success of immune checkpoint inhibitors have been rigorously evaluated in many studies [ 7 , 8 , 9 , 10 , 11 , 12 ]. In our previous study, we demonstrated that PD-L1 expression level correlated with RFS in relapsed aggressive non-muscular invasive bladder carcinoma of the luminal molecular subtype (GATA3-expressing NMIBC) [ 12 , 25 ]. Kang et al showed that the FGFR3 expression level and its gene mutation status associated it with survival in primary pT1 bladder cancer [ 19 ].…”

“…For each case, histologic diagnosis was determined along with assessment of individual risk for the tumor recurrence and progression in accordance with European Organization for Research and Treatment of Cancer (EORTC) risk tables [28] and World Health Organization (WHO) classification [29]. Bladder tumors histologically presented by 18 urothelial papillary carcinomas and 2 micropapillary cancers were designated into low grade (12) and high-grade (8) malignancies.…”

“…Besides, different laboratories showed that expression levels of the programmed death (PD-1) receptor and its ligand 1 (PD-L1) may broadly vary depending on NMIBC grade and molecular subtype [ 10 ]. Moreover, check-point inhibitors’ clinical success closely relates to the tumor immune microenvironment [ 11 ], while differences in relapse-free survival (RFS) of patients with luminal, basal, and double-negative NMIBC of high- and low-malignant grade are strictly associated with previously utilized treatment [ 12 ].…”

“…In our previous study, we found that PD-L1 expression status was associated with RFS for luminal NMIBCs in the group without previous frontline intervention, and with RFS in the group of patients with luminal relapsed bladder cancer who previously used Bacillus Calmette-Guerin (BCG) [ 12 ]. We investigated here the prognostic roles of microRNA-200a, microRNA-145, FGFR3 expression, and mutation status in association with PD-L1 expression in patients with primary luminal NMIBC.…”