Yüksek Dereceli Kas-İnvaziv Olmayan Mesane Kanserinde PD-L1 Ekspresyonunun BCG İmmünoterapisine Direnç Gelişmesi ve Tümör Progresyonuna Etkisi

Abstract

Medical records of patients with primary high-grade non-muscle invasive bladder carcinoma (NMIBC) who was diagnosed between 2004 and 2017 at our institution and treated with at least 6 cycles of adjuvant intravesical BCG immunotherapy were retrospectively reviewed. Seventy patients with treatment failure (refractory, relapsing and progressive NMIBC) following intravesical BCG immunotherapy and 71 patients with a complete response to BCG who remained recurrence-free for at least 2 years were included in the study. A total of 166 formalin-fixed paraffin-embedded tissue samples obtained prior to BCG therapy (117) and at the time of recurrence (49) were analysed for Programmed Cell Death Ligand-1 (PD-L1) expression by SP-142 immunohistochemistry (IHC) test (Ventana, Arizona, USA). PD-L1 IHC scoring was based on percentage of PD-L1+ tumor infiltrating immune cells (IC) covering the tumor area. Prior to BCG therapy, PD-L1 expression was more frequent in pT1 tumors compared to pTis/pTa tumors (%54.0 vs %23.3, p=0.05). In pT1 tumors with co-existing CIS and in pT1b tumors which shows deep lamina propria invasion, the frequency of PD-L1 expression were noted even higher (%60.0 and %69.6 respectively). The frequency of PD-L1 expression was 71.4% in refractory NMIBC (p=0.050). In NMIBC, no association was demonstrated between PD-L1 expression and recurrence/progression-free survival. In multivariable analysis, every one more BCG cycle following induction BCG therapy was associated with a decrease in probability of recurrence and progression (p=0.009 and p=0.040). In coexistence of two and more variant histology with urothelial carcinoma, a decrease in the probability of progression-free survival was also noted (p=0.004). A significant decrease in the levels of PD-L1 expression was noted in patients with non-muscle invasive superficial recurrence and with refractory recurrence in the first 6 months (p=0.029 and p=0.012). However, no PD-L1 down/up regulation was observed during BCG therapy in either patients who had muscle-invasive progression or patients who had lymph node/distant site metastasis in the later disease course. Pre-treatment and post-treatment levels of PD-L1 expression were stable in these patients. According to the findings of the study, despite being associated with some unfavorable histopathologic factors, PD-L1 expression does not have any prognostic significance for recurrence and progression. In overall, PD-L1 expression level is not affected by BCG therapy. Therefore it is considered that PD-L1 analysis performed at the time of bladder carcinoma diagnosis seems adequate for reflection of tumor microenvironment and for selection of patients who benefit from anti-PD-L1 antibody therapy. But as an exception, BCG refractory patients who have quite frequent PD-L1 expression prior to treatment have significantly decreased levels of PD-L1 expression after BCG therapy.