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The prognostic value of PD-L1 expression in upper tract urothelial carcinoma varies according to platelet count.

ABSTRACT: Programmed cell death ligand-1 (PD-L1) is a ligand for programmed cell death-1 (PD-1) that negatively regulates T-cell activation and plays a crucial role in suppressing anti-tumor host immunity. Although PD-L1 is a promising immunotherapy target in various cancers, including urothelial carcinoma (UC), the prognostic significance of PD-L1 in UC is unclear. As platelets help protect tumor cells from immune elimination in the circulatory system, we hypothesized that tumor PD-L1 and circulating platelets might synergistically promote tumor metastasis, and that the prognostic significance of PD-L1 might vary according to platelet count. We immunohistochemically examined tumor PD-L1 expression in 271 patients with upper tract UC, which revealed PD-L1 positivity in 31 of 271 cases (11%). The associations of tumor PD-L1 expression with outcomes varied among patients with high or low platelet counts (P_interaction < 0.004). Among patients with high platelet counts (N = 136), PD-L1 positivity (N = 15) was significantly associated with shorter metastasis-free survival (univariate hazard ratio [HR]: 6.23, 95% confidence interval [CI]: 2.95-13.1; multivariate HR: 2.68, 95% CI: 1.27-5.64) and shorter overall survival (univariate HR: 4.92, 95% CI: 2.14-11.3, multivariate HR: 2.78, 95% CI: 1.19-6.51). In contrast, among patients with low platelet counts (N = 135), PD-L1 positivity (N = 16) was not significantly associated with these outcomes. Our results suggest that tumor PD-L1 expression and platelet count might interact and help regulate tumor progression. Although a larger prospective study is needed to validate our findings, this relationship is important to consider, as immunotherapies targeting the PD-1/PD-L1 axis have gained significant attention as promising therapies for UC.

SUBMITTER: Miyama Y

PROVIDER: S-EPMC6143937 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Background: Several studies investigating the role of PD-L1 in upper tract urothelial carcinoma (UTUC) patients after radical nephroureterectomy (RNU) to predict prognosis had been published and great controversy existed among them. We, therefore, in the meta-analysis, reported the association between PD-L1 and survival in UTUC patients who underwent RNU. Methods: We searched the PubMed, Cochrane Library, EMBASE, and Web of Science by April 1, 2020. Hazard ratio (HR) and odds ratio (OR) were adopted to evaluate relationships between PD-L1 and survival outcomes, and tumor features, respectively. We formulated clinical questions and organized following the PICOS strategy. Results: Eight retrospective studies incorporating 1406 patients were included. The pooled positive rate of PD-L1 in UTUC patients was 21.0% (95% CI = 13.0-30.0%, I 2 = 95.3%). Furthermore, higher PD-L1 in tumor tissues was related to shorter cancer-specific survival (CSS) in radically resected UTUC patients (HR = 1.63, 95% CI = 1.17-2.26, I 2 = 0.0%), but was not associated with overall survival (OS) (HR = 1.49, 95% CI = 0.76-2.91, I 2 = 74.9%). Subgroup analyses indicated associations between higher PD-L1 and shorter CSS in both Caucasus (HR = 1.72, 95% CI = 1.02-2.92, I 2 = 0.0%) and Asian (HR = 1.57, 95% CI = 1.03-2.39, I 2 = 23.1%) UTUC patients. Furthermore, PD-L1 was related to tumor grade of UTUC (High vs. Low, OR = 3.56, 95% CI = 1.82-6.97, P = 0.000) and invasive depth (pT3+pT4+pT2 vs. pT1+pTa/pTis, OR = 2.53, 95% CI = 1.07-5.96, P = 0.001). In the cumulative meta-analysis, results indicated that the 95% CIs narrowed as the pooled results gradually moved near the null. Conclusions: PD-L1 overexpression was related to worse survival outcomes in UTUC patients after RNU. It may be useful to incorporate PD-L1 into prognostic tools to select appropriate treatment strategies for UTUC. PD-L1 can also be clinically used for survival anticipation, risk stratification, and patient counseling. However, the pooled findings should be considered tentative until ascertained by more researches.

Project description:BackgroundDespite a similar histologic appearance, upper tract urothelial carcinoma (UTUC) and urothelial carcinoma of the bladder (UCB) tumors have distinct epidemiologic and clinicopathologic differences.ObjectiveTo investigate whether the differences between UTUC and UCB result from intrinsic biological diversity.Design, setting, and participantsTumor and germline DNA from patients with UTUC (n=83) and UCB (n=102) were analyzed using a custom next-generation sequencing assay to identify somatic mutations and copy number alterations in 300 cancer-associated genes.Outcome measurements and statistical analysisWe described co-mutation patterns and copy number alterations in UTUC. We also compared mutation frequencies in high-grade UTUC (n=59) and high-grade UCB (n=102).Results and limitationsComparison of high-grade UTUC and UCB revealed significant differences in the prevalence of somatic alterations. Genes altered more commonly in high-grade UTUC included FGFR3 (35.6% vs 21.6%; p=0.065), HRAS (13.6% vs 1.0%; p=0.001), and CDKN2B (15.3% vs 3.9%; p=0.016). Genes less frequently mutated in high-grade UTUC included TP53 (25.4% vs 57.8%; p<0.001), RB1 (0.0% vs 18.6%; p<0.001), and ARID1A (13.6% vs 27.5%; p=0.050). Because our assay was restricted to genomic alterations in a targeted panel, rare mutations and epigenetic changes were not analyzed.ConclusionsHigh-grade UTUC tumors display a spectrum of genetic alterations similar to high-grade UCB. However, there were significant differences in the prevalence of several recurrently mutated genes including HRAS, TP53, and RB1. As relevant targeted inhibitors are being developed and tested, these results may have important implications for the site-specific management of patients with urothelial carcinoma.Patient summaryComparison of next-generation sequencing of upper tract urothelial carcinoma (UTUC) with urothelial bladder cancer identified that similar mutations were present in both cancer types but at different frequencies, indicating a potential need for unique management strategies. UTUC tumors were found to have a high rate of mutations that could be targeted with novel therapies.

Project description:Objectives:The aim of this study was to investigate the prognostic effect of amplified in AIB1 and EIF5A2 expression on postoperative intravesical recurrence for upper urinary tract urothelial carcinoma (UTUC) and improve postoperative risk stratification and prediction of intravesical chemotherapy benefit. Materials and methods:We evaluated immunohistochemical expression of AIB1 and EIF5A2 in 109 UTUC patients to determine the predictive significance in intravesical recurrence. A prognostic model was developed based on univariate and multivariate analyses. Results:Intravesical recurrence occurred in 18 out of the 109 (16.5%) patients during the follow-up period. Significant associations of high expression of AIB1 and EIF5A2 with shortened bladder recurrence interval (median: 24 months vs 46 months, P=0.021; 28 months vs 39 months, P=0.002) were demonstrated. In different subsets of UTUC patients, high expression of AIB1 was a prognostic indicator in high grade (P=0.006) and pT2-4 (P=0.007), and high expression of EIF5A2 for high grade (P=0.014), pT2-4 (P=0.002) and pN0 (P=0.009). Moreover, in multivariate analysis, AIB1 and EIF5A2 expression (P=0.034 and 0.022, respectively) together with pN stage (P=0.009) provided significant independent predictors for intravesical recurrence after surgery for UTUC. Surgical approach with radical nephroureterectomy (RNU) was an informative factor toward good oncologic outcomes for intravesical recurrence (P=0.056). Based on a prognostic model with these factors, patients with UTUC were classified into the low-risk group and the high-risk group. In a subset analysis, the patients in the high-risk group were found to have a favorable response to intravesical chemotherapy (P=0.047). A nomogram based on the multivariate analysis was developed to predict intravesical recurrence accurately and guide postoperative intravesical instillations. The concordance index (c-index) of this model was 0.806. Conclusion:High expression of AIB1 and EIF5A2 were independent predictors for intravesical recurrence after RNU and might be able to predict which patients benefit from postoperative intravesical chemotherapy.

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The prognostic value of PD-L1 expression in upper tract urothelial carcinoma varies according to platelet count.

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