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Expression of Nectin-4 and PD-L1 in Upper Tract Urothelial Carcinoma.

ABSTRACT: Enfortumab vedotin is a novel antibody-drug conjugate targeting Nectin-4, which is highly expressed in urothelial carcinoma. However, the expression status of Nectin-4 in upper tract urothelial carcinoma (UTUC) remains unclear. The relationship between Nectin-4 and Programmed Death Ligand 1 (PD-L1) in UTUC is also ambiguous. We performed immunohistochemical analysis of 99 UTUC tissue microarray to assess the expression of Nectin-4 and PD-L1 in UTUC. Nectin-4-positivity was detected in 65 (65.7%) samples, and PD-L1 was detected in 24 (24.2%) samples. There was no correlation between the expression of Nectin-4 and PD-L1. Patients with strong Nectin-4-expressing tumors had a significantly higher risk of progression (p = 0.031) and cancer-specific mortality (p = 0.036). Strong Nectin-4 expression was also an independent predictor of disease progression in the high-risk group (pT3 ? or presence of lymphovascular invasion or lymph node metastasis) (Hazard ratio, 3.32 [95% confidence interval, 1.20-7.98; p = 0.027]). In conclusion, we demonstrated that Nectin-4 expression rate in UTUC was 65.7% and independent of PD-L1 expression. Strong Nectin-4 expression was associated with worse progression-free survival in high-risk UTUC. These findings suggested that enfortumab vedotin may be effective in a broad range of patients with UTUC, regardless of PD-L1 expression.

SUBMITTER: Tomiyama E

PROVIDER: S-EPMC7432817 | biostudies-literature | 2020 Jul

REPOSITORIES: biostudies-literature

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Expression of Nectin-4 and PD-L1 in Upper Tract Urothelial Carcinoma.

Tomiyama Eisuke E Fujita Kazutoshi K Rodriguez Pena Maria Del Carmen MDC Taheri Diana D Banno Eri E Kato Taigo T Hatano Koji K Kawashima Atsunari A Ujike Takeshi T Uemura Motohide M Takao Tetsuya T Yamaguchi Seiji S Fushimi Hiroaki H Yoshimura Kazuhiro K Uemura Hirotsugu H Netto George J GJ Nonomura Norio N

International journal of molecular sciences 20200729 15

Enfortumab vedotin is a novel antibody-drug conjugate targeting Nectin-4, which is highly expressed in urothelial carcinoma. However, the expression status of Nectin-4 in upper tract urothelial carcinoma (UTUC) remains unclear. The relationship between Nectin-4 and Programmed Death Ligand 1 (PD-L1) in UTUC is also ambiguous. We performed immunohistochemical analysis of 99 UTUC tissue microarray to assess the expression of Nectin-4 and PD-L1 in UTUC. Nectin-4-positivity was detected in 65 (65.7%) ...[more]

PMID: 32751328

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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: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:Insulin-like growth factor-1 receptor (IGF1R) is a transmembrane tyrosine kinase receptor that plays a crucial role in cell proliferation, growth, differentiation, and apoptosis. IGF1R overexpression has been observed in several cancers, including invasive bladder carcinomas, as a potential prognostic factor. Given known biologic differences between upper and lower urinary tract urothelial carcinoma, we assessed the expression status and prognostic significance of IGF1R in upper tract urothelial carcinoma (UTUC). Two tissue microarrays (TMAs) were built from 99 Japanese patients with non-metastatic UTUC submitted to radical nephroureterectomy between 1997 and 2011. TMAs were constructed with triplicate tumor and paired benign urothelium. Membranous IGF1R staining was evaluated using immunohistochemistry. Two scoring methods were applied (Her2-score and H-score). The highest score was assigned to each tumor. IGF1R positivity was defined as Her2-score ??1+. Association with clinicopathologic parameters and outcome was assessed using hazard ratios (HR) with 95% confidence intervals (CI) and adjusted P values. We found positive IGF1R expression in 70% of UTUC. Outcomes were as follows: tumor recurrence, 33%; tumor progression, 59%; overall mortality, 33%; and cancer-specific mortality, 30%. IGF1R was not associated with any clinicopathologic features. In addition, IGF1R expression was not associated with tumor recurrence (HR?=?0.54, CI?=?0.25-1.1, P?=?0.11), tumor progression (HR?=?1.6, CI?=?0.8-3.1, P?=?0.19), overall mortality (HR?=?1.5, CI?=?0.68-3.4, P?=?0.31), or cancer-specific mortality (HR?=?1.6, CI?=?0.68-3.8, P?=?0.27). Positive IGF1R expression was found in more than two thirds of UTUC. This finding provides a rationale to investigate IGF1R as a potential therapeutic target in UTUC. In contrast to bladder cancer, IGF1R expression in UTUC did not correlate with outcome, further pointing to biologic differences between UTUC and bladder cancer.

Dataset Information

Expression of Nectin-4 and PD-L1 in Upper Tract Urothelial Carcinoma.

Publications

Expression of Nectin-4 and PD-L1 in Upper Tract Urothelial Carcinoma.

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