Abstract PR03: Can immunologic biomarkers (CD4/CD8/CD25/CD138) predict tumor recurrence and progression in NMIBC?
Authors: Melinda Lillesand, Vebjørn Kvikstad, Ok Målfrid Mangrud, Einar G. Gudlaugsson, Bianca van Diermen-Hidle, Ivar Skaland, Jan P.A. Baak, Emiel A.M. Janssen
Journal: Clinical Cancer Research (2020)

Abstract Urothelial carcinoma is the most common type of carcinoma of the urinary bladder in the Western world. Currently TNM stage and WHO grade are the most important histopathologic parameters to classify patients into low- and high-risk groups and to decide appropriate treatment. However, as differentiating between stage Ta and T1 on surgical specimens is difficult and grade has only poor to fair reproducibility, these parameters do not precisely predict tumor recurrence or stage progression. As a consequence, patients undergo an intensive follow-up regimen and as such the treatment cost per patient for bladder cancer is one of the highest among all cancer types. Therefore, better prognostic and predictive markers are warranted. The aim of the present study was to clarify whether CD8+, CD4+, CD25+, and/or CD138+ immune cell markers, as well as quantitative features Ki67, mitotic activity index (MAI), and mean nuclear area of the 10 largest nuclei (MNA), can identify non-muscle invasive bladder cancer (NMIBC) patients at high risk for tumor recurrence and stage progression. Tissue samples from 183 patients diagnosed with primary NMIBC were obtained by transurethral resection of the bladder (TURB) or from biopsies. Sections were stained by immunohistochemistry using monoclonal antibodies for T lymphocyte subsets (CD4+, CD8+, and CD25+), plasma cells (CD138+) and Ki67. MAI and MNA were assessed on HES (hematoxylin, erythrosine, and saffron) stained sections. A highly reproducible, interactive image analysis system was used for quantification of all immune cell markers and Ki67. MAI and MNA were counted manually. Out of all the investigated markers, only Ki67 showed significance with tumor recurrence (95% CI, 0.4-0.9; p=0.05) in a 10-year follow-up. The group with high Ki67 (&amp;gt;39%) had significantly longer recurrence-free survival than the group with lower values. Furthermore, out of all the examined immunologic markers, only CD25+ was significantly associated with stage progression in a survival analysis (95% CI, 1.8-106.2; p=0.001). The group of patients with high CD25+ (&amp;gt;0.24%) had significantly shorter progression-free survival than the group with lower values. The median values of MAI and CD25+ were significantly higher in pT1 tumors than pTa tumors (median 16.0, 2.5 for MAI and 0.1%, 0.95% for CD25+ respectively; p&amp;lt;0.001). In univariate analysis age, WHO73, WHO04, Stage, MAI10, and CD25 were all correlated with significant differences in progression-free survival. Furthermore, using survival analysis, the combination of MAI and CD25+ could define a group of patients with 100% (N=81/183) progression-free survival (95% CI, 1.6-4.1; p&amp;lt;0.001). In a multivariate analysis including (age, WHO73, WHO04, combination CD25/MAI10), the combination of CD25/MAI10 was the single most prognostic feature. In conclusion, our study suggests that MAI and CD25+ could be used to identify NMIBC at risk for progression of disease. In addition, Ki67 could be a candidate for assessing the risk of recurrence in NMIBC. This abstract is also being presented as Poster A06. Citation Format: Melinda Lillesand, Vebjørn Kvikstad, Ok Målfrid Mangrud, Einar G. Gudlaugsson, Bianca van Diermen-Hidle, Ivar Skaland, Jan P.A. Baak, Emiel A.M. Janssen. Can immunologic biomarkers (CD4/CD8/CD25/CD138) predict tumor recurrence and progression in NMIBC? [abstract]. In: Proceedings of the AACR Special Conference on Bladder Cancer: Transforming the Field; 2019 May 18-21; Denver, CO. Philadelphia (PA): AACR; Clin Cancer Res 2020;26(15_Suppl):Abstract nr PR03.