Abstract 4690: Combined analysis of Aldh1, Survivin and EpCAM expression, representing important hallmarks of cancer, predicts clinical prognosis in colorectal cancer.
Authors: Goossens-Beumer Inès , Zeestraten Eliane , Benard Anne , Christen Tim , Reimers Marlies , Keijzer Rob , Liefers Gerrit-Jan , Morreau Hans , Putter Hein , van de Velde Cornelis , Kuppen Peter 
Published: August 2014

Abstract
Background: Current treatment of colorectal cancer patients is solely based on TNM stage. Biomarkers to further refine this staging system are warranted. Tumor aggressiveness might be related to the number of cancer hallmarks possessed by a tumor. Expression level of a specific biomarker may represent gain of those cancer hallmarks represented by this marker. Combining such biomarkers might add to needed discriminative value and biological- and clinical significance. We therefore investigated combined expression of Aldh1, Survivin and EpCAM, which together reflect the main cancer hallmarks, in relation to clinical outcome of colorectal cancer patients.
Methods: Immunohistochemistry was performed using a tumor tissue micro array of colorectal cancer patients (N=410). Percentage of cells positive for individual markers was scored. Patients were divided into groups based on median expression. Individual markers and their combination were assessed for associations with overall survival, disease specific survival and recurrence free survival. Complete covariate- and marker expression data were available for 249 patients (study cohort) for uni- and multivariate survival analysis, performed with automated stepwise backward Cox regression.
Results: In single marker analyses, increased expression of Aldh1 and Survivin, and decreased expression of EpCAM was associated with poor clinical outcome in colorectal cancer, and designated clinically unfavorable marker expression. Based on these results, the three biomarkers were combined into four groups (groups 0, I, II and III). Group number represented the number of markers that showed unfavorable expression in the tumor. Reference group 0 contained patients with favorable marker expression for all markers. Group I, group II and group III contained patients with unfavorable marker expression of respectively one, two or three of the markers. No correlation with clinicopathological parameters was found. Combined expression of all three markers (Group I / Group II / Group III, compared to Group 0) was shown to be a strong independent prognostic factor of tumor recurrence rates and patient survival in the multivariate analyses: overall survival (HR= 1.33 / 2.05 / 5.39, P&lt; 0.001), disease specific survival (HR= 2.39 / 4.54 / 12.18, P&lt; 0.001) and recurrence free survival (HR= 2.35 / 5.18 / 12.90, P&lt; 0.001). Increase in group number was associated with higher hazard ratios, indicating that gain of cancer hallmarks was associated with more aggressive tumors.
Discussion: Our data demonstrated that combined expression level of Aldh1, Survivin and EpCAM, together representing the main cancer hallmarks, reflected tumor aggressiveness and hence predicted survival and recurrence in colorectal cancer patients. Including the analysis of these biomarkers may therefore complement the current TNM staging system.
Citation Format: Inès Goossens-Beumer, Eliane Zeestraten, Anne Benard, Tim Christen, Marlies Reimers, Rob Keijzer, Gerrit-Jan Liefers, Hans Morreau, Hein Putter, Cornelis van de Velde, Peter Kuppen. Combined analysis of Aldh1, Survivin and EpCAM expression, representing important hallmarks of cancer, predicts clinical prognosis in colorectal cancer. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4690. doi:10.1158/1538-7445.AM2013-4690