S2040 Tumor Infiltrating Lymphocytes and RHAMM Expression Predict Prognosis in Patients with Rectal Cancer

Abstract

Background: Pre-therapeutic molecular-based tumor expression profiling represents an opportunity for the development of more efficient treatment regimens. The identification of rectal cancer patients with poor clinical outcome at diagnosis would have a significant impact on the selection of pre-operative treatment modalities. Aim: The aim of this study was to evaluate the independent prognostic effect of 8 immunohistochemical protein markers on a large cohort of untreated rectal tumors leading to the identification of patients with adverse prognosis. Methods: Immunohistochemistry on 482 pre-operatively untreated rectal cancer resections was performed using a tissue microarray for 7 tumor markers involved in colorectal tumor progression (MST1, RKIP, APAF-1, RHAMM, EphB2, p53 and Ki67) and for CD8+ tumor infiltrating lymphocytes (TILs). Complete clinico-pathological data was available for all cases. Tumors were randomized into matched test and validation sets (Group 1, Group 2, N = 241 each). Univariate survival analysis was performed. Significant markers common to both groups were combined into multi-marker phenotype combinations and KaplanMeier plots on both groups were evaluated. The independent prognostic factors were entered into multivariable analysis with T stage, N stage, gender, tumor diameter and age. Results: In Group 1, absence of TILs (p=0.012), loss of RKIP (p=0.014) and RHAMM positivity (p<0.001) demonstrated significant adverse prognosis. In Group 2, absence of TILs (p<0.001), negative Ki67 (p=0.012) and RHAMM positivity (p< 0.001) were associated with worse survival time. TILs and RHAMM expression were common to both groups. Multi-marker combinations of TILs and RHAMM were analyzed. Significantly worse survival time was demonstrated in patients with TIL-/ RHAMM + tumors in both Groups 1 and 2 (p< 0.001, each). In multivariable analysis, absence of TILs (p = 0.003; HR = 1.8 (1.2-2.6)) and RHAMM positivity (p< 0.001; HR = 2.0 (1.4-2.7)) both demonstrated strong independent adverse prognostic value. Conclusion: Our results highlight a significantly poorer clinical outcome in patients with absence of CD8+TILs and simultaneous RHAMM positivity. The combined immunohistochemical analysis of these markers on pre-operative tumor biopsies may serve as an additional tool in the selection of patients for pre-operative treatment regimens.