Abstract P6-05-27: p53, c-Myc and EGFR protein interactions confer worse prognosis in patients with triple negative breast cancer (TNBC)
Authors: S Lakis, T Koletsa, I Kostopoulos, C Papadimitriou, D Skarlos, A Koutras, E Res, F Matsiakou, H Linardou, V Kotoula, G Fountzilas
Journal: Cancer Research (2013)

Abstract Background - aim: TNBC is a heterogeneous disease comprising different molecular subtypes that are mostly defined by gene expression profiling and are related to patient outcome. Herein, we investigated the prognostic significance of molecular subtype-related, surrogate protein markers. Methods: Immunohistochemistry was applied on tissue microarrays containing a series of 330 centrally assessed TNBC from early high-risk breast cancer patients treated with anthracyclines and/or taxanes. The following markers were examined (in parentheses: cut-offs for low/high and negative/positive): Ki67 (14%); p53 (10%); c-Myc (10%); P-cadherin (10%); E-cadherin (10%); Claudin-7 (H-score median: 105); CK5 (1%); EGFR (1%); androgen receptor (AR [1%]). Results: The majority of tumors (269/327, 81.5%) were grade-III ductal carcinomas of no special type. Tumors were frequently positive for Ki67 (239/314, 76.1%), E-cadherin (193/271, 71.2%), P-cadherin (249/302, 82.5%) and expressed markers of the basal phenotype (CK5+ and/or EGFR+, 268/316, 84.8%). Grade-III, Ki67-high carcinomas and tumours positive for E- and P-cadherin were more prevalent among those of basal phenotype (Fisher's exact p&amp;lt;0.001). Tumors expressing low levels of Claudin-7 were infrequently positive for AR and EGFR proteins (p = 0.015 and p = 0.003, respectively). AR positivity was more frequent among CK5 negative, grade I-II, and Ki67-low tumors (p = 0.021, p = 0.05 and p = 0.011 respectively). When examined individually, none of these markers was related to patient outcome. An interaction was noticed between p53 and c-Myc immunopositivity (Wald's p = 0.028 for disease-free [DFS] and p = 0.005 for overall survival [OS]). Among patients with c-Myc negative tumors, patients with p53 positive tumors (n = 63) had shorter median DFS (46.8 months) and OS (56 months) (HR 1.9; 95%CI 1.0-3.9; p = 0.049 and HR 2.28; 95%CI 1.0-4.8; p = 0.031, respectively) as compared to those with p53 negative tumors (n = 56; median DFS 69 months, OS 70 months). Similarly, in the absence of p53, c-Myc expression correlated with shorter median OS (44.5 months) (HR 2.1; 95%CI 1.0-4.5; p = 0.038) but showed only a trend for shorter DFS as compared to c-Myc negative tumors. p53 protein status was a discriminating factor for EGFR negative tumors (Wald's p = 0.052), whereby p53 positive tumors (n = 54) were associated with reduced DFS as compared to p53 negative tumors (n = 68; median DFS: 47 vs. 68.8 months; HR 2.1; 95%CI 1.1-4.0; p = 0.025). Accordingly, EGFR immunopositivity conferred a trend for shorter DFS within p53 negative cases. Conclusions: In the current study, it was not possible to assign prognostic significance to individual proteins that have been introduced as surrogate markers for gene expression-based molecular subtypes in TNBC. By contrast, significant interactions involving the status of p53 and c-Myc or EGFR were observed. It seems that aberrant p53 adversely influences tumor behaviour in the absence of c-Myc and EGFR, while the opposite is also effective but to a lesser extent. These findings are hypothesis generating and need to be pursued in sufficiently powered studies for validating the apparently mutually exclusive adverse effects of p53, c-Myc and EGFR on tumor behaviour. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P6-05-27.