A Large-Scale Tissue Microarray Study Confirms the Prognostic Value of P-Cadherin Expression in Breast Cancer and Association with Her2+ and Basal Subtypes
G Turashvili, S McKinney, O Goktepe, S Leung, D Huntsman, S Aparicio. BC Cancer Research Centre, Vancouver, BC, Canada; University of British Columbia, Vancouver, BC, Canada
Background: P-cadherin (P-cad) is a calcium-dependent cell-cell adhesion glycoprotein in the adherens-type junctions, mainly promoting homotypic interactions in epithelium. P-cad expression is restricted to the myoepithelial cells in normal breast tissue, and aberrant staining has also been described in invasive breast tumors. Several small studies have reported that P-cad is a marker of poor outcome in breast cancer patients.
Design: A tissue microarray was constructed from 4,444 cases of invasive breast carcinoma linked to treatment and outcome information, and P-cad expression was evaluated using immunohistochemistry (IHC). Median follow-up was 12.5 years. The IHC-based definition of cancer subtypes was as follows: luminal (ER+ or PR+, HER2-), luminal/HER2+ (ER+ or PR+, HER2+), HER2+ (ER-, PR-, HER2+), and basal (ER-, PR-, HER2-, CK5/6+ or EGFR+). Clinical covariate and biomarker associations were assessed using contingency tables and significance of associations determined using Pearson's Chi-square or Fisher's exact test. Survival and relapse associations were visually assessed using Kaplan-Meier plots, with significance assessed using Logrank and Breslow tests and Cox proportional hazards regression analysis.
Results: P-cad was expressed in 50% (1875/3745) of cases, and P-cad+ patients showed significantly poorer short term (0-10 years) overall survival. P-cad staining was strongly associated with HER2+ and basal carcinoma subtypes (p<0.0005). The patients with P-cad+ tumors showed poorer disease-specific survival, distant relapse-free survival, loco-regional relapse-free survival and any relapse-free survival in univariable models (p<0.05). In a multivariable Cox model containing standard clinical covariates and tumor subtypes, P-cad did not show independent prognostic value. P-cad expression was positively associated with histologic grade, chemotherapy treatment, Ki67, epidermal growth factor receptor (EGFR), cytokeratin 5/6 (CK5/6), p53, YB-1 and HER2 expression (p<0.002), and negatively associated with age at diagnosis, ER, PR and Bcl-2 expression (p<0.0005).
Conclusions: This study shows the value of P-cad expression as a marker of poor prognosis in a large breast cancer series. P-cad positivity is associated with high-grade tumor subtypes and well-established markers of poor prognosis, and may represent a promising therapeutic target.
Monday, March 22, 2010 1:00 PM
Poster Session II # 56, Monday Afternoon