Biological characteristics in triple negative high risk breast cancer and their clinical implications

Abstract

20032 Background: Hormone receptor and Her2neu negative breast cancer (triple negative, TN) presents an aggressive biological subtype with decreased survival. Basal-like BC identified by gene expression arrays (Perou CM, et al. Nature 2000) may be associated with TN breast cancer. Several studies defined the origin of TN or BBC breast cancer in a progenitor epithelial cell that is undifferentiated. Other studies investigated the association of TN with EGFR expression or BRCA1 mutations. The aim of our study was to analyze the expression of stem cell or basal markers in TN high risk breast cancer. Methods: We examined 236 patients from central tumour bank from high risk breast cancer patients (>9 positive LN), who were randomized to the WSG AM-01 trial (phase III tandem HDC versus DD CT). The following markers were profiled by IHC in TMA for all patients: ER, PR, Her2neu, MIB-1, EGFR, p53, Ck 5/6, CK17, c-kit, p63, Vimentin, ABCA3, and BCRP. Their correlation with survival was studied. Results: 65 patients (30%) of 218 patients assessable for hormone receptor and Her2neu staining, were identified as TN, surprisingly not indicating any higher incidence of TN tumors in this selected high risk collective, when compared to other more heterogeneous populations. This phenotype was significantly more frequent in premenopausal women, and was significantly associated with G3, MIB1 and EGFR, CK5/6 and 17, c-kit, vimentin, p53 and BCRP expression. No association with p63 and ABCA3 was found. Poor grading, MIB1+, CK5/6 and 17, c-kit, vimentin and BCRP+ strongly correlated with relapse. Patients with TN tumors had significantly worse overall survival (p = 0.002) in comparison to the remaining group. Conclusions: The triple negative BC-type is frequent in patients with multiple positive lymph nodes and has a poor prognosis. Its association with age and basal and progenitor cell molecular markers suggests correlation with BRCA1 mutations as a potential marker for resistance to alkylating agents (Sorlie, PNAS 2003). Modern experimental (chemo)-therapy designs in this subgroup should take into account the higher incidence of EGFR and basal stem cell marker expression, p53 mutations, the poor differentiation, the expression of chemoresistance markers and the high proliferative activity. No significant financial relationships to disclose.