Identification of a basal-like subtype and comparative effect of epirubicin-based chemotherapy and sequential epirubicin followed by docetaxel chemotherapy in the PACS 01 breast cancer trial: 33 markers studied on tissue-microarrays (TMA)

Abstract

509 Background: Immunohistochemical profiling studies with TMA classified breast cancer by luminal, normal breast like, HER-2 overexpressing, and basal-like subtypes. The aim of this study was to evaluate the impact of these subclasses in terms of therapeutic benefit for patients (pts) with node positive operable breast cancer included in the phase III trial PACS01. Methods: Among the 1999 pts randomized, 1100 paraffin blocs were collected for TMA. Pts were treated with either arm A: 6 cycles of FEC100 (546 pts) or arm B: docetaxel 100 mg/m2 replaced FEC100 for the last 3 cycles (554 pts). The median follow up was 5 years. The 33 analysed markers explored different pathways: cellular differentiation (CK5/6,8/18,14, P-Cadherin, E-cadherin, α-catenin, β-catenin, AF6, MUC1, Cav1, moesin, Cd10, CD44), proliferation/apoptosis (AuroraA, Tacc2/3, Ki67, CyclinD1, Bcl2, p21, p27), ER related (ER, PR, Gata3), and oncogene/ antioncogene (P53, HER2, EGFR1, Pten, Cmet, Fhit, FGFR, Angiogenin, topoisomeraseIIα). All antibodies were evaluated in quick score. Results: In terms of metastases free survival (MFS) 16 markers harboured a statistical significant value under 20%. The hierarchical clustering for 80% of complete data, identify a cluster of pts (n=531) characterized by the positive expression of EGFR1, Moesin, Pcadherin, and p53, considered as basal-like subtype (BLST). This cluster presented a pejorative predictive value both in Log-rank test (LR) (p=0.002) and in Cox multivariate analysis (HR=0.65; p=0.009), confirmed in overall survival (OS) (LR p<0.0001; cox HR=0.46, p<0.001). BLST pts had a significantly better MFS (LR p=0.05) in the arm B, confirmed in OS (LR p=0.005), as for a more theoretical basal signature and ER negativity (LR MFS p=0.0033, OS p=0.0052; cox MFS HR=0.71 p=0.04, OS HR=0.51 p=0.003). For a second cluster considered as luminal subtype (ER positive and BLST parameters negatives) no difference was observed whatever the arm. Conclusions: The basal-like profile identified in this study is significantly associated to a worst prognostic, but also to a better response to sequential FEC/docetaxel chemotherapy. [Table: see text]