Investigating the predictive value of topoisomerase II alpha (TOP2A) gene, mRNA and protein levels in anthracycline-treated estrogen receptor (ER) negative breast cancer (BC) patients.

11065 Background: Anthracycline-based regimens are among the most active chemotherapies in BC. However, their clinical use is associated with rare but significant toxicities and their efficacy remains concentrated on a subset of BC patients. TOP2A, the molecular target of anthracyclines, has repeatedly been suggested to be a potential marker of response to this therapy. Here we aimed to investigate: 1/ the correlation between the gene, mRNA and protein levels of TOP2A; 2/ the genes differentially expressed between TOP2A amplified and normal tumors; and 3/ the predictive value of TOP2A gene, mRNA and protein levels, in a prospective neoadjuvant trial designed primarily to identify markers of response to epirubicine in ER-negative patients (to eliminate the confounding effect of indirect ovarian suppression in ER+ BC).,We analyzed TOP2A at the gene level using fluorescence in situ hybridization (Vysis triple probe), at the mRNA level using Affymetrix and at the protein level by immunohistochemistry (KiS1) in a series of 121 samples.,1/ We observed a correlation between the mRNA levels and the FISH ratios (rho=0.37, p=0.007), but no correlation between the mRNA and IHC levels. 2/ 10% of the samples showed TOP2A amplification. We identified a list of genes differentially expressed between TOP2A amplified and non-amplified tumors. A large number of these genes were located on the TOP2A amplicon, such as RARA, CDC6, WIRE, 3/15% of the patients had a pathological complete response. TOP2A amplification, which was exclusively observed in HER2 amplified cases (=32% of them), was predictive of response (kappa= 0.44, p=0.01). 61% of the samples overexpressed TOP2A (>10% of positively stained cells) but these protein levels, as well as the mRNA levels were not predictive of response.,This study, which is the first to evaluate the predictive value of TOP2A in patients treated by epirubicin single-agent, shed light on the genes differentially expressed by TOP2A amplified tumors and suggests TOP2A gene levels, but not mRNA and protein levels, to be associated with response to anthracyclines. Since the trial is ongoing, these results will be validated on the next series of patients. No significant financial relationships to disclose.