Predicting the efficacy of anthracyclines in breast cancer (BC) patients: Results of the neoadjuvant TOP trial.


523 Background: Anthracycline-based regimens are among the most active and used chemotherapies in BC. Here, we report the results of the prospective TOP trial ( NCT00162812 ) which was specifically designed to identify markers of response/resistance to preoperative epirubicin (100 mg/m2 q2 or q3wks) in estrogen receptor-negative (ER-) BC patients. METHODS Using pre-epirubicin biopsies, we analyzed TOP2A by fluorescence in situ hybridization (Abbott triple probe) and by immunohistochemistry (KiS1) and generated gene expression profiles (HG133Plus2.0). We used publicly available gene expression data from the BIG1-00, trial (EORTC-10094), which compared in a preoperative setting an anthracycline-based (A) to a taxane-based (T) regimen, to validate some of our results. RESULTS 149 patients were included in the TOP trial and 14.5% had a complete pathological response (pCR). TOP2A amplification (11% of the cases) was exclusively observed in HER-2 amplified cases (33% of the cases), and was highly predictive of pCR (k = 0.35, p = 0.0002 - half of the patients with TOP2A amplification experienced pCR). Neither the protein levels nor the mRNA levels were predictive of pCR. Chromosome17 (Ch17) polysomy was observed in 68% of the samples and was not associated with pCR. TOP2A gene expression module (made of genes located closely to TOP2A), was predictive of response both in the HER-2+ patients of the TOP trial and in the ER-/HER-2+ of the BIG1-00 patients treated with A but not with T [Area Under the Curve (AUC): 0.86 (p = 0.00001) in TOP trial and 0.81 (p = 0.0005) in A-arm BIG1-00 trial]. Stroma expression module defined previously was associated with pCR in both trials (TOP and in the ER- BIG1-00 patients treated with A but not with T, especially in HER-2- patients [AUC: 0.31 (p = 0.01) in TOP trial and 0.33 (p = 0.02) in A-arm/BIG1-00 trial]. CONCLUSIONS This trial, which is the first to prospectively evaluate the predictive value of TOP2A, supports TOP2A gene amplification as predictive marker of response. Ch17 polysomy, observed in ∼2/3 of these ER- patients, was not predictive of response. Finally, our results suggest that gene expression modules also predict relative response/resistance to anthracyclines, both in HER-2+ and HER-2- patients. No significant financial relationships to disclose.


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@article{Desmedt2009PredictingTE, title={Predicting the efficacy of anthracyclines in breast cancer (BC) patients: Results of the neoadjuvant TOP trial.}, author={Christine Desmedt and Evandro de Azambuja and Denis P Larsimont and Ghizlane Rouas and Angelo di Leo and Suzette Delaloge and Caroline Duhem and V D'hondt and Martine J. Piccart and Christos Sotiriou}, journal={Journal of clinical oncology : official journal of the American Society of Clinical Oncology}, year={2009}, volume={27 15_suppl}, pages={523} }