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Predicting the efficacy of anthracyclines in breast cancer (BC): The results of the TOP trial and their validation in the BIG 00-01 trial.

par Desmedt, Christine ;de Azambuja, Evandro ;Larsimont, Denis ;Haibe-Kains, Benjamin ;Lallemand, Françoise;Rouas, Ghizlane;Selleslags, Jean;Delaloge, Suzette;Duhem, Caroline;Kains, Jean-Pierre;Carly, Birgit;Maerevoet, Marie ;Vindevoghel, Anita;Cardoso, Fatima ;Durbecq, Virginie ;Nogaret, Jean-Marie ;Veys, Isabelle ;Schobbens, Jean;Noterman, Danièle ;Salgado, Roberto;Di Leo, Angelo ;D'Hondt, Veronique ;Piccart-Gebhart, Martine ;Sotiriou, Christos
Référence AACR Annual Meeting(100th: April 2009: Denver, Colorado, USA), AACR Annual Meeting - Online publication, page (1893)
Publication Publié, 2009

Abstract de conférence

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Abstract 1893 - Session : Molecular Markers for Detection and Predicting Therapeutic Response - Background: Anthracycline-based regimens are among the most active chemotherapies in BC. However, their use is associated with rare but significant toxicities and their efficacy may be restricted on a subset of BC patients (pts). Controversial results have been reported regarding the predictive value of topoisomerase II alpha (TOP2A), the molecular target of anthracyclines. Here, we report the results of the prospective TOP trial (NCT00162812) which was designed to identify markers of response/resistance to preoperative epirubicin in estrogen receptor (ER)-negative BC pts.Methods: Using pre-treatment biopsies, we analyzed TOP2A by fluorescence in situ hybridization (FISH, Abbott triple probe) and by immunohistochemistry (IHC, KiS1) and generated gene expression profiles (HG133Plus2.0). We used the publicly available data from the BIG00-01 trial (EORTC-10094;NCT00017095), which compared in a preoperative setting an anthracycline-based (A) to a taxane-based (T) regimen, to validate our results.Results: a) 149 pts were included in the TOP trial and 14.5% had a complete pathological response (pCR). b) A statistically significant correlation was observed between the mRNA levels (201292_s_at) and the FISH ratios (rho=0.42, p=0.00004), between mRNA and IHC (rho= 0.25, p=0.02) but not between FISH and IHC. c) TOP2A amplified tumors were characterized by an increased expression of genes telomeric to TOP2A and a decreased expression of HER2 and genes in its close proximity. d) TOP2A amplification (11% of the cases) was exclusively observed in HER2 amplified cases (=33% of the cases), and was predictive of pCR (k= 0.35, p=0.0002 - half of the patients with TOP2A amplification having a pCR). d). 57% of the samples overexpressed TOP2A but neither the protein levels nor the mRNA levels were predictive of pCR. e) Interestingly, a TOP2A gene expression module was predictive of response both in the HER2+ patients of the TOP trial and in the ER-/HER2+ patients of the BIG00-01 treated with A but not with T [Area Under the Curve (AUC): TOP: 0.86 (p=0.00001) and A-arm/BIG00-01: 0.81 (p= 0.0005)]. f) Stroma gene expression module defined previously (Desmedt et al. Clin Can Res2008) was associated with decreased pCR rates in the TOP trial and in ER-negative BIG00-01 pts treated with A but not with T, especially in HER2- pts [AUC: TOP: 0.31 (p=0.01) and A-arm/BIG00-01: 0.33 (p= 0.015)].Conclusions: This trial, which is the first to prospectively evaluate the predictive value of TOP2A in pts treated with epirubicin single-agent, supports TOP2A gene amplification, but not mRNA or protein overexpression, as a predictive marker. The analyses also shed light on the genes differentially expressed between TOP2A amplified and not amplified tumors. Finally, our results suggest that gene expression modules also predict relative efficacy to anthracyclines, both in HER2 positive and negative BC pts.