Multifactorial Approach to Predicting Resistance to Anthracyclines
-
Published:2011-04-20
Issue:12
Volume:29
Page:1578-1586
-
ISSN:0732-183X
-
Container-title:Journal of Clinical Oncology
-
language:en
-
Short-container-title:JCO
Author:
Desmedt Christine1, Di Leo Angelo1, de Azambuja Evandro1, Larsimont Denis1, Haibe-Kains Benjamin1, Selleslags Jean1, Delaloge Suzette1, Duhem Caroline1, Kains Jean-Pierre1, Carly Birgit1, Maerevoet Marie1, Vindevoghel Anita1, Rouas Ghislane1, Lallemand Françoise1, Durbecq Virginie1, Cardoso Fatima1, Salgado Roberto1, Rovere Rodrigo1, Bontempi Gianluca1, Michiels Stefan1, Buyse Marc1, Nogaret Jean-Marie1, Qi Yuan1, Symmans Fraser1, Pusztai Lajos1, D'Hondt Véronique1, Piccart-Gebhart Martine1, Sotiriou Christos1
Affiliation:
1. From the Institut Jules Bordet; Machine Learning Group, Université Libre de Bruxelles; Hôpitaux Iris Sud–Site Etterbeek-Ixelles; Hopital Saint-Pierre, Brussels; Clinique Saint-Pierre, Ottignies; Clinique Ste Elisabeth, Namur; International Drug Development Institute, Louvain-La-Neuve, Belgium; Hospital of Prato, Prato, Italy; Institut Gustave Roussy, Villejuif, France; Centre Hospitalier du Luxembourg, Luxembourg, Luxembourg; and University of Texas MD Anderson Cancer Center, Houston, TX.
Abstract
Purpose Validated biomarkers predictive of response/resistance to anthracyclines in breast cancer are currently lacking. The neoadjuvant Trial of Principle (TOP) study, in which patients with estrogen receptor (ER) –negative tumors were treated with anthracycline (epirubicin) monotherapy, was specifically designed to evaluate the predictive value of topoisomerase II-α (TOP2A) and develop a gene expression signature to identify those patients who do not benefit from anthracyclines. Patients and Methods The TOP trial included 149 patients, 139 of whom were evaluable for response prediction analyses. The primary end point was pathologic complete response (pCR). TOP2A and gene expression profiles were evaluated using pre-epirubicin biopsies. Gene expression data from ER-negative samples of the EORTC (European Organisation for Research and Treatment of Cancer) 10994/BIG (Breast International Group) 00-01 and MDACC (MD Anderson Cancer Center) 2003-0321 neoadjuvant trials were used for validation purposes. Results A pCR was obtained in 14% of the evaluable patients in the TOP trial. TOP2A amplification, but not protein overexpression, was significantly associated with pCR (P ≤ .001 v P ≤ .33). We developed an anthracycline-based score (A-Score) combining three signatures: a TOP2A gene signature and two previously published signatures related to tumor invasion and immune response. The A-Score was characterized by a high negative predictive value ([NPV]; NPV, 0.98; 95% CI, 0.90 to 1.00) overall and in the human epidermal growth factor receptor 2 (HER2) –negative and HER2-positive subpopulations. Its performance was independently confirmed in the anthracycline-based arms of the two validation trials (BIG 00-01: NPV, 0.83; 95% CI, 0.64 to 0.94 and MDACC 2003-0321: NPV, 1.00; 95% CI, 0.80 to 1.00). Conclusion Given its high NPV, the A-Score could become, if further validated, a useful clinical tool to identify those patients who do not benefit from anthracyclines and could therefore be spared the non-negligible adverse effects.
Publisher
American Society of Clinical Oncology (ASCO)
Subject
Cancer Research,Oncology
Cited by
164 articles.
订阅此论文施引文献
订阅此论文施引文献,注册后可以免费订阅5篇论文的施引文献,订阅后可以查看论文全部施引文献
|
|