Gene Expression Profiling in Breast Cancer: Understanding the Molecular Basis of Histologic Grade To Improve Prognosis

作者：Christos P. Sotiriou, Pratyaksha Wirapati, Sherene Loi, Adrian L. Harris, Steve Fox, Johanna Smeds, Hans Nordgren, Pierre Farmer, Viviane Praz, Benjamin Haibe‐Kains, Christine Desmedt, Denis Larsimont, Fátima Cardoso, Hans L. Peterse, Dimitry S.A. Nuyten, Marc E Buyse, Marc J. van de Vijver, Jonas C. S. Bergh, Martine J Piccart, Mauro Delorenzi · 发表于：JNCI Journal of the National Cancer Institute · 年份：2006 · DOI：10.1093/jnci/djj052 · 被引用次数：2134 · 研究领域：Breast Cancer Treatment Studies、Gene expression and cancer classification、Bioinformatics and Genomic Networks

BACKGROUND: Histologic grade in breast cancer provides clinically important prognostic information. However, 30%-60% of tumors are classified as histologic grade 2. This grade is associated with an intermediate risk of recurrence and is thus not informative for clinical decision making. We examined whether histologic grade was associated with gene expression profiles of breast cancers and whether such profiles could be used to improve histologic grading. METHODS: We analyzed microarray data from 189 invasive breast carcinomas and from three published gene expression datasets from breast carcinomas. We identified differentially expressed genes in a training set of 64 estrogen receptor (ER)-positive tumor samples by comparing expression profiles between histologic grade 3 tumors and histologic grade 1 tumors and used the expression of these genes to define the gene expression grade index. Data from 597 independent tumors were used to evaluate the association between relapse-free survival and the gene expression grade index in a Kaplan-Meier analysis. All statistical tests were two-sided. RESULTS: We identified 97 genes in our training set that were associated with histologic grade; most of these genes were involved in cell cycle regulation and proliferation. In validation datasets, the gene expression grade index was strongly associated with histologic grade 1 and 3 status; however, among histologic grade 2 tumors, the index spanned the values for histologic grade 1-3 tumors. A...