Comprehensive Genomic Analysis Identifies Novel Subtypes and Targets of Triple-Negative Breast Cancer

作者：Matthew D. Burstein, Anna Tsimelzon, Graham M. Poage, Kyle R. Covington, Alejandro Contreras, Suzanne A.W. Fuqua, Michelle I. Savage, C. Kent Osborne, Susan G. Hilsenbeck, Jenny C. Chang, Gordon B. Mills, Ching C. Lau, Powel H. Brown · 发表于：Clinical Cancer Research · 年份：2014 · DOI：10.1158/1078-0432.ccr-14-0432 · 被引用次数：1418 · 研究领域：Breast Cancer Treatment Studies、Breast Lesions and Carcinomas、Cancer Genomics and Diagnostics

PURPOSE: Genomic profiling studies suggest that triple-negative breast cancer (TNBC) is a heterogeneous disease. In this study, we sought to define TNBC subtypes and identify subtype-specific markers and targets. EXPERIMENTAL DESIGN: RNA and DNA profiling analyses were conducted on 198 TNBC tumors [estrogen receptor (ER) negativity defined as Allred scale value ≤ 2] with >50% cellularity (discovery set: n = 84; validation set: n = 114) collected at Baylor College of Medicine (Houston, TX). An external dataset of seven publically accessible TNBC studies was used to confirm results. DNA copy number, disease-free survival (DFS), and disease-specific survival (DSS) were analyzed independently using these datasets. RESULTS: We identified and confirmed four distinct TNBC subtypes: (i) luminal androgen receptor (AR; LAR), (ii) mesenchymal (MES), (iii) basal-like immunosuppressed (BLIS), and (iv) basal-like immune-activated (BLIA). Of these, prognosis is worst for BLIS tumors and best for BLIA tumors for both DFS (log-rank test: P = 0.042 and 0.041, respectively) and DSS (log-rank test: P = 0.039 and 0.029, respectively). DNA copy number analysis produced two major groups (LAR and MES/BLIS/BLIA) and suggested that gene amplification drives gene expression in some cases [FGFR2 (BLIS)]. Putative subtype-specific targets were identified: (i) LAR: androgen receptor and the cell surface mucin MUC1, (ii) MES: growth factor receptors [platelet-derived growth factor (PDGF) receptor A; c-Kit]...