Abstract
Triple-negative breast cancer (TNBC) is a molecularly heterogeneous cancer that is difficult to treat. Despite the role it may play in tumor progression and response to therapy, microenvironmental (stromal) heterogeneity in TNBC has not been well characterized. To address this challenge, we investigated the transcriptome of tumor-associated stroma isolated from TNBC (n = 57). We identified four stromal axes enriched for T cells (T), B cells (B), epithelial markers (E), or desmoplasia (D). Our analysis method (STROMA4) assigns a score along each stromal axis for each patient and then combined the axis scores to subtype patients. Analysis of these subtypes revealed that prognostic capacity of the B, T, and E scores was governed by the D score. When compared with a previously published TNBC subtyping scheme, the STROMA4 method better captured tumor heterogeneity and predicted patient benefit from therapy with increased sensitivity. This approach produces a simple ontology that captures TNBC heterogeneity and informs how tumor-associated properties interact to affect prognosis. Cancer Res; 77(17); 4673-83. ©2017 AACR.
Highlights
In clinical practice, breast cancer is stratified into subtypes defined by differential protein expression of the estrogen receptor (ER) and progesterone receptor (PR), as well as expression and/or genomic amplification of human epidermal growth factor receptor 2 (HER2)
To investigate stromal heterogeneity across Triple-negative breast cancer (TNBC) tumors, 57 patient samples were selected based on negative ER, PR, and HER2 status according to clinical-pathological reports (Supplementary Table S2)
Tumor nonepithelial compartments were separately isolated by laser capture microdissection (LCM) and subjected to microarray-based gene expression profiling
Summary
Breast cancer is stratified into subtypes defined by differential protein expression of the estrogen receptor (ER) and progesterone receptor (PR), as well as expression and/or genomic amplification of human epidermal growth factor receptor 2 (HER2). The 10%–15% of breast carcinomas that lack expression/amplification of ER, PR, or HER2 form a subtype that is termed triple-negative breast cancer Tumors of the TNBC subtype are associated with earlier age of onset, higher grade at presentation, and overall poorer patient prognosis [2]. Despite extensive efforts, this subtype still lacks targeted therapies and these tumors are generally treated with untargeted chemotherapy and radiation [3, 4]. Previous studies, including several high-throughput profiling efforts, have indicated that the TNBC subtype has higher levels of
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