Molecular Anatomy of Breast Cancer Stroma and Its Prognostic Value in Estrogen Receptor–Positive and –Negative Cancers

• Published in: Journal of clinical oncology Vol. 28; no. 28; pp. 4316 - 4323
• Main Authors: Bianchini, Giampaolo, Qi, Yuan, Alvarez, Ricardo H, Iwamoto, Takayuki, Coutant, Charles, Ibrahim, Nuhad K, Valero, Vicente, Cristofanilli, Massimo, Green, Marjorie C, Radvanyi, Laszlo, Hatzis, Christos, Hortobagyi, Gabriel N, Andre, Fabrice, Gianni, Luca, Symmans, W Fraser, Pusztai, Lajos
• Format: Journal Article
• Language: English
• Published: Alexandria, VA American Society of Clinical Oncology 01-10-2010
• Subjects: Amyloid beta-Protein Precursor - genetics; Antineoplastic Agents, Hormonal - therapeutic use; B-Lymphocytes - pathology; Biological and medical sciences; Biopsy, Fine-Needle; Breast Neoplasms - drug therapy; Breast Neoplasms - genetics; Breast Neoplasms - pathology; Chi-Square Distribution; Collagen Type IV - genetics; Extracellular Matrix Proteins; Female; Gene Expression Profiling; Gene Expression Regulation, Neoplastic; Gynecology. Andrology. Obstetrics; Humans; Mammary gland diseases; Medical sciences; Metagenome - genetics; Neoplasm Recurrence, Local; Phospholipid Transfer Proteins - genetics; Prognosis; Proportional Hazards Models; Prospective Studies; Protease Nexins; Protein-Serine-Threonine Kinases - genetics; Receptors, Cell Surface - genetics; Receptors, Estrogen - genetics; Receptors, Transforming Growth Factor beta - genetics; Survival Analysis; Tamoxifen - therapeutic use; Tumors; Mammary gland diseases; Estrogen receptor; Breast disease; Cancerology; Prognosis; Stroma; Breast cancer; Malignant tumor; Anatomy; Cancer; Hormonal receptor
• ISSN: 0732-183X; 1527-7755
• DOI: 10.1200/JCO.2009.27.2419

The purpose of this study was to identify genes enriched in breast cancer stroma, assess the stromal gene expression differences between estrogen receptor (ER) -positive and -negative cancers, and separately determine their prognostic value in these two subtypes of breast cancers.
We compared gene expression profiles of pairs of fine-needle (stroma-poor) and core-needle (stroma-rich) biopsies from 37 cancers to identify stroma-associated genes. We defined stromal metagenes and tested their prognostic values in 684 node-negative patients who received no systemic adjuvant therapy and 259 tamoxifen-treated patients.
We identified 293 probe sets overexpressed in core biopsies; these included five highly coexpressed gene clusters (metagenes) corresponding to immune functions and extracellular matrix components. These genes showed quantitative and qualitative differences between ER-positive and ER-negative cancers. A B-cell/plasma cell metagene showed strong prognostic value in ER-positive highly proliferative cancers, a lesser prognostic value in ER-negative cancers, and no prognostic value in ER-positive cancers with low proliferation. The hazard ratio for distant relapse in the lowest compared with the highest tertile of the pooled prognostic data set was 4.29 (95% CI, 2.04 to 9.01; P = .001) in ER-positive cancers and 3.34 (95% CI, 1.60 to 6.97; P = .001) in ER-negative cancers. This remained significant in multivariate analysis including routine variables and other genomic prognostic scores. As a result of quantitative differences in this metagene between ER-positive and ER-negative cancers, different thresholds apply in the two subgroups. Other stromal metagenes had inconsistent prognostic value.
Among ER-negative and ER-positive highly proliferative cancers, a subset of tumors with high expression of a B-cell/plasma cell metagene carries a favorable prognosis.