Molecular anatomy of breast cancer stroma and its prognostic value in estrogen receptor-positive and -negative cancers.
OBJECTIVE
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.


METHODS
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.


RESULTS
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.


CONCLUSIONS
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.
Bianchini
Giampaolo
G
Department of Breast Medical Oncology, Unit 1354, The University of Texas M. D. Anderson Cancer Center, PO Box 301439, Houston,TX 77230-1439, USA.
Qi
Yuan
Y
Alvarez
Ricardo H
RH
Iwamoto
Takayuki
T
Coutant
Charles
C
Ibrahim
Nuhad K
NK
Valero
Vicente
V
Cristofanilli
Massimo
M
Green
Marjorie C
MC
Radvanyi
Laszlo
L
Hatzis
Christos
C
Hortobagyi
Gabriel N
GN
Andre
Fabrice
F
Gianni
Luca
L
Symmans
W Fraser
WF
Pusztai
Lajos
L
D016564:Amyloid beta-Protein Precursor / Q000235:genetics; D018931:Antineoplastic Agents, Hormonal / Q000627:therapeutic use; D001402:B-Lymphocytes / Q000473:pathology; D044963:Biopsy, Fine-Needle; D001943:Breast Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D016009:Chi-Square Distribution; D024141:Collagen Type IV / Q000235:genetics; D016326:Extracellular Matrix Proteins; D005260:Female; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D054892:Metagenome / Q000235:genetics; D009364:Neoplasm Recurrence, Local; D049294:Phospholipid Transfer Proteins / Q000235:genetics; D011379:Prognosis; D016016:Proportional Hazards Models; D011446:Prospective Studies; D058255:Protease Nexins; D017346:Protein Serine-Threonine Kinases / Q000235:genetics; D000077294:Receptor, Transforming Growth Factor-beta Type II; D011956:Receptors, Cell Surface / Q000235:genetics; D011960:Receptors, Estrogen / Q000235:genetics*; D018125:Receptors, Transforming Growth Factor beta / Q000235:genetics; D016019:Survival Analysis; D013629:Tamoxifen / Q000627:therapeutic use
D016564:Amyloid beta-Protein Precursor; D018931:Antineoplastic Agents, Hormonal; C502625:COL4A2 protein, human; D024141:Collagen Type IV; C490607:ECM1 protein, human; D016326:Extracellular Matrix Proteins; C493430:PLTP protein, human; D049294:Phospholipid Transfer Proteins; D058255:Protease Nexins; D011956:Receptors, Cell Surface; D011960:Receptors, Estrogen; D018125:Receptors, Transforming Growth Factor beta; D013629:Tamoxifen; D017346:Protein Serine-Threonine Kinases; D000077294:Receptor, Transforming Growth Factor-beta Type II