Abstract | PURPOSE: The cell surface receptors tumor necrosis factor-related apoptosis-inducing ligand receptor 1 (TRAIL-R1) and TRAIL-R2 transmit apoptotic signals, and agents that activate these receptors are in clinical development. We sought to determine the expression and prognostic value of TRAIL-R1 and TRAIL-R2 in early-stage breast cancer. EXPERIMENTAL DESIGN: Tissue microarrays containing specimens from 655 breast cancer patients with 20-year follow-up were employed and evaluated with our automated quantitative analysis (AQUA) system. The system uses cytokeratin to define pixels as breast cancer ( tumor mask) within the array spot, and measures intensity of TRAIL receptor expression using Cy5 conjugated antibodies within the mask. AQUA scores were correlated with clinical and pathologic variables. TRAIL-R1 and TRAIL-R2 expression were similarly studied on 95 unmatched normal breast specimens. RESULTS: TRAIL-R1 expression was not associated with survival. High TRAIL-R2 expression strongly correlated with decreased survival (P = 0.0005). On multivariate analysis, high TRAIL-R2 expression remained an independent prognostic marker, as did nodal status and tumor size. High TRAIL-R2 expression correlated strongly with lymph node involvement (P = 0.0003). TRAIL-R2 expression was stronger in malignant specimens than in normal breast epithelium (P < 0.0001). CONCLUSIONS: High TRAIL-R2 expression was independently associated with decreased survival in breast cancer. The biological basis and the sensitivity of high TRAIL-R2 expressing cells to TRAIL agonists and/or chemotherapy are subject to further investigation. Evaluation of TRAIL-R2 expression in early-stage breast cancer may identify a subset of patients requiring more aggressive or pathway-targeted adjuvant treatment. Clinical trials involving TRAIL-R2 agonists should stratify patients based on TRAIL-R2 expression.
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Authors | Mary M McCarthy, Mario Sznol, Kyle A DiVito, Robert L Camp, David L Rimm, Harriet M Kluger |
Journal | Clinical cancer research : an official journal of the American Association for Cancer Research
(Clin Cancer Res)
Vol. 11
Issue 14
Pg. 5188-94
(Jul 15 2005)
ISSN: 1078-0432 [Print] United States |
PMID | 16033835
(Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S., Research Support, U.S. Gov't, P.H.S.)
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Chemical References |
- Receptors, TNF-Related Apoptosis-Inducing Ligand
- Receptors, Tumor Necrosis Factor
- TNFRSF10A protein, human
- TNFRSF10B protein, human
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Topics |
- Adult
- Aged
- Aged, 80 and over
- Breast Neoplasms
(genetics, pathology)
- Case-Control Studies
- Female
- Follow-Up Studies
- Gene Expression Profiling
- Humans
- Middle Aged
- Multivariate Analysis
- Oligonucleotide Array Sequence Analysis
- Prognosis
- Receptors, TNF-Related Apoptosis-Inducing Ligand
- Receptors, Tumor Necrosis Factor
(biosynthesis, genetics)
- Survival Analysis
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