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Risk estimation of distant metastasis in node-negative, estrogen receptor-positive breast cancer patients using an RT-PCR based prognostic expression signature

Andrew Tutt12*, Alice Wang3, Charles Rowland3, Cheryl Gillett4, Kit Lau3, Karen Chew5, Hongyue Dai6, Shirley Kwok3, Kenneth Ryder2, Henry Shu3, Robert Springall4, Paul Cane7, Blair McCallie3, Lauren Kam-Morgan8, Steve Anderson8, Horst Buerger9, Joe Gray10, James Bennington11, Laura Esserman12, Trevor Hastie13, Samuel Broder3, John Sninsky3, Burkhard Brandt9 and Fred Waldman115

Author Affiliations

1 Breakthrough Breast Cancer Research Unit, King's College, London, UK

2 Guy's Hospital, London, UK

3 Celera, LLC, Alameda, CA, USA

4 Guy's and St Thomas' Hospital Breast Research Tissue & Data Bank, London, UK

5 Comprehensive Cancer Center, University of California San Francisco, San Francisco, CA, USA

6 Rosetta Inpharmatics, A wholly owned subsidiary of Merck & Co. Inc., Seattle, WA, USA

7 Cellular Pathology Department, St Thomas' Hospital, London, UK

8 Laboratory Corporation of America, Triangle Park, NC, USA

9 Institute of Tumor Biology, University Medical Center, University of Hamburg, Hamburg, Germany

10 Life Sciences Division, Lawrence Berkeley National Laboratory, Berkeley, CA, USA

11 Department of Pathology, California Pacific Medical Center, San Francisco, CA, USA

12 Carol Franc Buck Breast Cancer Center, University of California San Francisco, San Francisco, CA, USA

13 Departments of Statistics, and Health Research & Policy, Stanford University, Stanford, CA, USA

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BMC Cancer 2008, 8:339  doi:10.1186/1471-2407-8-339

Published: 21 November 2008



Given the large number of genes purported to be prognostic for breast cancer, it would be optimal if the genes identified are not confounded by the continuously changing systemic therapies. The aim of this study was to discover and validate a breast cancer prognostic expression signature for distant metastasis in untreated, early stage, lymph node-negative (N-) estrogen receptor-positive (ER+) patients with extensive follow-up times.


197 genes previously associated with metastasis and ER status were profiled from 142 untreated breast cancer subjects. A "metastasis score" (MS) representing fourteen differentially expressed genes was developed and evaluated for its association with distant-metastasis-free survival (DMFS). Categorical risk classification was established from the continuous MS and further evaluated on an independent set of 279 untreated subjects. A third set of 45 subjects was tested to determine the prognostic performance of the MS in tamoxifen-treated women.


A 14-gene signature was found to be significantly associated (p < 0.05) with distant metastasis in a training set and subsequently in an independent validation set. In the validation set, the hazard ratios (HR) of the high risk compared to low risk groups were 4.02 (95% CI 1.91–8.44) for the endpoint of DMFS and 1.97 (95% CI 1.28 to 3.04) for overall survival after adjustment for age, tumor size and grade. The low and high MS risk groups had 10-year estimates (95% CI) of 96% (90–99%) and 72% (64–78%) respectively, for DMFS and 91% (84–95%) and 68% (61–75%), respectively for overall survival. Performance characteristics of the signature in the two sets were similar. Ki-67 labeling index (LI) was predictive for recurrent disease in the training set, but lost significance after adjustment for the expression signature. In a study of tamoxifen-treated patients, the HR for DMFS in high compared to low risk groups was 3.61 (95% CI 0.86–15.14).


The 14-gene signature is significantly associated with risk of distant metastasis. The signature has a predominance of proliferation genes which have prognostic significance above that of Ki-67 LI and may aid in prioritizing future mechanistic studies and therapeutic interventions.