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BMC Cancer
Published in: BMC Cancer 1/2008

Open Access 01-12-2008 | Research article

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

Authors: Andrew Tutt, Alice Wang, Charles Rowland, Cheryl Gillett, Kit Lau, Karen Chew, Hongyue Dai, Shirley Kwok, Kenneth Ryder, Henry Shu, Robert Springall, Paul Cane, Blair McCallie, Lauren Kam-Morgan, Steve Anderson, Horst Buerger, Joe Gray, James Bennington, Laura Esserman, Trevor Hastie, Samuel Broder, John Sninsky, Burkhard Brandt, Fred Waldman

Published in: BMC Cancer | Issue 1/2008

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Abstract

Background

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.

Methods

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.

Results

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).

Conclusion

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.
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Metadata
Title
Risk estimation of distant metastasis in node-negative, estrogen receptor-positive breast cancer patients using an RT-PCR based prognostic expression signature
Authors
Andrew Tutt
Alice Wang
Charles Rowland
Cheryl Gillett
Kit Lau
Karen Chew
Hongyue Dai
Shirley Kwok
Kenneth Ryder
Henry Shu
Robert Springall
Paul Cane
Blair McCallie
Lauren Kam-Morgan
Steve Anderson
Horst Buerger
Joe Gray
James Bennington
Laura Esserman
Trevor Hastie
Samuel Broder
John Sninsky
Burkhard Brandt
Fred Waldman
Publication date
01-12-2008
Publisher
BioMed Central
Published in
BMC Cancer / Issue 1/2008
Electronic ISSN: 1471-2407
DOI
https://doi.org/10.1186/1471-2407-8-339

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