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Breast Cancer Research
Published in: Breast Cancer Research 5/2008

Open Access 01-10-2008 | Research article

A candidate molecular signature associated with tamoxifen failure in primary breast cancer

Authors: Julie A Vendrell, Katherine E Robertson, Patrice Ravel, Susan E Bray, Agathe Bajard, Colin A Purdie, Catherine Nguyen, Sirwan M Hadad, Ivan Bieche, Sylvie Chabaud, Thomas Bachelot, Alastair M Thompson, Pascale A Cohen

Published in: Breast Cancer Research | Issue 5/2008

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Abstract

Introduction

Few markers are available that can predict response to tamoxifen treatment in estrogen receptor (ER)-positive breast cancers. Identification of such markers would be clinically useful. We attempted to identify molecular markers associated with tamoxifen failure in breast cancer.

Methods

Eighteen initially ER-positive patients treated with tamoxifen requiring salvage surgery (tamoxifen failure [TF] patients) were compared with 17 patients who were disease free 5 years after surgery plus tamoxifen adjuvant therapy (control patients). cDNA microarray, real-time quantitative PCR, and immunohistochemistry on tissue microarrays were used to generate and confirm a gene signature associated with tamoxifen failure. An independent series of 33 breast tumor samples from patients who relapsed (n = 14) or did not relapse (n = 19) under tamoxifen treatment from a different geographic location was subsequently used to explore the gene expression signature identified.

Results

Using a screening set of 18 tumor samples (from eight control patients and 10 TF patients), a 47-gene signature discriminating between TF and control samples was identified using cDNA arrays. In addition to ESR1/ERα, the top-ranked genes selected by statistical cross-analyses were MET, FOS, SNCG, IGFBP4, and BCL2, which were subsequently validated in a larger set of tumor samples (from 17 control patients and 18 TF patients). Confirmation at the protein level by tissue microarray immunohistochemistry was observed for ER-α, γ-synuclein, and insulin-like growth factor binding protein 4 proteins in the 35 original samples. In an independent series of breast tumor samples (19 nonrelapsing and 14 relapsing), reduced expression of ESR1/ERα, IGFBP4, SNCG, BCL2, and FOS was observed in the relapsing group and was associated with a shorter overall survival. Low mRNA expression levels of ESR1/ERα, BCL2, and FOS were also associated with a shorter relapse-free survival (RFS). Using a Cox multivariate regression analysis, we identified BCL2 and FOS as independent prognostic markers associated with RFS. Finally, the BCL2/FOS signature was demonstrated to have more accurate prognostic value for RFS than ESR1/ERα alone (likelihood ratio test).

Conclusions

We identified molecular markers including a BCL2/FOS signature associated with tamoxifen failure; these markers may have clinical potential in the management of ER-positive breast cancer.
Appendix
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Metadata
Title
A candidate molecular signature associated with tamoxifen failure in primary breast cancer
Authors
Julie A Vendrell
Katherine E Robertson
Patrice Ravel
Susan E Bray
Agathe Bajard
Colin A Purdie
Catherine Nguyen
Sirwan M Hadad
Ivan Bieche
Sylvie Chabaud
Thomas Bachelot
Alastair M Thompson
Pascale A Cohen
Publication date
01-10-2008
Publisher
BioMed Central
Published in
Breast Cancer Research / Issue 5/2008
Electronic ISSN: 1465-542X
DOI
https://doi.org/10.1186/bcr2158

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