Research article

Evaluation of biological pathways involved in chemotherapy response in breast cancer

Attila Tordai^1,2 , Jing Wang³ , Fabrice Andre⁴ , Cornelia Liedtke¹ , Kai Yan³ , Christos Sotiriou⁵ , Gabriel N Hortobagyi¹ , W Fraser Symmans and Lajos Pusztai¹

¹Department of Breast Medical Oncology, The University of Texas M. D. Anderson Cancer Center, PO Box 301439, Houston, TX 77230-1439, USA

²Department of Molecular Diagnostics, National Medical Center, Szabolcs utca 33-35, 1135 Budapest, Hungary

³Department of Bioinformatics and Computation Biology, The University of Texas M. D. Anderson Cancer Center, PO Box 301439, Houston, TX 77230-1439, USA

⁴Unit UPRES03535, Institut Gustave Roussy, 39 Rue Camille Desmoulins, 94805 Villejuif, France

⁵Jules Bordet Institut, 121 Boulevard de Waterloolaan, Brussels 1000, Belgium

author email corresponding author email

Breast Cancer Research 2008, 10:R37doi:10.1186/bcr2088

Published:	29 April 2008

Abstract

Introduction

Our goal was to examine the association between biological pathways and response to chemotherapy in estrogen receptor-positive (ER⁺) and ER-negative (ER^-) breast tumors separately.

Methods

Gene set enrichment analysis including 852 predefined gene sets was applied to gene expression data from 51 ER^- and 82 ER⁺ breast tumors that were all treated with a preoperative paclitaxel, 5-fluoruracil, doxorubicin, and cyclophosphamide chemotherapy.

Results

Twenty-seven (53%) ER^- and 7 (9%) ER⁺ patients had pathologic complete response (pCR) to therapy. Among the ER^- tumors, a proliferation gene signature (false discovery rate [FDR] q = 0.1), the genomic grade index (FDR q = 0.044), and the E2F3 pathway signature (FDR q = 0.22, P = 0.07) were enriched in the pCR group. Among the ER⁺ tumors, the proliferation signature (FDR q = 0.001) and the genomic grade index (FDR q = 0.015) were also significantly enriched in cases with pCR. Ki67 expression, as single gene marker of proliferation, did not provide the same information as the entire proliferation signature. An ER-associated gene set (FDR q = 0.03) and a mutant p53 gene signature (FDR q = 0.0019) were enriched in ER⁺ tumors with residual cancer.

Conclusion

Proliferation- and genomic grade-related gene signatures are associated with chemotherapy sensitivity in both ER^- and ER⁺ breast tumors. Genes involved in the E2F3 pathway are associated with chemotherapy sensitivity among ER^- tumors. The mutant p53 signature and expression of ER-related genes were associated with lower sensitivity to chemotherapy in ER⁺ breast tumors only.