Evaluation of biological pathways involved in chemotherapy response in breast cancer

Attila Tordai , Jing Wang , Fabrice Andre , Cornelia Liedtke , Kai Yan , Christos Sotiriou , Gabriel N Hortobagyi , Fraser W Symmans and Lajos Pusztai

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


Published:	29 April 2008

Abstract (provisional)

Introduction

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

Methods

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

Results

Twenty-seven (53%) ER-negative and 7 (9%) ER-positive patients had pathologic complete response (pCR) to therapy. Among the ER-negative cancers, a proliferation gene signature (FDR q=0.1), the Genomic Grade Index (FDR q =0.044) and the E2F3 pathway (FDR q =0.22, p=0.07) signature were enriched in the pCR group. Among the ER-positive cancers, 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-positive cancers with residual cancer.

Conclusion

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