Evaluation of biological pathways involved in chemotherapy response in breast cancer

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. © 2008 Tordai et al.; licensee BioMed Central Ltd.