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.

Figure 1

Distribution of P values computed from the unequal variance t test in patients with estrogen receptor (ER)-negative and ER-positive tumors. (a) Gene expressions were compared between ER-negative tumors that had pathologic complete response and those that had a lesser response to preoperative chemotherapy. The resulting P values for all comparisons were modeled as beta-uniform mixture. The straight line indicates the contribution of the uniform component, and the curved line is the fitted beta-distribution from the observed values. Deviation above the straight line indicates P values that may represent true discovery. (b) Distribution of P values in patients with ER-positive tumors.

Figure 2

Gene set enrichment results for estrogen receptor-negative breast tumors. Running enrichment scores (RESs) and the location of each probe set within the complete rank-ordered gene list for each gene set. The dotted line on the left indicates the position of the maximum RES, and the dotted line on the right indicates the zero position of the ranking metric score. (a) Proliferation set (probe set n = 74). (b) Genomic grade index (probe set n = 242). (c) E2F3 pathway (probe set n = 173). Heat maps corresponding to these plots are provided in Supplementary Figure 1. pCR, pathologic complete response; RD, residual disease.

Figure 3

Gene set enrichment results for estrogen receptor (ER)-positive breast tumors. Results are presented as in Figure 2. (a) Proliferation set. (b) Genomic grade index. (c) ER-associated genes (probe set n = 201). (d) Mutant p53 gene signature (probe set n = 25). Heat maps corresponding to these plots are provided in Supplementary Figure 2. pCR, pathologic complete response; RD, residual disease.