Evaluation of biological pathways involved in chemotherapy response in breast cancer

Breast Cancer Res. 2008;10(2):R37. doi: 10.1186/bcr2088. Epub 2008 Apr 29.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Antineoplastic Combined Chemotherapy Protocols / therapeutic use*
  • Breast Neoplasms / chemistry
  • Breast Neoplasms / drug therapy*
  • Breast Neoplasms / genetics*
  • Breast Neoplasms / metabolism
  • Breast Neoplasms / pathology
  • Breast Neoplasms / surgery
  • Chemotherapy, Adjuvant
  • Cyclophosphamide / administration & dosage
  • Doxorubicin / administration & dosage
  • Drug Resistance, Neoplasm*
  • E2F3 Transcription Factor / drug effects
  • E2F3 Transcription Factor / metabolism*
  • Female
  • Fluorouracil / administration & dosage
  • Gene Expression Profiling
  • Gene Expression Regulation, Neoplastic
  • Genes, p53 / drug effects*
  • Humans
  • Ki-67 Antigen / metabolism
  • Lymphatic Metastasis
  • Middle Aged
  • Mutation
  • Neoadjuvant Therapy / methods
  • Neoplasm Staging
  • Paclitaxel / administration & dosage
  • Receptors, Estrogen / analysis*
  • Receptors, Estrogen / genetics
  • Signal Transduction / drug effects*
  • Treatment Outcome

Substances

  • E2F3 Transcription Factor
  • E2F3 protein, human
  • Ki-67 Antigen
  • Receptors, Estrogen
  • Doxorubicin
  • Cyclophosphamide
  • Paclitaxel
  • Fluorouracil