Evaluation of biological pathways involved in chemotherapy response in breast cancer.
BACKGROUND
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.


CONCLUSIONS
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.
Tordai
Attila
A
Department of Breast Medical Oncology, The University of Texas M, D, Anderson Cancer Center, PO Box 301439, Houston, TX 77230-1439, USA.
Wang
Jing
J
Andre
Fabrice
F
Liedtke
Cornelia
C
Yan
Kai
K
Sotiriou
Christos
C
Hortobagyi
Gabriel N
GN
Symmans
W Fraser
WF
Pusztai
Lajos
L
D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D001943:Breast Neoplasms / Q000737:chemistry / Q000188:drug therapy* / Q000235:genetics* / Q000378:metabolism / Q000473:pathology / Q000601:surgery; D017024:Chemotherapy, Adjuvant; D003520:Cyclophosphamide / Q000008:administration & dosage; D004317:Doxorubicin / Q000008:administration & dosage; D019008:Drug Resistance, Neoplasm; D050699:E2F3 Transcription Factor / Q000187:drug effects / Q000378:metabolism*; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D016158:Genes, p53 / Q000187:drug effects*; D006801:Humans; D019394:Ki-67 Antigen / Q000378:metabolism; D008207:Lymphatic Metastasis; D008875:Middle Aged; D009154:Mutation; D020360:Neoadjuvant Therapy / Q000379:methods; D009367:Neoplasm Staging; D017239:Paclitaxel / Q000008:administration & dosage; D011960:Receptors, Estrogen / Q000032:analysis* / Q000235:genetics; D015398:Signal Transduction / Q000187:drug effects*; D016896:Treatment Outcome
D050699:E2F3 Transcription Factor; C098319:E2F3 protein, human; D019394:Ki-67 Antigen; D011960:Receptors, Estrogen; D004317:Doxorubicin; D003520:Cyclophosphamide; D017239:Paclitaxel; D005472:Fluorouracil