Patterns of resistance and incomplete response to docetaxel by gene expression profiling in breast cancer patients.
OBJECTIVE
Chemotherapy for operable breast cancer decreases the risk of death. Docetaxel is one of the most active agents in breast cancer, but resistance or incomplete response is frequent.


METHODS
Core biopsies from 24 patients were obtained before treatment with neoadjuvant docetaxel (four cycles, 100 mg/m(2) every 3 weeks), and response was assessed after chemotherapy. After 3 months of neoadjuvant chemotherapy, surgical specimens (n = 13) were obtained, and laser capture microdissection (LCM; n = 8) was performed to enrich for tumor cells. From each core, surgical, and LCM specimen, sufficient total RNA (3 to 6 microg) was extracted for cDNA array analysis using the Affymetrix HgU95-Av2 GeneChip (Affymetrix, Santa Clara, CA).


RESULTS
From the initial core biopsies, differential patterns of expression of 92 genes correlated with docetaxel response (P = .001). However, the molecular patterns of the residual cancers after 3 months of docetaxel treatment were strikingly similar, independent of initial sensitivity or resistance. This relative genetic homogeneity after treatment was observed in both LCM and non-LCM surgical specimens. The residual tumor after treatment in tumors that were initially sensitive indicates selection of a residual and resistant subpopulation of cells. The gene expression pattern was populated by genes involved in cell cycle arrest at G(2)M (eg, mitotic cyclins and cdc2) and survival pathways involving the mammalian target of rapamycin.


CONCLUSIONS
A specific and consistent gene expression pattern was found in residual tumors after docetaxel treatment. These profiles provide therapeutic targets that could lead to improved treatment.
Chang
Jenny C
JC
Breast Center, Department of Medicine, Baylor College of Medicine, 1 Baylor Plaza, MS 600, Houston, TX 77030, USA. jcchang@breastcenter.tmc.edu
Wooten
Eric C
EC
Tsimelzon
Anna
A
Hilsenbeck
Susan G
SG
Gutierrez
M Carolina
MC
Tham
Yee-Lu
YL
Kalidas
Mamta
M
Elledge
Richard
R
Mohsin
Syed
S
Osborne
C Kent
CK
Chamness
Gary C
GC
Allred
D Craig
DC
Lewis
Michael T
MT
Wong
Helen
H
O'Connell
Peter
P
D000328:Adult; D000972:Antineoplastic Agents, Phytogenic / Q000627:therapeutic use*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics*; D017024:Chemotherapy, Adjuvant; D000077143:Docetaxel; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D005260:Female; D020869:Gene Expression Profiling; D006801:Humans; D008875:Middle Aged; D020360:Neoadjuvant Therapy; D020411:Oligonucleotide Array Sequence Analysis; D043823:Taxoids / Q000627:therapeutic use*
D000972:Antineoplastic Agents, Phytogenic; D043823:Taxoids; D000077143:Docetaxel