Endocrine therapy is the most effective systemic treatment for patients with 
hormone-receptor-positive (HR(+)) breast cancer. Unfortunately, efficacy is 
often limited by the onset of resistance, which is almost inevitable for 
patients with advanced disease. Several patterns of endocrine resistance are 
recognizable clinically, including: A) tumors that are inherently insensitive to 
all attempts at estrogen receptor (ER) targeting despite expression of ER 
(pan-endocrine therapy resistance); B) tumors that are estrogen dependent but 
resistant to one or more specific endocrine therapies (agent-selective 
resistance); and C) tumors that initially respond but subsequently progress 
(acquired resistance). Current insights into the molecular basis for these 
resistance patterns are rudimentary, but are most clearly illuminated by 
investigations that focus on the crosstalk between the ErbB or HER peptide 
growth factor family and the ER. The data are sufficiently compelling to be 
addressed by ongoing clinical trials that examine combinations of endocrine 
agents and either trastuzumab (Herceptin; Genentech, Inc.; South San Francisco, 
CA) or ErbB-specific tyrosine kinase (TK) inhibitors. Preliminary data from a 
small "proof of concept" phase II study of letrozole (Femara; Novartis 
Pharmaceuticals Corporation; East Hanover, NJ) and trastuzumab demonstrated 
durable responses despite tamoxifen (Nolvadex; AstraZeneca Pharmaceuticals; 
Wilmington, DE) resistance. Efficacy was variable, however, despite the 
selection of patients on the basis of ER and ErbB-2 coexpression. Complicating 
matters further, resistance often occurs in the absence of any evidence for ErbB 
TK family member expression. In the absence of a clear target, common downstream 
signal transduction proteins that are known to intersect with the ER pathway can 
be inhibited to address resistance, including G proteins with 
farnesyltransferase inhibitors and molecular target of rapamycin (mTOR) with 
rapamycin analogues. With a number of phase III clinical trials now under way, 
major advances in the endocrine treatment of advanced disease are possible.