ER ER ER ER - Endocrine Reviews

especially in endocrine-resistant cells, and suggest that targeting such pathways
simultaneously with the ER pathway may be an effective therapy.
Proof of principle for therapies that specifically target growth factor pathways in breast
cancer has already been provided with the HER2 monoclonal antibody trastuzumab
(Herceptin). Successful clinical use of trastuzumab has been demonstrated in HER2-
positive breast cancer, and significant activity has been seen as first-line monotherapy,
with up to a 48% clinical benefit rate in HER2-positive tumors, and a 34% objective
response rate in tumors reported positive for HER2 amplification by FISH (164). Thus, it
is hoped that various small molecule TKIs and STIs might also prove effective anti-
cancer strategies in the appropriate setting. Early phase II clinical studies have been
initiated with EGFR/HER2 TKIs, FTIs, and more recently mTOR antagonists, as
monotherapy in patients with advanced (often heavily pretreated) disease; such studies,
however, have been somewhat disappointing, with low clinical response rates and rapid
disease progression (83).
The EGFR inhibitor gefitinib, an orally active, low-molecular-weight, selective EGFR-
tyrosine kinase inhibitor, has been studied in patients with breast cancer. There have
been several phase II monotherapy studies of gefitinib in patients with advanced breast
cancer (165-167). Overall, the data are relatively disappointing. The only trial in the
metastatic setting to report a significant number of responses includes patients with ER-
positive tumors progressing on tamoxifen (167), a setting in which preclinical models
have shown the best evidence of activity for gefitinib. Pharmacodynamic studies
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