Purpose: Increased growth factor signaling may contribute to tamoxifen resistance. This randomized phase II trial assessed tamoxifen plus placebo or the epidermal growth factor receptor inhibitor gefitinib in estrogen receptor (ER)–positive metastatic breast cancer.

Experimental Design: Patients with newly metastatic disease or recurred after adjuvant tamoxifen (stratum 1), or recurred during/after adjuvant aromatase inhibitor (AI) or after failed first-line AI (stratum 2), were eligible. Primary variables were progression-free survival (PFS; stratum 1) and clinical benefit rate (CBR; stratum 2). A 5% or more improvement in response variables with gefitinib was considered to warrant further investigation. Outcome was correlated with biomarkers measured on the primary tumor.

Results: In stratum 1 (n = 206), the PFS HR (gefitinib:placebo) was 0.84 (95% CI, 0.59–1.18; median PFS 10.9 versus 8.8 months). In the stratum 1 endocrine therapy–naïve subset (n = 158) the HR was 0.78 (95% CI, 0.52–1.15), and the prior endocrine-treated subgroup (n = 48) 1.47 (95% CI, 0.63–3.45). In stratum 1, CBRs were 50.5% with gefitinib and 45.5% with placebo. In stratum 2 (n = 84), CBRs were 29.2% with gefitinib and 31.4% with placebo. Biomarker analysis suggested that in stratum 1 there was greater benefit with gefitinib in patients who were ER-negative or had lower levels of ER protein.

Conclusions: In stratum 1, the improved PFS with gefitinib plus tamoxifen met the protocol criteria to warrant further investigation of this strategy. In stratum 2, there was a numerical disadvantage for gefitinib; additional investigation after AI therapy is not warranted. Studies of predictive biomarkers are needed to subset appropriate patients. Clin Cancer Res; 17(5); 1147–59. ©2011 AACR.