A Phase II Placebo-Controlled Trial of Neoadjuvant Anastrozole Alone or With Gefitinib in Early Breast Cancer

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Abstract
Purpose: Increased epidermal growth factor receptor (EGFR) expression may promote breast cancer resistance to endocrine therapy. We have therefore investigated whether neoadjuvant gefitinib, an EGFR inhibitor, might overcome biologic and clinical resistance to neoadjuvant anastrozole in a phase II placebo-controlled trial. Patients and Methods: Postmenopausal women with stage I to IIIB hormone receptor–positive early breast cancer received anastrozole 1 mg daily for 16 weeks and were randomly assigned at a ratio of 2:5:5 to receive, in addition, gefitinib 250 mg/d orally for 16 weeks: placebo 1 tablet/d orally for 2 weeks and then gefitinib for 14 weeks or placebo for 16 weeks. The primary end point was biologic change in proliferation as measured by Ki67 at 2 and 16 weeks; the main secondary end point was overall objective response (OR). Results: Two hundred six women were randomly assigned. Mean changes in Ki67 with anastrozole and gefitinib versus anastrozole alone were −77.4% and −83.6%, respectively, between baseline and 16 weeks (geometric mean ratio = 1.37; 95% CI, 0.79 to 2.39; P = .26), −80.1% and −71.3% between baseline and 2 weeks (geometric mean ratio = 0.70; 95% CI, 0.39 to 1.25; P = .22) and −19.3% and −43% (geometric mean ratio = 1.42; 95% CI, 0.86 to 2.35; P = .16) between 2 and 16 weeks. ORs in the combination and anastrozole alone groups were 48% and 61% (estimated difference = −13.1%; 95% CI, –27.3% to 1.2%), respectively, with a nonsignificant trend against the combination (P = .08) and 48% versus 72% (estimated difference = −24.1%; 95% CI, –45.3% to −2.9%) in the progesterone-receptor–positive subgroup, which was significant (P = .03) and consistent with Ki67 changes. Common treatment-related adverse events included diarrhea, rash, alopecia, dry skin, and nausea. There was no evidence of a pharmacokinetic interaction. Conclusion: Addition of gefitinib to neoadjuvant anastrozole had no additional clinical or biologic effect, failing to support our original hypothesis.

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