Originally published as JCO Early Release 10.1200/JCO.2006.09.6578 on August 6 2007

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

Ian E. Smith, Geraldine Walsh, Anthony Skene, Antonio Llombart, José Ignacio Mayordomo, Simone Detre, Janine Salter, Emma Clark, Patrick Magill, Mitch Dowsett

From the Royal Marsden Hospital and Institute of Cancer Research; Royal Marsden Hospital, London; Royal Bournemouth Hospital, Bournemouth; AstraZeneca, Macclesfield, United Kingdom; Hospital Arnau I Vilanova, Lleida; and Hospital Lozano Blesa, Zaragoza, Spain.

Address reprint requests to Ian E. Smith, MD, Breast Unit, The Royal Marsden Hospital, Fulham Rd, London, SW3 6JJ United Kingdom; e-mail: ian.smith{at}rmh.nhs.uk

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.

published online ahead of print at www.jco.org on August 6, 2007.

Supported by a research grant from AstraZeneca.

Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.

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