Originally published as JCO Early Release 10.1200/JCO.2005.08.326 on June 6 2005

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Phase II and Tumor Pharmacodynamic Study of Gefitinib in Patients with Advanced Breast Cancer

José Baselga, Joan Albanell, Amparo Ruiz, Ana Lluch, Pere Gascón, Vicente Guillém, Sonia González, Silvia Sauleda, Irene Marimón, Josep M. Tabernero, Maria T. Koehler, Federico Rojo

From the Vall d'Hebron University Hospital; Hospital Clinic, Barcelona; Instituto Valenciano de Oncologia; Universitat de Valencia, Hospital Clínico Universitario de Valencia and CESAT Valencia, Spain; and AstraZeneca, Wilmington, DE

Address reprint requests to José Baselga, MD, Chairman and Professor of Medicine, Medical Oncology Service, Vall d'Hebron University Hospital, P. Vall d'Hebron 119-129 08035 Barcelona, Spain; e-mail: jbaselga{at}vhebron.net.

PURPOSE: To evaluate the antitumor activity and pharmacodynamic/biologic effect of gefitinib 500 mg/day monotherapy in patients with previously treated, advanced breast cancer.

METHODS: In this phase II multicenter trial, the primary objective was assessment of the tumor response rate with gefitinib; secondary objectives included analysis of the pharmacodynamic and biologic profiles in healthy and tumor tissue.

RESULTS: Of 31 assessable patients, 12 (38.7%) had stable disease, including 3 (9.7%) with recurrent breast cancer that stabilized for 6 months. No complete or partial responses were observed. Pretreatment tumor samples were available in all patients. In addition, paired baseline and on-treatment (day 28) assessable skin and tumor biopsies were available in 27 and 16 patients, respectively. Sequential immunohistochemical studies in skin and tumor biopsies demonstrated complete inhibition of epidermal growth factor receptor (EGFR) phosphorylation in both healthy and malignant tissues. The downstream consequences of receptor blockade were distinct in skin and tumor samples: while phosphorylation of mitogen-activated protein kinase was inhibited in both tissues, gefitinib treatment induced p27 and a decrease in Ki67 in skin but not in tumors. Furthermore, gefitinib did not inhibit the activated form of Akt in the tumors.

CONCLUSION: This study demonstrates a good correlation between the degree of inhibition of EGFR in skin and in breast tumors. The lack of significant clinical activity of gefitinib in our study population is not due to lack of receptor inhibition in these tumors but rather to lack of EGFR dependence in the tested population.

Terms in blue are defined in the glossary, found at the end of this issue and online at www.jco.org.

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

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