Blockade of growth factor receptors in ductal carcinoma in situ inhibits epithelial proliferation

Abstract

Background: Ductal carcinoma in situ (DCIS) expresses c-erbB-2 receptor and epidermal growth factor receptor (EGFR). The aim of this study was to determine whether blocking of c-erbB-2 receptor with a humanized monoclonal antibody, 4D5 (Herceptin™), or of EGFR with an epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI), ZD1839 (Iressa™), would decrease epithelial proliferation in DCIS. Methods: DCIS tissue from 18 women undergoing surgery was implanted into 16 to 20 athymic nude mice per experiment (eight xenografts per mouse). Treatment commenced 2 weeks after implantation and consisted either of twice-weekly intraperitoneal injections of 4D5 10 mg/kg or of daily gavage with ZD1839 at 100-200 mg/kg for 14 days; appropriate controls were included. Xenografts were removed on days 14, 21 and 28. Proliferation was assessed by counting 1000 epithelial cells after Ki67 immunostaining. Results: ZD1839 inhibited proliferation compared with that in controls after 14 days (P<0.01), whereas 4D5 did not. Conclusion: Proliferation in DCIS was decreased by EGFR tyrosine kinase inhibition but not by cerbB-2 receptor blockade. ZD1839, an orally active and selective EGFR-TKI, has potential as adjuvant therapy in DCIS.