P1-04-05: T-DM1 and Pertuzumab as New Tools for HER2 Specific Antibody-Therapy Against Breast Cancer Stem Cells in HER2−Positive Mammary Carcinoma.

Abstract

Abstract Trastuzumab (Herceptin®) has significantly improved the overall survival of patients with HER2−positive breast cancer. The efficacy of this treatment depends significantly on antibody-dependent cell mediated cytotoxicity (ADCC). However, while trastuzumab can direct NK cells towards tumor cells and thereby promote tumor cell lysis, spheroid-forming tumor-initiating cells are largely spared. Consequently, populations of surviving cells showed greatly enhanced clonogenicity in vitro and tumorigenicity in vivo. Low HER2 levels and reduced expression of activating NK cell ligands provide likely explanations for the escape of these cells from HER2−directed NK cell-dependent therapies. Moreover, recent data show that unproductive interactions between immune cells and cancer cells can induce a process called “epithelial-to-mesenchymal transition” (EMT) which enables previously differentiated cancer cells to acquire stem cell-like properties as evidenced by a CD44highCD24low breast cancer stem cell signature and aldehyde dehydrogenase positivity. We thus investigated whether new HER2−specific antibodies could enhance NK-cell mediated target cell lysis or inhibit the induction of tumor stem cells. The antibody pertuzumab also binds to the HER2−receptor. It inhibits homo- and heterodimerization of the HER2 receptor with other member of the HER family, in particular the dimerization of HER2/HER3 receptors. We were able to show that the combination of trastuzumab and pertuzumab leads to increased antibody-binding on breast cancer cells and breast cancer stem cells, resulting in enhanced ADCC. This correlates with the clinically observed synergy between trastuzumab and pertuzumab as observed for example in the Neosphere trial, a neoadjuvant study for HER2−positive breast cancer. Trastuzumab emtansine (T-DM1) is an antibody-drug conjugate which combines trastuzumab with the tubulin inhibitor maytansine. Interestingly, treatment with T-DM1 largely prevented the NK cell-dependent induction of the EMT markers Twist and Snail and the characteristic downregulation of E-cadherin. Thus, T-DM1 apparently interferes with EMT and may hence prevent the re-induction of the stem cell phenotype. In line with the presumed effect against cancer stem cells, T-DM1 significantly attenuated the clonogenic potential of FACS-sorted trastuzumab-unresponsive cancer stem cells. Accordingly, our data show that these new therapeutics may be more effective against cancer stem cells and thereby promise a more sustained treatment of HER2−positive breast cancer. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P1-04-05.