T-DM1, a novel antibody-drug conjugate, is highly effective against uterine and ovarian carcinosarcomas overexpressing HER2

• DOI: 10.1007/s10585-014-9688-8
• Publication Date: 2014-11-14T14:23:41Z
• Authors: Roberta Nicoletti; Salvatore Lopez; Stefania Bellone; Emiliano Cocco; Carlton L. Schwab; Jonathan D. Black; Floriana Centritto; Liancheng Zhu; Elena Bonazzoli; Natalia Buza; Pei Hui; Delia Mezzanzanica; Silvana Canevari; Peter E. Schwartz; Thomas J. Rutherford; Alessandro D. Santin
• Keywords: Ovarian Neoplasms; Immunoconjugates; Receptor, ErbB-2; Antibody-Dependent Cell Cytotoxicity; Antineoplastic Agents; Mice, SCID; Trastuzumab; Ado-Trastuzumab Emtansine; Antibodies, Monoclonal, Humanized; Xenograft Model Antitumor Assays; 3. Good health; Mice; 03 medical and health sciences; 0302 clinical medicine; Carcinosarcoma; Cell Line, Tumor; Uterine Neoplasms; Animals; M Phase Cell Cycle Checkpoints; Female; Maytansine; Cell Proliferation

Ovarian and uterine carcinosarcoma (CS) are characterized by their aggressive clinical behavior and poor prognosis. We evaluated the efficacy of trastuzumab-emtansine (T-DM1), against primary HER2 positive and HER2 negative CS cell lines in vitro and in vivo. Eight primary CS cell lines were evaluated for HER2 amplification and protein expression by fluorescence in situ hybridization, immunohistochemistry, flow cytometry and qRT-PCR. Sensitivity to T-DM1-induced antibody-dependent-cell-mediated-cytotoxicity (ADCC) was evaluated in 4-h-chromium-release-assays. T-DM1 cytostatic and apoptotic activities were evaluated using flow cytometry based proliferation assays. In vivo activity of T-DM1 was also evaluated. HER2 protein overexpression and gene amplification were detected in 25 % (2/8) of the primary CS cell lines. T-DM1 and T were similarly effective in inducing strong ADCC against CS overexpressing HER2 at 3+ levels. In contrast, T-DM1 was dramatically more effective than T in inhibiting cell proliferation (P < 0.0001) and in inducing G2/M phase cell cycle arrest in the HER2 expressing cell lines (shift of G2/M: mean ± SEM from 14.87 ± 1.23 to 66.57 ± 4.56 %, P < 0.0001). Importantly, T-DM1 was highly active at reducing tumor formation in vivo in CS xenografts overexpressing HER2 (P = 0.0001 and P < 0.0001 compared to T and vehicle respectively) with a significantly longer survival when compared to T and vehicle mice (P = 0.008 and P = 0.0001 respectively). T-DM1 may represent a novel treatment option for the subset of HER2 positive CS patients with disease refractory to chemotherapy.