1. Academic Validation
  2. Superior in vitro and in vivo activity of trastuzumab-emtansine (T-DM1) in comparison to trastuzumab, pertuzumab and their combination in epithelial ovarian carcinoma with high HER2/neu expression

Superior in vitro and in vivo activity of trastuzumab-emtansine (T-DM1) in comparison to trastuzumab, pertuzumab and their combination in epithelial ovarian carcinoma with high HER2/neu expression

  • Gynecol Oncol. 2017 Oct;147(1):145-152. doi: 10.1016/j.ygyno.2017.07.009.
Gulden Menderes 1 Elena Bonazzoli 1 Stefania Bellone 1 Gary Altwerger 1 Jonathan D Black 1 Katherine Dugan 1 Francesca Pettinella 1 Alice Masserdotti 1 Francesco Riccio 1 Anna Bianchi 1 Luca Zammataro 1 Christopher de Haydu 1 Natalia Buza 2 Pei Hui 2 Serena Wong 2 Gloria S Huang 1 Babak Litkouhi 1 Elena Ratner 1 Dan-Arin Silasi 1 Masoud Azodi 1 Peter E Schwartz 1 Alessandro D Santin 3
Affiliations

Affiliations

  • 1 Department of Obstetrics, Gynecology, and Reproductive Sciences, Yale University School of Medicine, CT 06520, USA.
  • 2 Department of Pathology, Yale University School of Medicine, CT 06520, USA.
  • 3 Department of Obstetrics, Gynecology, and Reproductive Sciences, Yale University School of Medicine, CT 06520, USA. Electronic address: alessandro.santin@yale.edu.
Abstract

Background: Epithelial ovarian Cancer (EOC) remains the most lethal gynecologic malignancy. The objective of this study was to compare the anti-tumor activity of HER2/neu-targeting monoclonal Antibodies, trastuzumab (T), pertuzumab (P), combination of trastuzumab and pertuzumab (T+P) and trastuzumab-emtansine (T-DM1) in EOC with high HER2/neu expression.

Methods: Primary EOC cell lines were established and cell blocks were analyzed for HER2/neu expression. Cytostatic, apoptotic and antibody-dependent cell-mediated cytotoxicity (ADCC) activities of T, P, T+P and T-DM1 were evaluated in vitro. The in vivo antitumor activity was tested in xenograft models with 3+ HER2/neu expression.

Results: High (3+) HER2/neu expression was detected in 40% of the primary EOC cell lines. T, P, T+P, and T-DM1 were similarly effective in inducing strong ADCC against primary EOC cell lines expressing 3+ HER2/neu. The combination of T and P was more cytostatic when compared with that of T or P used alone (p<0.0001 and p<0.0001, respectively). T-DM1 induced significantly more Apoptosis when compared with T+P (p<0.0001). Finally, T-DM1 was significantly more effective in tumor growth inhibition in vivo in EOC xenografts overexpressing HER2/neu when compared to T alone, P alone and T+P (p=0.04).

Conclusion: In vitro and in vivo experiments with 3+ HER2/neu expressing EOC revealed limited anti-tumor activity of T or P. T-DM1 showed superior anti-tumor activity to T and P as single agents and as a combination. Our preclinical data support the design of clinical studies with T-DM1 for the treatment of chemotherapy-resistant EOC overexpressing HER2/neu.

Keywords

Epithelial ovarian carcinoma; HER2/neu; Pertuzumab; T-DM1; Trastuzumab.

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