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
  • 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: [email protected].
PMID: 28705408 DOI: 10.1016/j.ygyno.2017.07.009
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.
Products