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

Authors

Gulden Menderes, Department of Obstetrics, Gynecology, and Reproductive Sciences, Yale University School of Medicine, CT 06520, USA.
Elena Bonazzoli, Department of Obstetrics, Gynecology, and Reproductive Sciences, Yale University School of Medicine, CT 06520, USA.
Stefania Bellone, Department of Obstetrics, Gynecology, and Reproductive Sciences, Yale University School of Medicine, CT 06520, USA.
Gary Altwerger, Department of Obstetrics, Gynecology, and Reproductive Sciences, Yale University School of Medicine, CT 06520, USA.
Jonathan D. Black, Department of Obstetrics, Gynecology, and Reproductive Sciences, Yale University School of Medicine, CT 06520, USA.
Katherine Dugan, Department of Obstetrics, Gynecology, and Reproductive Sciences, Yale University School of Medicine, CT 06520, USA.
Francesca Pettinella, Department of Obstetrics, Gynecology, and Reproductive Sciences, Yale University School of Medicine, CT 06520, USA.
Alice Masserdotti, Department of Obstetrics, Gynecology, and Reproductive Sciences, Yale University School of Medicine, CT 06520, USA.
Francesco Riccio, Department of Obstetrics, Gynecology, and Reproductive Sciences, Yale University School of Medicine, CT 06520, USA.
Anna Bianchi, Department of Obstetrics, Gynecology, and Reproductive Sciences, Yale University School of Medicine, CT 06520, USA.
Luca Zammataro, Department of Obstetrics, Gynecology, and Reproductive Sciences, Yale University School of Medicine, CT 06520, USA.
Christopher de Haydu, Department of Obstetrics, Gynecology, and Reproductive Sciences, Yale University School of Medicine, CT 06520, USA.
Natalia Buza, Department of Pathology, Yale University School of Medicine, CT 06520, USA.
Pei Hui, Department of Pathology, Yale University School of Medicine, CT 06520, USA.
Serena Wong, Department of Pathology, Yale University School of Medicine, CT 06520, USA.
Gloria S. Huang, Department of Obstetrics, Gynecology, and Reproductive Sciences, Yale University School of Medicine, CT 06520, USA.
Babak Litkouhi, Department of Obstetrics, Gynecology, and Reproductive Sciences, Yale University School of Medicine, CT 06520, USA.
Elena Ratner, Department of Obstetrics, Gynecology, and Reproductive Sciences, Yale University School of Medicine, CT 06520, USA.
Dan-Arin Silasi, Department of Obstetrics, Gynecology, and Reproductive Sciences, Yale University School of Medicine, CT 06520, USA.
Masoud Azodi, Department of Obstetrics, Gynecology, and Reproductive Sciences, Yale University School of Medicine, CT 06520, USA.
Peter E. Schwartz, Department of Obstetrics, Gynecology, and Reproductive Sciences, Yale University School of Medicine, CT 06520, USA.
Alessandro D. Santin, Department of Obstetrics, Gynecology, and Reproductive Sciences, Yale University School of Medicine, CT 06520, USA. Electronic address: alessandro.santin@yale.edu.

Document Type

Article

Publication Title

Gynecologic oncology

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.

First Page

145

Last Page

152

DOI

10.1016/j.ygyno.2017.07.009

Publication Date

10-1-2017

Recommended Citation

Menderes, Gulden; Bonazzoli, Elena; Bellone, Stefania; Altwerger, Gary; Black, Jonathan D.; Dugan, Katherine; Pettinella, Francesca; Masserdotti, Alice; Riccio, Francesco; Bianchi, Anna; Zammataro, Luca; de Haydu, Christopher; Buza, Natalia; Hui, Pei; Wong, Serena; Huang, Gloria S.; Litkouhi, Babak; Ratner, Elena; Silasi, Dan-Arin; Azodi, Masoud; Schwartz, Peter E.; and Santin, Alessandro D., "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" (2017). Obstetrics and Gynecology. 180.
https://scholar.bridgeporthospital.org/obgyn/180

Identifier

28705408 (pubmed); NIHMS893434 (mid); PMC5605415 (pmc); 10.1016/j.ygyno.2017.07.009 (doi); S0090-8258(17)31026-0 (pii)