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Gynecol Oncol. 2017 Oct;147(1):145-152. doi: 10.1016/j.ygyno.2017.07.009. Epub 2017 Jul 10.

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.

Author information

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

PMID:
28705408
PMCID:
PMC5605415
DOI:
10.1016/j.ygyno.2017.07.009
[Indexed for MEDLINE]
Free PMC Article

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