In vitro activity of pertuzumab in combination with trastuzumab in uterine serous papillary adenocarcinoma

Abstract

BACKGROUND: Uterine serous papillary adenocarcinoma (USPC) is a rare but highly aggressive variant of endometrial cancer. Pertuzumab is a new humanised monoclonal antibody (mAb) targeting the epidermal growth factor type II receptor (HER2/neu). We evaluated pertuzumab activity separately or in combination with trastuzumab against primary USPC cell lines expressing different levels of HER2/neu. METHODS: Six USPC cell lines were assessed by immunohistochemistry (IHC), flow cytometry, and real-time PCR for HER2/neu expression. c-erbB2 gene amplification was evaluated using fluorescent in situ hybridisation (FISH). Sensitivity to pertuzumab and trastuzumab-induced antibody-dependent cell-mediated cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC) was evaluated in 5 h chromium release assays. Pertuzumab cytostatic activity was evaluated using proliferation-based assays. RESULTS: Three USPC cell lines stained heavily for HER2/neu by IHC and showed amplification of the c-erbB2 gene by FISH. The remaining FISH-negative USPCs expressed HER2/neu at 0/1 þ levels. In cytotoxicity experiments against USPC with a high HER2/neu expression, pertuzumab and trastuzumab were similarly effective in inducing strong ADCC. The addition of complementcontaining plasma and interleukin-2 increased the cytotoxic effect induced by both mAbs. In low HER2/neu USPC expressors, trastuzumab was more potent than pertuzumab in inducing ADCC. Importantly, in this setting, the combination of pertuzumab with trastuzumab significantly increased the ADCC effect induced by trastuzumab alone (P ¼ 0.02). Finally, pertuzumab induced a significant inhibition in the proliferation of all USPC cell lines tested, regardless of their HER-2/neu expression. CONCLUSION: Pertuzumab and trastuzumab induce equally strong ADCC and CDC in FISH-positive USPC cell lines. Pertuzumab significantly increases tratuzumab-induced ADCC against USPC with a low HER2/neu expression and may represent a new therapeutic agent in patients harbouring advanced/recurrent and/or refractory USPC.

Pertuzumab in Combination with Trastuzumab Shows Significantly Enhanced Antitumor Activity in HER2-Positive Human Gastric Cancer Xenograft Models

“…ADCC activity is one of the key mechanisms of the antitumor activity of trastuzumab (36). Moreover, recent reports showed that pertuzumab also had ADCC activity (19,37). Antiangiogenic activity is also shown as the mechanism of antitumor activity of trastuzumab (12).…”

HER2/neu in Endometrial Cancer: A Promising Therapeutic Target With Diagnostic Challenges

“…In vitro studies have demonstrated that trastuzumab results in antibody-dependent cellular cytotoxicity in the range of 25% to 60% against HER2-overexpressing USC, which can be augmented by both IL-2 and simultaneous administration of the heterodimerization inhibitor pertuzumab (Omnitarg, Genentech). 58,59,70 Recent case reports also showed evidence of in vivo clinical activity of trastuzumab in patients with advanced or recurrent endometrial carcinoma. 53,71,72 However, no significant activity was observed in the GOG-181B phase II trial of singleagent trastuzumab in advanced or recurrent endometrial carcinoma patients.…”

Development and Analytical Validation of a BT-474 Anti-Proliferation Assay Targeting HER2

“…Overexpression of these glycoproteins exists in most tumor cells and will promote tumor cell proliferation and their resistance to therapy. For example, overexpression of HER1 was found in 40% of gliomas (Wong et al 1992), while overexpression of HER2 occurs in most breast cancer cells (EI-Sahwi et al 2010). Based on the fact that the expression level of EGFR was different (mostly higher) in tumor cells compared to that in normal cells, the inhibition of EGFRs expression and their related signal transduction pathways will prevent cancer cells proliferation and their survival.…”