Combination effects of herceptin, pertuzumab and bevacizumab in a HER2-overexpressing breast cancer xenograft model.
Authors: Alami N , Sun Y , De P , Benmassaoud AM , Wang Y , Leyland-Jones B 
Published: December 2010

Abstract #4058

Background: The HER2 receptor is overexpressed in 20-25% of breast cancer patients and is associated with poor prognosis. Trastuzumab, a humanized monoclonal antibody directed against the HER2 receptor, used alone or in combination with chemotherapy, has shown significant clinical benefit in improving survival in metastatic patients, as well as improving survival in early breast cancer. However, resistance to trastuzumab often develops within 1 year of treatment initiation. Recent studies have shown that trastuzumab in combination with pertuzumab or bevacizumab may have clinical benefit in selected HER2 overexpressing breast cancer patients. In the present study, we investigated whether blockade of HER homo- and heterodimer pairs in combination with an anti-VEGF, could more effectively inhibit tumor growth in a HER2 overexpressing breast cancer model.&#x2028; Material and Methods: Nude mice bearing subcutaneous BT474 HER2-R (a resistant derivative cell line) xenograft tumors were treated with trastuzumab (T) (10 or 20 mg/kg), pertuzumab (P) (15 mg/kg once weekly after an initial 30 mg/kg loading dose), bevacizumab (B) (5mg/kg), as single agents or in doublets and triplets combination therapies with T at 10 mg/kg. Endpoints include tumor volume, HER signaling, angiogenic biomarkers and occurrence of metastasis.&#x2028; Results: T (at its highest dose) and B, as single courses, showed significant anti-tumor activity as compared with the non-treated group. P or T (at its lowest dose) were not effective at inhibiting tumor growth. Combined treatment with P and B significantly inhibited tumor growth as compared with either agent alone or T alone. Time to tumor progression (tumors reaching 2.5 times baseline size) was 26 days for T + B & T + P, and 30 days for P+B as compared with 15 for P, 20 for H (20mg/kg) and 25 days for B, as single agents. In the mice treated with the triple combination, tumor volumes decreased after treatment initiation achieving a complete tumor regression on day 47 with no tumor regrowth up to day 80. Preliminary mechanistic studies showed that P and T as single agents or in combination caused a decrease of HER2 phosphorylation and downstream AKT activation. No further decrease of HER2 signaling was observed with the triple combination.&#x2028; Discussion: Our results confirm that inhibiting tumour angiogenesis by targeting VEGF has anti-tumor effects. Time to progression was delayed in mice treated with T+P compared with mice treated with a double dose of T, confirming that increasing the dosage of a single anti-HER agent is not as effective as using a combination regimen of inhibitors with different mechanisms of action. Complete tumor regression was achieved when B was combined with P and T at its lower dose, suggesting crosstalk between the VEGF pathway with both the epidermal growth factor receptor (EGFR) and HER2 pathways. Ongoing experiments, IHC and angiogenic biomarker analysis, will provide additional insight into the mechanism of action of T+P+B in this tumor model.

Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 4058.