Abstract P4-02-06: Molecular imaging with trastuzumab and pertuzumab of HER2-positive breast cancer in mice: a step towards personalized medicine

• Published in: Cancer research (Chicago, Ill.) Vol. 72; no. 24_Supplement; pp. P4 - P4-02-06
• Main Authors: Collin, B, Oudot, A, Vrigneaud, J-M, Moreau, M, Raguin, O, Duchamp, O, Tizon, X, Denat, F, Varoqueaux, N, Brunotte, F, Fumoleau, P
• Format: Journal Article
• Language: English
• Published: 15.12.2012
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/0008-5472.SABCS12-P4-02-06

Abstract Introduction: The accurate and reliable assessment of HER2 status is an essential step in the diagnostic workup and selection of targeted treatment strategy in breast cancer patients. However, current ex vivo methods do not evaluate HER2 status possible discordance between primary tumor and distant metastases, nor immediate response to therapeutic intervention. Non-invasive imaging of HER2 expression could be a relevant alternative with additional benefits such as a better selection of patients for HER2-targeted therapies and the possible optimization of treatment strategies. Recent clinical trials suggest a better efficacy of trastuzumab/pertuzumab doublet but a lower activity of pertuzumab monotherapy over trastuzumab alone. Aim: The aim of our study was therefore to evaluate preclinically the use of radiolabeled DOTAGA (2, 2′, 2″-(10-(2,6-dioxotetrahydro-2H-pyran-3-yl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetic acid) conjugated trastuzumab and pertuzumab for SPECT/CT (Single Photon Emission Computed Tomography/Computed Tomography) HER2 imaging purposes. Methods: Trastuzumab and pertuzumab were conjugated to a new bifunctional chelating agent: DOTAGA anhydride (DOTA analog) and subsequently radiolabeled with the gamma-emitter Indium 111. The functionality of [111In]-DOTAGA-antibodies analogs was evaluated by in vitro saturation assays using HER2-overexpressing human breast cancer cell line (HCC1954). In vivo biodistribution was studied by SPECT/CT imaging at 24h, 48h and 72h after intravenous injection of [111In]-DOTAGA-antibodies in subcutaneous BT474 tumor-bearing rodents. Results: [111In]-DOTAGA-trastuzumab and [111In]-DOTAGA-pertuzumab showed respectively 2.6 and 2.7 DOTAGA/antibody. Both [111In]-DOTAGA-trastuzumab and [111In]-DOTAGA-pertuzumab achieved a radiochemical purity > 95%. Biological activity of [111In]-DOTAGA-trastuzumab and [111In]-DOTAGA-pertuzumab was maintained: the affinity determined on HER2 expressing HCC1954 cell lines, was 5.5 and 5.6 nM. SPECT/CT imaging experiments in tumor-bearing rodents and gamma-counting of organs both showed that at 72h post-injection, more than 60 % of the activity was localized in the tumor (66.9±0.9 %ID/g for [111In]-DOTAGA-trastuzumab and 63.8±6.3 %ID/g for [111In]-DOTAGA-pertuzumab) and that an excess of non-radiolabeled corresponding antibody significantly shifted down tumor-targeting (to 17.6±2.4 %ID/g for [111In]-DOTAGA-trastuzumab and 8.7±0.8 %ID/g for [111In]-DOTAGA-pertuzumab. Conclusions: Our results demonstrate a similar HER2 binding of trastuzumab and pertuzumab. Both radiolabeled [111In]-DOTAGA-trastuzumab and [111In]-DOTAGA-pertuzumab should be considered and might be promising tools for molecular imaging diagnosis of HER2 overexpression in breast cancer. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P4-02-06.