Effective treatment of ductal carcinoma in situ with a HER-2- targeted alpha-particle emitting radionuclide in a preclinical model of human breast cancer.

// Takahiro Yoshida 1, *, $ , Kideok Jin 1, * , Hong Song 2 , Sunju Park 1 , David L. Huso 3, @ , Zhe Zhang 1 , Han Liangfeng 1 , Charles Zhu 4 , Frank Bruchertseifer 5 , Alfred Morgenstern 5 , George Sgouros 2 , Saraswati Sukumar 1 1 Department of Oncology, Johns Hopkins University School of Medicine, Maryland, USA 2 Department of Radiology and Radiological Science, Johns Hopkins University School of Medicine, Maryland, USA 3 Department of Molecular and Comparative Pathobiology, Johns Hopkins University School of Medicine, Maryland, USA 4 Department of Biomedical Engineering, Rutgers University, Piscataway, NJ, USA 5 European Commission, Joint Research Centre, Institute for Transuranium Elements, Karlsruhe, Germany $ Current address: Department of Surgery, Tokushima University, 3-18-15 Kuramoto-cho, Tokushima, Japan * These authors have contributed equally to this work @ Deceased Correspondence to: Saraswati Sukumar, e-mail: saras@jhmi.edu George Sgouros, e-mail: gsgouros@jhmi.edu Keywords: intraductal, radioimmunotherapy, trastuzumab, ductal carcinoma in situ, breast cancer Received: August 05, 2015      Accepted: March 31, 2016      Published: April 23, 2016 ABSTRACT The standard treatment for ductal carcinoma in situ (DCIS) of the breast is surgical resection, followed by radiation. Here, we tested localized therapy of DCIS in mice using the immunoconjugate 225 Ac linked-trastuzumab delivered through the intraductal (i.duc) route. Trastuzumab targets HER-2/neu, while the alpha-emitter 225 Ac (half-life, 10 days) delivers highly cytotoxic, focused doses of radiation to tumors. Systemic 225 Ac, however, elicits hematologic toxicity and at high doses free 213 Bi, generated by its decay, causes renal toxicity. I.duc delivery of the radioimmunoconjugate could bypass its systemic toxicity. Bioluminescent imaging showed that the therapeutic efficacy of intraductal 225 Ac-trastuzumab (10-40 nCi per mammary gland; 30-120 nCi per mouse) in a DCIS model of human SUM225 cancer cells in NSG mice was significantly higher (p<0.0003) than intravenous (120 nCi per mouse) administration, with no kidney toxicity or loss of body weight. Our findings suggest that i.duc radioimmunotherapy using 225 Ac-trastuzumab deserves greater attention for future clinical development as a treatment modality for early breast cancer.