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

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.