Abstract A high incidence (∼75%) of primary breast cancers are estrogen receptor positive (ER+), and a large fraction of these patients can pursue chemopreventive therapies. However, due to adverse side effects, only 5% to 20% of the women at high risk who could benefit from chemotherapeutics enroll in preventive treatment. There is a clear need for alternative preventive strategies that minimize side effects and improve enrollment and compliance. Selective estrogen receptor modulators, such as tamoxifen (TMX), have been shown to reduce ER+ breast cancer incidence by up to 50% among high-risk women. Importantly, along with raloxifene, it is one of only two FDA-approved drugs for breast cancer prevention. TMX has been in use for over 40 years and has a proven record in pre- and post-menopausal women. However, the drug is marred by side effects, the most common being symptoms of menopause. Further, women treated systemically and chronically with TMX were found to have an increased incidence of endometrial carcinoma. Although rare, this side effect, along with other serious adverse effects (such as blood clots, strokes, and cataracts), has resulted in a debate concerning TMX use in cancer prevention. As the key for breast cancer chemoprevention relies upon long-term delivery of drugs while circumventing side effects, we have developed a novel local delivery strategy for the constant and sustained administration of TMX. We maintain a long-term, local release of TMX in mammary tissues by utilizing a novel implantable nanochannel Delivery System (nDS). The nDS consists of a bioinert, implantable, and mechanically robust silicon membrane which houses an exact number of densely packed slit-nanochannels as small as 2.5 nm with tight tolerances on size, geometry, and surface properties. Providing steady levels of TMX at the mammary gland target through nDS delivery maximizes the therapeutic index while limiting the unwanted secondary effects, which will ultimately improve patient compliance. In this work we chemically induced tumorigenesis in Sprague-Dawley rats by N-methyl-N-nitrosourea (NMU) injection to promote development of estrogen-dependent tumors. We performed ovariectomies seven days after NMU injection to mimic post-menopausal biology. nDS implants loaded with either TMX or PEG400 (negative control) were inserted under the left abdominal mammary gland to determine effects of nDS-TMX on tumor growth and biomarkers. Utilizing LC/MS we were able to determine the amount of TMX released from the nDS. Rats were examined for palpable tumors to assess breast tumor incidence, latency to onset, and multiplicity. Our results show that the nDS implant enables the effective delivery of TMX in this breast tumor model. Further, this technology has the potential to rapidly provide long-term breast cancer protection with significant improvement in the quality of life of patients at high risk, thereby saving thousands of lives every year. Citation Format: Carly S. Filgueira, Eugenia Nicolov, Andrea Ballerini, R. Lyle Hood, Priya Jain, Giacomo Bruno, Alessandro Grattoni. Local and sustained delivery of tamoxifen for the prevention of ER+ breast cancer using a nanochannel delivery platform. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1320.