Abstract P5-14-04: A novel implant to deliver localized hormonal therapy to prevent and treat breast cancer

Abstract

Abstract Most cancer treatment and prevention strategies include removal of the respective organ or systemic therapy. Early interception and cancer prevention is fraught with uncertainties in individual risk assessment and the absence of early surrogate markers to monitor efficacy. Hence, cancer prevention studies typically require large patient numbers. They are performed in unselected populations without clearly defined risk and benefits are often small or diluted. Hence, even successful strategies with documented benefit such as tamoxifen, have found only poor uptake in the at-risk population. Many women and providers are deterred by the low benefits to risk ratio of systemic tamoxifen exposure. The opportunity to selectively treat with an effective agent would limit the need for surgery and circumvent systemic exposure. We propose a less toxic and less debilitating approach to prevent and treat early stage breast cancer by utilizing the slow release of anti-estrogens from silastic tubing as a local drug delivery device to the breast. Our in vitro and in vivo data demonstrate consistent release of active fulvestrant through at least 52 weeks. Extrapolating from the amount of residual drug left in the tubing after 52 weeks suggests that drug release could be maintained sufficiently to and beyond 5 years. Silastic tubing released fulvestrant at clinically relevant concentrations and associated with inhibition of ER signaling and cell proliferation in vitro. In vivo anti-tumor activity was comparable to systemic administration of the anti-estrogen. The silastic tubing preferentially delivered the anti-estrogen to mammary tissue with minimal accumulation in major organs and 20-fold lower concentrations in adjacent (abdominal) and distant fat (thoracic) pads. Consistent with fulvestrant penetrance through tumors, local delivery was more effective in reducing Ki-67 immediately adjacent to the tubing but maintained concentrations comparable to systemic therapy throughout the entire tumors. We further demonstrated that human fat cells readily take up fulvestrant and then transfer the drug to breast cancer cells. These findings support the use of local drug delivery through the human breast tissue and surrounding fatty tissue. Mammary tissues are rapidly cleared of fulvestrant upon removal of the drug-loaded tubing. This would allow the long term implantation of a drug delivery device designed to be emptied or refilled. Local drug delivery is ideally suited in a setting of local disease or recurrence with minimal risk for systemic metastases with the goal of producing high concentrations without systemic application of the drug. Our data support the concept of a local silastic tubing device as a means to locally deliver an anti-estrogen in three major applications: early interventions for localized tumors, such as ductal carcinoma in situ (DCIS) or early stage breast cancer with low metastatic potential, prevention of breast cancer in women at higher risk due genetic predisposition, or used in concert with systemic therapy to provide a localized therapeutic boost. Overall, the use of implantable silastic tubing for local drug delivery represents a promising approach and introduces a potential paradigm shift in prevention and treatment of breast cancer. Citation Format: Munster PN, Park J, Desai P, Garcia E, Cheng S, Greier S, Pawlowska N, Chaudhuri AR, Thomas S. A novel implant to deliver localized hormonal therapy to prevent and treat breast cancer [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P5-14-04.