Abstract P6-13-13: Developing silastic tubing for local delivery of hormonal therapy: A novel approach to breast cancer prevention

Abstract

Abstract Background: For women at high risk for breast cancer, preventative interventions are limited to bilateral mastectomy with or without oophorectomy or prolonged anti-estrogen therapy. For many, these two options are unacceptable due to drug related toxicity or the irreversible consequences of prophylactic surgery. As such, many women will choose neither preventive measures. This highlights the need for prevention alternatives that are less invasive, less toxic, and less permanent. Ideally, only the tissue at risk should be treated. Therefore, we have developed a novel approach to release an anti-estrogen to the breast tissue only, with the goal to reach high breast tissue concentrations with minimal systemic exposure. Method: Cultured ER-positive breast cancer cells were used to validate the activity of fulvestrant released from the silastic tubing. CD-1 mice were used to demonstrate accumulation of fulvestrant released from the silastic tubing in the target breast tissue. LC-MS/MS was used to quantify released fulvestrant in both in vitro and in vivo experiments. Results: After 10 cm of silastic tubing was loaded with dry fulvestrant (0.076 mg/cm), it was placed in tissue culture media. Media was collected and replaced with fresh media every 3.5 days for 30+ weeks. It was then used to treat MCF7 and T47D cancer cells for 3 days. Within 7 days, fulvestrant released from the tubing was sufficient to modulate the ER signaling pathway of both cell lines and inhibit cell growth comparable to cells directly treated with a clinically feasible concentration of fulvestrant (100 nM). LC-MS/MS analysis demonstrated a fulvestrant release rate of rate of 10.7 ng fulvestrant per cm of tubing per day in culture media. To date, sustained release at this rate has been confirmed for 7+ months. To ascertain differential uptake of fulvestrant in the mammary tissue, we implanted fulvestrant-loaded tubing proximal to the inguinal mammary fat pad of CD-1 female mice and characterized biodistribution of fulvestrant. Various organs (blood, heart, lung, liver, kidney, and mammary fat pad) were harvested over time post-implantation. Using LC-MS/MS, we determined that fulvestrant preferentially accumulates in the mammary fat pad (175 nM), with minimal to no detection in other organs. Summary: Our data from in vitro and in vivo breast cancer models suggest that implantable silastic tubing has the capacity for long-term release of the anti-estrogen fulvestrant at high local concentrations that are sufficient to inhibit ER signaling and tumor cell proliferation with minimal systemic exposure. Further work is underway to design the optimal design for delivery. If successful, this option will provide a more acceptable alternative for breast cancer prevention and allow women at high risk to delay or forgo bilateral mastectomies. Citation Format: Park J, Thomas S, Zhong A, Piper M, Terranova Barberio M, Munster PN. Developing silastic tubing for local delivery of hormonal therapy: A novel approach to breast cancer prevention. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P6-13-13.