Abstract
Broad use of germline testing has identified an increasing number of women at risk for breast cancer with a need for effective chemoprevention. We report a novel method to selectively deliver various anti-estrogens at high drug levels to the breast tissue by implanting a device comprised of silastic tubing. Optimized tubing properties allow elution of otherwise poorly bioavailable anti-estrogens, such as fulvestrant, into mammary tissue in vitro and in vivo with levels sufficient to inhibit estrogen receptor activation and tumor cell proliferation. Implantable silastic tubing delivers fulvestrant selectively to mouse mammary fat tissue for one year with anti-tumor effects similar to those achieved with systemic fulvestrant exposure. Furthermore, local delivery of fulvestrant significantly decreases cell proliferation, as assessed by Ki67 expression, most effectively in tumor sections adjacent to tubing. This approach may thereby introduce a potential paradigm shift and offer a promising alternative to systemic therapy for prevention and early interception of breast cancer.
Highlights
Breast cancer continues to impact the lives of many women
Raloxifene, a newer selective estrogen receptor modulator (SERM), with similar benefits to tamoxifen has been approved for prevention but is limited to only postmenopausal women
We provide evidence that implantable silastic tubing can be used for long-term controlled release of fulvestrant at therapeutic concentrations sufficient to inhibit estrogen receptor signaling activation and induce apoptosis in breast cancer cells in vitro
Summary
Breast cancer continues to impact the lives of many women. Over 250,000 women are diagnosed with breast cancer each year and more than 40,000 will die from the disease in 20171. Approved breast cancer prevention strategies are limited They include risk-reducing surgery, such as bilateral mastectomy and oophorectomy, or systemic treatment with anti-estrogens such as tamoxifen. The pro-estrogenic effects of tamoxifen in non-breast tissues, present significant increased risk for endometrial cancer, and strokes are a discernible risk in older women. The limited acceptable choices for breast cancer prevention strategies in an increasing number of young women emphasize a strong need for other options. Anti-estrogens delivered locally to the breast would be a promising alternative to current breast cancer prevention measures with the hope of eliminating or delaying the need for surgical interventions, such as prophylactic mastectomies, or reduce the impact from adverse side effects of systemic treatment. The goal of localized treatment is to effectively deliver the active drug to the appropriate tissue and maintain the desired therapeutic spatial distribution of the drug while minimizing systemic exposure
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