Abstract CN13-03: Intraductal route of breast cancer prevention and therapy: from preclinical studies to Phase I trials
Authors: Sukumar Saraswati , Stearns Vered , Khouri Nagi , Jacobs Lisa , Jeter Stacie , Powers Penny , Rudek Michelle , Gabrielson Edward , Zhang Zhe , Tsangaris Theodore 
Published: May 2012

Abstract
CN13-03
We hypothesized that it is possible to prevent and treat breast cancer by accessing the mammary ductal network through the teat. This intraductal approach, which delivers a high dose of drug locally to the tumors but a low dose systemically, could be an alternative approach to therapy and prevention of breast cancer.
Our previous work has demonstrated the effectiveness of intraductal administration of pegylated liposomal doxorubicin, (PLD) and 4-hydroxytamoxifen (4-OHT) using the rat N-methyl N’-nitrosourea (MNU)-induced and the spontaneous, HER2/neu transgenic mouse (neu-N) models of breast cancer. 4-OHT had a preventive effect in the rat MNU-induced models, and PLD had a preventive and therapeutic effect in both the rat and Her2/neu transgenic mouse models (Murata et al, Cancer Res. 2006). Recently we evaluated the effectiveness of other drugs such as carboplatin, methotrexate, Abraxane, 5-Fluorouracil and PLD by whole mount analysis of the treated mammary glands, histopathology following H&E staining, and immunohistochemistry for the proliferation marker, Ki67. We found that carboplatin, 5FU and PLD-treated groups showed significant protection in the prevention setting. PLD had long term effects on the mammary gland structure and function in treated rats and mice. In response to pregnancy, significantly reduced proliferation and milk production was observed in PLD treated Her2/neu mice compared to vehicle treated mice. The litter size and weight at birth were normal in the PLD treated group. Notably, unlike the control group, the PLD-treated Her2/neu transgenic mice remained protected from spontaneous tumor development despite exposure to vast hormonal modulations inherent to pregnancy.
Based on the preclinical findings, we initiated a clinical trial to determine the feasibility, safety, and maximum tolerated dose of PLD administered into one duct of women with breast cancer awaiting a mastectomy. PLD was administered using a dose escalation schema based on our preclinical pharmacokinetic and safety data. Serial doxorubicin and doxorubicinol concentrations were determined in plasma and tissue by LC/MS/MS. At the time of mastectomy, blue dye was injected into the treated duct and tissue was obtained for pharmacokinetic and biomarker analysis. To date 14 women entered the study, and doses of 0 to 10 mg PLD per were tested without serious adverse events. Intraductal PLD was associated with a dose-dependent increase in both systemic and local exposure to doxorubicin and doxorubicinol. Neither doxorubicin nor the metabolite was detected in contralateral breast tissue. Doxorubicin and doxorubicinol were detectable in the breast tissue and plasma of women receiving the highest dose (10 mg/duct). Systemic exposure (in plasma) was lower than with conventionally administered PLD. No inflammatory or morphological changes were seen in the breast tissue. The study established safety and feasibility of administering PLD in an outpatient setting. Higher doses of PLD will be tested to achieve the maximum tolerated dose. Future studies will evaluate other agents administered to one or more ducts.
In summary, these approaches may find particular use in treatment of DCIS as a safer alternative to surgery, and prevention of breast cancer in women at high risk of developing breast cancer due to inherited mutations or other factors. High local, but low circulating levels of drug, and thereby lower systemic toxicity are the major advantages of the ductal access to breast cancer treatment. This study demonstrates that intraductal injection provides more direct access to breast lesions, and has potential in the prevention and neo-adjuvant therapy of breast cancer.
Citation Information: Cancer Prev Res 2008;1(7 Suppl):CN13-03.