Preclinical and Clinical Evaluation of Intraductally Administered Agents in Early Breast Cancer

Abstract

Most breast cancers originate in the epithelial cells lining the breast ducts. Intraductal administration of cancer therapeutics would lead to high drug exposure to ductal cells and eliminate preinvasive neoplasms while limiting systemic exposure. We performed preclinical studies in N-methyl-N’-nitrosourea–treated rats to compare the effects of 5-fluorouracil, carboplatin, nanoparticle albumin-bound paclitaxel, and methotrexate to the previously reported efficacy of pegylated liposomal doxorubicin (PLD) on treatment of early and established mammary tumors. Protection from tumor growth was observed with all five agents, with extensive epithelial destruction present only in PLD-treated rats. Concurrently, we initiated a clinical trial to establish the feasibility, safety, and maximum tolerated dose of intraductal PLD. In each eligible woman awaiting mastectomy, we visualized one ductal system and administered dextrose or PLD using a dose-escalation schema (2 to 10 mg). Intraductal administration was successful in 15 of 17 women with no serious adverse events. Our preclinical studies suggest that several agents are candidates for intraductal therapy. Our clinical trial supports the feasibility of intraductal administration of agents in the outpatient setting. If successful, administration of agents directly into the ductal system may allow for “breast-sparing mastectomy” in select women.

A Feasibility Study of the Intraductal Administration of Chemotherapy

“…Recent preclinical studies in rats examined intraductal treatment with either cytotoxic agents such as carboplatin, nanoparticle albumin-bound paclitaxel or PLD, or DNA-damaging antimetabolites such as 5-fluorouracil or methotrexate (29). While all drugs tested exhibited some protection from tumor growth, PLD-treated ducts also exhibited a loss of density of ductal outgrowth, and 5-fluorouracil was associated with the greatest antitumor effect.…”

“…These anatomical distinctions underscore the importance of testing the safety and feasibility of intraductal therapy in humans. To that end, Stearns and colleagues recently conducted a clinical trial in which 17 women scheduled for mastectomy for invasive carcinoma were treated with intraductal PLD in one duct per breast (29). Instillation of the drug into the duct was achievable and no serious adverse events were reported, supporting the potential of this approach.…”

“…For example, Okugawa and colleagues showed that rats with N-methyl N'-nitrosourea (MNU)-induced breast tumors exhibited significant reduction in tumor burden and total number of mammary carcinomas when treated with intraductal paclitaxel (27). Similarly, Sukumar and colleagues have shown that intraductal administration of various anticancer drugs, such as pegylated liposomal doxorubicin (PLD), 4-hydroxytamoxifen carboplatin, methotrexate, nanoparticle albuminbound paclitaxel, and 5-fluorouracil was associated with a significant reduction in tumor formation or protected against tumor development in the MNU model, and also minimized the toxic effects of the drugs (28,29). The same group has also shown that in the HER2/neu transgenic mouse (neu-N) model, which spontaneously develops neu-overexpressing multifocal mammary adenocarcinoma beginning at approximately 4 to 5 months of age, intraductal PLD treatment resulted in significantly reduced risk of developing breast tumors.…”

Combining the strength of genomics, nanoparticle technology, and direct intraductal delivery for breast cancer treatment

“…We used i.duc injection of slow-release liposomal doxorubicin (Doxil) to successfully eliminate preneoplasias in both the HER/2 neu transgenic mouse and carcinogen-induced rat mammary tumor models [5] and to delay carcinoma formation by using curcumin [6]. We [7] and others [8] also demonstrated the feasibility and safety of the i.duc approach by using Doxil in women undergoing mastectomy for breast cancer. However, the use of DNA-synthesis-targeted drugs carries the risk of iatrogenic cancer in the distant future.…”

Intraductal Injection for Localized Drug Delivery to the Mouse Mammary Gland

“…Intraductal delivery of chemotherapeutic agents in both breast cancer patients and mouse models has previously been shown to be highly effective with no evidence of systemic toxicity or long-term histopathological changes [3][4][5][6] . Furthermore, tumor cell injection and lentiviral vector delivery of oncogenes have been shown previously to be feasible via intraductal injection [7][8][9][10] .…”