Research ArticleBreast Cancer

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

Science Translational Medicine  26 Oct 2011:
Vol. 3, Issue 106, pp. 106ra108
DOI: 10.1126/scitranslmed.3002368

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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.

Footnotes

  • * These authors contributed equally to this work.

  • Present address: Department of Surgery, Shiga University of Medical Science, Seta, Tsukinowa-cho, Otsu, Shiga 520-2192, Japan.

  • § Present address: Cancer Center of the Rockies, 2121 East Harmony Road, Suite 150, Fort Collins, CO 80528, USA.

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