Because most breast cancers arise from ductal epithelial cells, enormous opportunities exist in targeting therapy directly into the ductal system. Additionally, intraductal therapy is less likely to cause systemic toxicity and adverse effects. Currently, there are a number of phase 1 feasibility and safety trials evaluating the intraductal approach to breast cancer prevention and treatment.
Current clinical trials are based on intriguing initial animal studies by Murata et al. [40
] that involved intraductal administration of the active tamoxifen metabolite 4-hydroxytamoxifen (4-OHT) and pegylated liposomal doxorubicin (PLD) into transgenic mouse models of breast cancer. Results from the study demonstrated that not only was the intraductal administration of chemopreventive or chemotherapeutic drugs significantly more effective in preventing tumor development and promoting tumor regression, but there were also lower circulating levels of the agents and, as a result, no evidence of systemic toxicity. 4-OHT was found to be as effective as subcutaneous tamoxifen in the prevention of tumors, and intraductal administration of PLD caused complete regression in 24 of 25 tumors with a tumor-free 3-month follow-up period. PLD was also found to be protective against tumor formation. Toxicity studies showed no myelosuppression and peak levels of drug were significantly lower for intraductal versus intravenous injection.
As a result of the encouraging efficacy and safety data from these animal studies, a number of clinical trials are being conducted to explore the possibility of intraductal therapy in humans, primarily in the setting of DCIS or early-stage invasive cancer. Stearns et al. [41
] at Johns Hopkins University School of Medicine have completed a phase 1 trial to determine the feasibility, safety, and maximum tolerated dose of PLD administered into one duct of women awaiting mastectomy. Preliminary data reveal that doxorubicin concentrations were not detectable in plasma, nipple aspirate fluid, or breast tissue [41
]. Although histologic findings have not yet been reported, the safety of this intervention in women awaiting surgery for cancer appears promising.
In a similar Phase 1 study, Love and colleagues [42
] conducted a dose-escalation study in Beijing, China to determine safety and evaluate histopathologic response to either intraductal carboplatin or PLD instilled into 5 to 8 ducts in 32 women 2 to7 days prior to mastectomy for breast cancer. Three dose levels were used, with the highest level approaching the dose used intravenously. At the highest doses of PLD, patients experienced tenderness and mild erythema and breast swelling, but no serious adverse events were noted. In the carboplatin group, both inflammatory responses and epithelial changes increased in a dose-dependent fashion. In the PLD group, no inflammatory changes were seen, but there was a marked increase of epithelial response to PLD treatment compared with the carboplatin-treated patients, including epithelial attenuation in the terminal ductal-lobular units (Fig. ).
Fig. 2 Mastectomy specimen in a patient treated with intraductal pegylated liposomal doxorubicin (PLD). All patients in the study underwent surgery 2 to 5 days following PLD administration. Cannulated ducts were concurrently injected with dye to enable (more ...)
In a study directly targeted to test the practicality and efficacy of intraductal PLD treatment for DCIS, Love and Mahoney [44
••] are testing intraductal PLD in the neoadjuvant setting. In patients with core biopsy-proven DCIS, 20 mg of PLD (10 cm3
) is injected intraductally followed by a 6-week observation period before scheduled surgery. The study end points are regression of the lesion on surgical pathology, decreased markers in ductal fluid, and changes on MRI before and after treatment. Thus far, four patients have received the full drug dose into the duct harboring DCIS, with two women reporting mild to moderate breast inflammatory reactions that responded to anti-inflammatory medications. Initial evaluation of histology of surgical specimens has confirmed a tissue response of inflammation, squamous metaplasia, and fat necrosis [44
••]. This trial continues to accrue patients, and the investigators plan to collect data on tissue markers in the DCIS as well as in the cell pellet specimens collected at the time of PLD injection. Although women in this study will undergo surgery, the long-term implications of the trial may be to facilitate future treatment of DCIS with intraductal therapy alone. In addition, if this approach is effective in stripping cancer precursor cells from the ducts, intraductal injection of ablative agents in unaffected, high-risk women may allow for true loco-regional chemoprevention.