Intraductal Therapy of DCIS: A Presurgery Study

Institution: Dr. Susan Love Research Foundation
Investigator(s): Susan  Love , M.D., M.B.A. -
Award Cycle: 2007 (Cycle 13) Grant #: 13OB-0185 Award: $851,559
Award Type: Translational Research Award
Research Priorities
Innovative Treatments>Gene therapy and other treatments: new frontiers



Initial Award Abstract (2007)

Ductal Carcinoma In Situ (DCIS), an early stage, non-invasive breast cancer, is treated with the same methods of surgery, radiation and hormone medications as more advanced forms. Historical studies show that most DCIS remains dormant and only 30-40% of cases will ever progress to invasive cancer. As more women are being diagnosed by mammography with this pre-cancer, which is not life-threatening, they are asking why they should be subjected to the more extreme treatments. The breast ducts are the microscopic pipelines that bring milk down to the nipple during breast feeding. Breast cancer starts in the epithelial cells that form the thin lining on the surface of the ducts, like tiles. With advances in technology it is possible to enter the duct system through the nipple and by procedure called ductoscopy to visualize the interior of the duct system. As an extension of this “intraductal approach” it is possible to introduce drugs or other agents into the duct system to destroy or reset the abnormal cells that are present in women bearing DCIS lesions. This novel treatment strategy may eventually save countless women from undergoing mutilating surgery and debilitating treatments.

The aim of this project is to test the practicality and efficacy of a local treatment of the affected breast duct itself. We plan to use a currently approved drug, called Pegylated Liposomal Doxorubicin or PLD, by introducing it directly into the ductal system bearing DCIS lesions. In preliminary studies, our collaborators have tested this drug in rodents and humans for side effects. In rat studies, the intraductal administration of PLD can eradicate breast cancer at low doses and without the systemic side-effects seen with treatments administered via the IV (blood) route. Preliminary studies have shown that intraductal PLD is well tolerated in women, but we do not have studies demonstrating efficacy in treating DCIS.

In this study, women who have been diagnosed with DCIS on the basis of an abnormal mammogram and a biopsy (a stereotactic core) done by the radiologist will be referred to our trial. A breast PET scan and ductal lavage will be done before the treatment for a baseline. The woman will then have the duct with DCIS cannulated and a small amount of contrast material will be placed to make sure the correct duct is being treated. Then, the PLD will be introduced into the duct. Surgery will be planned for 4-6 weeks later. A day or two prior to surgery imaging tests, such as mammography and PET scans, of the breast will be repeated. The type of surgery to be done will not be affected by participation in the study. After surgery, the pathology will be studied and the women followed by their breast surgeon for at least two years, as usual. If indicated, patients will be referred for consultation with medical and/or radiation oncologists.

This will be the first observational study of intraductal therapy. It can open a new era in the management of breast cancer, especially the earliest DCIS stages where women are typically over-treated.




Final Report (2012)

Ductal Carcinoma in Situ (DCIS), is an early stage, non-invasive breast cancer where the cells are still confined within the limits of the milk duct. While less than half of the cases of DCIS will progress, an increasing number of women diagnosed with this disease are still being treated with the more drastic methods of surgery, radiation and hormone medications. This translational grant was funded by CBCRP to examine the safety and feasibility of injecting an approved chemotherapy drug (Pegylated Liposomal Doxorubicin or PLD) directly into the breast duct. This drug was chosen because in preliminary studies, PLD was well tolerated in women but we did not have studies demonstrating its effectiveness in DCIS. A total of 13 women participated in this study and 7 women received the medicine in their breast duct. Recruitment was stopped in this study until more information from a study at Johns Hopkins University in which PLD was used in mice could be reviewed. Because of the results of the study using mice, the Data and Safety Monitoring Board and Principal Investigators agreed to stop recruiting women for this study. It is important to note that the women in our study did not report any bad experiences after receiving PLD. Another barrier encountered was that when the doctor injected the medication into the duct, the duct collapsed in 6 women. This could be because DCIS makes the lining of the duct more fragile. The investigators still believe that this method of delivery should be explored in a larger study with a different medicine and that this direct delivery method could be a promising treatment for DCIS. We have been examining the data that was collected on these 13 women, specifically looking at MRI data, pathology information and mammography images from the 7 women that received the medication in their ducts. While we recruited less than the 30 women that we originally had planned to enroll, we did meet some specific aims of the study. Specifically, we believe that drugs to treat DCIS can be delivered directly into the breast duct, although we now know because of our study that PLD should not be one of the drugs considered for future studies.




Symposium Abstract (2010)

Susan M. Love, M.D.,F.A.C.S.; M. Ellen Mahoney, M.D., F.A.C.S.; Dixie J. Mills, M.D.,F.A.C.S.;  (Dr. Susan Love Foundation)

Background: Previous animal models have demonstrated the effect of intraductal administration of cytotoxic agents in treating and preventing breast cancers originating in the epithelial cells. Two human safety trials have been conducted with women undergoing mastectomies. This study will test the safety and feasibility of this approach neoadjuvantly in women with ductal carcinoma-in-situ.

Methods:Thirty women with (DCIS) diagnosed by minimally invasive biopsy techniques are being recruited for an IRB approved study testing the effects of neoadjuvant pegylated liposomal doxorubicin (Doxil) delivered through the affected duct on histology and imaging. The affected duct is cannulated and a ductogram performed to document both absence of perforation and presence of dye in the diseased duct. 20 mg (10 cc) of Doxil is then instilled into the duct. Six weeks later, just prior to the planned surgery, the MRI is repeated. Biomarkers are being examined in the cores and surgical tissue, pre and post injection.

Results:To date fourteen women have consented to the study. The first was not treated because of technical difficulties with the ductogram. Of the remaining thirteen women, three sustained perforated ducts and were not treated, in two women we were unable to cannulate the duct; five received the full dose of drug into the correct duct and one had a smaller dose into an adjacent duct, the seventh woman had a placebo dose of saline injected. The treatment has been very well-tolerated by all 7 subjects, with only some pain and local erythema noted. Pathology results have shown some decrease in mitotic activity, squamous metaplasia, fat necrosis and inflammation. Biomarker changes are being analyzed.

Challenges:The rural setting of this study has on the one hand limited recruitment while serving as a source of pride to the community as a whole with substantial support from local clinicians and the work maintains high visibility. The fact that this study has been successful in a community setting is evidence of the translatability of the concept. The approach is acceptable to women and appears to be well tolerated.

Summary: This research is feasible in a community setting. We are testing the concept of using the ductal system itself as a drug delivery system to affect the natural history of a disease confined to the duct. We are testing our ability to correctly identify the orifice of the affected duct by inspection of the mammogram. The treatment appears to be well-tolerated by the patients.



Intraductal therapy of ductal carcinoma in situ: a presurgery study.
Periodical:Clinical Breast Cancer
Index Medicus:
Authors: Mahoney ME, Gordon EJ, Rao JY, Jin Y, Hylton N, Love SM.
Yr: 2010 Vol: 13 Nbr: 4 Abs: Pg:280-286

Status of Intraductal Therapy for Ductal Carcinoma in Situ
Periodical:Current Breast Cancer Report
Index Medicus: Curr Breast Cancer Rep.
Authors: Flanagan M, Love S, Hwang ES.
Yr: 2007 Vol: 2 Nbr: 2 Abs: Pg:75-82