Johns Hopkins Kimmel Cancer Center researchers are studying whether delivering chemotherapy drugs directly to breast "plumbing" might make treatment of early breast cancer easier on the patient and at least as good as surgery or radiation.
A report on successful tests of intraductal therapy in rats and mice published in the January 15 issue of Cancer Research has paved the way for one of the first preliminary clinical trials in women with breast cancer, currently under way in women with breast cancer scheduled for a mastectomy at Johns Hopkins.
For more than a decade, researchers have been studying how to diagnose breast cancer earlier by extracting fluid from the vast network of tiny milking-producing ducts in the breast. The idea is based on the finding that most breast cancers sprout from cells lining the milk ducts. This same idea led Kimmel Cancer Center researcher Saraswati Sukumar, Ph.D., to explore the possibility of treating early breast cancers by using hair-thin catheters to inject chemotherapy through openings at the nipple directly into the place where they started - the milk ducts.
Sukumar likens the procedure to pouring detergent down the kitchen sink to rid the pipes of unwanted material. Because early breast cancers are less likely to have escaped the ducts, intraductal therapy may have at least as good a chance to cure as radiation or surgery.
"We'd like to develop a treatment option for early breast cancers that minimizes disfigurement and spares normal tissues," says Sukumar who is the Barbara B. Rubenstein Professor of Oncology at Hopkins' Kimmel Cancer Center.
Standard treatments for early breast cancer, called ductal carcinoma in situ (DCIS), include radiation and surgery to remove the tumor via a lumpectomy or mastectomy. Chemotherapy, reserved for disease that has spread beyond the ducts, is not typically used to treat DCIS because conventional methods of delivering the drugs through an arm or chest vein would unnecessarily send the toxic chemicals coursing throughout the entire body.
"We found that, in animal models, injecting chemotherapy into the milk ducts confines most of the drug to the breasts, leaving other tissues unharmed," says Sukumar.
Building on observations made by her lab on rat models using drugs that block estrogen, Sukumar began tests in mouse models three years ago by using a chemotherapy drug called doxorubicin. The mice were bred to develop breast cancers that were genetically similar to treatment-resistant ones in humans.
First, researchers injected mice that had palpable tumors with a slow-release formulation of low dose doxorubicin directly into their mammary ducts. At the end of the observation period, this group had tumors less than half the size of those receiving the drug intravenously. Then, the scientists increased the drug dose, and, initially, tumors in both groups remained small. But that changed when 56 days later, tumors in the IV group ballooned - almost as large as control mice getting no treatment - while tumors in the intraductal group fared much better. Eight of 10 tumors in the intraductal group disappeared in 20 days. Some of the tumors grew back, but remained small compared with the IV group. At the end of the 91-day study period, four of the 10 tumors had not come back.
Sukumar also believes that injecting chemotherapy agents or prevention drugs like tamoxifen into the breast ducts could be one option for women at high risk for the disease.
To test this premise, her team injected doxorubicin via IV or intraductally into 40 mice bred to develop breast cancer. Control mice received injections of saline or no treatment. Mice receiving IV therapy were twice as likely to develop breast cancer (32 tumors in 170 mammary glands) than those receiving a single intraductal dose (13 tumors in 196 glands). Increasing the number of intraductal injections to two per mammary gland completely protected all 10 mice (100 glands) from developing the cancer while all intravenously treated mice succumbed to the disease. The scientists found similar results using a derivative of tamoxifen in rat models.
Phase I studies in breast cancer patients have begun to test the feasibility and safety of the procedure. Among the potential side effects that Sukumar's team, headed by Vered Stearns, M.D., breast cancer specialist at the Kimmel Cancer Center, will be studying in the trial are pain, inflammation, and changes in the structure of the duct network. Other areas for study include image-guided injections that could be rigged as "duct-detectors" to help pinpoint early lesions, as well as different chemotherapy drugs and dosing schedules.
More than 200,000 cases of breast cancer are diagnosed in the U.S. annually. DCIS accounts for 20 - 40 percent of these cases, according to researchers.
This research was funded by the American Cancer Society, Department of Defense, Susan G. Komen Foundation and NIH/National Cancer Institute.
Additional authors include Satoshi Murata from the Shiga University of Medical Science; Scott Kominsky, Mustafa Vali, Zhe Zhang, Elizabeth Garrett-Mayer, Dorian Korz, David Huso, Sharyn D. Baker, James Barber, Elizabeth Jaffee, and R. Todd Reilly at Johns Hopkins.
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