Drugs via nipple treat breast cancer
JOHNS HOPKINS (US) — A better route for delivering drugs to fight early breast cancer may be the most direct: through the nipple.
The nipple approach has proven highly effective in rats, both in eliminating cancers and in preventing tumors from forming, Johns Hopkins University researchers say. Early safety tests in human patients revealed no major side effects.
The encouraging results, published in Science Translational Medicine on Oct. 26, are expected to lead to more advanced clinical trials of the so-called intraductal treatment for early breast cancer.
“Our results support the theory that, by treating the breast tissue directly, we can reach a much more potent drug concentration where it is needed, with far fewer adverse effects on tissues outside the breasts,” says oncologist Vered Stearns, co-director of the breast cancer program at the Kimmel Cancer Center. She supervised the clinical part of the study.
Saraswati Sukumar, who supervised the animal tests and co-directs the breast cancer program with Stearns, began intraductal research more than a decade ago. Because most breast cancers originate from cells lining the milk ducts, she reasoned, early or preventive therapies should be delivered directly to the ducts via the nipple rather than intravenously.
In 2006, Sukumar and her colleagues reported on an initial successful test of the technique using the chemotherapy drug doxorubicin against early ductal breast cancers in rats.
For the current study, Stearns set up a small clinical trial to assess Sukumar’s technique in 17 breast cancer patients. Starting first with dextrose—essentially sugar water—and later using escalating doses of the same formulation administered to Sukumar’s rats, she infused patients’ breast ducts via a small catheter placed into the nipple.
The technique wasn’t used in this case to treat the cancer; the patients in the study all had established breast tumors and were awaiting mastectomies. But Stearns was able to show that single doses of pegylated liposomal doxorubicin, or PLD, delivered to breast ducts caused only mild side effects, including mild nipple pain and breast fullness.
A comparison of 12 patients receiving PLD intraductally with three patients treated with PLD by the standard intravenous route also was revealing, Stearns said.
“Intraductal delivery of PLD resulted in much higher concentration in the breast compared to the circulation, whereas in the women with intravenous doses we saw relatively high concentrations in the blood but very little, if any, in the breast,” she says.
In the animal portion of the new study, Sukumar’s lab examined the intraductal effectiveness of four standard anticancer drugs, 5-fluorouracil (5FU), carboplatin, methotrexate and paclitaxel, all compared with PLD. Of these drugs, intraductal 5FU prevented the most cancers compared to no drug or to intravenous delivery. It also shrank established breast tumors with striking effectiveness, completely eliminating them in 10 of 14 treated rats, she says.
“As both a preventive and a therapy, 5FU worked extremely well in these tests,” Sukumar adds.
5FU has the additional advantage, she notes, of sparing breast ducts the kind of damage caused by PLD, which at therapeutic doses can destroy large parts of the ductal lining. But perhaps the most intriguing outcome of these tests, she said, was that preventive treatment of only four mammary glands in rats—which have a total of 12—showed a strong effect in preventing tumors in the untreated glands as well.
“We think that 5FU, at the high concentration achieved with intraductal delivery, elicits an immune response that can suppress tumor formation in the other ducts,” Sukumar says. “This is an attractive feature, because some breast ducts in women are ‘blind ducts’ that are unconnected to the nipple and, therefore, unreachable directly with intraductal therapy.”
Sukumar and Stearns say the next step is to set up a further clinical study with 5FU. The goal is to use intraductal therapy to suppress tumors in patients with a high genetic risk for breast cancer or premalignant lesions in their breast ducts.
“In principle, one could do such a procedure every 10 years or so to keep one’s breasts tumor-free, as an alternative to having the breasts removed,” Sukumar says.
The study was funded by the National Cancer Institute, Windy Hill Medical Center, the Mary Kay Ash Foundation and the Susan Love Research Foundation. Other contributors, besides Sukumar and Stearns, included co-first author Tsuyoshi Mori, now at the Shiga Institute of Medical Science in Japan.
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