Cancer is a disease of excess. Cells become malignant when they lose the signals that tell them to stop growing and dividing; therefore, the cells most susceptible to becoming cancerous are those that are already used to proliferating. Whereas most neurons last a lifetime, epithelial cells (found in the skin as well as intestinal and ductal linings) replicate often: the skin is renewed every two months and intestinal epithelium every 3-6 days. Due to this rapid growth, as well as the fact that these cells are more often exposed to chemical or physical damage, 80-90 percent of human malignancies originate from epithelial cells (think about skin cancer) and are referred to as carcinomas.
The same is true of breast cancers, which frequently arise from mutations in the epithelial cells lining the lactiferous ducts that connect the mammary glands to the skin surface, i.e. nipple. Treatment options often are limited to removal of the breast (prophylactic mastectomy) or years of estrogen therapy (e.g. tamoxifen). The problem with the latter option is that it affects the whole body and commonly leads to negative side effects such as nausea, blood clots, stroke, and uterine cancer.
A new treatment option may soon be available thanks to the work of an interdisciplinary team of clinicians and bench researchers at the Johns Hopkins School of Medicine. Led by the directors of the Hopkins Breast Cancer Program, Vered Stearns and Saraswati Sukumar, the team hypothesized that “administration of agents directly into the breast ductal system through the nipple (intraductal) could prevent the development of new tumors or the progression of preinvasive neoplasms.” Following tests of this theory in both an animal model and phase 1 clinical trial, their promising results are summarized well in the Editor’s note preceding their paper in Science Translational Medicine:
The authors first tested intraductal treatment with five different chemotherapeutic agents, including paclitaxel and doxorubicin, on rats with mammary tumors, at doses comparable to what might be used in the clinic in actual patients. Compared to saline-treated or untreated control animals, the rats treated intraductally had fewer tumors in the mammary glands, with minimal side effects. Stearns et al. then enrolled 17 women in a phase 1 clinical trial to examine intraductal treatment using one chemical agent, pegylated liposomal doxorubicin. Their localized delivery to the breast ducts resulted in considerably lower systemic concentrations of the drug compared to intravenous administration, suggesting that the intraductal approach is a less toxic alternative to standard chemotherapy. This clinical trial also indicates that approved agents can be delivered to the breast ducts in an outpatient setting. Longer-term studies in more women will be necessary to determine the efficacy of intraductal chemotherapy.
According to the press release from Johns Hopkins:
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 ten years or so to keep one’s breasts tumor-free, as an alternative to having the breasts removed,” Sukumar says.
We had the opportunity to correspond with both researchers and asked them about their current experiments and how the technology may be applied in the clinic:
Shiv Gaglani, Medgadget: According to the press release, the next step is to set up a clinical trial with the chemotherapeutic agent you used, 5-fluorouracil (5-FU). Can you discuss the progress of this and/or other current experiments that you are working on related to intraductal delivery of breast cancer drugs?
Sukumar: In the current study, we had considerable success with both prevention of preneoplastic lesions and therapy of established mammary tumors in rats using 5-FU administered through the nipple opening or in other words, by the intraductal route. Interestingly, it appeared that even if you treat only 4 of the mammary glands on one side of the animal, the remaining 10 mammary glands of the rat were afforded considerable antitumor protection. Following up on this observation, Dr.Tsuyoshi Mori, a surgeon working in my laboratory collaborated with Dr. Yoshimura, a cancer immunologist also in our cancer center, to find out whether immune mechanisms were involved in preventing tumors in the untreated glands. In unpublished early work they observed that immune cells were activated as a result of intraductal treatment with 5-FU and could possibly account for the reduced tumor development in the uninjected glands. Additional work is ongoing to substantiate these observations. Our currrent experiments are also directed towards determining safety and efficacy of 5-FU in the long term, and to test slow release formulations of novel and known drugs.
Medgadget: How do you foresee intraductal therapy being applied (e.g. bolus injection, constitutive/regulated implantable pump, etc)? Are there any devices that have been made specifically for ductal delivery?
Stearns: Ideally, a woman will come in for a mammogram and if at high risk or diagnosed with a pre-malignant lesion will have the intervention. We envision that the drugs will be given over a few minutes in an outpatient setting. I am hopeful that such a procedure can be accomplished every few years.
Sukumar: We foresee bolus injection of a slow release formulation that would allow exposure of the epithelium to the drugs over a period of time, rather than have it escape into the circulation because of the small size of the molecules. Much like endoscopy of the colon prescribed every 5 years, intraductal treatment every 5-10 years could clear the ducts of any new outgrowths and thereby serve as a preventive strategy for breast cancer.
Devices are currently under development. In the published study, catheters already in use for performing ductography were used.
Medgadget: Do you foresee this being applied to treat males with ductal carcinoma/breast cancer?
Sukumar: Yes, the ductal tree in men is the same as women, although very rudimentary. The tumors also appear most often in the epithelial cells lining the duct. So yes, an identical approach will be applicable to men and women.
Stearns: One caveat: because breast cancer is rare in males and there is no adequate screening test, most are diagnosed with invasive breast cancer, a setting that requires systemic therapy. Therefore intraductal therapy may not be as useful in males as it may be in females.
Science Translational Medicine article: Preclinical and Clinical Evaluation of Intraductally Administered Agents in Early Breast Cancer
Johns Hopkins Press Release: Through-the-Nipple Breast Cancer Therapy Shows Promise in Early Tests