Breast canal treatment for early breast cancer

image: Dr. Guannan Wang performs an intraductal injection under a microscope
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Administration of a targeted immunotoxin into the mammary ducts via openings in the nipple eliminated all visible and invisible precancerous lesions in laboratory studies conducted by researchers from the Johns Hopkins Kimmel Cancer Center, breast cancer at a very early stage.

A description of the work done in mice, which the authors believe provides a strong preclinical basis for conducting feasibility and safety trials with patients with stage 0 breast cancers, is published in the June 8 issue. of the magazine Proceedings of the National Academy of Sciences.

Stage 0 breast cancer, also known as ductal carcinoma in situ (DCIS), is characterized by the presence of abnormal precancerous cells inside the milk ducts of the breast and affects approximately 69,000 women each year in the United States. -United. Many women undergo breast removal surgery and radiation treatments for these very early cancers, and in some cases they receive chemotherapy or hormone treatments, says the study’s lead author. Saraswati Sukumar, Ph.D.professor of oncology and pathology at Johns Hopkins.

“In our research, we have proposed an alternative treatment in which injecting the drug immunotoxin through the duct could result in the clearing of DCIS,” says Sukumar. “To our surprise, the drugs killed all the lesions present in this mammary duct. I had never seen such dramatic results in my life.

During their investigations, the researchers first evaluated the cell-killing effects of HB21(Fv)-PE40, a targeted immunotoxin, in four cell lines of different molecular subtypes of breast cancer. The toxin consists of HB21, a monoclonal antibody – a protein that can bind to a specific target (in this case, the human transferrin receptor, a carrier protein found in breast cancers). HB21 is fused to PE40, a fragment of a bacterial toxin that shuts down protein production in cells and leads to cell death. The results showed that the treatment induced potent anti-cancer effects on all cell lines. The researchers also administered the treatment to about 10 mice to test for toxins circulating in the blood after treatment, and found no toxins five to 30 minutes after injection.

Next, they injected HB21(Fv)-PE40 into the mammary ducts of two mouse models of DCIS: MCF7 and SUM225. In MCF7 mice, the treatment was given once a week for three weeks. The treatments were monitored by non-invasive imaging. To compare, they also administered the treatment into the body and delivered the HB21 antibody alone into the ducts of some mice. Both models represented all classifications of common types of human breast cancers: estrogen and progesterone receptor positive and human epidermal growth factor 2 (HER2) receptor negative, estrogen and progesterone receptor negative and HER2 positive.

In the MCF7 model, those who received treatment injections of toxin into the body had slower tumor growth. However, the tumors recurred after discontinuation of treatment around day 26. In contrast, in the model that received the conduit treatment, the tumors disappeared within two weeks of completing two of the three treatments, and no recurrence was detected by imaging even after 61 days.

On day 32, investigators performed pathological examinations of the mammary glands – two from each group. They found that tumor cells were absent and the architecture was consistent with normal mammary glands. A similar analysis of samples remaining after 61 days showed invasive tumors in the model receiving only HB21, small tumors in those treated in the body cavity, and no tumors in those receiving the toxin treatment through the ducts.

In the SUM225 model, a pilot experiment with toxin treatment showed tumor clearance as early as two weeks of treatment, as seen by imaging. No recurrence was observed until the end of the experiment on day 48. A second experiment tested the same dose and a dose of 1/10th of the treatment, as well as the HB21 antibody alone, in certain samples. The majority of mammary glands were tumor-free after full intraductal treatment, with weaker effects seen with the lower dose. SUM225 tumors have been found to grow aggressively in the conduit location. Pathological studies demonstrated that the HB21 antibody alone had little effect, while immunotoxin conjugate treatment showed a significant effect on tumor reduction.

The treatment was well tolerated, with no side effects from the toxin or the injection.

Since most low-grade DCIS will not progress, active surveillance and hormone therapy are recommended, with larger lesions often being treated more aggressively, Sukumar says. “This larger, higher-grade DCIS may be the lesions where intraductal immunotoxin instillation would be most beneficial,” she says. The big advantage is that administering the immunotoxin intraductally allows it to reach all cancerous lesions of the ductal tree, even eliminating those that are not visible on breast imaging.

“A possible clinical study would look something like this,” Sukumar says. “A week or two before surgery, investigators can give women a low dose of HB21(Fv)-PE40 through a single channel and slowly use increasing doses to determine if any immunotoxin is leaking from the channels into the bloodstream and affects liver function. They would also examine the ducts after the breasts were removed to look for changes in the tissues and their effects on precancerous lesions.

The study co-authors were Guannan Wang, Alok Kumar, Preethi Korangath, Priya Pai and Kathleen Gabrielson of Johns Hopkins, Wanjun Ding of RenMin Hospital of Wuhan University, China, and Tapan Bera, Junxia Wei and Ira Pastan of the National Cancer Institute.

The work was supported by the Janine Goebel Fund and the John Fetting Fund for Breast Cancer Prevention.


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