WEDNESDAY, NOVEMBER 10, 1999
"Breast Nipple Aspirate Analysis: A Window to Breast Cells, Risk of Cancer and Response to Preventive Measures"

There has been great interest in today's topic. Looking at cells can give you a window onto breast health. If you can find atypical cells before they become cancerous it gives you a lead time for treatment. The best example of this is the pap smear which has cut the mortality rate from cervical cancer by 90%.

Dr. Susan Love, internationally known breast surgeon, researcher, author, and lecturer was our guest for the evening. She has been working for a long time on looking at the fluid that comes out of the nipple. The breast has glands that surround a series of 6 to 8 ducts which function to carry the milk to the nipple. Ninety percent of all breast cancers arise from the lining of the ducts. Early researchers including Nick Petrakis have looked at nipple fluids for the last 25 years. He began an enormous body of work looking at cells from different body fluids that looked atypical. He found that if you had atypical cells in nipple aspirate fluid your chances of developing breast cancer were 4 to 5 times higher. Researchers from Berkeley and Santa Barbara have had similar findings.The problem was that extracting the fluid from the nipple has been extremely cumbersome.

For the last 10 years Dr. Love has been focusing on DCIS (ductal carcinoma in situ). She felt that rather than just remove a breast lump, one should find the duct the generated the abnormal tissue, and remove it as well. Dr. Helene Smith, a molecular biologist at UCSF and herself a breast cancer patient, found that if there were molecular changes in the tissue near the DCIS, the risk of recurrence was much higher. This supports the idea that when something is wrong, the whole duct is at risk. Dr. Love decided to concentrate her area of study to accessing the ducts. This is important in diagnosis, for anatomically localizing a lesion, and to use as gene therapy to eliminate the "bad duct". We must find a way to see which cells are "thinking about" becoming cancer before they are too far along, because by the time you can see breast cancer on a mammogram or you can feel it, it has been there for 8 to 10 years. We need the type of screening procedure we have for cervical cancer, so that we can screen patients and identify problems and reverse them before they become cancer.

Because all breast cancers start in the ducts, it is necessary for us to find an easy way to access these cells in order to prevent cancer. Dr. Love started by putting a small scope into the ducts when women were asleep during mastectomy. She couldn't get very far because the duct pathway breaks up into small branches very quickly. She then thought that instead of biopsy she would try to "wash out" the cells that were in the duct. Over the years different methods were tried, but she has now come up with a catheter that works well. She determined that the pattern of holes in the nipple was three dimensional, and that each nipple contained about 6-8 holes (three in the middle, and 3-4 around the perimeter). A single duct starts with a small duct which goes into a lacteriferous sinus and then breaks up into branches which end in lobules. The catheter only needs to be inserted about 1/2 cm., just up to the sinus. Saline is injected, and this fluid is then drawn back. This method allows all cells to be washed out of the duct. Thousands of cells can be extracted in this manner. In the older method, a suction cup was placed over the nipple, and only a few drops of fluid were obtained. The new procedure is not painful, but novocaine is used to numb the nipple. Clinical trials are now going on at 11 sites in the United States, including UCSF. Fifty patients have already been tested. Cancer was actually found in one patient with a normal mammogram. What is hoped is that we will be able to provide a diagnosis of precancer, before cancer has had a chance to develop. The duct can be seen as a pipe and the cells that first develop along the lining are like "rust", pathologists call this hyperplasia (too many cells). When these cells get "funny looking", it is termed atypical hyperplasia. When the cells get more atypical, but are still confined within the duct they are termed ductal carcinoma in situ (DCIS). When they break out of the duct into the fat, you have invasive or infiltrating ductal carcinoma, or what we commonly call breast cancer. The aspiration technique will allow us to find the precancer, before DCIS, when it is reversible. The method for reversal could include tamoxifen. In the tamoxifen prevention trials, patients with atypical hyperplasia who took tamoxifen had an 88% decrease in their chances of developing cancer. At the very least this will give us additional individual information to add to the statistical information we already have about breast cancer and risk.

This trial (Duct Lavage Study-Windy Hill) is a first step, using the catheter for finding the ducts and taking fluid from the breast. Once the procedure is established, patients' ducts can be washed. If the cells are positive, a treatment can be administered and then a further extraction at 3 or 6 months can test the efficacy of the treatment. This would eliminate the 5 or so years we now need to spend in prevention trials. Another issue is that we do not really know what happens to breast fluid when women are not nursing. It is possible that evironmental elements like pesticides get caught in the breast duct and sit there, potentially contributing to changes in the cells. It may turn out to be positive to have your ducts washed out periodically. The most important thing will be to get in before breast cancer develops and stop it from happening. Those eligibile for the study include high risk women (according to the Gail index), and women who have had cancer in one breast and are off tamoxifen. The trial is low risk, and anyone over 18 who meets the criteria can be involved. Currently there are 5 other high risk trials open. One is looking at tamoxifen vs. soy vs. placebo in high risk women. Leah Millheiser was introduced as the organizer of the high risk clinic. She can be reached at (415)353-7560 if you have any questions about the high risk clinic or any of the trials.

QUESTIONS

What is the follow-up if there are atypical cells? The patient's doctor will be notified and all options will be given. The options currently for atypical hyperplasia are for close follow-up or tamoxifen. Surgery is not an option, so the treatment options will not change unless a malignancy is found. At the Breast Center, all patients will get an evaluation, MRI may be used.

Why can't people on tamoxifen be included? Tamoxifen may reduce the amount of atypical cells present in the duct. In this first study we want people who are more likely to have them. This is also true for drugs like Arimidex. Inflammatory breast cancer in one breast will not make you ineligible in the other breast.

If the one examined duct does not show atypical cells, must you check the other ducts? The amount of fluid is positively related to abnormality, so if you check the ducts with fluid, that may be enough, at least for the first study.

Where are the other sites for the study? Dana Farber and Beth Israel in Boston, Johns Hopkins, M.D. Anderson, Baylor, UCLA, Santa Barbara, Menlo Park, as well as Milan, Italy. The cytology is all being read at UCSF.

How frequently can or should this procedure be done? We really do not know because we do not know how long it takes the cell to repopulate, so 2-3 months between procedures is probably not long enough. The procedure can reasonably be done every 6 months to a year. It may be that the only people you want to repeat it on are the women with atypical cells to begin with, remembering that the lowest risk is in women with no cells in their fluid. The treatment should be thought of as similar to colonoscopy, if it is normal, it needn't be repeated for 5 years.

Do you take into consideration the timing in the menstrual cycle? We know that it is affected by hormones, but are not tracking that information. Women are being asked where they are in their cycle and it may be looked at later.

Is there any method to open up the duct to improve access? Several drugs have been tried, but prolactin causes breast cancer in rats and oxytocin nasal spray causes uterine cramps. The safest way is to try to do this without drugs. With practice, it becomes easier to find the ducts.

Could this same procedure work on sentinel lymph nodes? This wouldn't work because the lymph vessels are very fragile and even smaller than ducts. It may not be totally out of the question, but we are certainly not ready to do this yet.

Any way to know if this procedure is damaging to the breast? Normal saline is being used, so no in that sense. If you push isolated atypical cells along they will not reattach in another location, cancer cannot be spread this way. Also, although we will occasionally find cancer, we expect to find women with atypical hyperplasia.

Are you planning to share the results with the patient? The patient can either find out the results or not at the discretion of the site. At UCSF we will follow the patient's wishes.

What about menopause? Works just as well before or after. People on hormones can be part of the study. Works very well in premenopausal women where we don't currently have many benign tools that are also low tech.

Is there a high correlation between atypical cells and breast cancer? The highest risk is in women with family history and atypical hyperplasia. We should be able to work with the women on the STAR trial (comparing tamoxifen with raloxifene) and see what happens to women with positive cells after they take one of these medications. Dr. Britt-Marie Ljung, pathologist here at UCSF, sees the same type of cells in the breast aspirate that she sees in biopsy material.

Is the chemical composition of the fluid the same in all women? It seems that whatever you have been exposed to will be concentrated in the breast milk, sort of like a window on environmental exposure. Nicotine will show up within minutes, and research in the Central Valley has shown higher than normal concentrations of pesticides in breast fluid (although women in this area seem to have lower than normal incidence of breast cancer). It may be that a combination of risk factors or a gene/environment interaction rather than an individual factor causes breast cancer.

Can these studies be done on the post-mastectomy breast? Yes, a lot of the research to develop the catheter was done on the post-surgical breast, with permission from the patient.

If the tumor is deep, will there be tumor cells all the way to the nipple? Even if the cancer is distant, there will still be a link to the duct. The catheter goes in just a little way, but we are squirting enough fluid to wash the whole duct and find any cells that are there.

What is the risk with this procedure? Very low. Taking the worst scenario, perforation of the duct, you are only squirting saline, there is no risk of infection, so this might become a routine screening procedure for high risk women.