If breast cancer is detected early, it is an eminently curable disease. Currently, mammography is the most common method for detection of breast cancer. Although it is a powerful technique, it is difficult to read accurately in young women due to the relatively high density of the breast. In addition, the expense of the equipment and sophistication needed for accurate interpretation of the mammogram makes it impossible to use in most countries of the world. For more than 20 years, scientists have been trying to develop a PAP-like test for breast cancer. Pathologists examined the tiny droplets of fluid that were obtained by aspirating the breast using the breast pump. However, many women did not yield fluid or yielded too little for reliable diagnosis. A few experts could get fluid from women¿s breasts by this method, but most investigators failed. The methods in use were thus crude and cumbersome. New methods needed to be developed for obtaining good fluid from all the ductal openings in the breast and to apply tests that would reliably detect breast cancer cells. Ideally, the collection method should be able to sample the entire length of the breast trees, and the tests should be good enough to detect every woman¿s cancer.

In this study, we hypothesize that by using a combination of molecular and cytologic tests performed on cells obtained by washing the entire length of the ducts, we will be able to provide tools for early detection of breast cancer. Two recent developments in our cancer center will facilitate studies designed to test this hypothesis. We have helped to develop a facile ductal lavage (DL) technique using cannulating catheters that ¿flush¿ each duct to yield thousands of ductal cells. Second, we have developed a panel of markers consisting of three genes, Cyclin D2, Twist, and retinoic acid receptor ?2, which are abnormally ¿methylated¿ in breast cancer cells. Our work indicates that together this panel can detect nearly 100% of breast cancers. More importantly, the cancer cells can be detected even when they are mixed in with a large number of normal breast cells or white blood cells.

We will perform the study in two phases. In the first phase, we will test the reliability of our detection methods when applied to patient ductal cell samples. This will be done by testing the fluid/cells obtained from mammary ducts of patients who have confirmed biopsy-proven breast cancer. How will we know which duct carries the cancerous lesion? To do this, we have developed a viewing method using a flexible endoscope that can be inserted into the duct, which photographs the tumor residing in the duct. This duct will then be flushed, cells will be collected, and tests will be run on these cells. Cells from the other breast of the same patient will serve as ¿normal¿ controls.

The second aim will test the markers in ductal wash fluid of women with a high risk of developing breast cancer. These women include those who have previously had cancer in one breast, those who have mammographically abnormal lesions, and patients who have had lobular carcinoma. The results of our tests will be compared to those obtained by histopathology performed on the surgically removed tissue, cytopathology, and mammography.

This work could ultimately lead to a ¿PAP test¿ for the breast, leading to the detection of the earliest cellular precursors of cancer. This test will also be useful to gauge responses of women to new therapies and new prevention trials. In the long term, we hope to develop an inexpensive kit that would be available to all women of the world.