The first sign
For Anne-Renee Hartman, MD, abnormal cells within the breast may hold the key not only to detecting the forerunners of cancer cells, but also to preventing tumors and understanding how they develop, step by step. Since arriving at Dana-Farber late last year, she has continued research she began at Stanford University. In a current study, women who are at high risk for breast cancer—either because they have a family history or because they carry a mutation in the BRCA1 or BRCA2 breast cancer genes—are screened for precancerous cells three ways: by mammography, magnetic resonance imaging (MRI), or a relatively new technique called ductal lavage. In the latter procedure, needle-thin catheters are inserted into some of the breast's milk ducts through the nipple, which has been numbed with an anesthetic ointment. Using a syringe-like device, a technician injects a salt-and-water solution into the duct, then draws the solution—which has picked up cells from the lining of the duct—back out. Dr. Hartman and a breast pathologist then examine the cells under a microscope to see if they have abnormalities such as odd-looking nuclei or other structures that indicate they're likely to become cancerous.
Anne-Renee Hartman, MD, is studying new ways of detecting precancerous cells in the breast.
While at Stanford, Dr. Hartman and her colleagues published a report on 46 women who participated in a pilot study of ductal lavage. MRI revealed a breast cancer in one woman that had been missed by mammography. Several others had premalignant masses that were picked up by the MRI but undetected by mammography. And ductal lavage showed atypical—or abnormal—cells in many of the women.
But the study also pointed out some shortcomings of these techniques. For one, many of the MRIs that found supposedly abnormal breast tissue turned out to be incorrect. For another, ductal lavage was performed in only three ducts of each breast, although breasts generally have six to eight ducts each, leaving open the possibility that atypical cells were lurking in unchecked areas. And, lastly, although doctors know that atypical breast cells often evolve into cancer cells, they don't know how quickly it happens or the precise genetic steps involved.
"There's a great deal of debate over the appropriate group for MRI screening," Dr. Hartman remarks. "MRIs are more sensitive at picking up abnormal tissue than mammography and may therefore be most useful in young women, whose breasts tend to be more dense. But it might be too sensitive, producing false alarms and needlessly raising women's anxiety. We need more clinical trials— such as the one we're conducting—to determine who benefits the most."
Dr. Hartman is also using cells collected through ductal lavage to chart the trail of genetic errors that occur as precancerous cells become cancerous. Specifically, she hopes to find when in the course of this transformation women with a normal and abnormal copy of the BRCA1 gene lose the normal copy, accelerating the cancer process. In addition, she is working with Dana-Farber's Alan D'Andrea, MD, to understand the connection between the childhood disease Fanconi anemia and breast cancer, as well as when in the cancer process certain genes break free from their normal controls.
"I believe we're going to make the biggest dent in breast cancer by targeting very early cell abnormalities, preventing abnormal tissue from progressing to cancer," Dr. Hartman says. "It is crucial to understand when mutations and loss of function of these genes occur so we know what stages and genes to target in our prevention efforts."
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