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    Research Grants Awarded

    Deuterium Labeling in DCIS: A Novel In Vivo Measure of Cell Proliferation

    Study Section:
    Detection, Diagnosis and Prognosis

    Scientific Abstract:
    Ductal carcinoma in situ (DCIS) may or may not progress to invasive cancer. Unfortunately, we lack markers to predict which lesions put a woman at high risk of developing invasive breast cancer or having a recurrence after treatment and which lesions may remain contained or disappear entirely. Because of our inability to risk stratify, current standard of care for all women with DCIS is to aggressively treat with a combination of surgery, radiation, and hormonal therapy; similar to how invasive breast cancer is treated. Potential prognostic markers include estrogen receptor status, expression of cyclin D1, p21, and p27, HER-2, -3, and -4, clinicopathologic features and cell proliferation as assessed by Ki-67. Absence of HER-4 expression, high nuclear grade and high proliferation by Ki-67 are independent predictors of DCIS recurrence in some retrospective studies. However, none of these markers are robust enough to stratify treatment. Since there is a general premise that DCIS cannot progress to invasive cancer without cell division, accurate measurement of cell division may be particularly useful. Current methods for measuring cell division are problematic as they rely on subjective observation instead of objective measurement, introducing inter-observer variability. Further, these indirect methods rely on the presence of cell-cycle associated antigens, which are often inaccurate. Accordingly, a safe, automated, objective, direct measure of cell division may have prognostic utility. We have recently developed such a method to measure normal and invasive breast cell division. Women drink a few ounces of a non-toxic stable isotope of water (heavy water) for 10-14 days, then DNA deuterium labeling, and thus cell division, was measured with a mass spectrometer. A recent published study demonstrated the ability of this method to differentiate chronic lymphocytic leukemia (CLL) patients with aggressive disease needing immediate treatment, from those with less aggressive disease and who do better if they wait to start treatment. We believe this method could be just as valuable in the setting of DCIS. Our aims are to 1) use this method to determine the range and variability of DCIS cell division rates, and to 2) compare this test to other prognostic markers. If developed in DCIS, as in CLL, this method may aid in stratification of DCIS treatment so that aggressive treatment may be reserved only for women at highest risk for disease progression.

    Lay Abstract:
    Ductal carcinoma in situ (DCIS) is a group of preinvasive breast cancer lesions that may or may not progress to invasive cancer. Unfortunately, we lack tests to predict which DCIS lesions may put a woman at high risk of developing invasive breast cancer and which lesions may remain contained or disappear entirely. Because of the inability to risk stratify, the current standard of care for all women with DCIS is to aggressively treat with a combination of surgery, radiation, and hormonal therapy; similar to how invasive breast cancer is treated. There are few tests that may help predict prognosis. These include testing DCIS cells for hormone receptors, cell-division regulatory proteins, and physical characteristics. Thus far, none of these tests are proven robust enough to stratify treatment. There is a general premise that since DCIS cannot progress to invasive cancer without cell division, accurate measurement of cell division may be particularly helpful in determining prognosis. Methods for measuring cell division are problematic as they rely on subjective observation instead of objective measurement, introducing inter-observer variability. Further, these methods are indirect measures relying on the presence of proteins associated with cell division, which are misleading in some cases. Accordingly, a safe, automated, objective, direct measure of cell division may be valuable to women and their physicians when treating DCIS. We have recently developed such a method to measure cell division which relies on having women drink a few ounces of a non-toxic stable isotope of water called “heavy water” for 10-14 days, then measuring cell division with an instrument called a mass spectrometer. It has also been developed for use in another cancer called chronic lymphocytic leukemia (CLL). In a recently published study, researchers were able to differentiate CLL patients with aggressive disease needing immediate treatment, from those with less aggressive disease and who do better if they wait to start treatment. We believe this method could be as valuable in aiding DCIS prognosis. Our aims are to 1) use this method to determine the range and variability of DCIS cell division rates, and to 2) compare this test to other prognostic tests. If developed in DCIS as in CLL, this method may hold great promise for future stratification of DCIS treatment so that aggressive treatment may be reserved only for women at highest risk for disease progression.