Drug – bio-affecting and body treating compositions – In vivo diagnosis or in vivo testing – Magnetic imaging agent
Reexamination Certificate
2002-12-12
2004-05-18
Jones, Dameron L (Department: 1616)
Drug, bio-affecting and body treating compositions
In vivo diagnosis or in vivo testing
Magnetic imaging agent
C424S001110, C424S001650, C424S009100, C424S009400, C424S009500, C424S001450, C530S313000
Reexamination Certificate
active
06737039
ABSTRACT:
BACKGROUND OF THE INVENTION
Breast cancer is one of the most prevalent forms of cancer in women and one of the leading causes of cancer deaths in women. Mammography, or radiographic imaging of breast tissue, has proven to be an effective procedure for detecting and diagnosing early stage breast tumors. As currently performed, however, mammography does not detect all breast cancers. The ability of mammography to detect early stage tumors varies among women, depending on the characteristics of the breast tissue examined. Detection of breast lesions are particularly problematic in women with radiologically “dense” breasts, i.e., breast tissue exhibiting a dense parenchymal pattern upon mammography. The radiographic density of the breast tissue can obscure breast lesions, making detection more difficult and increasing the likelihood that the lesion will be overlooked. Such false negative mammograms result in delay in the diagnosis, and subsequent treatment, of breast cancer.
The problem of detecting lesions in radiologically dense breasts is not a minor one. Approximately 25-50% of women have been reported to have a dense parenchymal pattern upon mammography (see e.g., Threat, B., et al. (1980)
Cancer
45:2550-2556; Jackson, V. P., et al. (1993)
Radiology
188:297-301; van Gils, C. H., et al. (1995)
Br. J. Radiol.
68:1133-1135), although the prevalence of dense breasts decreases with age (e.g., to approximately 6% in women over 60, as reported Threat, B., et al., supra). An association between radiologic breast density and an increased risk for breast cancer has been reported in numerous clinical studies (see e.g., Wolfe, J. N. (1976)
Cancer
37:2486-2492; Krook, P. M., et al. (1978)
Cancer
41:1093-1097; Threat, B., et al., supra; Andersson, I., et al. (1981)
Radiology
138:59-62; Saftlas, A. F. and Szklo, M. (1987)
Epidemiol. Rev.
9:146-174; Warner, E., et al. (1992)
Cancer Det. Prevent.
16:67-72; Ma, L., et al. (
1992
)
J. Natl. Cancer Inst.
84:781-785; Ciatto, S. and Zappa, M. (1993)
Eur. J Radiol.
17:122-125; Oza, A. M. and Boyd, N. F. (1993)
Epidemiol. Rev.
15:196-208; Jenks, S. (1994)
J. Natl. Cancer Inst.
86:578-580; Boyd, N. F., et al. (1995)
J. Natl. Cancer Inst.
87:670675). The observed increased cancer risk associated with breast density has been attributed to a combination of 1) breast parenchymal patterns being an actual risk factor in the development of breast tumors and 2) “masking” of early stage tumors in dense breasts (see e.g., Egan, R. I. and Mosteller, R. C. (1977)
Cancer
40:2087-2090; Saftlas, A. F. and Szklo, M., supra; Oza, A. M. and Boyd, N. F., supra). Because of the reported association between breast density and cancer incidence, women with dense breasts are recommended to have more frequent mammograms, which exposes these women to the additional risks associated with mammography itself.
Few solutions to the problem of imaging the radiographically dense breast have been proposed. Approaches to improve detection of breast lesions in dense breasts have focused on the development of alternative imaging modalities to mammography, such as ultrasonography, transillumination, thermography, computed tomography, magnetic resonance imaging, radionuclide imaging and digital mammography, which may provide better resolution of lesions in dense breasts (see e.g., Jackson, V. P., et al. (1993)
Radiology
188:297-301; Braeuning, M. P., et al. (1995)
Breast Cancer Res. Treat.
35:31-38). Use of an alternative imaging procedure, however, likely would require large expenditures by health care providers for new equipment and personnel training, which may hinder widespread application of this approach. Additional strategies for improving the detection of lesions in dense breast tissue are still needed, especially strategies that can be used with traditional mammography.
SUMMARY OF THE INVENTION
This invention provides improved methods for detecting lesions in dense breast tissue. The methods of the invention generally feature administration to a subject of a luteinizing hormone releasing hormone (LHRH) antagonist in an amount and for a period of time sufficient to reduce the density of breast tissue prior to imaging the breast tissue, for example by mammography, to detect a lesion in the breast tissue.
In one embodiment, the invention provides a method for reducing breast density in a subject. The method comprises administering to the subject an LHRH antagonist in an amount and for a period of time sufficient to reduce breast density in the subject prior to generating an image of the breast tissue.
In another embodiment, the invention provides a method for detecting a lesion in breast tissue in a subject. This method comprises:
administering to the subject an LHRH antagonist in an amount and for a period of time sufficient to reduce the density of the breast tissue in the subject; and
generating an image of the breast tissue such that a lesion in the breast tissue is detected.
The breast lesion to be detected can be, for example, a malignant or benign breast tumor. The image of the breast tissue can be detected, for example, by standard film screen mammography or by an alternative procedure for visualizing breast tissue, such as ultrasonography, transillumination, thermography, computed tomography, magnetic resonance imaging, radionuclide imaging or digital mammography.
The invention further provides a packaged formulation for reducing breast density in a subject prior to generating an image of the subject's breast tissue. This packaged formulation comprises an LHRH antagonist packaged with instructions for using the LHRH antagonist for reducing breast density in the subject prior to generating an image of the subject's breast tissue.
DETAILED DESCRIPTION OF THE INVENTION
The present invention provides methods and compositions for improved detection of lesions in dense breast tissue. The methods of the invention generally feature administration to a subject of an LHRH antagonist in an amount and for a period of time sufficient to reduce breast density in the subject, prior to generating an image of the subject's breast tissue. LHRH is a natural hormone produced by the hypothalamus that interacts with the LHRH receptor (LHRH-R) in the pituitary to stimulate production of luteinizing hormone (LH). LHRH antagonists inhibit the LHRH receptor such that release of LH is inhibited, which ultimately leads to decreased circulating levels of sex hormones (e.g., estrogens in women) and induces a temporary castrate state. While not intending to be limited by mechanism, these decreased levels of circulating estrogens resulting from LHRH antagonist treatment are thought to lead to, or at least contribute to, decreased radiological breast density. This mechanism is consistent with, for example, the observation that breast densities in post-menopausal women are significantly reduced compared to pre-menopausal women.
In order that the invention may be more readily understood, certain terms used herein are first defined.
The term “LHRH antagonist”, as used herein, refers to a compound that inhibits the luteinizing hormone releasing hormone receptor such that release of LH is inhibited. LHRH antagonists have been described in the art; see e.g., U.S. Pat. No. 5,470,947 to Folkers et al.; Folkers et al., PCT Publication No. WO 89/01944; U.S. Pat. No. 5,413,990 to Haviv; U.S. Pat. No. 5,300,492 to Haviv; U.S. Pat. No. 5,371,070 to Koerber et al.; U.S. Pat. No. 5,296,468 to Hoeger et al.; U.S. Pat. No. 5,171,835 to Janaky et al.; U.S. Pat. No. 5,003,011 to Coy et al.; U.S. Pat. No. 4,431,635 to Coy; U.S. Pat. No. 4,992,421 to De et al.; U.S. Pat. No. 4,851,385 to Roeske; U.S. Pat. No. 4,801,577 to Nestor, Jr. et al.; and U.S. Pat. No. 4,689,396 to Roeske et al. Preferred LHRH antagonists are those having low histamine-releasing activity (e.g., an ED
50
for histamine release in a standard in vitro histamine release assay of at least 3 &mgr;g/ml, more preferably at least 5 &mgr;g/ml, and still more preferably at least 10 &mgr;g/ml) and that exhibit water s
DeConti, Jr. Giulio A.
Jones Dameron L
Laccotripe Zacharakis Maria
Lahive & Cockfield LLP
Praecis Pharmaceutics, Inc.
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