Chemistry: molecular biology and microbiology – Measuring or testing process involving enzymes or... – Involving antigen-antibody binding – specific binding protein...
Reexamination Certificate
1999-03-01
2001-09-25
Caputa, Anthony C. (Department: 1642)
Chemistry: molecular biology and microbiology
Measuring or testing process involving enzymes or...
Involving antigen-antibody binding, specific binding protein...
C435S007100, C435S007210, C436S501000, C436S503000, C436S064000
Reexamination Certificate
active
06294349
ABSTRACT:
BACKGROUND OF THE INVENTION
This invention relates generally to the use of salivary biomarkers to diagnose breast cancer and, more particularly, to diagnostically differentiate between women with carcinoma of the breast, women with benign tumors, and healthy controls.
Breast cancer is the second leading cause of death among women in the United States. Approximately 1 woman in every 10 will develop breast cancer in her lifetime. Recent statistics estimate that 44,000 women will die of breast cancer, while 150,000 new female cases of breast cancer will be diagnosed in the next year.
It has been shown that screening for breast cancer can reduce breast cancer mortality. Among women aged 50 and older, studies have demonstrated a 20% to 40% reduction in breast cancer mortality for women screened by mammography and clinical breast examination. However, among women between 40 to 49 years of age, the mortality rate is reduced only 13% to 23%. These results suggest that further methods of screening could potentially reduce the mortality in the younger age group of women.
While physical examination and mammography are useful screening procedures for the early detection of breast cancer, they can produce a substantial percentage of false positive and false negative results especially in women with dense parenchymal breast tissue. For example, the probability of having a false negative mammographic examination is 20% to 25% among women between 40 to 49 years of age and 10% among women 50 to 69 years of age. Consequently, screening will result in a number of negative biopsy results yielding a high percentage of false positives. There is also a demonstrated lack of sensitivity in detecting cancerous lesions in younger women yielding a significant percentage of false negatives.
There has also been a clear need for added modalities of screening to help diagnose cancer in younger women. Increased technology in the field of mammography has allowed more reliable detection of small lesions of the breast; while, researchers in the field of breast cancer continue to seek additional adjunct diagnostic procedures to further enhance cancer screening and, thereby, to reduce mortality rates.
During the past three decades, cancer researchers have made extensive use of immunohistochemistry to detect expression of specific biomarkers that may be used as adjunct diagnostic procedures in the diagnosis of certain tumors. (Grizzle WE. Biomarkers—The New Frontier in the Pathology of Invasive and Preinvasive Neoplasias. Biotechnic and Histochemistry, 72(2):59-61, 1997; Grizzle W E, Myers R B, Manne U. The Use of Biomarker Expression to Characterize Neoplastic Processes. Biotechnic and Histochemistry, 72(2):96-104, 1997.) Tumor markers such as c-erbB-2 (erb) and Cathespin-D (CD) have been assayed in tissue and shown to correlate with aggressive lesions. The majority of the investigations performed have used these markers in tissues and serum.
With respect to specific cancer antigens in saliva, Chien found that saliva contained CA 125, a glycoprotein complex that is a recognized or accepted tumor marker for epithelial ovarian cancer. (Chien D X, Schwartz P E, CA 125 Assays for Detecting Malignant Ovarian Tumors. Obstetrics and Gynecology, 75(4):701-704, 1990.) In comparing salivary CA 125 concentrations among healthy controls, women with benign lesions, and those with ovarian cancer, Chien found a significantly elevated CA 125 concentration among the ovarian cancer group as compared to the nonmalignant controls. Boyle detected and identified tumor-specific mutations using radio-labeled oligonucleotide in preoperative salivary samples of individuals suffering from head and neck squamous cell carcinoma. These findings were demonstrative in 71% of the patients studied. (Boyle J O, Mao L, Brennan J A, Koch W M, Eisele D W, Saunders J R, Sidransky D. Gene Mutations in Saliva as Molecular Markers for Head and Neck Squamous Cell Carcinomas. Am J Surgery, 168(5):429-32, 1994.)
SUMMARY OF THE INVENTION
However, such antigens are not diagnostic for breast cancer, and the aforementioned tumor biomarkers (e.g., CA 125, erb and CD) have not been tested for their presence in saliva. While the diagnostic methods of the prior art have generally progressed, such innovations have not been extended to all areas of diagnosis. There is a need for a method to more fully utilize recent technological advances and apply them to the detection and treatment of breast carcinomas.
Accordingly, it is an object of the present invention to use saliva as a diagnostic medium and/or as part of a non-imvasive protocol for the detection and differential diagnosis of breast carcinomas, thereby overcoming various deficiencies and shortcomings of the prior art, including those outlined above.
It can be another object of the present invention to identify one or more biomarkers present in saliva, as having diagnostic value and/or as can be used in post-treatment monitoring or therapy. Likewise, it can be another object to provide one or more biomarkers as part of a diagnostic panel for the initial detection, follow-up screening for detection, reoccurrence of breast cancer in women, response to chemotherapy and/or surgical treatment of the disease state.
It would be understood by those skilled in the art that one or more aspects of this invention can meet certain objectives, while one or more other aspects can meet certain other objectives. Each objective may not apply equally, in all instances, to every aspect of the present invention. As such, these objectives—in light of the prior art regarding diagnosis of breast cancer—can be viewed in the alternative with respect to any one aspect of the present invention.
Other objects, features, benefits and advantages of the present invention will be apparent from this summary and the following inventive examples, and will be readily apparent to those skilled in the art having knowledge of the nature and detection of cancer biomarkers and their use in the diagnosis of corresponding disease states. Such objects, features, benefits and advantages will be apparent from the above as taken in conjunction with the accompanying examples, tables, data and all reasonable inferences to be drawn therefrom.
In part, the present invention is a method of using a salivary biomarker to differentially diagnose and/or detect reoccurrence of breast carcinoma. The method includes (1) using a human saliva specimen to provide a salivary biomarker for that individual and diagnostic for carcinoma of the breast, (2) comparing the individual biomarker with a biomarker reference, and (3) differentially identifying the diagnosis for the individual as indicated by the biomarker comparison. The biomarker reference can be made up of a panel of constituents and can be developed using malignant tunor, benign tumor and control group populations. Each referenced biomarker constituent can have associated with it a range of values comparable to a corresponding individual biomarker.
In preferred embodiments, the individual biomarker is one constituent of a biomarker panel, and the reference panel includes one or more biomarkers identified as having diagnostic value. Such biomarkers can include cancer antigen 15-3, tumor suppressor oncogene protein 53 and oncogene c-erbB-2. In highly preferred embodiments of the inventive method, the presence of oncogene c-erbB-2 and/or an increased expression of protein identifies an individual as having a malignant carcinoma.
Each individual biomarker constituent can be associated with a concentration value, for comparison with a corresponding reference constituent. In one embodiment of the present invention, the concentration of cancer antigen 15-3 for an individual having a malignant breast tumor is at least about 100 percent higher than such a concentration for an individual having a benign tumor. Likewise, in a preferred methodology, the concentration of oncogene protein 53 for an individual having a malignant breast tumor is at least about 25 percent lower than an individual having a benign tumor. Such different
Bigler Lenora G.
Streckfus Charles F.
Thigpen James Tate
Caputa Anthony C.
Hunt Jennifer
Reinhart, Boerner, Van Deuren, Norris & Rieselbach, s.c.
University of Mississippi Medical Ctr.
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