Chemistry: molecular biology and microbiology – Measuring or testing process involving enzymes or... – Involving nucleic acid
Reexamination Certificate
2000-09-26
2001-07-17
Caputa, Anthony C. (Department: 1642)
Chemistry: molecular biology and microbiology
Measuring or testing process involving enzymes or...
Involving nucleic acid
C435S004000, C435S007100, C435S007210, C435S007230, C435S063000, C435S064000
Reexamination Certificate
active
06261766
ABSTRACT:
FIELD OF THE INVENTION
This invention relates to the detection of prostate- specific antigen (PSA) in female breast tumor extract as a prognostic or predictive indicator for breast carcinoma. The presence of prostate-specific antigen in breast tumors is associated with earlier disease stage, younger women and better survival. PSA is associated with tumors which have estrogen and/or progesterone receptors.
BACKGROUND OF THE INVENTION
Considerable research and related diagnosis has been undertaken in this field of healthcare. In order to facilitate reference to prior art developments and procedures, journal articles are listed at the end of this specification and are hereinafter referenced by number.
Breast cancer is a leading cause of mortality and morbidity among women (
1
-
4
). One of the priorities in breast cancer research is the discovery of new biochemical markers which could be used for diagnosis, prognosis and monitoring (
4
,
5
). Breast cancer is one of a few cancers that is dependent on steroid hormones and their receptors. Currently, estrogen and progesterone receptor analysis is performed routinely as an aid in prognosis and selection of therapy (
4
-
6
).
Current indicators for diagnosing and monitoring breast tumors include: tumor size, estrogen receptors, progesterone receptors, age, aneuploidy, mitotic activity and Ki67 (
29
). The prognostic usefulness of these factors depends on their ability to evaluate which patients with breast cancer require aggressive therapeutic treatment and which patients should be monitored.
Mutation of the p53 tumor suppressor gene is one of the most comDonly known genetic defects in human cancer, including breast cancer and results in mutant protein accumulating to high concentrations. Overexpression of p53 protein expression has been found to be an independent predictor of early disease recurrence (
29
). The accumulation of p53 protein has been found to be an independent marker of shortened survival (
30
). The majority of tumors that do not produce mutant p53 protein are estrogen and/or progesterone receptor-positive (
14
).
Prostate cancer is a leading cause of mortality and morbidity among men (
7
,
8
). Prostate tissue and cancer is also dependent on steroid hormones and therapy that takes advantage of this is currently routinely used (
9
-
10
). One of the hallmarks of prostate cancer is the appearance in serum, at elevated concentrations, of a 30-33-KD glycoprotein, prostate specific antigen (PSA) (
11
). PSA is secreted by the epithelial cells of prostatic tissue and is currently widely used as a tumor marker for diagnosing and monitoring prostatic carcinoma.
Previous iuuunohistochemical studies found no PSA immunoreactivity in breast or other tumors (
17
) or found occasional PSA immunoreactivity with polyclonal but not monoclonal antibodies, suggesting cross-reactivity effects (
18
). PSA levels in female serum are undetectable in 90% of women. A few women do have traces of PSA which are thought to be produced in the periurethral glands.
We have surprisingly discovered the presence of PSA in breast tumor.
SUMMARY OF THE INVENTION
We have discovered that breast tumors have the ability to produce PSA which can be used as a prognostic indicator. PSA production in breast tumors is associated with estrogen and/or progesterone receptor presence, but not the p53 tumor suppressor gene protein. PSA-positive tumors are associated with younger women and earlier disease state. PSA is a favourable prognostic indicator because it is associated with estrogen and progesterone receptors, with lower disease stage and with improved patient survival. PSA positive tumors respond to endocrine treatment, particularly estrogen receptor-negative tumors.
An object of the invention is in the analysis of PSA in female breast tumor extracts which is useful for prognosis, diagnosis or monitoring.
A significant benefit which follows from this invention is that PSA analysis defines a subgroup of patients which may have a different prognosis from that of other breast tumor patients.
According to an aspect of the invention, a method of detecting PSA in breast tumor extracts to provide a breast tumor prognosis comprises:
a) providing a breast tumor extract from a woman;
b) assaying for the presence of PSA; and
c) upon detection of PSA, categorizing the woman as a PSA-positive patient.
According to an aspect of the invention, the PSA positive classification indicates hormonal treatment for the breast tumor condition is required.
According to an aspect of the invention, a method is provided for measuring PSA, based on time-resolved fluorometry (TR-FIA) (
12
,
13
) which is approximately 40-fold more sensitive than the commercially available and widely used immunometric techniques. This method has been thoroughly evaluated and can easily and precisely quantify PSA at levels of 0.05 &mgr;g/L or higher.
In accordance with a preferred aspect of the invention, an ultrasensitive detection method for prostate-specific antigen in breast tumor extract involving time-resolved fluoroimmunoassay is provided. Breast tumor extract is incubated with monoclonal anti-PSA antibody. Biotinylated polyclonal antibody specific to PSA is added to bind to any bound PSA. Alkaline phosphatase-labelled streptavidin (SA-ALP) is added. The activity of ALP is measured by adding the substrate 5-fluorosalicyl-phosphate and then adding Tb
3+
-EDTA to form a fluorescent chelate. Fluorescence is measured during a specific time interval to indicate the presence of PSA. The presence or absence of PSA can be used as a prognostic and predictive indicator of breast carcinoma.
REFERENCES:
patent: 5688658 (1997-11-01), Diamandis
patent: A2187283 (1987-09-01), None
patent: WOA9201936 (1992-02-01), None
ACTA Cytologica, vol. 33, No. 6, 1989 F.C. Schmitt, et al., pp. 899-902, “Cytology and Immunocytochemistry of Bilateral Breast Metastases from Prostratic Cancer”.
Clinical Biochemistry, vol. 21, No. 3, Jun. 1988, p. 139-150, Diamandis, E.P., Immunoassays with Time-Resolved Fluorescence Spectroscopy: Principles and Applications.
Bas. App. Histochem., vol. 33, 1989, pp. 25-29, M. Papotti et al., “Immunocytochemical Detection of Prostate-Specific Antigen (PSA) in Skin Adnexal and Breast Tissues and Tumors”.
Eur. J. Clin. Chem. Clin. Biochem. vol. 29, 1991, pp. 787-794, W.G. Wood et al., “The Establishment and Evaluation of Luminescent-Labelled Immunometric Assays for Prostate-Specific Antigen-alpha1-Antichymotrypsin Complexes in Serum”.
Clinical Chemistry, vol. 39, No. 10, 1993, pp. 2108-2114, H. Yu et al., “Ultrasensitive Time-Resolved Immunofluorometric Assay of Prostate-Specific Antigen in Serum and Preliminary Clinical Studies”.
Banner & Witcoff , Ltd.
Caputa Anthony C.
Harris Alana M.
Nordion International Inc.
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