| PATENT NUMBER | This data is not available for free |
| PATENT GRANT DATE | 08.08.2000 |
| PATENT TITLE |
Methods for diagnosing benign prostatic diseases |
| PATENT ABSTRACT |
The present invention relates to novel methods for diagnosing benign prostatic diseases (BPD), such as benign prostatic hyperplasia, prostatitis, or glandular atrophy, in a male human patient without requiring a biopsy. The total prostate specific antigen (PSA) level in the blood or serum of the patient is measured. If the patient has a total PSA level of between about 2.5 ng/ml and 10.0 ng/ml, then the free PSA level in the blood or serum of the patient is measured. The proportion of free PSA to total PSA is calculated. If this proportion is equal to or greater than about 25%, then the patient is diagnosed as having BPD. Optionally, if the patient has a total PSA level of between 10.1 ng/ml and 20.0 ng/ml, then the free PSA level in the blood or serum of the patient can also be measured. The proportion of free PSA to total PSA is calculated. If this proportion is equal to or greater than about 25%, then the patient is diagnosed as having BPD. |
| PATENT INVENTORS | This data is not available for free |
| PATENT FILE DATE | February 25, 1999 |
| PATENT REFERENCES CITED |
Jacobsen, Steven J. et alia: "Comparability of the Tandem-R and IMx assays for the Measurement of Serum Prostate-Specific Antigen": vol. 44, No. 4: 512-518, 1994. Leinonen, Jari et alia: "Double Label Time-Resolved Immunofluorometric Assay of Prostate-Specific Antigen and of its Complex with .beta..sub.1 -antichymotrypsin": Clin. Chem.; vol. 39, No. 10: 2098-2103, 1993. Tillyer, Colin R. et alia: "Disagreement between the Roche Cobas Core and Hybritech TANDEM-E PSA assays when measuring free, complexed and total serum prostate specific antigen": Ann. Clin. Biochem.: 31:501-505, 1994. |
| PATENT PARENT CASE TEXT | This data is not available for free |
| PATENT CLAIMS |
What is claimed is: 1. A method for determining the risk of a patient having prostatic adenocarcinoma (CAP) comprising: a) measuring the total prostate specific antigen (PSA) level in the blood or serum of a patient; b) measuring the free PSA level in the blood or serum of a patient only if the patient has a total PSA level of between about 2.5 ng/mL and about 10.0 ng/mL; c) calculating the proportion of the free PSA level to the total PSA level for the patient (F/T); d) comparing the patient F/T proportion to a list of probabilities expressed as a percentage for CAP, said probabilities being in relationship to F/T proportions based on a patient population, wherein said population has a clinically significant risk of CAP at an F/T proportion of about less than 0.25, (25%). 2. A method for determining the risk of a patient having prostatic adenocarcinorna (CAP) comprising: a) measuring the total prostate specific antigen (PSA) level in the blood or serum of a patient; b) measuring the free PSA level in the blood or serum of a patient only if the patient has a total PSA level of between 10.1 ng/mL and about 20.0 ng/mL; c) calculating the proportion of the free PSA level to the total PSA level for the patient (F/T); d) comparing the patient F/T proportion to a list of probabilities expressed as a percentage for CAP, said probabilities being in relationship to F/T proportions based on a patient population, wherein said population has a clinically significant risk of CAP at an F/T proportion of about less than 0.25, (25%). -------------------------------------------------------------------------------- |
| PATENT DESCRIPTION |
TECHNICAL FIELD The present invention relates to novel methods for diagnosing benign prostatic diseases (BPD), such as benign prostatic hyperplasia, prostatitis, or glandular atrophy, in a male human patient without requiring a biopsy. The total prostate specific antigen (PSA) level in the blood or serum of the patient is measured. If the patient has a total PSA level of between 2.5 ng/ml and 10.0 ng/ml, then the free PSA level in the blood or serum of the patient is measured. The proportion of free PSA to total PSA is calculated. If this proportion is equal to or greater than about 25%, then the patient is diagnosed as having BPD. Optionally, if the patient has a total PSA level of between 10.1 ng/ml and 20.0 ng/ml, then the free PSA level in the blood or serum of the patient can also be measured. The proportion of free PSA to total PSA is calculated. If this proportion is equal to or greater than about 25%, then the patient is diagnosed as having BPD. BACKGROUND ART Prostate specific antigen (PSA) is recognized as a molecular marker for prostatic adenocarcinoma (CAP). Blood or serum based immunoassays measuring the total PSA level have been commercially available for a number of years. However, the detection of total PSA does not necessarily mean that a patient has CAP. In order to distinguish CAP, a total PSA test has to satisfy two elements: a high sensitivity--the ability to detect disease when present, and a high specificity--the ability to detect true negatives and avoid false positives. From clinical experience, total PSA tests have become generally accepted as being predictive of CAP if the total PSA level is greater than 10.0 ng/ml. Total PSA values between 0.0 ng/ml and about 3.9 ng/ml have been considered generally predictive of no disease being present, with a value of about 3.5 ng/ml being used for men under 60 years old and about 2.5 ng/ml being used for men under 50 years old. (See Oesterling, J. E., Cooner, W. H., Jacobsen, S. J., Guess H. A., and Lieber, M. M.: "Influence of Patient Age on the Serum PSA Concentration and Important Clinical Observations": Urol. Clin. North Am.; Vol. 20: 671-680, 1993.) PSA is primarily organ-specific, not cancer specific. Thus, PSA in blood or serum can result not only from CAP, but also from normal or hyperplastic prostate tissues. Historically, a total PSA test cannot reliably distinguish BPD from CAP at less than 10.0 ng/ml. Studies have found that 43% (136/319) of patients with organ-confined CAP have a total PSA value within the normal range of less than 4.0 ng/ml. Moreover, about 25% (148/597) of men with BPD have a total PSA value above 4.0 ng/ml. (See Oesterling, J. E.: "Prostate Specific Antigen: A Critical Assessment of the Most Useful Tumor Marker for Adenocarcinoma of the Prostate", J. Urol., Vol: 145: 907-923, 1991.) Standard medical practice is to biopsy patients over 60 years old having total PSA levels of between 4.0 ng/ml and 10.0 ng/ml because about 30% of those patients have CAP. Likewise, patients between 50 years and 60 years old whose total PSA falls between 3.5 ng/ml and 10.0 ng/ml and patients under 50 years old whose total PSA falls between 2.5 ng/ml and 10.0 ng/ml are also biopsied under current medical practice. One proposed method for detecting CAP is disclosed in Ser. No. WO 92/01936 to Hans Lilja et al., (Lilja application), filed Jul. 22, 1991, under the Patent Cooperation Treaty (PCT). In general, the Lilja application discloses using immunoassays to measure free PSA and a complexed form of PSA. Free PSA is a 33 kDa single chain glycoenzyme that is produced by the epithelial cells lining the acini and prostatic ducts of the prostate gland. Complexed PSA refers primarily to a 9OkDa complex of PSA bound to alpha 1- antichymotrypsin (ACT) protein. Free PSA and complexed PSA, and their proportions are applied in the diagnosis of patients with CAP. Throughout, the specification discloses using a combination of a free PSA to total PSA (F/T) proportion and a complexed PSA to total PSA (C/T) proportion for use in diagnosing CAP. No prostate needle biopsy were performed on the patients, and the patients covered a full range of total PSA values. The text provides no guidance as to specifically how one uses these proportions. DISCLOSURE OF TIE INVENTION The present invention relates to a method for diagnosing BPD in a male human patient without requiring a biopsy. Presently, if a patient has a total PSA level of 4.0 ng/ml to 10.0 ng/ml, then he is considered to be in a "gray" diagnostic zone and must undergo a prostate needle biopsy, an anesthetic-free operation performed transrectally involving substantial pain and discomfort, especially if a sextant biopsy is performed which requires taking six samples. The present method eliminates the need for about one-third of those patients to undergo such a biopsy. (See Luderer, A. A., et alia, "Measurement of the Proportion of Free to Total Prostate-Specific Antigen Improves Diagnostic Performance of Prostate-Specific Antigen in The Diagnostic Gray Zone of Total Prostate-Specific Antigen", Urol., Vol. 46: 187-194, 1995.) In an embodiment for those patients in the gray diagnostic zone, the method comprises four steps. First, one measures the total PSA level in the blood or serum of the patient. Second, one measures the free PSA level in the blood or serum of a patient, but only if he has a total PSA level of between about 2.5 ng/rnl and about 10.0 ng/ml. If the patient has a total PSA level below 2.5 ng/ml, then he is diagnosed to have BPD. If the patient has a total PSA level above 10.0 ng/ml, then he is presumed to have CAP and must be biopsied. Third, one calculates the proportion of free PSA to total PSA. Fourth and finally, one diagnoses the patient as having BPD if the calculated proportion of free PSA to total PSA is equal to or greater than about 25%. Optionally, if the patient is between 50 years old and under 60 years old, one can use a lower cutoff level of 3.5 ng/ml, and if the patient is at least 60 years old, then one can perform the same steps using a lower cutoff level of 4.0 ng/ml. A report for a diagnosis of BPD in a male human patient without requiring a biopsy according to the above embodiment comprises listing a total PSA level of between 2.5 ng/ml, (optionally 3.5 ng/ ml for those between 50 years old and under 60 years old, and 4.0 ng/ml for those at least 60 years old), and 10.0 ng/ml and listing a free PSA to total PSA proportion equal to or greater than about 25%. The present invention also relates to a method for diagnosing BPD in a male human patient who traditionally was assumed to have CAP, i.e., patients having a total PSA level of 10.1 ng/ml to 20.0 ng/ml. Unlike in the past, these patients can be screened and identified as having BPD, rather than CAP. In this second embodiment, the present method also comprises four steps. First, one measures the total PSA level in the blood or serum of the patient. Second, one measures the free PSA level in the blood or serum of a patient. Third, one calculates the proportion of free PSA to total PSA. Fourth and finally, one diagnoses the patient as having BPD if the calculated proportion of free PSA to total PSA is equal to or greater than about 25%. The physician can use this method either with or without performing a transrectal biopsy. While the standard of care in a particular region may initially dictate that a physician perform such biopsies, the present method does not require one in order to be effective in diagnosing patients with BPD. A report for a diagnosis of BPD in these higher total PSA patients comprises listing a total PSA level of between about 10.0 ng/ml and about 20.0 ng/ml and listing a free PSA to total PSA proportion equal to or greater than about 25%. Thus, the present methods allow the physician to diagnose BPD in patients having a total PSA level extending from about 2.5 ng/ml up to 20.0 ng/ml. BRIEF DESCRIPTION OF THE DRAWINGS FIG. 1 is a diagrammatic view of the total PSA assay used in the present invention. FIG. 2 is a diagrammatic view of the free PSA assay used in the present invention. FIG. 3 is a graph showing the distribution of total PSA levels for BPD patients and CAP patients in Example 1. FIG. 4 is a view of a pathology report according to the present invention. FIG. 5 is a graph showing the distribution of F/T proportions for BPD patients and CAP patients in Example 1. FIG. 6 is a graph showing the cumulative percent distribution of total PSA levels for BPD patients and CAP patients in Example 2. FIG. 7 is a graph showing the cumulative percent distribution of F/T proportions for BPD patients and CAP patients in Example 2. BEST MODES FOR CARRYING OUT THE INVENTION Assays In preferred embodiments described below, the present method uses two immunoassays, however any specific binding assay that measures either free PSA or total PSA is suitable for the present methods. The first assay is a total PSA sandwich immunoassay manufactured by Tosoh Medics, Inc. (Tosoh) of Foster City, Calif. The assay is an immunoenzymetric assay using dual murine monoclonal antibodies. FIG. 1 shows diagrammatically how, in the final sandwich configurations, this first assay captures both free PSA (10) and complexed PSA/ACT (12) using a capture antibody (14) and an enzyme labeled antibody (16). The second assay is a free PSA immunoassay manufactured developed by Immuno Corp. for Dianon Systems, Inc. (Dianon) of Stratford, Conn. This free PSA test is designed to detect free PSA in serum using an IRMA coated tube format. Free PSA binds to a tube coated by a monoclonal antibody which selectively binds free PSA but not complexed PSA. After washing, an I.sup.125 labeled polyclonal antibody against free PSA is reacted with the bound free PSA. The physician is given a result that expresses a proportion of free PSA to total PSA. FIG. 2 shows diagrammatically how in the final sandwich configuration, this second assay captures free PSA (10), but the capture antibody (14) does not specifically bind to the complex of the PSA/ACT complex (12) and radiolabelled antibody (16). |
| PATENT EXAMPLES | This data is not available for free |
| PATENT PHOTOCOPY | Available on request |
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