MXPA98002404A

MXPA98002404A - Novedous methods to diagnose adenocarcinoma prostat

Info

Publication number: MXPA98002404A
Application number: MXPA/A/1998/002404A
Authority: MX
Inventors: A Luderer Albert; D Carlson Grant; Yating Chen; F Soriano Thomas; F Thiel Robert
Original assignee: D Carlson Grant; Yating Chen; A Luderer Albert; F Soriano Thomas; Thiel Robert P
Priority date: 1995-09-29
Filing date: 1998-03-27
Publication date: 1999-06-01

Abstract

The present invention relates to a method for diagnosing prostatic adenocarcinoma (CAP) in a male human patient, without requiring a biopsy. The level of total prostate specific antigen (PSA) in the patient's blood or serum is measured. If the patient has a total PSA level between 2.5 ng / ml and 20.0 ng / ml, then the level of free PSA in the patient's serum or blood is measured. The ratio of free PSA (10) to total PSA (12) is calculated. If this ratio is less than about 7% then the patient is diagnosed as having CAP. The present method can also be used in patients who have a total PSA of at least 10.0 ng / ml but also have a negative prostate biopsy.

Description

NOVEDOUS METHODS FOR DIAGNOSING PROSTATIC ADENOCARCINOMA TECHNICAL FIELD The present invention relates to a method for diagnosing prosthetic adenocarcinoma (CAP = prostatic adenocarcinoma) in a male human patient, without requiring a biopsy. The total level of prostate specific antigen (PSA = prostate specific antigen) is measured in the patient's blood or serum. If the patient has a total PSA level between 2.5 ng / ml and 20.0 ng / ml, then the level of free PSA in the patient's blood or serum is measured. The ratio of free PSA to total PSA is calculated. If this ratio is less than about 7%, then the patient is diagnosed as having CAP. The present invention can also be used in patients who have a total PSA of at least 10.1 ng / ml, but also has a negative prostate biopsy. PRIOR TECHNIQUE It is recognized that prostate specific antigen (PSA = prostate specific antigen) is a molecular marker for prosthetic adenocarcinoma (CAP). Blood or serum-based assays measuring the total PSA level have been commercially available for a number of years. However, the detection of total SQ PSA necessarily means that a patient has CAP. In order to distinguish CAP, a total PSA test has to satisfy two elements: high sensitivity - the ability to detect disease when present, and high specificity - the ability to detect real negatives and avoid false positives. From clinical experience, total PSA tests have been accepted as predictive of CAP if the total PSA level is greater than 10.0 ng / ml. Total PSA values between 0.0 ng / ml and approximately 3.9 ng / ml have been predicted with no disease present, with a value of approximately 2.5 ng / ml used for men under 60 years of age. PSA is primarily organ specific, not cancer specific. In this way, PSA in blood or serum can result not only from CAP but also from normal or hyperplastic prostate tissues. Less than 10.0 ng / ml, or a total PSA test can not distinguish benign prostatic disease, such as benign prostatic hyperplasia (or BPH = Benign prostatic hyperplasia) CAP. Studies have found that 43% (136/319) of patients with CAP confined to the organ have a total PSA value in the normal range of less than 4.0 ng / ml. Furthermore, approximately 25% (148/597) of men with benign prostatic disease have a total PSA value of 4.0 ng / ml. (See Oesterling, JE, "Prostate Specific Antigen: A Critical Evaluation of the Most Useful Tumor Marker for Prostate Adenocarcinoma", J. Urol., Vol: 145, 907, 923, 1991.) . The standard medical practice is to biopsy patients who have total PSA levels between 4.0 ng / ml and 10.0 ng / ml because approximately 30% of those patients have CAP. A proposed method for detecting CAP is described in Patent Application Serial No. WO 92/01936 issued to Hans Lilja et al., (Request by Lilja), filed on July 22, 1991, under the Patent Cooperation Treaty (PCT). = Patent Cooperation Treaty). In general, Lilja's application describes using immunoassays to measure free PSA and a complexed form of PSA. Free PSA is a single-chain glycoenzyme of 33 kDa that is produced by the epithelial cells that line the prostate lobes and ducts of the prostate gland. Complexed PSA refers primarily to a 90 kDa complex of PSA linked to alpha l-antichymotrypsin (ACT) protein. Free PSA and complexed PSA, and their proportions are applied in the diagnosis of patients with CAP. Through it, the specification describes using a combination of a ratio of free PSA to total PSA (F / T) and a ratio of PSA complexed to total PSA (C / T) for use in diagnosing CAP. Prostate needle biopsies were not performed in patients, and the patients covered a wide range of total PSA values. The text does not provide guidance as to how these proportions are specifically used. SUMMARY OF THE INVENTION The present invention relates to a method for diagnosing CAP in a male human patient without requiring a biopsy. Currently, if a patient has a total PSA level of 4.0 ng / ml at 10.0 ng / ml, then he or she must undergo a prostate needle biopsy, an anesthetic-free operation that is performed transrectally, involving substantial pain and discomfort, especially if a sextant biopsy is performed that requires taking six samples. The present method eliminates the need for approximately 30% of these patients to undergo such a biopsy for initial diagnosis. A patient who is diagnosed with CAP due to the use of proportional cutting <; 7% F / T will require a prostate biopsy to locate the proportion and situation of CAP in your prostate. In addition, currently if a patient has a total PSA level of 10.1 ng / mL and a prostate biopsy has been performed that is negative, the doctor is in a dilemma as to whether he should continue patient biopsies now or send the patient home and wait six months. Values below 7% for the F / T PSA 5 ratio indicate the presence of CAP and the immediate need to confirm the extent and location of disease with a biopsy. As it is used for patients, in general, the present method comprises four stages. First, the PSA level in the patient's blood or serum is measured. Second, the free PSA level in the blood or serum of a patient is measured, but only if it has a total PSA level between 2.5 ng / ml and 20.0 ng / ml. (As in the past, if the patient has a total PSA level less than 2.5 ng / ml, then he is diagnosed as having benign prostate disease.) If the patient has a total PSA level of 20.0 ng / ml, then he is diagnosed as having has CAP). In third, the proportion of free PSA to total PSA is calculated. Fourth and finally, it is diagnosed that the patient has CAP if the calculated ratio of free PSA to total PSA is less approximately 7%. Another embodiment of the present invention is a report for the diagnosis of a male human patient who has CAP without requiring bipedality. This report comprises listing a total PSA level between 2 5 ng / ml and 20.0 ng / ml and listing a ratio of free PSA to total PSA that is less than about 7%. As it is used for patients who have a total PSA level of at least 10.1 ng / ml and have already undergone bipedal, but with negative results, the present method also comprises three stages. First, the level of free PSA in the blood or serum of the patient is measured. (Optionally, the total PSA level in the patient's blood or serum can be re-measured.) Then, the ratio of free PSA to total PSA is calculated. Finally, the patient who has CAP is diagnosed if the calculated ratio of free PSA to total PSA is less than about 7%, without requiring an additional prostate biopsy to confirm CAP. A further embodiment of the present invention is a report for diagnosis of a male human patient who has CAP which has a total PSA level of at least 10.1 ng / ml and has a negative prostate biopsy without requiring an additional prostate bipedal confirm CAP That report comprises a listing of a total PSA level between 20.1 ng / ml and 10.1 ng / ml and a listing of the ratio of free PSA to total PSA that is less than about 7%. BRIEF DESCRIPTION OF THE DRAWINGS Figure 1 is a diagrammatic view of the total PSA test employed in the present invention. Figure 2 is a diagrammatic view of the free PSA test employed in the present invention. Figure 3 is a view of the pathology report according to the present invention.

Figure 4 is a view of a pathology report according to the present invention where it has already been determined that the patient has a total PSA level of at least 10.1 but had a negative biopsy. Figure 5 is a graph showing a distribution of F / T ratio versus the probability that a patient has CAP. PREFERRED MODALITIES Tests In a preferred embodiment, the present method comprises two in one test. The first assay is a total PSA sandwich immunoassay manufactured by Tosoh Medies, Inc. (Tosoh) of Foster City, california. The assay is an in-one-enzyme assay using dual murine monoclonal antibodies. Figure 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 test is a free PSA immunoassay that is manufactured by Immuno S.A. for Dianon Systems, Inc. (Dianon) of Stratford, Connectícut. This free PSA test is designed to detect free PSA in serum using a tube format coated with IRMA.

Free PSA is linked to a tube coated with a monoclonal antibody that selectively binds free PSA but not PSA complexed. After washing, a polyclonal antibody labeled with l12s against free PSA is reacted with bound free PSA. The doctor is given a result that expresses a ratio of free PSA to total PSA. Figure 2 shows diagramatically how in the final sandwich configuration, this second assay captures free PSA, (10), but the capture antibody (14) specifically does not bind to the PSA / ACT complex (12) and radio antibody. labeled (16). Example In a clinical study to validate the present invention, 334 patients were tested. Classified as "BENIGNO" 90 men were identified as between 45 years of age and 75 years of age, who have benign prostate disease histologically confirmed by prostate biopsy with sextant needles and no history of cancer. The average age was 65. Classified co or "CAP", 174 men were identified as between 45 years of age and 75 years of age and who had primary CAP histologically confirmed by needle prostate biopsy. The average age was 67. None of the previous patients received any form of prostate-related treatment before blood extraction. Total PSA using the Tossh test described above according to the manufacturer's instructions. Free PSA was measured using the Dianon assay described above according to the manufacturer's instructions. The sample of patients was divided based on age between those over 60 years of age and those 60 years and younger. In addition, it was divided into those with a total PSA level between 2.5 ng / ml and 10.0 ng / ml and those with a total PSA level between 10.1 and 20.0 ng / ml. These separations were determined based on a logistic regression to estimate the relative contribution of free PSA, total PSA, and age to the probability that a patient will be confirmed to have CAP in sextant six core bicones, performed. Table i establishes results of a total PSA test for patients in the range of 2.5 to 10.0 ng // ml. Table 1 CAP CAPIGN BENIGNO BENIGNO CAP BENIGNO Patient age 60 and below > 60 All ages No. of patients 12 47 78 127 90 174 (Total PSA level) Average 6.2 5.7 6.4 5.9 6.3 5.8 Average 6.5 5.5 6.3 5.6 6.3 5.6 Table l (Continued) CAP BENIGNO STATES CAP BENIGNO CAP BENIGNO Patient age 60 and below > 60 All ages Standard deviation * 2.3 1.8 1.8 1.9 1.9 95% CL ** (4.7-7.8) (5.9-6.8) (5.9-6.7) (5.1-6.2) (5.6-6.3) (5.6-6.1) Values p 0.45 0.10 0.05 Standard deviation ** 95% confidence level for the average p values for means using the Wilcoxon test comparing mean values between BENIGN patients and with CAP.

As can be seen from these data, the total PSA test does not discriminate between patients with benign prostate disease and CAP in the range of 2.5 to 10.0 ng / ml. The failure to discriminate is consistent regardless of the age of the patients. Table 2 establishes the test results of free PSA at total PSA for patients in Table 1. Table 2 CAP CAPIGN BENIGNO BENIGNO CAP BENIGNO STATE Patient age 60 and below > 60 All ages No. of Table 2 (Continued) STATUS CAP BENIGNO CAP BENIGNO CAP BENIGNO Patient age 60 and below > 60 All ages Patients 12 47 78 127 90 174 (F / T PSA%) Average - 11 17 16 22 14 21 Average 11 17 14 20 13 19 Standard deviation * 5 8 8 10 8 10 9955 %% CCLL **** ((88--1155)) (13-17) (13--16) (15-20) (20-24) (19--22) Values p 0.007 > 0.0001 > 0.001 Standard Deviation 95% confidence level for the average *** p values for means using the test Ixcoxon comparing mean values between BENIGN patients and with CHAP.

It can be clearly seen that the use of the total free PSA test produces a separation of the average values of patients who have CAP from those who have benign prostate disease. This separation is significant through all ages. For patients who have a total PSA level between 10.1 ng / ml and 20.0 ng / ml, Table 3 shows that the addition of calculating the F / T ratio PSA does not indicate how to differentiate between all patients who have CAP and those who They have benign prostate disease. However, Table 3 shows that the addition of calculating the F / T PSA ratio indicates that you can differentiate between patients who have CAP and those who have benign prostate disease if the patients are over 60, approximately 60 and with less than 60. Table 3 CONDITION OF CAP BENIGNO CAP BENIGNO CAP BENIGNO Patient age 60 and below > 60 All ages No. of Patients 4 5 38 23 42 28 (Total PSA level) Average 13.6 12.1 14.1 13.5 14.1 13.3 Medium 12.7 12.2 14.0 12.4 14.0 12.3 Standard deviation * 3.8 1.3 2.3 2.9 2.5 2.7 95% CL "(7.4 a (10.5 a (13.4 a (12.3 a (13.3 a (12.2 19.7) 13.8) 14.9) 14.9) 14.9) to 14.3) p values 0.62 0.33 0.15 (F / T PSA%) Average 13 14 13 20 13 19 Table 3 (Cont.) STATE CAP BENIGNO CAP BENIGNO CAP BENIGNO Patient age 60 and below > 60 All; s ages Average 10 15 12 20 12 17 Standard deviation * 9 5 5 10 5 9 95% CL ** (0-27) (13-17) (11-15) (9-20) (16-25) (16-23) Values p 0.46 0.001 0.002 * Standard deviation 95% confidence level for average p values for means using the ilcoxon test comparing mean values between BENIGN patients and with CAP.

However, it has been discovered that a logit linear-log model of the above data in Tables i to 3, reveals that the use of a cut-off level > 7% for the F / T PSA ratio, allows the doctor to differentiate between CAP patients and patients with benign prostate disease. Table 4 demonstrates the findings of this model.

Table 4 Percentage probability that the patient has CAP Patient age 60 and below > 60 All ages SA Total "< 10.0 > 10.0 < 10.0 > 10.0 < 10.0 > 10.0 > (F / T PSA) < 7% 84 92 95 98 92 97 > 7% -15% 26 45 56 75 48 71 16% -25% 10 20 28 48 25 46 > 25% 3 7 10 21 9 20 Based on the linear model logit ** "< 10.0" refers to a total PSA range between 2.5 and 10.0 ng / ml, while "< 10.0" refers to a range of total PSA between 10.1 and 20.0 ng / ml.

In total, the model predicts a 95% probability for a patient who has CAP that can be confirmed by prostate biopsy with sextant using the ratio cut < 7% F / T. For patients in the total PSA range of 2.5 to 10.0 ng / ml, the use of a cut-off F / T ratio of < 7% gives a total probability of 92% of the patient having CAP. As recognized by the doctors, a probability greater than 80% in these cases is considered sufficient to diagnose CAP, absent any contraindications. Figure 5 shows the distribution of the F / T ratio in the sample patients. Clearly, CAP patients can be separated from patients with benign prostate disease by using the cut mark with proportion >7% F / T. Using the present method, and in view of the above clinical data, the following scenario can be expected for every 100 prostate biopsies performed in men who have an F / T ratio of less than approximately 7% - approximately 90 will have a diagnosis of CAP confirmed by the bopsy. In a time of increased interest regarding the costs of health care and unnecessary medical procedures, the present invention provides a powerful cynical tool that saves costs for the urologist. Used in the present method, doctors can reliably order a prostate biopsy for a patient for the first time, which has a total PSA level between 2.5 ng / ml and 10.0 ng / ml, or re-order a prostate biopsy for those present that have a total PSA level of between at least 10.0 ng / ml to 20.0 ng / ml but have had a previous negative biopsy. Figures 3 and 4 illustrate pathology reports that use the present method. In Figure 3, the report includes a results view of a first trial for total PSA. The total PSA level for the patient is between 2.5 ng / ml and 10.0 ng / ml. It also includes a list of a calculation that occurs from a free PSA test-the ratio of free PSA to total PSA. The F / T ratio is less than about 7%. Finally, the report includes a diagnosis of the patient who has CAP. Figure 4 is a report for a patient that is measured again. The report includes a list of results and a first trial for total PSA, showing a total PSA level of at least about 10.1 ng / ml. It also includes a list of a calculation that occurs from a free PSA test - the ratio of free PSA to total PSA. The F / T ratio is less than about 7%. Finally, the report includes a diagnosis of a patient with CAP. All publications or unpublished patent applications mentioned herein are incorporated by reference herein. Other embodiments of the present invention are not presented, which are apparent to those skilled in the art now or during the term of any patent granted, and thus are within the spirit and scope of the present invention.

Claims

CLAIMS l.- Method for diagnosing prosthetic adenocarcinoma (CAP) in a male human patient, without requiring a prostate biopsy, characterized in that it comprises: a) measuring the level of total prostate specific antigen (PSA) in the patient's blood or serum; b) measure the level of free PSA in the blood or serum of a patient, only if it has a total PSA level between 2.5 ng / ml and 20.0 ng / ml; c) calculate the ratio of free PSA to total PSA; and d) diagnosing the patient having CAP if the calculated ratio of free PSA to total PSA is less than about 7%. .2.- Method to diagnose prosthetic adenocarcinoma (CAP) in a male human patient who has a measured level of total prostate specific antigen (PSA) of at least 10.1 ng / ml and has a negative prostate biopsy without requiring a biopsy of the prostate. additional prostate to confirm CAP, characterized in that it comprises: a) measuring the level of free PSA in the blood or serum of the patient; b) calculate the ratio of free PSA to total PSA; and c) diagnose the patient having CAP if the calculated ratio of free PSA to total PSA is less than about 7%. 3. The method for diagnosing prosthetic adenosarcinoma (CAP) according to claim 2, characterized in that the level of total prostate specific antigen (PSA) in the patient's blood or serum is also re-measured. 4. The method for diagnosing prosthetic adenocarcinoma (CAP) according to claim 2, characterized in that the level of total prostate specific antigen (PSA) in the blood or serum of the patient is between 10.1 ng / ml and 20.0 ng / ml. 5. - The method for diagnosing prosthetic adenocarcinoma (CAP) according to claim 3, characterized in that the level of specific prostate-specific antigen (PSA) in the blood or serum of the patient is between 10.1 ng / ml and 20.0 ng / ml . 6. A report for a diagnosis of CAP in a male human patient, without requiring a prostate biopsy, characterized because it includes a list of total PSA level between 2.5 ng / ml and 20.0 ng / ml and a list of the proportion of Free PSA to total PSA that is less than about 7%. 7. A report to diagnose CAP in a male human patient who has a total prostate-specific antigen (PSA) level of at least 10.1 ng / ml and has a negative prostate biopsy without requiring an additional prostate biopsy confirm CAP, which comprises a list of total PSA level of at least 10.1 ng / ml and a listing of the ratio of free PSA to total PSA that is less than about 7%.