MXPA97006415A - Novedosos metodos to diagnose prostatic diseases benig - Google Patents

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 human, male patient, without requiring a biopsy. The total level of prostate specific antigen (PSA) is measured in the patient's blood or serum. If the patient has a total PSA level between approximately 2.5 ng / ml and 10.0 ng / ml, then the free level of PSA in the blood or serum of this patient is measured. The ratio of free PSA to total PSA is calculated. If this ratio is equal to, or greater than, approximately 25%, then it is diagnosed that the patient has a BPD, optionally, if the patient has a total PSA level between 10.1 ng / ml and 20.0 ng / ml, then the Free level of PSA in the blood or serum of the patient can also be measured. The ratio of free PSA to total PSA is calculated. If this ratio is equal to or greater than 25%, then it is diagnosed that the patient has a B

Description

NEW METHODS TO DIAGNOSE BENIGN PROSTATIC DISEASES TECHNICAL FIELD The present invention relates to novel methods for diagnosing benign prostatic diseases (BPD), such as benign prostatic hyperplasia or glandular atrophy, in a human 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 10.0 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 equal to or greater than about 25%, then the patient is diagnosed as having BPD. Optionally, if the patient has a total PSA level between 10.1 ng / ml and 20.0 ng (ml), then the total PSA level in the patient's blood or serum can also be measured.The ratio of free PSA to total PSA is calculated If this ratio is equal to or greater than about 25%, then the patient is diagnosed with a BPD RELATED REQUESTS The present application is a partial continuation of Serial Number 393,214, filed on February 23, of PREVIOUS TECHNIQUE It is recognized prostate specific antigen (PSA) as a molecular marker for prostatic adenocarcinoma (CAP) Blood or serum-based immunoassays that measure the total PSA level have been commercially available for a number of years. Detection of total PSA does not necessarily mean that a patient has a CAP In order to distinguish CAP, a test of the total PSA has to satisfy two elements: a high sensitivity - the ability to detect true negative values and avoid false positive values. From clinical experience, total PSA tests have come to be generally accepted as a prediction of CAP if the total PSA level is greater than 10.0 ng / ml. The values of the total PSA between 0.0 ng / ml and about 3.9 ng / ml have been considered as a prediction that there is no disease present, with a value of approximately 3.5 ng / ml being used for men under 60 years of age. and around 2.5 ng / ml being used for men under 50 years of age. (See Oesterling, JE Cooner, WH Jacobsen, SJ Guess HA, and Lieber, MM: "Influence of Patient Age on the Suerum PSA Concentration and Important Clinical Observations" ("Influence of Patient Age on Concentration of PSA in Serum 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 can not reliably distinguish BPD from CAP at less than 10.0 ng / ml. Studies have found that 43% (136/319) of patients with CAP confined to organs have a total PSA value within the normal range of less than 4.0 ng / ml. Also, about 25% (148/597) of men with BPD have a total PSA value above 4.0 ng / ml (See Oesterling, JE: "Prostate Specific Antigen: A Critical Assessment of the Most Use ful Tumor Marker for Adenocarcinoma of the Prostate "(" Prostate Specific Antigen: A Critical Assessment of the Most Useful Markers of Tumors for Adenocarcinoma of the Prostate ", J. Urol, Vol: 145; 907-923, 1991.) Medical practice The standard is the biopsy of patients older than 60 years, who have total PSA levels between 4.0 ng / ml and 10.0 ng / ml, because around 30% of these patients have CAP, similarly, patients between 50 and 60 years old. , whose total PSA is between 3.5 ng / ml and 10.0 ng / ml and patients under 50 years of age, whose total PSA is between 2.5 ng / ml and 10.0 ng / ml, also undergo a biopsy under current medical practice. A proposed method for detecting CAP is described in the application Serial Number WO 92/01936 of Hans Lilja et al. , (Request of Lilja), presented on July 22, 1991, under the Patent Cooperation Treaty (PCT). In general, Lilja's application describes the use of immunoassays to measure free PSA and a complex form of PSA. Free PSA is a single chain glycoenzyme, 33 kDa, which is produced by the epithelial cells that cover the acini and prostatic ducts of the prostate gland. The PSA that has complexed refers primarily to a 90 kDa complex of PSA bound to the alpha 1-antichymotrypsin protein. Free PSA and PSA in complex, and their proportions, are applied in the diagnosis of patients with CAP. In all, the specification reveals the use of a combination of a ratio of free PSA to total PSA (F / T) and a ratio of PSA in complex to a total PSA (C / T) for use in the diagnosis of CAP. No needle biopsy of the prostate is performed on patients, and patients cover a full range of total PSA values. The test does not provide guidance on how to specifically use these proportions.

EXPOSITION OF THE INVENTION The present invention relates to a method for diagnosing BPD in a human male patient, without requiring a biopsy. Currently, if a patient has a total PSA level of 4.0 ng / ml up to 10.0 ng / ml, then it is considered to be in the "gray" diagnostic zone and must undergo a prostate needle biopsy, an operation without anesthetic performed transrectally, which implies pain and substantial discomfort, especially if a sextant biopsy is performed, which requires taking six samples. The present method eliminates the need for approximately one third of these patients to undergo such a biopsy. (See Luderer, AA, et al., "Measurement of the Proportion of Free to Total Prostate." Speci fie Antigen Improves Diagnostic Performance of Prostate- Spec i fie Antigen in The Diagnostic Gray Zone of Total Prostate-Specific Antigen "[" Measurement of the Proportion of the Specific Antigen of the Free to Total Prostate, Improves the Performance of the Diagnosis of the Prostate Specific Antigen in the Gray Zone of Diagnosis of the Specific Antigen Specific to the Total Prostate "], Urol., Vol. 46: 187-194, 1995.) In one modality for those patients in the gray diagnosis zone, the method comprises four stages. First, one measures the level of total PSA in the patient's blood or serum. Second, one measures the level of free PSA in the blood or serum of a patient, but only if it has a total PSA level between about 2.5 ng / ml and 10.0 ng / ml. If the patient has a total PSA level below 2.5 ng / ml, then it is diagnosed to have a BPD. If the patient has a total PSA level above 10.0 ng / ml, then he or she is presumed to have a CAP and must undergo a biopsy. Third, one calculates the proportion of the free PSA to the total PSA. Fourth and final, one diagnoses that the patient has a BPD if the calculated ratio of free PSA to total PSA is equal to or greater than about 25%. Optionally, if the patient is between 50 and 60 years of age, one can use a limit level of 3.5 ng / ml and if the patient is at least 60 years of age, then one can perform the same stages with the use of a lower limit level of 4.0 ng / ml. A report of a diagnosis of BPD in a human male patient, without requiring a biopsy, according to the above modality, comprises listing a total PSA level between 2.5 ng / ml (optionally 3.5 ng / ml for those between 50 and 60 years of age, and 4.0 ng / ml for those at least 60 years of age) and 10.0 ng / ral and list a ratio of free PSA to total PSA equal to or greater than about 25%. The present invention also relates to a method of diagnosing a BPD in a human male patient, who is traditionally assumed to have a CAP, ie, patients having a total PSA level of 10.1 ng / ml up to 20.0 ng / ml. Different from the past, these patients can be examined and identified as having a BPD, rather than a CAP. In this second embodiment, the present method also comprises four stages. First, the level of total PSA in the blood or serum of the patient is measured. Second, the level of free PSA in the patient's blood or serum is measured. Third, the ratio of free PSA to total PSA is calculated. Fourth and final, it is diagnosed that a patient has a BPD if the calculated ratio of free PSA to total PSA is equal to or greater than about 25%. The doctor can use this method with or without a transrectal biopsy. While the standards of care in a particular region may initially dictate that the physician perform such a biopsy, the present method does not require one for the purpose of effective diagnosis of patients with BPD. A report for the diagnosis of BPD in these patients with the highest total PSA, comprises listing a total PSA level between about 10.0 and 20.0 ng / ml and listing a ratio of free PSA to total PSA equal to or greater than about 25 %. Thus, the present methods allow a physician to diagnose BPD in patients who have a total PSA level ranging from 2.5 ng / ml to 20.0 ng / ml.

BRIEF DESCRIPTION OF THE DRAWINGS Figure 1 is a schematic view of the total PSA test used in the present invention. Figure 2 is a schematic view of the free PSA assay used in the present invention. Figure 3 is a graph showing the distribution of total PSA levels for patients with BPD and patients with CAP in Example 1. Figure 4 is a view of a pathology report according to the present invention. Figure 5 is a graph showing the distribution of the F / T ratios for patients with BPD and patients with CAP in Example 1. Figure 6 is a graph showing the cumulative distribution percentage of total PSA levels for patients with BPD and patients with CAP in Example 2. Figure 7 is a graph showing the percentage cumulative distribution of the proportions of F / T of patients with BPD and patients with CAP in Example 2. THE BEST MODES OF CARRYING OUT THE INVENTION Tests In the 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 test is a total PSA sandwich immunoassay, manufactured by Tosoh Medica, Inc. (Tosoh) of Foster City, California. The assay is an immunoenzyme assay using murine double monoclonal antibodies. Figure 1 shows schematically how, in the final sandwich configurations, this first test captures both the free PSA (10) and the complex PSA / ACT (12) using a capture antibody (14) and an antibody (16) labeling of enzyme. The second test is a free PSA immunoassay, manufactured and developed by Immuno Corp for Dianon Systems, Inc. (Dianon), of Stratford, Connecticut. This free PSA test is designed to detect free PSA in serum, with the use of an IRMA coated tube format. Free PSA binds to a tube coated with the monoclonal antibody that selectively binds free PSA, but not PSA in complex. After washing, a polyclonal antibody labeled T.125 against free PSA is reacted with bound free PSA. The physician is supplied with a result that expresses a proportion of the free PSA to the total PSA. Figure 2 shows schematically how in the final sandwich configuration, this second assay captures the free PSA (10), but the capture antibody (14) does not bind specifically to the complex (12) of the PSA / ACT and the antibody (16). ) radio-labeled.

Example 1 Patients with Minor Total PSA In a clinical study to validate the present invention, 434 patients were tested. Classified as "normal", 96 men were identified as being between 45 and 75 years of age and have a normal PSA (that is, less than 2.5 ng / ml of total PSA when they are under 60 and less than 4.0 if they are older than 60 years of age), a normal digital rectal exam (DRE) and no CAP history. The average age was 57 years. They were classified as "BPD", 222 men were identified as being between 45 and 75 years of age, who have BPD histologically confirmed by sextant needle prostate biopsy, and no history of cancer. The average age was 65 years. Classified as "CAP", 116 men were identified as being between 45 and 75 years of age and having a primary CAP histologically confirmed by needle prostate biopsy. The average age was 66 years. None of the previous patients received any form of treatment related to the prostate before drawing blood. The total PSA was measured using the Tosoh 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.

If one restricts the patient population to those 111 patients with CAP and 222 patients with BPD who have a total PSA range between 2.5 ng / ml and 10.0 ng / ml, the use of a total PSA test in blood or serum alone it does not provide any ability to distinguish clinically between patients with CAP or patients with BPD. Table 1 CAP BPD Average 6.3 5.9 Intermediate 6.1 5.6 95% confidence level for the Average (5.91- 6.69) (5.70-6.10) (There is no statistically significant difference in these results.) While adding the stage of measuring free PSA and calculating the ratio of a free PSA to a total PSA, they produce a marked clinical delineation between the average values for patients with CAP and the others, in the suspected group, have a total PSA level between 2.5 ng / ml and 10.0 ng / ml, there is no use for the average values alone as a diagnostic modality.

Table 2 CAP BPD Average (F / T%) 14.5 Intermediate 20.5 (F / T%) 13.0 18.5 Confidence level of 95% for the Average (13.3 - 15.7) (18.3 - 21.7) However, if patients are restricted to those with a total PSA of approximately 2.5 ng / ml to 10.0 ng / ml, and the sensitivity / specificity ratios are examined with respect to F / T ratios, then results are obtained significantly different One can differentiate certain patients with BPD with greater certainty with the use of the F / T ratio limit greater than about 25%. The following table shows the relationship between the ratio of F / T and the sensitivity / specificity: Table 3 Proportion of F / T PSA Sensitivity Speci fi cation < 7% 11% 98% < 10% 30% 92% < 12% 43% 84% < 15% 66% 69% < 20% 88% 47% < 25% 96% 22% < 30% 97% 13% (Here, the sensitivity is reported with respect to the CAP, so at a F / T ratio of <25%, the figure of 96% means that essentially all patients with CAP are present. Inverse, at a F / T ratio of> 25%, there are essentially no CAP patients, only patients with BPD are present.) Using the F / T ratio level of around 25% as a cut-off point for patients who have a total PSA between 2.5 and 10.0 ng / ml, a group of patients can be diagnosed where essentially all patients have BPD. These patients can proceed with a transrectal, invasive and painful needle biopsy.

Graphic evidence of the discrimination power of the present method can be found in Figures 3 and 5. Figure 3 shows a cumulative distribution in percent of blood or serum levels of total PSA in patients within the range of total PSA selected from about 2.5 to 10.0 ng / ml. You can easily see the minimum separation between patients with CAP and patients with BPD. Figure 5 shows the distribution of patients who have CAP or BPD, relative to the proportion of F / T PSA in the blood or serum levels of patients within the range of total selected PSA from 2.5 to 10.0 ng / ml. Clearly, CAP patients can be separated from certain BPD patients, using the approximately 25% mark. With the use of the present method and in view of the above clinical data, one can expect the following scenario if 1000 patients are examined, each with the minimum total PSA required. A total of 250 patients will have CAP. Of those, 96% will have a lower F / T ratio of around 25%. The majority of the 1000 patients (750) will have the BPD. Of these, 78%, or 585 patients, will have an F / R ratio of less than approximately 25%. The remaining 22% of patients with BPD will have an F / T ratio greater than approximately 25%. Using the present method to diagnose BPD, virtually none of the patients who have CAP and a total PSA between 2.5 and 10.0 ng / ml will escape detection. Also, about one third of BPD patients will be prevented from having to undergo a painful transrectal biopsy. In an era of increasing interest about the costs of health care and unnecessary medical procedures, the present method provides a powerful clinical tool that saves costs to the urologist. Patients can be easily diagnosed, which in the past was said to be related to the presence of cancer, but without evidence. Using the present method, a quarter of patients do not need biopsies. Likewise, about a third of the patients to whom they have undergone biopsies will have a CAP, a substantial hobbling of the current practice. Figure 4 illustrates a pathology report using the present method. The report includes a list of the results of a first trial for the total PSA. The total PSA level for the patient is between 2.5 and 10.0 ng / ml. It also includes a listing of a calculation that occurs from the free PSA test - the ratio of free PSA to total PSA. The proportion of F / T is equal to or greater than 25%. Finally, the report includes a diagnosis of the patient who has BPD.

Example 2 Patients with Greater Total PSA In a clinical study, to validate the present invention for traditionally diagnosed patients with CAP, 186 patients were tested. Classified as "normal", 96 men were identified being between 45 and 75 years of age and having a normal PSA (ie less than 2.5 ng / ml for the total PSA, if they are under 60 and 4.0 if they are over 60 years of age), a normal digital rectal exam (DRE) and no CAP history. The average age was 57 years. Classified as "BPD", 41 men were identified being between 45 and 75 years of age, who have a benign prostatic disease, histologically confirmed by sextant water prostate biopsy, and no history of cancer, although they had a level of total PSA blood between 10.1 and 20.0 ng / ml. The average age was 66 years. Classified as "CAP", 49 men were identified being between 45 and 75 years of age, who have a total PSA level between 10. and 20.0 ng / ml and who have a primary CAP, confirmed histologically by prostate biopsy of needle. The average age was 68 years. None of the previous patients received any form of treatment related to the prostate before drawing blood. The total PSA was measured using the Tosoh test, described above, according to the manufacturer's instructions. Free PSA was measured using the Dianon test, described above, according to the manufacturer's instructions. Table 4 presents the results of the total PSA test for patients in the range of 10.1 to 20.0 ng / ml. Table 4 STATE (Total PSA level) All ages Average 13.8 12.9 Intermediate 14.0 12. 0 Standard Deviation 2. 1 2 6 95% level of (13.2-14.4) (12. 1-13.2) confidence for the average (There is no statistically significant difference in these results.) As can be seen from these data, the total PSA test does not discriminate between the CAP and the BPD in the range of 10. l to 20.0 ng / ml. Table 5 shows the results of the test of proportion of free PSA to total PSA for patients in Table 4.

Table 5 CAP BPD Average (F / T%) 12.9 21.0 Intermediate (F / R%) 11.0 19.0 95% level of (11.3-14.5) (17.9-24.1) confidence for the average For patients who have a total PSA level between 10.1 and 20.0 ng / ml, Table 5 shows that the addition of calculating the ratio of F / T PSA does not indicate how to differentiate between all patients who have CAP and those who have BPD, as it was traditionally believed by practicing doctors. However, if the sensitivity / specificity ratios are examined with respect to the F / T ratios, then results that differ significantly are observed. Different BPD patients can be differentiated with greater certainty by using the F / T ratio limit greater than approximately 25%, even among patients who were traditionally believed to have CAP. The following table shows the relationship between the ratio of F / T and sensitivity / specificity.

Table 6 F / T PSA Sensitivity Specificity < 7% 20% 98% < 10% 45% 88% < 12% 57% 80% < 15% 69% 59% < 20% 90% 44% < 25% 98% 29% < 30% 100% 22% (Here, the sensitivity is reported with respect to the CAP, so at an F / T ratio of <25%, the figure of 96% means that essentially all patients with CAP are present. Inverse, at a F / T ratio of> 25%, there are essentially no CAP patients, only patients with BPD are present.) Using the F / T ratio level of around 25% as a cut-off point for patients who have a total PSA between 10.1 and 20.0 ng / ml, a group of patients can be diagnosed where essentially all patients have BPD. These patients can proceed to a transrectal, invasive and painful needle biopsy or if they have already had one and have a negative biopsy, they can be considered free of CAP.

The graphic evidence of the discrimination power of the present method can be found in Figures 6 and 7. Figure 6 shows the percentage of the cumulative distribution of patients who have CAP or BPD, in relation to blood or serum levels of total PSA in patients within the selected total PSA range of approximately 10.1 to 20.0 ng / ml. Poor discrimination may be noted between CAP patients and BPD patients. Figure 7 shows the distribution of patients who have CAP or BPD, relative to the proportion of F / T PSA in the blood or serum levels of patients within the range of total selected PSA from 10.1 to 20.0 ng / ml. The separation between CAP patients and BPD patients can easily be seen: With the use of the present method and in view of the above clinical data, one can expect the following scenario if 1000 patients are examined, each with total PSA minimum required. A total of 500 patients will have the CAP. Of these, 98% will have a lower F / T ratio of around 25%. Most of the remaining 500 patients will have BPD. Of these, 71%, or 355 patients, will have an F / T ratio of less than approximately 25%. The remaining 29% of patients with BPD will have an F / T ratio greater than approximately 25%. By the use of the present method to diagnose BPD, virtually none of the patients who have CAP and a total PSA between 10.1 and 20.0 ng / ml, will escape detection. Also, about 145 of patients with BPD can be prevented from having to undergo a painful transrectal biopsy. In a time of increasing interest about the costs of health care and unnecessary medical procedures, the present method provides a powerful clinical tool that saves costs to the urologist and can be more comfortable for the patient. Patients who have a total PSA level of 10.1 to 20.0 ng / ml can be diagnosed as not having CAP, while in the past they were supposed to have cancer. With the use of the present method, around 15% of patients do not require biopsies. Likewise, about 60% of patients undergoing biopsies will have a CAP, a substantial enrichment of the current practice. All patent applications, published or unpublished, mentioned herein, are incorporated herein by reference. Other embodiments of the present invention are not disclosed and will be obvious to those skilled in the art, now or during the period of issuance of any patent based thereon and are within the spirit and scope of the present invention.

Claims (15)

1. CLAIMS 1. A method to diagnose benign prostatic diseases (BPD) in a human male patient, this method includes: a) measuring the level of total prostate specific antigen (PSA) in the blood or serum of the patient; b) measuring the level of free PSA in the blood or serum of a patient, only if it has a total PSA level between approximately 2.5 and 20.0 ng / ml; c) calculate the proportion of the free PSA to the total PSA; and d) diagnose the patient with a BPD if the calculated ratio of free PSA to total PSA is equal to or greater than about 25%.
2. 2. The method of claim 1, wherein the patient also has a negative prostate biopsy.
3. 3. The method of claim 1, wherein the human male patient is at least 60 years of age and a total PSA level between about 4.0 and 10.0 ng / ml.
4. 4. The method of claim 3, wherein the patient also has a negative prostate biopsy. The method of claim 1, wherein the human male patient is between 50 and 60 years of age and has a total PSA level between about 3.
5. 5 and 10.0 ng / ml.
6. 6. The method of claim 5, wherein the patient has a negative prostate biopsy.
7. The method of claim 1, wherein the human male patient is less than 50 years of age and a total PSA level between about 2.5 and 10.0 ng / ml.
8. The method of claim 7, wherein the patient also has a negative prostate biopsy.
9. The method of claim 1, wherein the human male patient has a total PSA level between about 10.1 and 20.0 ng / ml.
10. The method of claim 9, wherein the patient has a negative prostate biopsy.
11. 11. A report for the diagnosis of benign prostate diseases (BPD) in a human being, which includes a list of the total PSA level between approximately 2.5 and 20.0 ng / ml, and a list of the proportion of free PSA Total PSA equal to or greater than approximately 25%.
12. The report of claim 11, wherein the male human patient is at least 60 years of age and the total PSA level is between about 4.0 and 10.0 ng.
13. 13. The report of claim 11, wherein the human male patient is between 50 and 60 years of age and the total PSA level is between 3.5 and 10.0 ng / ml.
14. 14. The report of claim 11, wherein the male human patient is less than 50 years of age, and the total PSA level is between 2.5 and 10.0 ng / ml.
15. 15. The report of claim 11, wherein the list of the total PSA level is between 10.1 and 20.0 ng / ml.