WO1997039351A1 - Nouveaux procedes de prediction et de detection precoce de l'adenome prostatique - Google Patents

Nouveaux procedes de prediction et de detection precoce de l'adenome prostatique Download PDF

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Publication number
WO1997039351A1
WO1997039351A1 PCT/US1997/006787 US9706787W WO9739351A1 WO 1997039351 A1 WO1997039351 A1 WO 1997039351A1 US 9706787 W US9706787 W US 9706787W WO 9739351 A1 WO9739351 A1 WO 9739351A1
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WIPO (PCT)
Prior art keywords
psa
total
cap
patient
proportion
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PCT/US1997/006787
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English (en)
Inventor
Herbert B. Carter
Daniel W. Chan
Alan W. Partin
Albert A. Luderer
Grant D. Carlson
Robert P. Thiel
Jay D. Pearson
Original Assignee
Carter Herbert B
Chan Daniel W
Partin Alan W
Luderer Albert A
Carlson Grant D
Thiel Robert P
Pearson Jay D
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
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Publication date
Application filed by Carter Herbert B, Chan Daniel W, Partin Alan W, Luderer Albert A, Carlson Grant D, Thiel Robert P, Pearson Jay D filed Critical Carter Herbert B
Publication of WO1997039351A1 publication Critical patent/WO1997039351A1/fr

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    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/53—Immunoassay; Biospecific binding assay; Materials therefor
    • G01N33/574—Immunoassay; Biospecific binding assay; Materials therefor for cancer
    • G01N33/57407—Specifically defined cancers
    • G01N33/57434—Specifically defined cancers of prostate

Definitions

  • the present invention relates to novel methods for the prediction and early detection of prostatic adenocarcinoma (CAP) by differentiating a benign prostatic condition, (BPD), such as benign prostatic hype ⁇ lasia, prostatitis, or glandular atrophy.
  • BPD benign prostatic condition
  • the present invention can be used as a longitudinal screening test for male patients who are younger than patients typically receiving serum or blood testing today.
  • the total prostate specific antigen (PSA) level and the free PSA levels in the blood or serum ofthe patient are measured.
  • the proportion of free PSA to total PSA is calculated. If this proportion is equal to or less than about 10%, then the patient is considered to be a high risk candidate for CAP, and thus, should receive at least an annual detailed evaluation ofthe status of his prostate. For patients having this proportion greater than 10%, the risk of CAP is reduced sufficiently so that the time between examinations can be extended beyond current practice.
  • PSA is recognized as a molecular marker for CAP.
  • Blood or serum based immunoassays measuring the total PSA level have been commercially available for a number of years. 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.
  • 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
  • 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
  • the patient has a total PSA level below 2.5 ng/ml, then he is presumed not to have a malignant lesion. If the patient has a total PSA level above 10.0 ng/ml, then he is presumed to have CAP and must be biopsied. The patient is presumed to have BPD if the calculated proportion of free PSA to total PSA is equal to or greater than about 25%. Confirmation ofthe significant improvement of diagnostic specificity by this work has been reported. (See Catalona, W. J., et alia, "The Valuation of Percentage of Free Prostate Specific Antigen to Improve Specificity of Prostate Cancer Screening", JAMA 274: 1214-1220, 1995.)
  • PSAV Prostate-Specific Antigen Levels in Men With and Without Prostate Disease
  • the optimal time at which PSAV should be evaluated is considered to be between 1.5 and 2.0 years.
  • the present invention relates to novel methods for the prediction and early detection of prostatic adenocarcinoma (CAP) by differentiating patients at a higher risk of getting CAP from normal patients and patients having or likely to get a benign prostatic condition, (BPD), such as benign prostatic hyperplasia, prostatitis, or glandular atrophy.
  • BPD benign prostatic condition
  • the present invention can be used as a longitudinal screening test for male patients who are younger than patients typically receiving serum or blood testing today.
  • the present screening technique would be used on an either an annual or biannual basis for males at least 35 years old.
  • the proportion of free PSA to total PSA is calculated. If this proportion is equal to or less than about from 8% to 12%, preferably 10%, then the patient is considered to be a higher risk candidate for CAP, and thus, should receive at least an annual detailed evaluation of the status of his prostate. For patients having this proportion greater than from about 8% to 12%, preferably 10%, - a lower risk patient, the risk of CAP is reduced sufficiently so that the time between detailed examinations can be extended beyond current practice.
  • the term “higher risk” includes a person having a statistically significant likelihood of developing detectable CAP within a range of up to about ten years in the future, while the term “lower risk” includes a person having a less than five percent chance of developing detectable CAP within the same time interval.
  • the present invention also includes reports as a result of having a CAP longitudinal screening test according to the present method.
  • a report for a selection for a male human patient as being at a higher risk for CAP comprises a listing of a calculated free PSA to total PSA proportion equal to or lesser than about from 8% to 12%, preferably 10% and an identification ofthe patient.
  • a report for a selection for a male human patient as being at a lower risk for CAP comprises a listing of a calculated free PSA to total PSA proportion greater than about 8% to 12%, preferably 10%, and an identification ofthe patient.
  • FIGURE 1 is a diagrammatic view ofthe total PSA assay used in the present invention.
  • FIGURE 2 is a diagrammatic view ofthe free PSA assay used in the present invention.
  • FIGURE 3 is a graph showing a statistical mixed effects analysis of using total PSA tests and years before a diagnosis of CAP.
  • FIGURE 4 is a graph showing a statistical mixed effects analysis of using free PSA tests and years before a diagnosis of CAP.
  • FIGURE 5 is a graph showing a statistical mixed effects analysis of using a calculated free PSA to total PSA proportion and years before a diagnosis of CAP.
  • FIGURE 6 is a graph the performance of a free PSA to total PSA proportion with respect to sensitivity, specificity, and lead time before clinical diagnosis.
  • FIGURE 7 is a graph of a the performance of calculated free PSA to total PSA proportions with respect to lead times.
  • the present method uses three specific immunoassays, however, any specific binding assay that measures either free PSA or total PSA is suitable for the present methods.
  • the first two assays are total PSA sandwich immunoassays. One is manufactured by Tosoh Medics, Inc. (Tosoh) of Foster City, California, the other by Hybritech, Inc. of San Diego, California. These assays are a type of immunoenzymetric 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 third assay is a free PSA immunoassay manufactured developed by Immuno Corp. for Dianon Systems. Inc. (Dianon) of Stratford, Connecticut.
  • 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.
  • an I '25 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.
  • FIGURE 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 ofthe PS A/ ACT complex (12) and radiolabelled antibody (16).
  • Example Total PSA and free PSA serum levels were assayed in a longitudinal retrospective case controlled study of 78 patients. Each subject had serum samples taken at two year intervals for twenty years prior to any diagnosis of prostate status. All serums were cryogenically stored at -70°C. Classified as "normal”, 26 males were identified as being between 50 years and 81 years old at diagnosis. (The age median at diagnosis was 61.2 years old.) The median number of years of follow-up prior to diagnosis was 15.4. These patients had a normal digital rectal examination (DRE), and had no prior history of CAP. Classified as "BPD”, 29 males were identified as being between 55 years old and 89 years old at the time of diagnosis.
  • DRE digital rectal examination
  • Classified as "CAP” 23 males were identified as being between 54 years old and 85 years old at the time of diagnosis, having primary CAP histologically confirmed by simple needle prostate biopsy.
  • Total PSA was measured using either the Hybritech assay or the Tosoh assay described above, in accordance with the manufacturer's instructions. Free
  • PSA was measured using the Dianon assay described above, in accordance with the manufacturer's instructions. Both total PSA levels and free PSA levels were measured from samples at study entry, midway to diagnosis, and at final diagnosis.
  • the results ofthe total PSA testing and free PSA testing of patient samples over time were analyzed to determine if any relationship could be revealed that was predictive of a patient being at either a higher risk or lower risk of getting CAP.
  • longitudinal mixed effects analyses were performed. Such an analysis comprises a mixed effects regression model that controls for concomitant variables when assessing the effect of PSA's interest.
  • the total PSA level, the free PSA level, or the calculated free PSA to total PSA proportion is treated as a random variable to account for the natural heterogeneity of these time dependent values.
  • the regressed PSA value has a confidence interval of 95% which is constructed using the parameters ofthe mixed effect model.
  • the criteria for a patient being positive for purposes of determining lead times from these analyses was that if a calculated free PSA to total PSA proportion was ever less than about 10%, then the patient was considered as positive for CAP.
  • FIGURE 3 shows the results of a statistical longitudinal mixed effects analysis ofthe total PSA testing. Separation of CAP cases and BPD cases from normal cases does not occur until approximately 2.9 years before diagnosis. Thus, total PSA testing is not an effective early predictive marker for a longitudinal screen that differentiates CAP.
  • FIGURE 4 shows the results of a statistical longitudinal mixed effects analysis ofthe free PSA testing. While separation of CAP cases from normal cases occurs at approximately 8 years before diagnosis, separation of CAP cases from BPD cases does not occur until diagnosis.. Thus, one must conclude reasonably that free PSA testing is not an effective early predictive marker for a longitudinal screen that differentiates CAP.
  • FIGURE 5 shows the results of a statistical longitudinal mixed effects analysis ofthe calculation of a free PSA to total PSA proportion.
  • FIGURE 6 The performance ofthe use of a free PSA to total PSA proportion with respect to lead times for predicting CAP is disclosed in FIGURE 6.
  • the lead time within this range is at about at least 10 years before CAP diagnosis. This lead time is particularly important in that identifying a patient before CAP has penetrated the prostatic capsule makes a major difference in the options available to the physician for treatment. Prior to penetration, the physician can select from nerve-sparing prostatectomy, radical prostatectomy, and chemotherapy. After penetration, chemotherapy is the only choice, and a limited one at best, once the cancer has metastasized to varied locations in the patient's bones.
  • FIGURE 7 The difference in predictive power is best seen in FIGURE 7, where clearly either free PSA testing or total PSA testing alone cannot support a conclusion that a patient is at a higher risk or a lower risk of getting CAP in the future.
  • the present method provides a powerful cost-saving clinical tool to the urologist and can be of great comfort to the patient. Patients can begin to be screened at an early age for CAP, 35 years old, which is about 15 years sooner than currently possible.

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Abstract

La présente invention se rapporte à de nouveaux procédés de prédiction et de détection précoce de l'adénome prostatique (CAP) par différentiation d'un état prostatique bénin (BPD) tel que l'hypertrophie de la prostate, la prostatite ou l'atrophie glandulaire. Cette invention peut être notamment utilisée comme test de dépistage longitudinal sur des hommes plus jeunes que ceux sur lesquels on a l'habitude de pratiquer aujourd'hui des tests sanguins et sériques. Au cours de ce test, on détermine la concentration totale d'antigènes spécifiques de la prostate (PSA) ainsi que leurs niveaux de concentration à l'état libre dans le sang ou le sérum. Et on calcule la proportion entre la concentration à l'état libre et la concentration totale d'antigènes spécifiques de la prostate. Si cette proportion est égale ou inférieure à une valeur comprise entre environ 8 % et 12 %, de préférence 10 %, on considère alors que le patient présente un haut risque d'adénome prostatique (CAP), et celui-ci devrait, en conséquence, faire faire chaque année des examens complets concernant l'état de sa prostate. Pour les patients dont la proportion est supérieure à une valeur comprise entre environ 8 % et 12 %, de préférence 10 %, le risque d'adénome prostatique est suffisamment réduit pour que ceux-ci puissent espacer les examens par rapport à la pratique courante.
PCT/US1997/006787 1996-04-12 1997-04-11 Nouveaux procedes de prediction et de detection precoce de l'adenome prostatique WO1997039351A1 (fr)

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9672329B2 (en) 2012-03-05 2017-06-06 Opko Diagnostics, Llc Methods and apparatuses for predicting risk of prostate cancer and prostate gland volume
US11761962B2 (en) 2014-03-28 2023-09-19 Opko Diagnostics, Llc Compositions and methods related to diagnosis of prostate cancer
US11921115B2 (en) 2015-03-27 2024-03-05 Opko Diagnostics, Llc Prostate antigen standards and uses thereof

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1997012245A1 (fr) * 1995-09-29 1997-04-03 Luderer Albert A Nouvelles methodes diagnostiques de carcinome prostatique

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1997012245A1 (fr) * 1995-09-29 1997-04-03 Luderer Albert A Nouvelles methodes diagnostiques de carcinome prostatique

Non-Patent Citations (4)

* Cited by examiner, † Cited by third party
Title
CANCER, 15 March 1996, Vol. 77, No. 6, DEMURA T. et al., "The Proportion of Free to Total Prostate Specific Antigen", pages 1137-1143. *
CLINICAL CHEMISTRY, July 1995, Vol. 41, No. 6, Part 2, WARD A.M., "Free/Total PSA Ratio as an Aid to the Diagnosis of Prostate Carcinoma", page 230, Abstract No. 867. *
SCANDINAVIAN JOURNAL OF CLINICAL LABORATORY INVESTIGATION, May 1995, Vol. 55, Supplement No. 221, PRESTIGIACOMA A.F., "Clinical Usefulness of Free and Complexed PSA", pages 32-34. *
THE JOURNAL OF UROLOGY, September 1995, Vol. 154, No. 3, OESTERLING J.E., "Free, Complexed and Total Serum Prostate Specific Antigen: the Establishment of Appropriate Reference Ranges for Their Concentrations and Ratios", pages 1090-1095. *

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9672329B2 (en) 2012-03-05 2017-06-06 Opko Diagnostics, Llc Methods and apparatuses for predicting risk of prostate cancer and prostate gland volume
CN108108590A (zh) * 2012-03-05 2018-06-01 阿克蒂克合伙公司 分析系统和方法
TWI638277B (zh) * 2012-03-05 2018-10-11 Ｏｐｋｏ診斷法有限責任公司 用於確定前列腺癌相關事件之機率之分析系統及方法
US10672503B2 (en) 2012-03-05 2020-06-02 Opko Diagnostics, Llc Methods and apparatuses for conducting analyses
US11761962B2 (en) 2014-03-28 2023-09-19 Opko Diagnostics, Llc Compositions and methods related to diagnosis of prostate cancer
US11921115B2 (en) 2015-03-27 2024-03-05 Opko Diagnostics, Llc Prostate antigen standards and uses thereof

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