CA2233687A1 - Novel methods for diagnosing prostatic adenocarcinoma - Google Patents
Novel methods for diagnosing prostatic adenocarcinoma Download PDFInfo
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Abstract
The present invention relates to a method for diagnosing prostatic adenocarcinoma (CAP) 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 20.2 ng/ml, then the free PSA level in the blood or serum of the patient is measured. The proportion of free PSA (10) to total PSA (12) is calculated. If this proportion is less than about 7 %, then the patient is diagnosed as having CAP. The present method can also be used on patients that have a total PSA of at least 10.1 ng/ml, but have also had a negative prostate biopsy.
Description
W O97/1224~ PCTrUS96/15586 NOVEL METHODS FOR DlAGNOSING
PROSTATIC ~DENOCARCINOM~
TECHNICAL FIELD
The present invention relates to a method for diagnosing prostatic adenocarcinoma (CAP) in a male hurr~n 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 20.0 ng/ml, then the free 10 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 less than about 7%, then the patient is diagnosed as having CAP. The present method can also be used on patients that have a total PSA of at least 10.1 ng/ml, but have also had a negative prostate biopsy.
BACKGROUND ART
Prostate specific antigen (PSA) is recognized as a molecular marker for 20 prostatic adenocarcinoma (CAP). Blood or serum based imm1-noassays measuring the total PSA level have been co~ ,ially available for a number of years. However, the detection of total PSA does not nPce~rily 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 25 negatives and avoid false positives. From clinical experience, total PSA tests have become 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/rnl have been predictive of no disease being present, with a value of about 2.5 ng/ml being used for men under 60 years old.
SUBSTITUTE StlEET (RULE 26) WO 97/12245 PCT~US96/15586 PSA is primarily organ-specific, not cancer specific. Thus. PSA in blood or serum can result not only from CAP, but also from norrnal or hyperplastic prostate tissues. Below 10.0 ng/ml, a total PSA test cannot distinguish benign prostatic disease, such as benign prostatic hyperplasia (or BPH) from CAP. Studies have found s 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) ofmen with benign prostatic disease have a total PSA value above 4.0 ng/ml. (See Oesterling, J. E., "Prostate Specific Antigen: A Critical ~es~m~nt ofthe Most Useful Tumor Marker for Adenocarcinoma ofthe Prostate", J. Urol., Vol:14~, 907-923, 1991.) Standard m~t1if ~l practice is to biopsy patients having total PSA levels of between 4.0 ng/ml and 10.0 ng/rnl because about 30% of those patients have CAP.
One proposed method for ~ tecting CAP is disclosed in Serial Number WO
92/01936 to Hans Lilja et al., (Lilja application), filed July 22, 1991, under the Patent ls Cooperation Treaty (PCT). In general, the Lilja application discloses usingimmlm~assays to ll,ea iule 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 90kDa complex of PSA bound to alpha 1 - antich~lllotly~aill (ACT) prote~n. Free PSA and complexed PSA, and their proportions are applied in the diagnosis of patients with CAP. Throughout, the specification discloses using a co~ ~Lion of a free PSA to total PSA (F/T) proportion and a complexed PSA to total PSA (C/T) proportion foruse in diagnosing CAP. No prostate needle biopsies were ~,c;lrolllled on the patients, and the patients covered a full range of total PSA values. The text provides no guidance as to specifi~lly how one uses these proportions.
SUBSTITUTE SHEET (RULE 26) WO 97/12245 PCT~US96/15586 SU M M A~Y O F T H E lN V~N l-lO N
The present invention relates to a method for diagnosing CAP in a male human patient without requiring a biopsy. Presently. if a patient has a total PSA level of 4.0 5 ng/ml to 10.0 ng/ml, then he must undergo a prostate needle biopsy, an ~n~osthetic-free operation performed t~ sre~,Lally involving snhst~nti~l pain and discomfort, çspeci~lly if a sextant biopsy is performed which requires taking six samples. The present method elimin~tes the need for about 30% of those patients to undergo such a biopsy for initial diagnosis. A patient diagnosed with CAP from the use of the <7% F/T
10 ~lopo,lion cutoffwould need a prostate biopsy to locate the extent and location of CAP in his prostate. Furthermore, presently, if a patient has a total PSA level of 10.1 ng/ml, and a prostate biopsy has been performed which is negative, the physician is in a quandary as to whether he should continue taking biopsies from the patient now or send the patient home and wait six months. Values of less than 7% for the F/T PSA
15 proportion indicate the presence of CAP and the i--.,-.edi~le need to confirm the extent and location of disease with a biopsy.
As used for p~tient~, in general, the present method comprises four steps.
First, one measures the PSA level in the blood or serum of the patient. Second, one 20 measures the free PSA level in the blood or serurn of a patient, but onlv if he has a total PSA level of between 2.5 ng/ml and 20.0 ng/ml. (As in the past, if the patient has a total PSA level below 2.5 ng/ml, then he is diagnosed to have benign prostaticdisease. If the patient has a total PSA level above 20.0 ng/ml, then he is diagnosed as having CAP.) Third, one calculates the proportion of free PSA to total PSA. Fourth 2s and finally, one diagnoses the patient as having CAP if the calculated proportion of free PSA to total PSA is less than about 7%. Another embodiment of the present invention is a report for a diagnosis of a male human patient having CAP withoutrequiring a biopsy. This report comprises listing a total PSA level of between 2.5 ng/ml and 20.0 ng/rnl and listing a free PSA to total PSA proportion which is less than 30 about 7%. As used for patients who have a total PSA level of at least l O. l ng/rnl and SUBSTITUTE SHEET (RULE 26) -W 097/12245 PCT~US96/15586 have already been biopsied. but with negative results, the present method also comprises three steps. First. one measures the free PSA level in the blood or serum of the patient. (Optionally. one can re-measure the total PSA level in the blood or serum of the patient.) Then one c~l~ul~tes the proportion of free PSA to total PSA. Finally.
s one diagnoses the patient as having CAP if the calculated proportion of free PSA to total PSA is less than about 7%, without requiring a further prostate biopsy to confirm CAP.
A further embodiment of the present invention is a report for a diagnosis of a 0 male human patient having CAP who has a total PSA level of at least 10. l ng/ml and has had a negative prostate biopsy without requiring a further prostate biopsy to confirIn CAP. This report comprises a listing a total PSA level of between 10.1 ng/ml and 20.0 ng/ml and a listing of a free PSA to total PSA proportion which is less than about 7%.
DESCRIPTION OF THE DRAWINGS
FIGURE 1 is a dia~ . "" ,~ view of the total PSA assay used in the present invention.
FIGURE 2 is a dia~ view of the free PSA assay used in the present invention.
FIGURE 3 is a view of a pathology report according to the present invention.
25 FIGURE 4 is a view of a pathology report according to the present invention wherein the patient has already been det~rminP-l to have a total PSA level of at least 10.1, but has had a negative biopsy.
FIGURE 5 is a graph showing the distribution of F/T proportions versus the 30 probability of a patient having CAP.
SUBSTITUTE SHEET (RULE 26) WO97/12245 PCT~US96/1~586 ~ ;~ED EMBODIn,qL~;NlL-;3 c Assavs In a prer~l.ed embodiment, the present method comprises two immlm~assays.
5 The first assay is a total PSA sandwich immllnl~assay m~nllf~ctured by Tosoh Medics, Inc. (Tosoh) of Foster City, California. The assay is an immnnoenzymetric assay using dual murine monoclonal antibodies. FIGTJRE 1 shows dia~ """~lir~11y 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 labelled o antibody ( 16).
The second assay is a free PSA immlm~assay m~n--f~rtured developed by Tmmlln~ Corp. for Dianon Systems, Inc. (Dianon) of Stratford, Cormecticut. This free PSA test is clrsip:n~ocl to detect free PSA in serum using an IRMA coated tube forrnat.
15 Free PSA binds to a tube coated by a monoclonal antibody which selectively binds free PSA but not complexed PSA. After washing, an I125 labelled 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 ia~,-""~ ir~lly how in the fin~l sandwich configuration, this second assay c~uLul~s 20 free PSA (10), but the capture antibody (14) does not specifically bind to the complex ofthe PSA/ACT complex (12) and radio-labelled antibody (16).
Example In a clinical study to validate the present invention, 334 patients were tested.25 Cl~ifi~cl as "BENIGN", 90 males were identified as being between 45 years old and 75 years old, having berlign prostate disease histologically confirmed by sextant needle prostate biopsy, and no history of cancer. The age mean was 65. Classified as "CAP", 174 males were identified as being between 45 years old and 75 years old and having primary CAP histologically confirmed by needle prostate biopsy. The age mean was30 67. None of the above patients received any form of prostate-related trç~tmrnt prior SUBSTI~IJTE Sl~r~T ~R~JL~ 2 WO 97/12245 PCTrUS96/15586 to blood draw. Total PSA was measured using the Tosoh assay described above, in accordance with the m~n~lf~rturer's instructions. Free PSA was measured using the Dianon assay described above, in accordance with the m~nllf~rturer's instructions.
The patient sample was split on the basis of age between those over 60 years old and those 60 years and under. It was further split between those having a total PSA level of between 2.5 ng/rnl and 10.0 ng/ml and those having a total PSA level of between 10.1 and 20.0 ng/rnl. These splits were ~let~rmin~l on the basis of a logistic regression to assess the relative contribution of free PSA, total PSA, and age to the 0 probability that a patient will be confiIIned as having CAP on sextant, six core biopsy performed.
Table 1 outlines the results of total PSA testing for patients in the 2.5 to 10.0 ng/ml range.
1S Table 1 STATUS CAP BENIGN CAP BENIGN CAP BENIGN
Patient Age60 and under >60 All ages No. Patients 12 47 78 127 90 174 (Total PSA level) Mean 6.2 5.7 6.4 5.9 6.3 5.8 Median 6.5 5.5 6.3 5.6 6.3 5.6 Std. Dev.* 2.3 1.8 1.8 1.9 1.9 1.9 95% CL** (4.7-7.8) (5.1-6.2) (5.9-6.8) (5.6-6.3)(5.9-6.7) (5.6-6.1) p-values *** 0.45 0.10 0.05 * standard deviation SUBSTITUTE SHEET (RULE 263 W O 97/12245 PCT~US96/1~586 ** 95% confidence level for the mean *** p-values for m~ n~ using the Wilcoxon test comparing median values between BENIGN and CAP patients s As can be seen from this data, total PSA testing does not dis~. "llillate between CAP
and benign prostate disease patients in the 2.5 to 10.0 ng/ml range. The failure to dis~ .~le is consistent regardless of patient age.
Table 2 outlines the results of free PSA to total PSA testing for the patients in lo Table 1.
Table 2 STATUSCAP BENIGN CAP BENIGN CAP BENIGN
Patient Age60 and under >60 All ages No. Patients 12 47 78 127 90 174 (F/T PSA %) Mean 11 17 16 22 14 21 Median 11 17 14 20 13 19 Std. Dev.* 5 8 8 10 8 10 95% CL** (8-15) (15-20) (13-17) (20-24) (13-16) (19-22) p-values *** 0.007 <0.0001<0.001 * standard deviation ** 95 % confi-len~e level for the mean *** p-values for m~ n~ using the Wilcoxon test comp~rin~ median values between BENIGN and CAP patients SUBSTITUTE S~Et T (RUL~ 263 One can clearly see that the use of free to total PSA testing produces a separation of the median values of patients having CAP from those havin~J benign prostate disease.
This separation is ~iEnifi~nt across all ages.
s For patients having a total PSA level of between 10.1 ng/rnl and 20.0 ng/ml, Table 3 shows that the addition of calculating the F/T PSA proportion does not indicate how to di~ele~ le between all patients having CAP and those having benign prostate disease. However, Table 3 does show that the addition of c~l~nl~ting the F/T
0 PSA proportion intli~tes that one can di~ .lli~e between patients having CAP and those having benign prostate disease if the ~Lic~ are over 60, rather than 60 and under.
Table 3 STATUS CAP BENIGN CAP BENIGN CAP BENIGN
Patient Age60 andunder >60 All ages No. Patients 4 5 38 23 42 28 (Total PSA level) Mean 13.6 12.1 14.1 13.5 14.113.3 Median 12.7 12.2 14.0 12.4 14.012.3 Std. Dev.* 3.8 1.3 2.3 2.9 2.52.7 2s 95 CL** (7.4 to(10.5 to(13.4 to(12.3 to(13.3 to (12.2 to 19.7) 13.8)14.9) 14.9) 14.9) 14.3) p-values *** 0.62 0.33 0.15 (F/T PSA %) SUBSTITUTE SffEET (PsULE 26 W O 97/12245 PCTrUS96/15586 Mean 13 14 13 20 13 19 Median 10 15 12 20 12 17 Std. Dev.* 9 5 5 10 5 9 95% CL** (0-27) (9-20) (13-17) (16-25) (11-15) (16-23) p-values *** 0.46 0.001 0.002 * standard deviation ** 95% confi~1~n~e level for the mean *** p-values for m~ n~ using the Wilcoxon test comparing median values between 10 BENIGN and CAP patients However, it has been discovered that a log-linear logit model of the above data in Tables 1 to 3 does reveal that the use of a <7% cutoff level for the F/T PSA
15 proportion enables the physician to ~ c.~ le between CAP patients and benign prostate disease patients. Table 4 demonstrates the fin-lin~ of this modeling.
Table 4 Percent probability that the patient has CAP
Patient Age 60 and under >60 All ages Total PSA** <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 SUBSTITUTE S~-ET ~.'J~ F 26~
WO 97/12245 PCTnUS96115586 * based on logit linear model ** "<10.0" refers to a total PSA range of between 2.5 and 10.0 ng/mL while ">10.0"
refers to a total PSA range of between 10.1 and 20.0 ng/rnl.
Overall, the model predicts a 95% probability for a patient having CAP that can be confirmed by sextant prostate biopsy using the <7% F/T proportion cutoff. Forpatients in the total PSA range of 2.5 to 10.0 ng/ml, the use of a F/T plopollion cutoff of <7% gives an overall 92% chance of the patient having CAP. As recognized by 1 o physicians, a probability of greater than 80% in these cases is regarded as snffi~ient to diagnose CAP, absent any contr~in-lirP~ti~-ns. FIGURE 5 shows the di~llibuLion ofthe F/T proportion in the sample patients. Clearly the CAP patients can be separatedbenign prostate disease patients by using the about <7% F/T proportion cutoffmark.
Using the present method, and in view of the above clinical data, one can expect the following scenario for every 100 prostate biopsies p~;lr~lllled on males having a F/T proportion of less than about 7% -- about 90 will have a diagnosis of CAP confirrn~cl by the biopsy. In a time of ~ncLca~illg concern about health care costs and nnn~ces~ry m~ 1 procedures~ the present method provides a powerful cost-saving clinical tool to the urologist. Using the present method, physicians can confidently order a prostate biopsy for a first-time patient having a total PSA level of between 2.5 ng/ml and 10.0 ng/ml, or reorder a prostate biopsy for those patients having a total PSA level of between at least 10.1 ng/ml to 20 ng/ml, but have had a prior negative biopsy.
FIGURE 3 and 4 illustrates pathology reports that use the present method. In FIGURE 3, the report includes a listing of the results of a first assay for total PSA.
The total PSA level for the patient is between 2.5 ng/ml and 10 ng/ml. It also includes a listing of a c~ nl~ti--n occurring from a free PSA assay -- the free PSA to total PSA
proportion. The F/T proportion is less than about 7%. Finally, the report includes a SUE~STI ~ E S.ri_~ i f~U~ -, 2~' WO 97/12245 PCT~US96/15586 diagnosis of the patient as having CAP. FIGURE 4 is a report for a patient that is being re-measured. The report includes a listing of the results of a first assay for total PSA, showing a total PSA level of at least about 10.1 ng/ml. It also includes a listing of a c~k ~ ti~ n occurring from a free PSA assay -- the free PSA to total PSA
s proportion. The F/T proportion is less than about 7%. Finally, the report includes a diagnosis of the patient as having CAP.
All publications or unpllhli~hPcl patent applications mentioned herein are hereby incorporated by reference thereto.
Other embodiments of the present invention are not presented here which are obvious to those of skill in the art, now or during the terrn of any patent issuing herefrom, and thus, are within the spirit and scope of the present invention.
SUBSTITUTE SffEET (RULE 2~
PROSTATIC ~DENOCARCINOM~
TECHNICAL FIELD
The present invention relates to a method for diagnosing prostatic adenocarcinoma (CAP) in a male hurr~n 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 20.0 ng/ml, then the free 10 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 less than about 7%, then the patient is diagnosed as having CAP. The present method can also be used on patients that have a total PSA of at least 10.1 ng/ml, but have also had a negative prostate biopsy.
BACKGROUND ART
Prostate specific antigen (PSA) is recognized as a molecular marker for 20 prostatic adenocarcinoma (CAP). Blood or serum based imm1-noassays measuring the total PSA level have been co~ ,ially available for a number of years. However, the detection of total PSA does not nPce~rily 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 25 negatives and avoid false positives. From clinical experience, total PSA tests have become 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/rnl have been predictive of no disease being present, with a value of about 2.5 ng/ml being used for men under 60 years old.
SUBSTITUTE StlEET (RULE 26) WO 97/12245 PCT~US96/15586 PSA is primarily organ-specific, not cancer specific. Thus. PSA in blood or serum can result not only from CAP, but also from norrnal or hyperplastic prostate tissues. Below 10.0 ng/ml, a total PSA test cannot distinguish benign prostatic disease, such as benign prostatic hyperplasia (or BPH) from CAP. Studies have found s 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) ofmen with benign prostatic disease have a total PSA value above 4.0 ng/ml. (See Oesterling, J. E., "Prostate Specific Antigen: A Critical ~es~m~nt ofthe Most Useful Tumor Marker for Adenocarcinoma ofthe Prostate", J. Urol., Vol:14~, 907-923, 1991.) Standard m~t1if ~l practice is to biopsy patients having total PSA levels of between 4.0 ng/ml and 10.0 ng/rnl because about 30% of those patients have CAP.
One proposed method for ~ tecting CAP is disclosed in Serial Number WO
92/01936 to Hans Lilja et al., (Lilja application), filed July 22, 1991, under the Patent ls Cooperation Treaty (PCT). In general, the Lilja application discloses usingimmlm~assays to ll,ea iule 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 90kDa complex of PSA bound to alpha 1 - antich~lllotly~aill (ACT) prote~n. Free PSA and complexed PSA, and their proportions are applied in the diagnosis of patients with CAP. Throughout, the specification discloses using a co~ ~Lion of a free PSA to total PSA (F/T) proportion and a complexed PSA to total PSA (C/T) proportion foruse in diagnosing CAP. No prostate needle biopsies were ~,c;lrolllled on the patients, and the patients covered a full range of total PSA values. The text provides no guidance as to specifi~lly how one uses these proportions.
SUBSTITUTE SHEET (RULE 26) WO 97/12245 PCT~US96/15586 SU M M A~Y O F T H E lN V~N l-lO N
The present invention relates to a method for diagnosing CAP in a male human patient without requiring a biopsy. Presently. if a patient has a total PSA level of 4.0 5 ng/ml to 10.0 ng/ml, then he must undergo a prostate needle biopsy, an ~n~osthetic-free operation performed t~ sre~,Lally involving snhst~nti~l pain and discomfort, çspeci~lly if a sextant biopsy is performed which requires taking six samples. The present method elimin~tes the need for about 30% of those patients to undergo such a biopsy for initial diagnosis. A patient diagnosed with CAP from the use of the <7% F/T
10 ~lopo,lion cutoffwould need a prostate biopsy to locate the extent and location of CAP in his prostate. Furthermore, presently, if a patient has a total PSA level of 10.1 ng/ml, and a prostate biopsy has been performed which is negative, the physician is in a quandary as to whether he should continue taking biopsies from the patient now or send the patient home and wait six months. Values of less than 7% for the F/T PSA
15 proportion indicate the presence of CAP and the i--.,-.edi~le need to confirm the extent and location of disease with a biopsy.
As used for p~tient~, in general, the present method comprises four steps.
First, one measures the PSA level in the blood or serum of the patient. Second, one 20 measures the free PSA level in the blood or serurn of a patient, but onlv if he has a total PSA level of between 2.5 ng/ml and 20.0 ng/ml. (As in the past, if the patient has a total PSA level below 2.5 ng/ml, then he is diagnosed to have benign prostaticdisease. If the patient has a total PSA level above 20.0 ng/ml, then he is diagnosed as having CAP.) Third, one calculates the proportion of free PSA to total PSA. Fourth 2s and finally, one diagnoses the patient as having CAP if the calculated proportion of free PSA to total PSA is less than about 7%. Another embodiment of the present invention is a report for a diagnosis of a male human patient having CAP withoutrequiring a biopsy. This report comprises listing a total PSA level of between 2.5 ng/ml and 20.0 ng/rnl and listing a free PSA to total PSA proportion which is less than 30 about 7%. As used for patients who have a total PSA level of at least l O. l ng/rnl and SUBSTITUTE SHEET (RULE 26) -W 097/12245 PCT~US96/15586 have already been biopsied. but with negative results, the present method also comprises three steps. First. one measures the free PSA level in the blood or serum of the patient. (Optionally. one can re-measure the total PSA level in the blood or serum of the patient.) Then one c~l~ul~tes the proportion of free PSA to total PSA. Finally.
s one diagnoses the patient as having CAP if the calculated proportion of free PSA to total PSA is less than about 7%, without requiring a further prostate biopsy to confirm CAP.
A further embodiment of the present invention is a report for a diagnosis of a 0 male human patient having CAP who has a total PSA level of at least 10. l ng/ml and has had a negative prostate biopsy without requiring a further prostate biopsy to confirIn CAP. This report comprises a listing a total PSA level of between 10.1 ng/ml and 20.0 ng/ml and a listing of a free PSA to total PSA proportion which is less than about 7%.
DESCRIPTION OF THE DRAWINGS
FIGURE 1 is a dia~ . "" ,~ view of the total PSA assay used in the present invention.
FIGURE 2 is a dia~ view of the free PSA assay used in the present invention.
FIGURE 3 is a view of a pathology report according to the present invention.
25 FIGURE 4 is a view of a pathology report according to the present invention wherein the patient has already been det~rminP-l to have a total PSA level of at least 10.1, but has had a negative biopsy.
FIGURE 5 is a graph showing the distribution of F/T proportions versus the 30 probability of a patient having CAP.
SUBSTITUTE SHEET (RULE 26) WO97/12245 PCT~US96/1~586 ~ ;~ED EMBODIn,qL~;NlL-;3 c Assavs In a prer~l.ed embodiment, the present method comprises two immlm~assays.
5 The first assay is a total PSA sandwich immllnl~assay m~nllf~ctured by Tosoh Medics, Inc. (Tosoh) of Foster City, California. The assay is an immnnoenzymetric assay using dual murine monoclonal antibodies. FIGTJRE 1 shows dia~ """~lir~11y 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 labelled o antibody ( 16).
The second assay is a free PSA immlm~assay m~n--f~rtured developed by Tmmlln~ Corp. for Dianon Systems, Inc. (Dianon) of Stratford, Cormecticut. This free PSA test is clrsip:n~ocl to detect free PSA in serum using an IRMA coated tube forrnat.
15 Free PSA binds to a tube coated by a monoclonal antibody which selectively binds free PSA but not complexed PSA. After washing, an I125 labelled 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 ia~,-""~ ir~lly how in the fin~l sandwich configuration, this second assay c~uLul~s 20 free PSA (10), but the capture antibody (14) does not specifically bind to the complex ofthe PSA/ACT complex (12) and radio-labelled antibody (16).
Example In a clinical study to validate the present invention, 334 patients were tested.25 Cl~ifi~cl as "BENIGN", 90 males were identified as being between 45 years old and 75 years old, having berlign prostate disease histologically confirmed by sextant needle prostate biopsy, and no history of cancer. The age mean was 65. Classified as "CAP", 174 males were identified as being between 45 years old and 75 years old and having primary CAP histologically confirmed by needle prostate biopsy. The age mean was30 67. None of the above patients received any form of prostate-related trç~tmrnt prior SUBSTI~IJTE Sl~r~T ~R~JL~ 2 WO 97/12245 PCTrUS96/15586 to blood draw. Total PSA was measured using the Tosoh assay described above, in accordance with the m~n~lf~rturer's instructions. Free PSA was measured using the Dianon assay described above, in accordance with the m~nllf~rturer's instructions.
The patient sample was split on the basis of age between those over 60 years old and those 60 years and under. It was further split between those having a total PSA level of between 2.5 ng/rnl and 10.0 ng/ml and those having a total PSA level of between 10.1 and 20.0 ng/rnl. These splits were ~let~rmin~l on the basis of a logistic regression to assess the relative contribution of free PSA, total PSA, and age to the 0 probability that a patient will be confiIIned as having CAP on sextant, six core biopsy performed.
Table 1 outlines the results of total PSA testing for patients in the 2.5 to 10.0 ng/ml range.
1S Table 1 STATUS CAP BENIGN CAP BENIGN CAP BENIGN
Patient Age60 and under >60 All ages No. Patients 12 47 78 127 90 174 (Total PSA level) Mean 6.2 5.7 6.4 5.9 6.3 5.8 Median 6.5 5.5 6.3 5.6 6.3 5.6 Std. Dev.* 2.3 1.8 1.8 1.9 1.9 1.9 95% CL** (4.7-7.8) (5.1-6.2) (5.9-6.8) (5.6-6.3)(5.9-6.7) (5.6-6.1) p-values *** 0.45 0.10 0.05 * standard deviation SUBSTITUTE SHEET (RULE 263 W O 97/12245 PCT~US96/1~586 ** 95% confidence level for the mean *** p-values for m~ n~ using the Wilcoxon test comparing median values between BENIGN and CAP patients s As can be seen from this data, total PSA testing does not dis~. "llillate between CAP
and benign prostate disease patients in the 2.5 to 10.0 ng/ml range. The failure to dis~ .~le is consistent regardless of patient age.
Table 2 outlines the results of free PSA to total PSA testing for the patients in lo Table 1.
Table 2 STATUSCAP BENIGN CAP BENIGN CAP BENIGN
Patient Age60 and under >60 All ages No. Patients 12 47 78 127 90 174 (F/T PSA %) Mean 11 17 16 22 14 21 Median 11 17 14 20 13 19 Std. Dev.* 5 8 8 10 8 10 95% CL** (8-15) (15-20) (13-17) (20-24) (13-16) (19-22) p-values *** 0.007 <0.0001<0.001 * standard deviation ** 95 % confi-len~e level for the mean *** p-values for m~ n~ using the Wilcoxon test comp~rin~ median values between BENIGN and CAP patients SUBSTITUTE S~Et T (RUL~ 263 One can clearly see that the use of free to total PSA testing produces a separation of the median values of patients having CAP from those havin~J benign prostate disease.
This separation is ~iEnifi~nt across all ages.
s For patients having a total PSA level of between 10.1 ng/rnl and 20.0 ng/ml, Table 3 shows that the addition of calculating the F/T PSA proportion does not indicate how to di~ele~ le between all patients having CAP and those having benign prostate disease. However, Table 3 does show that the addition of c~l~nl~ting the F/T
0 PSA proportion intli~tes that one can di~ .lli~e between patients having CAP and those having benign prostate disease if the ~Lic~ are over 60, rather than 60 and under.
Table 3 STATUS CAP BENIGN CAP BENIGN CAP BENIGN
Patient Age60 andunder >60 All ages No. Patients 4 5 38 23 42 28 (Total PSA level) Mean 13.6 12.1 14.1 13.5 14.113.3 Median 12.7 12.2 14.0 12.4 14.012.3 Std. Dev.* 3.8 1.3 2.3 2.9 2.52.7 2s 95 CL** (7.4 to(10.5 to(13.4 to(12.3 to(13.3 to (12.2 to 19.7) 13.8)14.9) 14.9) 14.9) 14.3) p-values *** 0.62 0.33 0.15 (F/T PSA %) SUBSTITUTE SffEET (PsULE 26 W O 97/12245 PCTrUS96/15586 Mean 13 14 13 20 13 19 Median 10 15 12 20 12 17 Std. Dev.* 9 5 5 10 5 9 95% CL** (0-27) (9-20) (13-17) (16-25) (11-15) (16-23) p-values *** 0.46 0.001 0.002 * standard deviation ** 95% confi~1~n~e level for the mean *** p-values for m~ n~ using the Wilcoxon test comparing median values between 10 BENIGN and CAP patients However, it has been discovered that a log-linear logit model of the above data in Tables 1 to 3 does reveal that the use of a <7% cutoff level for the F/T PSA
15 proportion enables the physician to ~ c.~ le between CAP patients and benign prostate disease patients. Table 4 demonstrates the fin-lin~ of this modeling.
Table 4 Percent probability that the patient has CAP
Patient Age 60 and under >60 All ages Total PSA** <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 SUBSTITUTE S~-ET ~.'J~ F 26~
WO 97/12245 PCTnUS96115586 * based on logit linear model ** "<10.0" refers to a total PSA range of between 2.5 and 10.0 ng/mL while ">10.0"
refers to a total PSA range of between 10.1 and 20.0 ng/rnl.
Overall, the model predicts a 95% probability for a patient having CAP that can be confirmed by sextant prostate biopsy using the <7% F/T proportion cutoff. Forpatients in the total PSA range of 2.5 to 10.0 ng/ml, the use of a F/T plopollion cutoff of <7% gives an overall 92% chance of the patient having CAP. As recognized by 1 o physicians, a probability of greater than 80% in these cases is regarded as snffi~ient to diagnose CAP, absent any contr~in-lirP~ti~-ns. FIGURE 5 shows the di~llibuLion ofthe F/T proportion in the sample patients. Clearly the CAP patients can be separatedbenign prostate disease patients by using the about <7% F/T proportion cutoffmark.
Using the present method, and in view of the above clinical data, one can expect the following scenario for every 100 prostate biopsies p~;lr~lllled on males having a F/T proportion of less than about 7% -- about 90 will have a diagnosis of CAP confirrn~cl by the biopsy. In a time of ~ncLca~illg concern about health care costs and nnn~ces~ry m~ 1 procedures~ the present method provides a powerful cost-saving clinical tool to the urologist. Using the present method, physicians can confidently order a prostate biopsy for a first-time patient having a total PSA level of between 2.5 ng/ml and 10.0 ng/ml, or reorder a prostate biopsy for those patients having a total PSA level of between at least 10.1 ng/ml to 20 ng/ml, but have had a prior negative biopsy.
FIGURE 3 and 4 illustrates pathology reports that use the present method. In FIGURE 3, the report includes a listing of the results of a first assay for total PSA.
The total PSA level for the patient is between 2.5 ng/ml and 10 ng/ml. It also includes a listing of a c~ nl~ti--n occurring from a free PSA assay -- the free PSA to total PSA
proportion. The F/T proportion is less than about 7%. Finally, the report includes a SUE~STI ~ E S.ri_~ i f~U~ -, 2~' WO 97/12245 PCT~US96/15586 diagnosis of the patient as having CAP. FIGURE 4 is a report for a patient that is being re-measured. The report includes a listing of the results of a first assay for total PSA, showing a total PSA level of at least about 10.1 ng/ml. It also includes a listing of a c~k ~ ti~ n occurring from a free PSA assay -- the free PSA to total PSA
s proportion. The F/T proportion is less than about 7%. Finally, the report includes a diagnosis of the patient as having CAP.
All publications or unpllhli~hPcl patent applications mentioned herein are hereby incorporated by reference thereto.
Other embodiments of the present invention are not presented here which are obvious to those of skill in the art, now or during the terrn of any patent issuing herefrom, and thus, are within the spirit and scope of the present invention.
SUBSTITUTE SffEET (RULE 2~
Claims (7)
1. A method for diagnosing prostatic adenocarcinoma (CAP) in a male human patient without requiring a prostate biopsy comprising:
a) measuring the total prostate specific antigen (PSA) level in the blood or serum of the patient;
b) measuring the free PSA level in the blood or serum of a patient only if he has a total PSA level of between 2.5 ng/ml and 20.0 ng/ml;
c) calculating the proportion of free PSA to total PSA; and d) diagnosing the patient as having CAP if the calculated proportion of free PSAto total PSA is less than about 7%.
a) measuring the total prostate specific antigen (PSA) level in the blood or serum of the patient;
b) measuring the free PSA level in the blood or serum of a patient only if he has a total PSA level of between 2.5 ng/ml and 20.0 ng/ml;
c) calculating the proportion of free PSA to total PSA; and d) diagnosing the patient as having CAP if the calculated proportion of free PSAto total PSA is less than about 7%.
2. A method for diagnosing prostatic adenocarcinoma (CAP) in a male human patient who has a measured total prostate specific antigen (PSA) level of at least 10.1 ng/ml and has had a negative prostate biopsy without requiring a further prostate biopsy to confirm CAP comprising:
a) measuring the free PSA level in the blood or serum of the patient;
b) calculating the proportion of free PSA to total PSA; and c) diagnosing the patient as having CAP if the calculated proportion of free PSAto total PSA is less than about 7%.
a) measuring the free PSA level in the blood or serum of the patient;
b) calculating the proportion of free PSA to total PSA; and c) diagnosing the patient as having CAP if the calculated proportion of free PSAto total PSA is less than about 7%.
3. The method for diagnosing prostatic adenocarcinoma (CAP) as in Claim 2 wherein one also re-measures the total prostate specific antigen (PSA) level in the blood or serum of the patient.
4. The method for diagnosing prostatic adenocarcinoma (CAP) as set forth in Claim 2 wherein one the total prostate specific antigen (PSA) level in the blood or serum of the patient is between 10. 1 ng/ml and 20.0 ng/ml.
5. The method for diagnosing prostatic adenocarcinoma (CAP) as set forth in Claim 3 wherein one the total prostate specific antigen (PSA) level 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 comprising a listing a total PSA level of between 2.5 ng/ml and 20.0 ng/ml and a listing of a free PSA to total PSA proportion which is less than about 7%.
7. A report for a diagnosis of CAP in a male human patient who has a measured total prostate specific antigen (PSA) level of at least 10.1 ng/ml and has had a negative prostate biopsy without requiring a further prostate biopsy to confirm CAP
comprising a listing a total PSA level of at least 10.1 ng/ml and a listing of a free PSA to total PSA proportion which is less than about 7%.
comprising a listing a total PSA level of at least 10.1 ng/ml and a listing of a free PSA to total PSA proportion which is less than about 7%.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US08/536,215 US5710007A (en) | 1995-09-29 | 1995-09-29 | Methods for diagnosing prostatic adenocarcinoma |
| US08/536,215 | 1995-09-29 | ||
| PCT/US1996/015586 WO1997012245A1 (en) | 1995-09-29 | 1996-09-27 | Novel methods for diagnosing prostatic adenocarcinoma |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA2233687A1 true CA2233687A1 (en) | 1997-04-03 |
Family
ID=29405951
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA 2233687 Abandoned CA2233687A1 (en) | 1995-09-29 | 1996-09-27 | Novel methods for diagnosing prostatic adenocarcinoma |
Country Status (1)
| Country | Link |
|---|---|
| CA (1) | CA2233687A1 (en) |
-
1996
- 1996-09-27 CA CA 2233687 patent/CA2233687A1/en not_active Abandoned
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