EP1068534A1 - Procede de differenciation du cancer de la prostate - Google Patents

Procede de differenciation du cancer de la prostate

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Publication number
EP1068534A1
EP1068534A1 EP99902563A EP99902563A EP1068534A1 EP 1068534 A1 EP1068534 A1 EP 1068534A1 EP 99902563 A EP99902563 A EP 99902563A EP 99902563 A EP99902563 A EP 99902563A EP 1068534 A1 EP1068534 A1 EP 1068534A1
Authority
EP
European Patent Office
Prior art keywords
psa
patients
pca
total
ratio
Prior art date
Legal status (The legal status 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 status listed.)
Withdrawn
Application number
EP99902563A
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German (de)
English (en)
Inventor
Maciej Kwiatkowski
Jonas Hugosson
Hans Lilja
Timo Lövgren
Kim Pettersson
Timo Piironen
Franz Recker
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Arctic Partners Oy AB
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Arctic Partners Oy AB
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Application filed by Arctic Partners Oy AB filed Critical Arctic Partners Oy AB
Publication of EP1068534A1 publication Critical patent/EP1068534A1/fr
Withdrawn legal-status Critical Current

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Classifications

    • 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
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2333/00—Assays involving biological materials from specific organisms or of a specific nature
    • G01N2333/90—Enzymes; Proenzymes
    • G01N2333/914—Hydrolases (3)
    • G01N2333/948—Hydrolases (3) acting on peptide bonds (3.4)
    • G01N2333/95—Proteinases, i.e. endopeptidases (3.4.21-3.4.99)
    • G01N2333/964—Proteinases, i.e. endopeptidases (3.4.21-3.4.99) derived from animal tissue
    • G01N2333/96425—Proteinases, i.e. endopeptidases (3.4.21-3.4.99) derived from animal tissue from mammals
    • G01N2333/96427—Proteinases, i.e. endopeptidases (3.4.21-3.4.99) derived from animal tissue from mammals in general
    • G01N2333/9643—Proteinases, i.e. endopeptidases (3.4.21-3.4.99) derived from animal tissue from mammals in general with EC number
    • G01N2333/96433—Serine endopeptidases (3.4.21)
    • G01N2333/96441—Serine endopeptidases (3.4.21) with definite EC number
    • G01N2333/96455—Kallikrein (3.4.21.34; 3.4.21.35)

Definitions

  • This invention relates to the differential diagnosis of prostate cancer from healthy controls or benign prostatic conditions by combination of results obtained by an analytically sensitive and specific immunoassay for human glandular kallikrein 2 (hK2) with those obtained by immunoassays specifically detecting various forms of prostate specific antigen (PSA or hK3 ) , most notably the free form of PSA.
  • the invention concerns the diagnosis of prostate cancer both in screening of asymptomatic individuals as well as in distinguishing between cancer and benign conditions in men presenting with clinical symptoms.
  • the invention reveals diagnostic improvements in that higher clinical sensitivities and/or specificities can be obtained both in relation to the conventionally used determination of total PSA, as well as to the more recently introduced method of determinating the proportion of complexed or free PSA to total PSA.
  • Suitable biological specimens for the immunoassay determinations are serum, plasma or whole blood samples.
  • hK2 Human glandular kallikrein 2
  • PSA prostate-specific antigen
  • Enzymatically active PSA is secreted into seminal fluid at high concentrations (0.2-5 mg/mL) [Christensson et al . Eur J Biochem 1990; 194:755-763, Ahlgren et al . 1995 J Androl 16:491-498].
  • PSA degrades the seminal vesicle derived gel-forming proteins causing liquefaction of semen and release of progressively motile spermatozoa [Lilja J Clin Invest 1985; 76:1899-1903].
  • Recently, recombinant hK2 was shown to convert in vi tro inactive recombinant proPSA into active mature PSA [Lovgren et al . Biochem Biophys Res Commun 1997; 238:549-555, Takayama et al. J Biol Chem 1997; 272:21582-21588, Kumar et al . Cancer Res 1997; 57:3111- 3114].
  • PSA active single-chain form of PSA forms stable covalent complexes with several extracellular protease inhibitors, such as ⁇ i-antichymotrypsin (ACT), 2 -macroglobulin (AMG), pregnancy-zone protein (PZP), protein C inhibitor (PCI), and cti-antitrypsin [Christensson et al . Eur J Biochem 1990; 194:755-763, Stenman et al . Cancer Res 1991; 51:222-226, Espana et al . Thromb Res 1991; 64:309-320, Christensson and Lilja Eur J Biochem 1994; 220:45-53, Zhang et al .
  • protease inhibitors such as ⁇ i-antichymotrypsin (ACT), 2 -macroglobulin (AMG), pregnancy-zone protein (PZP), protein C inhibitor (PCI), and cti-antitrypsin
  • PSA-F free form
  • PSA-T PSA-F + PSA-ACT + other quantitatively less important PSA-serpin complexes
  • hK2 is also expressed at fairly high levels in normal prostate epithelia [Chapdelaine et al . FEBS Lett 1988; 236:205-208]. In adenocarcinoma of the prostate, hK2 is expressed at even higher levels [Darson et al . Urology 1997; 49:857-862.]. hK2 can be detected in seminal plasma [Deperthes et al . Biochim Biophys Acta 1995; 1245:311- 316.], but it has not been purified (in large quantities) or characterized thoroughly. The physiological function of hK2 is not yet known, but the primary structure of hK2 suggests it is likely to possess a trypsin-like catalytic activity [Schedlich et al . DNA 1987; 6:429-437].
  • This invention relates to the use of sensitive immunoassays specific for human glandular kallikrein- hK2 for the differential diagnosis of prostate cancer from healthy control subjects or from subjects suffering from benign conditions of the prostate.
  • the immunoassays of hK2 can be performed on body fluids such as serum, plasma or whole blood samples obtained from the individuals under investigation.
  • hK2 as an efficient tumor marker is best realized by combining the measured hK2 concentrations with measured concentrations of different forms of prostate specific antigen (total PSA, compexed PSA, free PSA), most notably the free form of PSA.
  • this invention concerns a method for differentiating patients with cancer of the prostate (PCa) from patients with benign prostatic hyperplasia (BPH) and healthy male subjects without PCa, wherein the individual's body fluid concentration of human glandular kallikrein 2 (hK2) and prostate specific antigen (PSA) have been determined.
  • the method is characterized in that the combination of hK2 and PSA, wherein PSA means the free PSA, the complexed PSA or the total PSA, is used as marker distinguishing PCa patients from BPH and other non- PCa individuals .
  • the marker is the ratio hK2/F or the ratio F/hK2, wherein F is the concentration of free PSA.
  • the marker is the ratio hK2/F or the ratio F/hK2 multiplied by a quantity characterizing the PSA concentration.
  • concentration characterizing the PSA concentration can be free PSA, total PSA or complexed PSA (i.e. PSA complexed with ACT) or any quantity built up from two or all three of said terms (free PSA, total PSA or complexed PSA), such as the ratio "total PSA/free PSA” etc.
  • the marker is hK2/F times T ( (hK2 x T)/F), wherein T is the concentration of total PSA.
  • the marker is hK2/F times T/F ((hK2/F) x T/F), wherein T is the concentration of total PSA.
  • the cut off limit for the ratio is chosen in different ways depending on whether high detection sensitivity or high detection specificity is preferred.
  • the combination of hK2 and PSA, wherein PSA means the free PSA, the complexed PSA or the total PSA is performed by logistic regression analysis.
  • the logistic regression analysis combination is c[hK2, F], wherein F is free PSA.
  • the logistic regression analysis combination is c[hK2, F, T], wherein F is free PSA and T is total PSA.
  • the invention is most efficiently applied to a subset of patient samples restricted by intermediate concentrations of total PSA, i.e. concentrations of PSA where the diagnostic discrimination of cancer and non cancer conditions by total PSA alone is more unsecure and in which the cancers - if found - are likely to be organ confined and eligible for curative treatments.
  • concentrations of PSA concentrations of PSA where the diagnostic discrimination of cancer and non cancer conditions by total PSA alone is more unsecure and in which the cancers - if found - are likely to be organ confined and eligible for curative treatments.
  • concentrations of PSA concentrations of PSA where the diagnostic discrimination of cancer and non cancer conditions by total PSA alone is more unsecure and in which the cancers - if found - are likely to be organ confined and eligible for curative treatments.
  • Such an area is frequently defined as the total PSA range from 1 to 20 ⁇ g/L, preferably 3 or 4 to 10 ⁇ g/L.
  • the hK2 containing ratios or combinations through logistic regression analysis analysis of hK2 and other measured parameters can also be used to identify subgroups of the identified prostate cancer patients, more specifically those prostate cancers that are likely to remain indolent or progress slowly (organ confined or localized cancers of low Gleason score or grade) from those cancers that are likely to progress more aggressively (organ confined or localized cancers of high Gleason score or grade).
  • the invention thus concerns a method for differentiating patients with indolent or slowly progressive prostate cancers from patients with aggressively progressive prostate cancers, wherein the individual's body fluid concentration of human glandular kallikrein 2 (hK2) and prostate specific antigen (PSA) have been determined.
  • the method is characterized in that the combination of hK2 and PSA, wherein PSA means the free PSA, the complexed PSA or the total PSA, is used as marker distinguishing PCa patients with indolent or slowly progressive prostate cancers from patients with aggressively progressive prostate cancers.
  • the wording "combination of hK2 and PSA, wherein PSA means the free PSA, the complexed PSA or the total PSA" is the same as that discussed above.
  • the marker is preferably the ratio hK2/F or the ratio F/hK2, wherein F is the concentration of free PSA.
  • the marker is preferably the ratio hK2/F or the ratio F/hK2 multiplied by a quantity characterizing the PSA concentration, wherein the "quantity characterizing the PSA concentration" has the same meaning as presented above.
  • the marker is hK2/F times T/F ((hK2/F) x T/F), wherein T is the concentration of total PSA.
  • the cut off limit for the ratio is chosen in different ways depending on whether high detection sensitivity or high detection specificity is preferred.
  • the marker is a combination of hK2 and PSA, wherein PSA means the free PSA, the complexed PSA or the total PSA, said marker being a logistic regression analysis combination.
  • PSA means the free PSA, the complexed PSA or the total PSA
  • the logistic regression analysis combination is c[hK2, F], wherein F is free PSA
  • the logistic regression analysis combination is c[hK2, F, T], wherein F is free PSA and T is total PSA.
  • This invention relates to the use of sensitive immunoassays specific for human glandular kallikrein 2 (hK2) for the differential diagnosis of prostate cancer from healthy control subjects or from subjects suffering from benign conditions of the prostate.
  • hK2 human glandular kallikrein 2
  • the results from an immunoassay specific for hK2 applied to biological samples from patients to be screened ot tested for the presence of malignant or benign prostatic disorders are combined with those obtained from assays of the free fraction of PSA, in order to form a ratio of hK2 to free PSA (or vice versa free PSA to hK2) and identifying a cut-off limit or decision point that provides the best or otherwise desired separation of individuals likely to have prostate cancer, benign prostatic hyperplasia, or are likely to present with no prostatic lesions.
  • the cut-off selected varies depending on whether a high sensitivity or a high specificity is preferred in detecting the prostatic disorder (PCa or BPH).
  • Such ratios are e.g. hK2xPSA-T/PSA-F or (hK2/PSA-F ) x(PSA-T/PSA- F) - many other modified ratios with improved capability to separate prostate cancer from benign prostatic conditions and healthy conditions can be designed.
  • hK2 with PSA-F can be accomplished in another way (not involving formation of ratios or products), but through combination by logistic regression analysis.
  • Combinations by logistic regression analysis such as (hK2, PSA-F) or (hK2, PSA-F, PSA-T) frequently provide even better discrimination than ratios calculated from the individual measurements from each patient as illustrated in the ROC analyses described in the experimental section.
  • Logistic regression analysis is instrumental in providing the basis for various "risk analysis systems that can provide medical decision support" .
  • ANN artificial neural networks
  • NFN neuro fuzzy networks
  • MLP multilayer perceptron
  • LVQ learning vector quantization
  • the invention is most efficiently applied to a subset of patient samples restricted by intermediate concentrations of total PSA, i.e. concentrations of PSA where the diagnostic discrimination of cancer and non cancer conditions by total PSA alone is more unsecure and in which the cancers - if found - are likely to be organ confined and eligible for curative treatments.
  • concentrations of PSA where the diagnostic discrimination of cancer and non cancer conditions by total PSA alone is more unsecure and in which the cancers - if found - are likely to be organ confined and eligible for curative treatments.
  • Such an area is frequently defined as the total PSA range from 3 or 4 to 10 ⁇ g/L, but can be defined differently as regards both the lower limit (which can be even lower) or the higher limit (which can be even higher) .
  • the hK2 containing ratios or combinations through logistic regression analysis of hK2 and other measured parameters can also be used to identify subgroups among the identified prostate cancer patients, more specifically those prostate cancers that are likely to remain indolent or progress slowly from those cancers that are likely to progress more aggressively.
  • the Gleason score is presently the best established predictor (prognostic marker) of a tumors ' pathological potential. Poorly differentiated tumors (high Gleason scores) are characterized by aggressive disease , well differentiated tumors (low Gleason scores) have indolent courses (Cookson et al . J Urol 1997; 157:559).
  • PCa prostate cancer
  • BPH benign prostatic hyperplasia
  • SP2 Study population 2 (SP2).
  • SP2 consisted of 115 consecutive patients with lower urinary tract symptoms (mean total IPSS symptom score 18.9 ⁇ 8.0; obstructive 10.7 + 5.3 and irritative 8.2 + 3.2) admitted to the Clinic of Urology, Kantonsspital Aarau, Switzerland, between February 1995 and September 1997.
  • the inclusion criteria were: PSA-T between 3-10 ⁇ g/L on admission, no history of previous treatment of prostatic disease, no previous prostatic manipulation within 3 weeks, no signs of infection, no chronic catheter prior to admission.
  • Blood samples were obtained before any prostatic manipulation. After clot formation, the samples were centrifuged, serum was collected and frozen at -70 °C. The samples were thawed immediately prior to measurement.
  • SP3 Study population 3
  • SP3 consisted of 360 men, aged 51-66 years, participating in a population based prostate cancer screening study in the area of Gothenburg, Sweden, presented initially with a concentration of total PSA > 3 ⁇ g/L (Hugosson et al . Submitted).
  • TRUS and a TRUS guided sextant biopsy Prior to performing DRE, TRUS and a TRUS guided sextant biopsy, an additional serum sample was obtained. After clotting and centrifugation perfomed within 3 hours, the samples were frozen at -70 °C and thawed immediately before performing the immunoassays .
  • the sextant biopsies revealed prostate cancer in 80 men out of the 360 tested. 44 of these were of clinical grade Tic, 13 T2a, 12 T2b, 4 T2c, 4 T3a, 1 T3b and 2 T4.
  • Gleason scores were determined from histopathological examination of the needle biopsies .
  • Recombinant hK2 (rec hK2 )
  • recombinant PSA (rec PSA)
  • purified seminal PSA was obtained using procedures described earlier [Eerola et al . Prostate 1997; 31:84-90, Christensson et al . Eur J Biochem 1990; 194:755-763].
  • Anti- PSA Mabs H117 and H50 were from Abbot (USA)
  • anti-PSA Mab 2H11 was from Wallac Oy (Turku, Finland)
  • anti-PSA Mabs 36 and 10 were kindly supplied by Olle Nilsson, CanAg (Gothenburg, Sweden). Full description of the binding specificities of the Mabs have been described earlier [Piironen et al . Protein Science 1998; 7:259-269].
  • Microtitration wells coated with streptavidin, DELFIA 1 " 1234 Plate Fluorometer, DELFIA PSA Assay Buffer, DELFIA Wash Solution, DELFIA Enhancement Solution as well as the DELFIA ProstatusTM assay for PSA-T and PSA-F were from Wallac Oy (Turku, Finland) .
  • the hK2 assay was based on the previously published assay for hK2 in serum [Piironen et al . Clin Chem 1996; 42:1034- 1041] using the anti-PSA Mabs H50 and H117, with identical affinities for PSA and hK2 and the blocker Mab 2H11 fully specific for PSA [L ⁇ vgren et al . Biochem Biophys Res Commun 1995; 213:888-895, Piironen et al . Protein Science 1998; 7:259-269], but with certain important modifications.
  • the procedure to block PSA was further inforced by inclusion of two additional PSA- specific anti-PSA Mabs (Mabs 36 and 10). The incubation times were also modified.
  • the new assay protocol was as follows: 25 ⁇ L or 50 ⁇ L sample or standard were applied in streptavidin coated wells together with 50 ⁇ L DELFIA PSA Assay Buffer containing Mabs 2H11, 36 and 10 (2000 ng each/well) and incubated for 1 hour at room temperature. 50 ⁇ L PSA assay buffer containing biotinylated Mab H50 (200 ng/well) was added to the reaction mixture and the wells were incubated for 2 hours at room temperature. After a wash step, 200 ⁇ L PSA assay buffer containing Eu-labeled tracer Mab H117 (100 ng/well) was added and the wells were incubated for 1 hour at room temperature. Finally, after a second wash step, 200 ⁇ L enhancement solution per well was added and the fluorescence measured for 1 s in a plate fluorometer .
  • Cross-reaction with PSA as determined from recombinantly produced PSA was less than 0.1%.
  • the analytical detection limit was 0.01 ⁇ g/L of hK2.
  • Functional sensitivity i.e. the concentration at which assay CV:s of replicate determinations were below 20 percent ) was 0.05 ⁇ g/L for a sample volume of 25 ⁇ L (SP1) and 0.03 ⁇ g/L for a sample volume of 50 ⁇ L (SP2 and SP3).
  • the DELFIA Prostatus PSA F/T Dual assay (Wallac, Turku, Finland) using Mab combinations H117/H50 and H117/5A10 was used for detection of PSA-T and PSA-F respectively.
  • the Mab combination H117/H50 measures free PSA and PSA in complex with alpha-1-antichymotrypsin and other serpins in an equimolar fashion [Mitrunen et al . Clin Chem 1995; 41:1115- 1120] and also fully codetects hK2 [Lovgren et al . Biochem Biophys Res Commun 1995; 213:888-895]. Since the proportion of hK2 to PSA in serum is generally very low [Piironen et al .
  • the concentrations measured by the H117/H50 combination are hereafter routinely referred to as PSA-T concentrations.
  • the assay for PSA-F does not codetect hK2.
  • Receiver operating characteristics (ROC) plots were used for comparison of the specificity at different sensitivity levels for PSA-T, PSA- F, hK2, PSA-F/PSA-T, hK2/PSA-F and (hK2/PSA-F) (PSA-T/PSA- F) as well as with combinations through logistic regression analysis [Bangma et al .
  • the median percent free PSA was 82 percent higher in BPHs compared to PCa.
  • the median proportion of hK2 relative to PSA-F was 92 percent higher in PCa than in BPH, whereas the median value of the combination of these two ratios were 234 percent higher in PCa than in BPH.
  • the median proportion of hK2 relative to PSA-T was not significantly different for BPH and PCa.
  • Table 2 gives the median values and the lower and upper quartiles of the PCa and BPH groups for the measured variables PSA-T, PSA-F, PSA-ACT and hK2 as well as for ratios PSA-F/PSA-T, hK2/PSA-T, hK2/PSA-F, PSA-F/PSA-ACT, hK2xPSA-T/PSA-F and (hK2/PSA-F) x(PSA-T/PSA-F ) .
  • PSA-T values were closely similar for the two groups, 5.7 and 5.6 ⁇ g/L for the PCa and BPH groups respectively.
  • Statistical comparison Mann-Whitney of the two groups revealed significant discrimination only by two single parameters, PSA-F and hK2. Of the ratios tested, all but hK2/PSA-T resulted in highly significant discrimination of the two groups .
  • PSA-ACT to c[hK2, PSA-F, PSA-T] improve the performance (data not shown). This unequivocally showed that replacing PSA-T with PSA-ACT is fully feasible in maintaining but not significantly improving the differential diagnosis. Since PSA-T by the H117/H50 Mab combination detects the sum of PSA and hK2, we also checked whether correction of this concentration by subtraction of the hK2 concentration to give the "true" PSA-T concentration, would have any significant influence on the ROC analyses made: It had no significant effect.
  • hK2 correlated with high significance (p ⁇ 0.0001) with PSA-T, PSA-F and PSA-ACT in the BPH group, but with unimpressive correlation coefficients (r) 0.43, 0.56 and 0.29, respectively.
  • the Gleason score is the best established predictor (prognostic marker) of a tumors ' pathological potential. Poorly differentiated tumors (high Gleason scores) are characterized by aggressive disease, well differentiated tumors (low Gleason scores) have indolent courses (Cookson et al . J Urol 1997; 157:559).
  • hK2 on its own, like PSA, is an independent prostate cancer marker
  • the main conclusion from our studies is that the clinically most useful information of specific determinations of hK2 is to be found when it is combined with measurements of the forms of PSA and notably the free form of PSA. This is largely also a consequence of restricting the analysis to those patients still having a moderately increased PSA-T concentration, in which case a tumor is likely to be organ confined or localized and eligible for therapy interventions with a curative aim.
  • Study population 1 Median, 25th, and 75th percentiie levels in serum of PSA- T, PSA-F, hK2, PSA-ACT, PSA-F/PSA-T, hK2/PSA-T, hK2/PSA-F, PSA-F/PSA-ACT, hK2 ⁇ PSA-T/PSA-F and (hK2/PSA-F) ⁇ (PSA-T/PSA-F) for patients with benign prostatic hyperplasia (BPH) and prostate cancer (PCa).
  • BPH benign prostatic hyperplasia
  • PCa prostate cancer
  • Study population 2 Median, 25th, and 75th percentiie levels in serum of PSA- T, PSA-F, hK2, PSA-ACT, PSA-F/PSA-T, hK2/PSA-T, hK2/PSA-F, PSA-F/PSA-ACT, hK2 ⁇ PSA-T/PSA-F and (hK2/PSA-F) ⁇ (PSA-T/PSA-F) for patients with benign prostatic hyperplasia (BPH) and prostate cancer (PCa) within the total PSA range 3-10 ⁇ g/L.
  • BPH benign prostatic hyperplasia
  • PCa prostate cancer
  • Study population 3 Median, 25th, and 75th percentiie levels in serum of PSA- T, PSA-F, PSA-F/PSA-T, hK2, hK2/PSA-T, hK2/PSA-F, hK2 ⁇ PSA-T/PSA-F and (hK2/PSA-F) ⁇ (PSA-T/PSA-F) for participants in the Gothenburg screening study with (cancer) and without (benign) prostate cancer.
  • Statistical significant differences between the groups are tested with the non-parametric Mann Whitney-U test ( * denotes statistically significant i.e. p-value ⁇ 0.05).
  • Study population 3 Median, 25th, and 75th percentiie levels in serum of PSA-T, PSA-F, PSA-F/PSA-T, hK2, hK2/PSA-T, hK2/PSA-F, hK2 ⁇ PSA-T/PSA-F and (hK2/PSA-F) ⁇ (PSA-T/PSA-F) for participants in the Gothenburg screening study with (cancer) and without (benign) prostate cancer within the total PSA range 3-10 ⁇ g/L.
  • Statistical significant differences between the groups are tested with the non-parametric Mann Whitney-U test (* denotes statistically significant i.e. p- value > 0.05).
  • AUC (p ⁇ 0.05) compared to T or F/T are denoted with *.
  • Study population 3 Comparison of prostate cancer (PCa) patients with low (4-6) and high (7-8) Gleason grades. Statistically significant differences between patients with low and high Gleason scores are tested with the non-parametric Mann Whitney-U test (* denotes statistically significant i.e. p-value ⁇ 0.05).

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Abstract

L'invention concerne une méthode permettant de différencier les patients atteints d'un cancer de la prostate (PCa), de patients atteints d'hypertrophie de la prostate (BPH) et de sujets masculins sains qui ne sont pas atteints de PCa. Cette méthode consiste à déterminer la concentration de kallicréine glandulaire humaine 2 (hK2) et d'antigènes prostatiques spécifiques (PSA) dans le liquide organique d'un individu. Selon cette invention, on utilise une combinaison de hK2 et de PSA, dans laquelle PSA signifie le PSA libre, le PSA complexé ou le PSA total, en tant que marqueur permettant de distinguer les patients PCa des individus BPH et d'autres individus non PCa. En outre, l'invention concerne une méthode permettant de différencier les patients atteints d'un cancer de la prostate indolent ou à progression lente, des patients atteints d'un cancer de la prostate à progression extrêmement rapide.
EP99902563A 1998-03-04 1999-02-03 Procede de differenciation du cancer de la prostate Withdrawn EP1068534A1 (fr)

Applications Claiming Priority (3)

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FI980488 1998-03-04
FI980488A FI980488A (fi) 1998-03-04 1998-03-04 Uusi diagnostinen menetelmä
PCT/FI1999/000073 WO1999045398A1 (fr) 1998-03-04 1999-02-03 Procede de differenciation du cancer de la prostate

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EP1068534A1 true EP1068534A1 (fr) 2001-01-17

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WO (1) WO1999045398A1 (fr)

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FI990382A0 (fi) * 1999-02-23 1999-02-23 Arctic Partners Oy Ab Uusi diagnostinen menetelmä
EP1269194B1 (fr) * 2000-03-20 2007-03-07 Eastern Virginia Medical School Marqueurs du cancer de la prostate
US20050037447A1 (en) * 2003-07-08 2005-02-17 Yong-Chuan Wong Protein markers for human benign prostatic hyperplasia (BPH)
US8663600B2 (en) * 2005-02-17 2014-03-04 Diaprost Ab Diagnosis of prostate cancer
EP2913405B1 (fr) 2010-07-27 2016-11-09 Genomic Health, Inc. Procédé d'utilisation de l'expression génique pour déterminer le pronostic du cancer de la prostate
DK3011059T3 (da) 2013-06-20 2019-05-13 Immunexpress Pty Ltd Biomarkør-identifikation
WO2015117204A1 (fr) * 2014-02-06 2015-08-13 Immunexpress Pty Ltd Procédé de signature de biomarqueurs, et appareil et kits associés
SG10201808585TA (en) 2014-03-28 2018-11-29 Opko Diagnostics Llc Compositions and methods related to diagnosis of prostate cancer
ES2867798T3 (es) 2015-03-27 2021-10-20 Opko Diagnostics Llc Estándares del antígeno prostático y usos de estos
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