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EP1373899A1 - Methode pour un pronostic apres therapie d'un cancer de la prostate - Google Patents

Methode pour un pronostic apres therapie d'un cancer de la prostate

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Publication number
EP1373899A1
EP1373899A1 EP02709378A EP02709378A EP1373899A1 EP 1373899 A1 EP1373899 A1 EP 1373899A1 EP 02709378 A EP02709378 A EP 02709378A EP 02709378 A EP02709378 A EP 02709378A EP 1373899 A1 EP1373899 A1 EP 1373899A1
Authority
EP
European Patent Office
Prior art keywords
igfbp
tgf
patients
prostate cancer
level
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.)
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EP02709378A
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German (de)
English (en)
Inventor
Kevin M. Slawin
Shahrokh Shariat
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Baylor College of Medicine
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Baylor College of Medicine
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Publication date
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Publication of EP1373899A1 publication Critical patent/EP1373899A1/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Withdrawn legal-status Critical Current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
    • 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
    • G01N33/57484—Immunoassay; Biospecific binding assay; Materials therefor for cancer involving compounds serving as markers for tumor, cancer, neoplasia, e.g. cellular determinants, receptors, heat shock/stress proteins, A-protein, oligosaccharides, metabolites
    • G01N33/57488—Immunoassay; Biospecific binding assay; Materials therefor for cancer involving compounds serving as markers for tumor, cancer, neoplasia, e.g. cellular determinants, receptors, heat shock/stress proteins, A-protein, oligosaccharides, metabolites involving compounds identifable in body fluids

Definitions

  • Prostate cancer is the most commonly diagnosed cancer and the second leading cause of cancer death for men in the United States. In 1999, an estimated 179,300 men were diagnosed with prostate cancer and 37,000 died of this disease. Despite the identification of several new potential biomarkers for prostate cancer (e.g., p53, ⁇ 21, p27, and E-cadherin), prostate specific antigen (PSA) and the histologic Gleason score have remained the most powerful predictors of prostate cancer biology. In fact, the widespread use of PSA-based screening has dramatically increased the number of men diagnosed and treated for clinically localized prostate cancer over the past decade.
  • PSA prostate specific antigen
  • TGF- ⁇ i transforming growth factor ⁇ i
  • a pleiotropic growth factor that regulates cellular proliferation
  • chemotaxis a pleiotropic growth factor that regulates cellular proliferation
  • immune response a pleiotropic growth factor that regulates cellular proliferation
  • angiogenesis a pleiotropic growth factor that regulates cellular proliferation
  • chemotaxis a pleiotropic growth factor that regulates cellular proliferation
  • chemotaxis a pleiotropic growth factor that regulates cellular proliferation
  • chemotaxis a pleiotropic growth factor that regulates cellular proliferation
  • chemotaxis a pleiotropic growth factor that regulates cellular proliferation
  • chemotaxis a pleiotropic growth factor that regulates cellular proliferation
  • chemotaxis a pleiotropic growth factor that regulates cellular proliferation
  • chemotaxis a pleiotropic growth factor that regulates cellular proliferation
  • chemotaxis a
  • TGF- ⁇ i has been associated with tumor grade, pathological stage, and lymph node metastasis in patients with prostate cancer (Steiner et al., 1992; Eastham et al., 1995; Truong et al., 1993; Thompson et al., 1992).
  • elevated circulating levels of TGF- ⁇ ] have been found in patients with a variety of different tumors (Wakefield et al, 1995; Kong et al., 1999; Shirai et al., 1994; Eder et al., 1996; Junker et al., 1996).
  • IGFs Insulin-like growth factors
  • IGFBPs IGF binding proteins
  • IL-6 signaling occurs through a receptor complex consisting of a specific receptor and a signal- transducing component (gpl 30).
  • the soluble form of the IL-6 receptor (IL-6sR) which arises from proteolytic cleavage of membrane-bound IL-6 receptor, can augment IL-6 induced signaling by facilitating the binding of the IL-6/IL-6sR complex to membrane-bound gpl 30.
  • the invention provides a method to predict the disease- free status of a prostate cancer patient after therapy.
  • the method comprises contacting a physiological fluid sample from a patient prior to or after therapy for clinically localized prostate cancer with an agent that binds to TGF- ⁇ i so as to form a complex.
  • the method comprises contacting a physiological fluid sample from a patient after therapy for prostate cancer, e.g., a patient with clinically localized prostate cancer or having a clinical stage ⁇ T3a , with an agent that binds to TGF- ⁇ ] so as to form a complex.
  • the sample When the sample is collected "after" therapy for use in the methods of the invention, it may be collected at times up to five to six months or less, e.g., one, one and a half, two, three or four months, after therapy, including from one, two or more, e.g., three, four or five, days after therapy, up to one week after therapy, or more, e.g., at two or three weeks.
  • the amount or level of complex formation is then correlated to the risk of non-prostate confined disease or disease progression in the patient.
  • the fluid sample is a blood sample and more preferably a plasma sample.
  • the sample is obtained from a patient that has not received any previous therapy for prostate cancer, e.g., hormonal therapy, radiation therapy or brachytherapy.
  • Preferred agents that bind to TGF- ⁇ i include, but are not limited to, antibodies specific for TGF- ⁇ j and the TGF- ⁇ i receptor protein, e.g., type I or II.
  • a sample of "physiological body fluid” includes, but is not limited to, a sample of blood, plasma, serum, seminal fluid, urine, saliva, sputum, semen, pleural effusions, bladder washes, bronchioalveolar lavages, cerebrospinal fluid and the like.
  • a patient with "clinically localized prostate cancer” means that the patient has no detectable metastases, e.g., detectable by MRI, bone scan, CT scan, or PET scan.
  • the relationship between pre-operative or postoperative platelet-poor plasma TGF- ⁇ i levels and established markers of prostate cancer invasion, metastasis, and disease progression was determined in a large consecutive cohort of patients with prostate cancer, e.g., those undergoing radical prostatectomy.
  • One study group consisted of 120 consecutive patients who underwent radical prostatectomy (median follow-up of 53.8 months) for clinically localized prostate cancer.
  • Pre-operative platelet-poor plasma levels of TGF- ⁇ j were measured and correlated with clinical and pathological parameters.
  • TGF- ⁇ i levels were also measured in 44 healthy men without any cancer, in 19 men with prostate cancer metastatic to regional lymph nodes, and in 10 men with prostate cancer metastatic to bone. None of the patients were treated with hormonal or radiation therapy prior to sample collection.
  • Plasma TGF- ⁇ i levels in patients with lymph node metastases (14.2 ⁇ 2.6 ng/mL) and bone metastases (15.5 ⁇ 2.4 ng/mL) were significantly higher than those in radical prostatectomy patients (5.2 ⁇ 1.3 ng/mL) and healthy subjects (4.5 ⁇ 1.2 ng/mL) (P values ⁇ 0.001).
  • a larger cohort of 468 radical prostatectomy patients were employed to study marker interactions.
  • 278 patients had samples available at 6 to 8 weeks after post-radical prostatectomy.
  • the clinical stage of these patients was ⁇ T3a (47% cTl, 49% cT2, and 4% cT3a) and they had a median PSA of 8.2 ng/mL (range of 0.2 to 60 ng/mL).
  • the median age for these patients was 63 years (range 40 to 81) and the median follow up for them was about 51 months.
  • Fourteen percent (63/468) had PSA recurrence.
  • Post-operative plasma TGF- ⁇ i levels were found to be useful as a prognostic marker for prostate cancer progression.
  • serial measurements TGF- ⁇ i may be particularly useful to monitor the outcome of therapy, e.g., surgery, radiation, or hormonal therapy or brachytherapy, similarly to serial measurements of PSA.
  • post-therapy measurements of TGF- ⁇ i were found to be a stronger predictor than pre-therapy measurements of TGF- ⁇ i .
  • the invention provides a method to determine the risk of progression of a patient after therapy for prostate cancer.
  • the method comprises contacting a blood plasma sample from a patient after therapy for prostate cancer with an agent that binds to TGF- ⁇ j so as to form a complex. Then the amount or level of complex formation is correlated with the risk of progression.
  • the level of TGF- ⁇ i in body fluids of humans is prognostically useful, and may optionally be employed in conjunction with other markers for neoplastic disease such as those for prostate cancer, e.g., urinary plasminogen activator (UP A), urinary plasminogen activator receptor (UPAR), plasminogen activator inhibitor 1 (PAI-1), IL-6, IL-6sR, IGFBP-2, IGFBP-3, p53, p21, E- cadherin, and PSA, as well as Gleason scores, e.g., in a nomogram to predict stage and outcome in patients with prostate cancer.
  • UP A urinary plasminogen activator
  • UPAR urinary plasminogen activator receptor
  • PAI-1 plasminogen activator inhibitor 1
  • IL-6 IL-6sR
  • IGFBP-2 IGFBP-2
  • IGFBP-3 IGFBP-3
  • p53 p21
  • E- cadherin E- cadherin
  • the prognosis is based on a computer derived analysis of data of the amount, level or other value (score) for one or more markers for prostate cancer.
  • Data may be input manually or obtained automatically from an apparatus for measuring the amount or level of one or more markers.
  • the invention provides a nomogram that employs standard clinical and pathological measures of prostate cancer, as well as one or more serum/plasma proteins, including but not limited to, TGF- ⁇ i , IL6, IL6sR, IGFBP-2 and IGFBP-3 to predict outcomes in clinical situations for prostate cancer patients including pre-prostatectomy, post-prostatectomy, pre-radiation therapy, post-radiation therapy, recurrence after primary therapy, e.g., rising PSA after surgery or radiation therapy and metastatic disease.
  • serum/plasma proteins including but not limited to, TGF- ⁇ i , IL6, IL6sR, IGFBP-2 and IGFBP-3 to predict outcomes in clinical situations for prostate cancer patients including pre-prostatectomy, post-prostatectomy, pre-radiation therapy, post-radiation therapy, recurrence after primary therapy, e.g., rising PSA after surgery or radiation therapy and metastatic disease.
  • the invention also provides a prognostic method.
  • the method comprises contacting a physiological fluid sample from a patient prior to or after primary therapy for clinically localized prostate cancer with an agent that binds to TGF- ⁇ i so as to form a complex. Then complex formation is detected or determined and the amount or level of complex formation is employed to predict the patient's final pathological stage and/or biochemical progression, e.g., after therapy or in the absence of therapy.
  • the sample is a blood sample, and more preferably, a plasma sample.
  • the pre-operative or post-operative plasma levels of IL-6 and IL-6sR may be correlated with clinical and pathological parameters.
  • Plasma IL-6 and IL-6sR levels in patients with bone metastases were significantly higher than those in healthy subjects, in prostatectomy patients, or in patients with lymph node metastases (P values ⁇ 0.001).
  • pre-operative plasma IL-6, IL-6sR, and biopsy Gleason score were independent predictors of organ-confined disease (P values ⁇ 0.01) and PSA progression (P values ⁇ 0.028).
  • P 0.038
  • IL-6 and IL-6sR levels are elevated in men with prostate cancer metastatic to bone.
  • the pre-operative plasma level of IL-6 and IL-6sR are associated with markers of more aggressive prostate cancer and are predictors of biochemical progression after surgery.
  • the invention further provides a method in which a physiological fluid sample from a patient prior to or after primary therapy for clinically localized prostate cancer is contacted with an agent that binds to IL-6 or IL-6sR so as to form a complex. Then the amount or level of complex formation is correlated to the risk of non-prostate confined disease (disease progression), final pathological stage and/or biochemical progression.
  • the level of IL-6 and/or IL-6sR in body fluids of humans is prognostically useful, and may optionally be employed in conjunction with other markers for neoplastic disease such as those for prostate cancer, e.g., UPA, UPAR, PAI-1, TGF- ⁇ IGFBP-2, IGFBP-3, p53, p21, E-cadherin, and PSA, as well as Gleason scores, e.g., in a nomogram to predict stage and outcome in patients with prostate cancer.
  • the prognosis may be based on a computer derived analysis of data of the amount, level or other value for one or more markers for prostate cancer, and data may be input manually or obtained automatically.
  • pre-operative or post-operative plasma levels of IGF-I, IGFBP-2, and IGFBP-3 may be measured and correlated with clinical and pathological parameters.
  • IGFBP-2 levels in prostatectomy patients and in patients with lymph node metastases or bone metastases were significantly higher than those in healthy subjects (P values ⁇ 0.006).
  • Plasma IGBP-3 levels in patients with lymph node metastases and bone metastases were significantly lower than those in prostatectomy patients and healthy subjects (P values ⁇ 0.031).
  • IGFBP-2 levels are elevated in men with prostate cancer
  • IGFBP-3 levels are decreased in men with prostate cancer metastatic to regional lymph nodes and bone.
  • the pre-operative plasma IGFBP-2 level is associated with markers of more aggressive prostate cancer and is a predictor of biochemical progression after surgery.
  • the invention thus provides a method which comprises contacting a physiological fluid sample from a patient prior to or after primary therapy for clinically localized prostate cancer with an agent that binds to IGFBP-2 and optionally to IGFBP-3, so as to form a complex. Complex formation is then detected or determined, and correlated to the risk of non-prostate confined disease), final pathological stage and/or biochemical progression.
  • the level of IGFBP-2 and/or IGFBP-3 in body fluids of humans is prognostically useful, and may optionally be employed in conjunction with other markers for neoplastic disease such as those for prostate to predict stage and outcome in patients with prostate cancer, e.g., using a computer derived analysis of data of the amount, level or other value for one or more markers for prostate cancer.
  • the invention also provides an apparatus, comprising: a data inputmeans, for input of test information comprising the level or amount of at least one protein in a sample obtained from a mammal, wherein the protein is selected from the group consisting of TGF- ⁇ i, IGFBP-2, IL-6, IL-6sR and IGFBP-3; a processor, executing a software for analysis of the level or amount of the at least one protein in the sample; wherein the software analyzes the level or amount of the at least one protein in the sample and provides the risk of non-prostate confined disease in the mammal.
  • Figure 4 Kaplan-Meier estimates of PSA progression-free probability for the 120 patients with clinically localized prostate cancer treated with radical prostatectomy stratified into groups above or below the median IGFBP-2 level of 437.4 ng/mL.
  • FIG. 1 Kaplan-Meier estimates of PSA progression-free probability for the 120 patients with clinically localized prostate cancer treated with radical prostatectomy stratified into groups above or below the median IL-6 level of 1.9 ng/mL.
  • Figure 12. Multivariate Cox proportional hazards analysis of pre- operative prediction of various factors for PSA-progression free survival in 468 prostatectomy patients.
  • Figure 13. Comparison of predictive value of pre-operative versus postoperative levels of various factors for PSA-progression free survival in 468 prostatectomy patients.
  • the invention in its broadest sense is a method for predicting organ confined (local) disease status or the potential for progression of prostate cancer following primary therapy, e.g., the presence of occult metastases.
  • the method is particularly useful for evaluating patients at risk for recurrence of prostate cancer following primary therapy for prostate cancer.
  • the detection of pre- or post-operative TGF- ⁇ b IL-6, IL-6sR, IGFBP-2 or IGFBP-3 levels alone, or in conjunction with other markers for prostate cancer may be useful in predicting organ-confined disease status or the potential for progression in patients with clinically localized prostate cancer.
  • Non-invasive prognostic assays are provided by the invention to detect and/or quantitate TGF- ⁇ i, IL-6, IL-6sR, IGFBP-2 or IGFBP-3 levels in the body fluids of mammals, including humans.
  • an assay is useful in prognosis of prostate cancer.
  • assays provide valuable means of monitoring the status of the prostate cancer.
  • knowledge of the disease status allows the attending physician to select the most appropriate therapy for the individual patient. For example, patients with a high likelihood of relapse can be treated rigorously. Because of the severe patient distress caused by the more aggressive therapy regimens as well as prostatectomy, it would be desirable to distinguish with a high degree of certainty those patients requiring aggressive therapies as well as those which will benefit from prostatectomy.
  • the body fluids that are of particular interest as physiological samples in assaying for TGF- ⁇ h IL-6, IL-6sR, IGFBP-2 or IGFBP-3 according to the methods of this invention include blood, blood serum, semen, saliva, sputum, urine, blood plasma, pleural effusions, bladder washes, bronchioalveolar lavages, and cerebrospinal fluid. Blood, serum and plasma are preferred, and plasma, such as platelet-poor plasma, are the more preferred samples for use in the methods of this invention.
  • IGFBP-2 or IGFBP-3 levels in mammalian body fluids include affinity chromatography, Western blot analysis, immunoprecipitation analysis, and immunoassays, including ELISAs (enzyme-linked immunosorbent assays), RIA (radioimmunoassay), competitive EIA or dual antibody sandwich assays.
  • the interpretation of the results is based on the assumption that the TGF- ⁇ b IL-6, IL-6sR, IGFBP-2 or IGFBP-3 binding agent, e.g., a TGF- ⁇ i, IL-6, IL-6sR, IGFBP-2 or IGFBP-3 specific antibody, will not cross-react with other proteins and protein fragments present in the sample that are unrelated to TGF- ⁇ h IL-6, IL-6sR, IGFBP-2 or IGFBP-3.
  • the TGF- ⁇ b IL-6, IL-6sR, IGFBP-2 or IGFBP-3 binding agent e.g., a TGF- ⁇ i, IL-6, IL-6sR, IGFBP-2 or IGFBP-3 specific antibody
  • the method used to detect TGF- ⁇ i, IL-6, IL-6sR, IGFBP-2 or IGFBP-3 levels employs at least one TGF- ⁇ ,, IL-6, IL-6sR, IGFBP-2 or IGFBP-3 specific binding molecule, e.g., an antibody or at least a portion of the ligand for any of those molecules.
  • Immunoassays are a preferred means to detect TGF- ⁇ i, IL-6, IL-6sR, IGFBP-2 or IGFBP-3.
  • Representative immunoassays involve the use of at least one monoclonal or polyclonal antibody to detect and/or quantitate TGF- ⁇ i, IL-6, IL- 6sR, IGFBP-2 or IGFBP-3 in the body fluids of mammals.
  • the antibodies or other binding molecules employed in the assays may be labeled or unlabeled. Unlabeled antibodies may be employed in agglutination; labeled antibodies or other binding molecules may be employed in a wide variety of assays, employing a wide variety of labels.
  • Suitable detection means include the use of labels such as radionuclides, enzymes, fluorescers, chemiluminescers, enzyme substrates or co-factors, enzyme inhibitors, particles, dyes and the like.
  • labels such as radionuclides, enzymes, fluorescers, chemiluminescers, enzyme substrates or co-factors, enzyme inhibitors, particles, dyes and the like.
  • labeled reagents may be used in a variety of well known assays. See for example, U.S. Patent Nos. 3,766,162, 3,791,932, 3,817,837, and 4,233,402.
  • labeled TGF- ⁇ i, IL-6, IL-6sR, IGFBP-2 or IGFBP-3 peptides and/or polypeptides can be used to detect and/or quantitate TGF- ⁇ i, IL-6, IL-6sR, IGFBP-2 or IGFBP-3, respectively, in mammalian body fluids.
  • labeled anti-idiotype antibodies that have been prepared against antibodies reactive with TGF- ⁇ b IL-6, IL-6sR, IGFBP-2 or IGFBP-3 can be used.
  • TGF- ⁇ i may be present in various forms, e.g., latent and active, as well as fragments thereof, and that these various forms may be detected and/or quantitated by the methods of the invention if they contain one or more epitopes recognized by the respective binding agents.
  • TGF- ⁇ i a sandwich assay where two antibodies are used as a capture and a detection antibody, respectively, if both epitopes recognized by those antibodies are present on at least one form of, for example, TGF- ⁇ i, the form would be detected and/or quantitated according to such an immunoassay.
  • Such forms which are detected and/or quantitated according to methods of this invention are indicative of the presence of the active form in the sample.
  • TGF- ⁇ i , IL-6, IL-6sR, IGFBP-2 or IGFBP-3 levels may be detected by an immunoassay such as a "sandwich" enzyme-linked immunoassay (see Dasch et al., 1990; Danielpour et al., 1989; Danielpour et al., 1990; Lucas et al., 1990; Thompson et al., 1989; and Flanders et al., 1989).
  • an immunoassay such as a "sandwich" enzyme-linked immunoassay (see Dasch et al., 1990; Danielpour et al., 1989; Danielpour et al., 1990; Lucas et al., 1990; Thompson et al., 1989; and Flanders et al., 1989).
  • a physiological fluid sample is contacted with at least one antibody specific for TGF- ⁇ i, IL-6, IL-6sR, IGFBP-2 or IGFBP-3 to form a complex with said antibody and TGF- ⁇ i, IL-6, IL-6sR, IGFBP-2 or IGFBP-3. Then the amount of TGF- ⁇ i in the sample is measured by measuring the amount of complex formation.
  • Representative of one type of ELISA test is a format wherein a solid surface, e.g., a microtiter plate, is coated with antibodies to TGF- ⁇ i, IL-6, IL-6sR, IGFBP-2 or IGFBP-3 and a sample of a patient's plasma is added to a well on the microtiter plate.
  • TGF- ⁇ i, IL-6, IL-6sR, IGFBP-2 or IGFBP-3 antibodies e.g., antibodies that are linked to a detectable molecule such as an enzyme
  • enzyme substrate is added to the microtiter plate and incubated for a period of time to allow the enzyme to catalyze the synthesis of a detectable product, and the product, e.g., the absorbance of the product, is measured.
  • TGF- ⁇ IL-6, IL-6sR, IGFBP-2 or IGFBP-3 can be used to detect and/or quantitate the presence of TGF- ⁇ IL-6, IL-6sR, IGFBP-2 or IGFBP-3 in the body fluids of patients.
  • a competition immunoassay is used, wherein TGF- ⁇ i, IL-6, IL-6sR, IGFBP-2 or IGFBP-3 is labeled, and a body fluid is added to compete the binding of the labeled TGF- ⁇ i, IL-6, IL-6sR, IGFBP-2 or IGFBP-3 to antibodies specific for TGF- ⁇ ,, IL-6, IL- 6sR, IGFBP-2 or IGFBP-3.
  • Such an assay could be used to detect and/or quantitate TGF- ⁇ ,, IL-6, IL-6sR, IGFBP-2 or IGFBP-3.
  • binding agents having suitable specificity have been prepared or are otherwise available, a wide variety of assay methods are available for determining the formation of specific complexes.
  • Numerous competitive and non-competitive protein binding assays have been described in the scientific and patent literature and a large number of such assays are commercially available.
  • Exemplary immunoassays which are suitable for detecting a serum antigen include those described in U.S. Patent Nos.
  • the methods of the invention may be employed with other measures of prostate cancer biology to better predict disease-free status or for staging.
  • clinical and pathological staging criteria may be used, e.g., clinical and pathological stage, PSA levels, and Gleason scores, although the use of other criteria does not depart from the scope and spirit of the invention.
  • Tla - Tumor is incidental histologic finding with three of fewer microscopic foci.
  • Tib - Tumor is incidental histologic finding with more than three microscopic foci.
  • Tic - Tumor is non-palpable, and is found in one or both lobes by needle biopsy diagnosis.
  • T2 - Tumor is confined within the prostate.
  • T2a - Tumor present clinically or grossly, limited to the prostate, tumor
  • T2b - Tumor present clinically or grossly, limited to the prostate, tumor more than 1.5 cm in greatest dimension, or in only one lobe. Palpable, greater than half of 1 lobe but not both lobes.
  • T2c - Tumor present clinically or grossly, limited to the prostate, tumor more than 1.5 cm in greatest dimension, and in both lobes. Palpable, involves both lobes.
  • T3 - Tumor extends through the prostatic capsule.
  • T3a - Palpable tumor extends unilaterally into or beyond the prostatic capsule, but with no seminal vesicle or lymph node involvement. Palpable, unilateral capsular penetration.
  • T3b - Palpable tumor extends bilaterally into or beyond the prostatic capsule, but with no seminal vesicle or lymph node involvement. Palpable, bilateral capsular penetration.
  • T3c - Palpable tumor extends unilaterally and/or bilaterally beyond the prostatic capsule, with seminal vesicle and/or lymph node involvement. Palpable, seminal vesicle or lymph node involvement. T4 - Tumor is fixed or invades adjacent structures other than the seminal vesicles or lymph nodes.
  • PSA prostate-specific antigen
  • Plasma TGF- ⁇ i levels were assessed in 44 healthy patients without cancer, in 19 men with prostate cancer metastatic to regional lymph nodes, and in 10 patients with bone scan-proven, metastatic prostate cancer. Neither patients with metastatic lymph node disease nor patients with metastatic bone disease were treated with either hormonal or radiation therapy before plasma collection.
  • the healthy non-cancer group was composed of three sets of patients who presented consecutively to the Baylor Prostate Center's weekly prostate cancer screening program. They had no prior history of any cancer or chronic disease, a normal digital rectal examination, and a PSA of less than 2.0 ng/mL, a PSA range that has an estimated probability of prostate cancer detection of less than 1 % in the first 4 years after screening (Smith et al., 1996).
  • Serum and plasma samples were collected on an ambulatory basis at least 4 weeks after transrectal guided needle biopsy of the prostate, typically performed on the morning of the scheduled day of surgery after a typical pre- operative overnight fast.
  • Blood was collected into Vacutainer ® CPT TM 8 mL tubes containing 0.1 mL of 1 M sodium citrate anticoagulant (Becton Dickinson Vacutainer Systems, Franklin Lakes, NJ) and centrifuged at room temperature for 20 minutes at 1500 g.
  • the top layer corresponding to plasma was decanted using sterile transfer pipettes and immediately frozen and stored at -80°C in polypropylene cryopreservation vials (Nalgene, Nalge Nunc International, Rochester, NY).
  • TGF- ⁇ i levels were assessed from three synchronously drawn blood specimens obtained from 10 of the 44 healthy screening patients.
  • Plasma was separated using Vacutainer ® K ethylenediaminetetraacetic acid (EDTA) 5 mL tubes containing 0.057 mL of 15% K 3 EDTA solution, and Vacutainer ® CPTTM 8 mL tubes containing sodium citrate (Becton Dickinson Vacutainer Systems, Franklin Lakes, NJ).
  • Serum was separated using Vacutainer Brand SST Serum Separator TM tubes (Becton Dickinson Vacutainer Systems, Franklin Lakes, NJ).
  • Specimens were centrifuged at room temperature for 20 minutes at 1500 g, and plasma or serum decanted and frozen at -80°C until assessment. Prior to assay, an additional cenfrifugation step at 10,000 g for 10 minutes at room temperature was performed. The investigators were blinded to the nature of the collection formats. Analysis of variance was used to determine whether the collection format significantly affected measured TGF- ⁇ i levels. Pathological Examination
  • Biochemical progression was defined as a sustained elevation, on 2 or more occasions, of PSA > 0.2 ng/mL. The date of progression was assigned to the date of the first value > 0.2 ng/mL.
  • PSA relapse was the sole indication of progression in 14 patients, while 3 had clinical, in addition to biochemical evidence of progression.
  • the natural logarithm was used in all logarithmic transformations. Eight (53%) of the patients that progressed were treated with external beam radiation therapy limited to the prostatic fossa at the Cincinnati Hospital.
  • Radiation was delivered with 15 to 20 MV photons, and the four-fields technique (anteroposterior/posteroanterior and opposing laterals) with customized field sizes was used.
  • Total radiation therapy dose ranged from 60 to 66 Gy, delivered in daily fractions.
  • a complete response to salvage radiation therapy was defined as the achievement and maintenance of an undetectable serum PSA level. Radiation therapy was considered to have failed if the post-radiation serum PSA levels did not fall to, and remain at, an undetectable level.
  • Gleason score was evaluated as grade 2 to 6 versus grade 7 to 10. Differences in TGF- ⁇ i levels between patients who presumably had distant failure and those who presumably had local-only failure were tested by the Mann- Whitney test. Spearman's rank correlation coefficient was used to compare ordinal and continuous variables. Logistic regression was used for multivariate analysis of binary outcome variables. The Kaplan-Meier method was used to calculate survival functions and differences were assessed with the long rank statistic. Multivariate survival analysis was performed with the Cox proportional hazard regression model. Statistical significance in this study was set as P ⁇ 0.05. All reported P values are two-sided. All analyses were performed with SPSS statistical package (SPSS version 10.0 for Windows). Results
  • TGF- ⁇ i levels were studied.
  • Mean TGF- ⁇ i levels, measured in Vacutainer CPTTM citrate plasma, Vacutainer ® K 3 EDTA plasma, and Vacutainer ® BrandSSTTM serum from synchronously drawn blood specimens of 10 consecutive, healthy screening patients were 4.21 ⁇ 1.16 ng/mL, 8.34 ⁇ 2.94 ng/mL, and 23.89 ⁇ 5.35 ng/mL, respectively (Table 3).
  • TGF- ⁇ i levels measured in serum were 3-times higher than those in measured in citrate platelet-poor plasma and 6-times higher than those measured in EDTA platelet-poor plasma.
  • TGF- ⁇ i inter-collection format differences were statistically significant (P values ⁇ 0.001)
  • TGF- ⁇ i levels measured in specimens collected by all three sample formats were found to be highly correlated with each other (P values ⁇ 0.001).
  • Platelet-poor plasma from Vacutainer ® CPTTM sodium citrate tubes was used for TGF- ⁇ j measurements in the study described below.
  • +.P - values (two-sided) were calculated based on analysis of variance in a randomized complete block design for the assessment of the difference in TGF- ⁇ i levels between collection formats.
  • the overall PSA progression-free survival was 90.7 ⁇ 5.3 % (95% CI) at 3 years and 84.6 ⁇ 6.8 % (95% CI) at 5 years.
  • pre-operative multivariate model that included pre-operative TGF- ⁇ i, pre-operative PSA, clinical stage, and biopsy Gleason score
  • plasma TGF- ⁇ i level and Gleason score were both independent predictors of disease progression.
  • J Clinical stage was categorized as TI versus T2.
  • TGF- ⁇ i levels in the 44 healthy screening patients, the 19 patients with prostate cancer metastatic to regional lymph nodes, and the 10 patients with metastatic prostate cancer were 4.5 ⁇ 1.2 ng/mL (median 4.70, range 1.0-6.6), 14.24 ⁇ 2.6 ng/mL (median 14.95, range 8.0-19.2), and 15.51 ⁇ 2.4 ng/mL (median 15.20, range 12.4-19.3), respectively.
  • Plasma TGF- ⁇ i levels in patients with lymph node metastases and bone metastases were significantly higher than those in the initial cohort of 120 prostatectomy patients and healthy subjects (P values ⁇ 0.001).
  • plasma TGF- ⁇ i levels in the initial cohort of 120 prostatectomy patients were not significantly higher than those in healthy subjects (P - 0.053).
  • FIG. 2 shows box plots of the TGF- ⁇ i levels in 109 of the 120 consecutive prostatectomy patients who had at least 48 months of follow-up, stratified by progression status at 48 months, 44 healthy men without cancer, 19 men with prostate cancer metastatic to regional lymph nodes, and 10 men with prostate cancer metastatic to bone.
  • TGF- ⁇ ! levels were not different between healthy men, patients with organ confined disease who did not have disease progression, and patients with extracapsular disease who did not have disease progression (P values > 0.229).
  • TGF- ⁇ i levels in these three groups were significantly lower than in patients with biochemical progression who had organ confined disease, extracapsular disease, or seminal vesicle invasion, or in patients with lymph node metastases, or patients with bone metastases (P values ⁇ 0.005).
  • pre-operative platelet-poor plasma TGF- ⁇ i levels were found to be a powerful independent predictor of final pathologic stage and disease progression in patients with clinically localized prostate cancer. Within each pathological stage, patients who developed disease progression had significantly higher TGF- ⁇ i levels than their non-progressing counterparts. Furthermore, in patients that progressed, preoperative plasma TGF- ⁇ ! levels were significantly higher in patients with presumed distant failure than those with presumed local-only failure.
  • TGF- ⁇ i level was strongly associated with PSA and pathological stage, two established markers of biologically aggressive prostate cancer.
  • PSA pathological stage
  • TGF- ⁇ i and biopsy tumor grade but not PSA were independently predictors of advanced pathological stage.
  • An association between elevated TGF- ⁇ i levels and locally advanced prostate cancer has been previously reported (Ivanovic et al., 1995).
  • Ivanovic et al. found that patients with advanced pathological stage had a 2-fold and 4-fold increase in TGF- ⁇ i levels over patients with confined disease and healthy controls, respectively.
  • TGF- ⁇ i levels were analyzed in 109 of the 120 consecutive prostatectomy patients who had at least 48 months of follow-up, stratified by progression status by 48 months and it was found that pre-operative TGF- ⁇ i levels were significantly elevated in patients with biochemical progression irrespective of the pathologic stage. Thus, TGF- ⁇ ⁇ could be included in pre-operative nomograms for prediction of progression (Kattan et al., 1998).
  • TGF- ⁇ i levels were assessed in ten patients with bone-scan proven metastatic disease, in 19 men with prostate cancer metastatic to regional lymph nodes, and 44 healthy men without any cancer. In agreement with all, except one, previous reports, dramatically elevated levels of TGF- ⁇ i were found in patients with distant prostate cancer metastases (Ivanovic et al., 1995; Adler et al., 1999; Kakehi et al., 1996). The only study that did not detect any association between TGF- ⁇ i levels and metastases relied on serum samples, which can lead to aberrant TGF- ⁇ i levels (Wolff et al., 1999). Furthermore, Wolff et al.
  • TGF- ⁇ j levels between patients with clinical or pathological evidence of metastatic disease supports the potential use of plasma TGF- ⁇ i as a staging marker for prostate cancer that could provide clinically meaningful pathological stratification of the patients.
  • plasma TGF- ⁇ i as a staging marker for prostate cancer that could provide clinically meaningful pathological stratification of the patients.
  • no statistically significant difference was found in plasma TGF- ⁇ i levels between patients with pathologically localized prostate cancer and healthy men without cancer, limiting the value of TGF- ⁇ i as a diagnostic tool for early detection of localized prostate cancer (Kakehi et al., 1996; Wolff et al., 1999; Perry et al., 1997).
  • TGF- ⁇ i levels were found to be 3 to 6-times higher when measured in serum as compared to platelet-poor plasma. Since TGF- ⁇ i is present in platelet granules and is released upon platelet activation, the highly elevated levels of TGF- ⁇ i in serum are likely to derive from damaged platelets and not from the prostate, making quantification of TGF- ⁇ i in serum erroneous for evaluation of TGF- ⁇ i originated from or induced by the prostate. To ensure complete platelet removal, an additional centrifugation was performed in the present study, as recommended by Adler et al. (1999), and almost identical amounts of plasma TGF- ⁇ ! were observed.
  • TGF- ⁇ i values in the serum format were only weakly correlated with those in the plasma formats (correlation coefficients, 0.79 and 0.80), the plasma formats were strongly correlated with each other (correlation coefficient, 0.99).
  • the 2-times lower TGF- ⁇ i values obtained with the citrate plasma as compared to the EDTA plasma collection format may be due to dilution of the top plasma layer primarily by 1.0 mL of 0.1 mol/L sodium citrate anticoagulant, in the Vacutainer ® CPTTM tubes.
  • the pathologic stage of prostate cancer is known to be a strong predictor of progression after radical prostatectomy (Epstein et al., 1996). Nevertheless, 92.5% of the present patients had a pre-operative PSA level above 4 ng/mL; 32.5% had extraprostatic extension in their pathologic prostatectomy specimen, and 50% had a final pathological Gleason score of 7 and above, representative of patients undergoing radical prostatectomy for clinically localized prostate cancer.
  • the lower progression rate may be due to differences in surgical technique (Ohori et al., 1995; Epstein et al., 1996).
  • the positive margin rate in the present series was 13.3% compared with the 16% to 46% positive margin rates reported by others in patients with clinically localized prostate cancer (Ohori et al., 1995; Jones, 1990), which may have decreased the rate of progression due to local failure.
  • plasma TGF- ⁇ i levels are markedly elevated in men with prostate cancer metastatic to regional lymph nodes and bone.
  • the pre-operative plasma TGF- ⁇ i level is the strongest predictor of biochemical progression after surgery likely due to an association with occult metastatic disease present at the time of radical prostatectomy.
  • Plasma IGF-I, IGFBP-2, and IGFBP-3 levels were assessed in 44 healthy patients without cancer, in 19 men with prostate cancer metastatic to regional lymph nodes, and in 10 patients with bone scan-proven, metastatic prostate cancer. Neither patients with metastatic lymph node disease nor patients with metastatic bone disease were treated with either hormonal or radiation therapy before plasma collection.
  • the healthy non-cancer group was composed of three sets of consecutive patients who participated in a weekly prostate cancer screening program. They had no prior history of any cancer or chronic disease, a normal digital rectal examination, and a PSA of less than 2.0 ng/mL, a PSA range that has an estimated probability of prostate cancer detection of less than 1% in the first 4 years after screening (Smith, 1996).
  • Serum and plasma samples were collected on an ambulatory basis at least 4 weeks after transrectal guided needle biopsy of the prostate, typically performed on the morning of the scheduled day of surgery after a typical pre- operative overnight fast.
  • Blood was collected into Vacutainer ® CPTTM 8 mL tubes containing 0.1 mL of 1 M sodium citrate anticoagulant (Becton Dickinson Vacutainer Systems, Franklin Lakes, NJ) and centrifuged at room temperature for 20 minutes at 1500 g.
  • the top layer corresponding to plasma was decanted using sterile transfer pipettes and immediately frozen and stored at -80°C in polypropylene cryopreservation vials (Nalge Nunc, Rochester, NY).
  • the DSL-10-5600ACTIVE ® IGF-I Elisa kit and the DSL-10-6600ACTIVE ® IGFBP-3 Elisa kit were used, respectively (DSL, Webster, TX).
  • the DSL-7100 IGFBP-2 Radioimmunoassay kit (DSL) was used. Every sample was run in duplicate, and the mean was used for data analysis. Differences between the two measurements were minimal, as shown the intra-assay precision coefficient of variation of only 4.73 ⁇ 1.87% for IGF-I, 6.95 ⁇ 3.86% for IGFBP-2, and 8.78 ⁇ 4.07 for IGFBP- 3.
  • IGFBP-2 and IGFBP-3 levels were assessed in three synchronously drawn blood specimens obtained from 10 of the 44 healthy screening patients.
  • Plasma was separated using Vacutainer K 3 ethylenediaminetetraacetic acid (EDTA) 5 mL tubes containing 0.057 mL of 15% K 3 EDTA solution, and Vacutainer ® CPTTM 8 mL tubes containing sodium citrate (Becton Dickinson Vacutainer Systems, Franklin Lakes, NJ).
  • Serum was separated using Vacutainer ® Brand SST Serum SeparatorTM tubes (Becton Dickinson Vacutainer Systems, Franklin Lakes, NJ).
  • Specimens were centrifuged at room temperature for 20 minutes at 1500 g, and plasma or serum decanted and frozen at -80°C until assessment. The investigators were blinded to the nature of the collection formats. Analysis of variance was used to determine whether the collection format significantly affected measured IGFBP-2 and IGFBP-3 levels.
  • Each patient was scheduled to have a digital rectal examination and serum PSA postoperatively every 3 months for the first year, semiannually from the second through the fifth year, and annually thereafter.
  • a staging evaluation, including bone scan, prostascint, and/or PSA doubling time calculation was performed in 11 of the 15 patients who had PSA progression prior to the administration of salvage radiation or hormonal therapy.
  • Biochemical progression was defined as a sustained elevation, on 2 or more occasions, of PSA > 0.2 ng/mL.
  • the date of progression was assigned to the date of the first value > 0.2 ng/mL.
  • Two (1.7%) patients had lymph node positive disease at the time of radical prostatectomy, and surgery was consequently aborted prior to prostate removal. These patients were categorized as failures from the day after surgery.
  • PSA relapse was the sole indication of progression in 14 patients, while 3 had clinical, as well as biochemical evidence of progression.
  • Statistical Analysis Differences in plasma IGFBP-2 and IGFBP-3 levels were assessed using analysis of variance (AN OVA). Multiple comparisons were conducted, when the overall test was significant (one-way ANOVA followed by Fisher's least significant difference). Spearman's rank correlation coefficient was used to compare ordinal and continuous variables.
  • IGFBP-2 and IGFBP-3 levels were studied.
  • Mean IGFBP-2 and IGFBP-3 levels, measured in Vacutainer ® CPTTM citrate plasma, Vacutainer ® K EDTA plasma, and Vacutainer ® BrandSST TM serum from synchronously drawn blood specimens of 10 consecutive, healthy screening patients are shown in Table 7.
  • IGFBP-2 and IGFBP-3 levels measured in citrate plasma were 26% and 28%, respectively, lower than those measured in EDTA plasma, and 37% and 39%, respectively, lower than those measured in serum.
  • IGFBP-2 and IGFBP-3 inter-collection format differences were statistically significant (P values ⁇ 0.001), IGFBP-2 and IGFBP-3 levels measured in specimens collected by all three sample formats were found to be highly correlated with each other (P values ⁇ 0.001).
  • P values ⁇ 0.001 IGFBP-2 and IGFBP-3 levels measured in specimens collected by all three sample formats were found to be highly correlated with each other.
  • Plasma from Vacutainer CPTTM sodium citrate tubes was used for IGF-I, IGFBP-2, and IGFBP-3 measurements in the following study. Table 7
  • IGFBP-2 (ng/mL)
  • IGFBP-3 (ng/mL)
  • pre-operative multivariate model that included pre-operative IGFBP-2, pre-operative PSA, clinical stage, and biopsy Gleason score
  • biopsy Gleason score was the sole independent predictor of PSA progression (P values ⁇ 0.09).
  • IGFBP-3 level was adjusted for IGFBP-2 level, IGFBP-3 became an independent predictor of disease progression (P values ⁇ 0.040) and the association of IGFBP-2 with the risk of prostate progression strengthened (P values ⁇ 0.039).
  • fBiopsy Gleason Score was categorized as grade 2 to 6 versus grade 7 to 10.
  • JClinical stage was categorized as TI versus T2.
  • Plasma IGFBP-2 levels in the prostatectomy patients were significantly higher then those in the healthy subjects (median 340 ng/mL, range 237 - 495; P values ⁇ 0.006).
  • Plasma IGFBP-2 levels in patients with clinically localized prostate cancer, with lymph node metastases, or with bone metastases were not significantly different from each other (P values > 0.413).
  • Plasma IGFBP-3 levels in patients with lymph node metastases (median 2689 ng/mL, range 1613 - 3655) and bone metastases (median 2555 ng/mL, range 1549 - 3213) were significantly lower than those in the cohort of 120 prostatectomy patients (median 3217 ng/mL, range 1244 - 5452) and in healthy subjects (median 3344 ng/mL, range 1761 - 5020; P values ⁇ 0.031).
  • plasma IGFBP-3 levels in the prostatectomy patients were not significantly different than those in healthy subjects (P - 0.575). Discussion
  • IGFBP-2 levels were elevated in patients with non-metastatic and metastatic prostate cancer compared to levels in healthy subjects.
  • a significant association was found between pre-operative plasma IGFBP-2 levels and established markers of biologically aggressive prostate cancer, such as final pathologic stage and grade in patients with clinically localized prostate cancer.
  • pre-operative plasma IGFBP-2 was a robust independent predictor of final pathologic stage and disease progression in a large cohort of consecutive patients with long term follow-up after radical prostatectomy.
  • pre-operative plasma IGFBP-2 levels were not significantly different in patients with presumed distant failure than those with presumed local-only failure.
  • PSA is an IGFBP-3 protease, capable of acting as a co-mitogen with IGFs in the presence of IGFBP-3 (Cohen, 1992).
  • IGFBP-3 proteolysis by PSA (Cohen, 1994) and cathepsin D (Nunn et al., (1997) likely signify local effects rather then systemic effects, within the prostate or metastatic foci leading to local progression or metastasis growth.
  • Elevated serum PSA level has been correlated with decreased IGFBP-3 (Kanety, 1993).
  • IGF-I and BPH increase in follow-up doubling the number of cancer-free controls, as well as measurements of IGF-I levels in patients with regional lymph node metastases.
  • IGF-I levels increase in follow-up doubling the number of cancer-free controls, as well as measurements of IGF-I levels in patients with regional lymph node metastases.
  • no association was found between circulating IGF- I levels and established markers of biologically aggressive prostate cancer, disease progression, or metastasis.
  • Various independent studies have found no difference in IGF-I levels between patients with prostate cancer and healthy men.
  • IGF-I has been shown to stimulate the growth of BPH derived stromal cells in vitro (Sutkowski et al., (1999).
  • the mean IGFBP-2 and IGFBP-3 levels measured in Vacutainer ® CPT TM citrate plasma were 26% and 28%, respectively, lower than those measured in Vacutainer ® K 3 EDTA plasma, and 37% and 39%, respectively, lower than those measured in Vacutainer ® BrandSST serum.
  • IGFBPs may add to the biological relevance of IGFs in prostate cancer.
  • Other IGFBPs such as IGFBP-4 and IGFBP-5 have been associated with tumor grade in prostate specimens, and with tumor stage and serum PSA levels in patients.
  • IGF-I receptor mediates most of the mitogenic effects of IGFs, and experimental inhibition of the IGF-I receptor has resulted in suppression of adhesion, invasion, and metastases in prostate cancer (Kaplan, 1999).
  • circulating levels of IGFs may not be determinants of tissue bioactivity but rather may vary in parallel with autocrine or paracrine expression within tissues (Yakar, 1999). Since hepatic IGF-I and IGFBP-3 are the major contributors of circulating levels of these two IGFs, important autocrine and paracrine production occurring in other tissues such as the prostate may not be reflected by changes in systemic levels of these molecules.
  • IGFBP-2 levels are markedly elevated in men with prostate cancer.
  • the pre-operative plasma IGFBP-2 level is a robust predictor of final pathologic stage and biochemical progression after surgery. This association seems, however, not to be due to an association with occult metastatic disease present at the time of radical prostatectomy.
  • pre-operative circulating IGFBP-3 and IGF-1 levels are not independently associated with established markers of biologically aggressive prostate cancer or PSA progression- free survival. The lack of any association with markers of more aggressive prostate cancer or with prostate cancer progression may limit the clinical utility of IGF-I and IGFBP-3 as tumor markers for prostate cancer.
  • IL-6 and IL-6sR were correlated with clinical and pathological parameters in the 120 patients who underwent radical prostatectomy ( Figures 6-9 and Tables 11- 12). Plasma IL-6 and IL-6sR levels in patients with bone metastases were significantly higher than those in healthy subjects, in prostatectomy patients, or in patients with lymph node metastases (P values ⁇ 0.001).
  • pre-operative plasma IL-6, IL-6sR, and biopsy Gleason score were independent predictors of organ-confined disease (P values ⁇ 0.01) and PSA progression (P values ⁇ 0.028).
  • P 0.038
  • Biopsy Gleason Sumf 4.167 0.005 1.541-1 1.273 2.063 0.185 0.707-6.020
  • a cohort of 468 radical prostatectomy patients was employed to study marker interactions. Of these patients, 278 patients had samples available at 6 to 8 weeks after post-radical prostatectomy. The clinical stage of these patients was ⁇ T3a (47% cTl, 49% cT2, and 4% cT3a) and they had a median PSA of 8.2 ng/mL (range of 0.2 to 60 ng/mL). The median age for these patients was 63 years (range 40 to 81) and the median follow up for them was about 51 months. Fourteen percent (63/468) had PSA recurrence.
  • Post-operative plasma TGF- ⁇ i levels in these patients were found to be useful as a prognostic marker for prostate cancer progression (Figure 10).
  • serial measurements TGF- ⁇ ] may be particularly useful to monitor the outcome of therapy, e.g., surgery, radiation, or hormonal therapy or brachytherapy, similary to serial measurements of PSA.
  • post-therapy measurements of TGF- ⁇ i were found to be a stronger predictor of progression than pre-therapy measurements of TGF- ⁇ i ( Figure 13).
  • post-therapy levels of IL-6 and IL-6sR were not significant predictors of progression.
  • TGF-beta levels in prostate cancer patients just after therapy e.g., just after the prostate is removed at radical prostatectomy
  • Danielpour D et al.: Immunodetection and quantitation of the two forms of transforming growth factor-beta (TGF- ⁇ 1 and TGF- ⁇ 2) secreted by cells in culture. Journal of Cellular Physiology 138: 79-86, 1989. Danielpour D: Improved sandwich enzyme-linked immunosorbent assays for transforming growth factor ⁇ j. Journal of immunological methods 158:
  • Jones EC Resection margin status in radical retropubic prostatectomy specimens: relationship to type of operation, tumor size, tumor grade and local tumor extension. J Urol 144: 89-93, 1990.
  • Wakefield LM Letterio JJ, Chen T, et al: Transforming growth factor-betal circulates in normal human plasma and is unchanged in advanced metastatic breast cancer.

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Abstract

La présente invention concerne une technique permettant de déterminer un pronostic pour des patients atteint d'un cancer de la prostate, par exemple un cancer de la prostate cliniquement localisé.
EP02709378A 2001-02-07 2002-02-07 Methode pour un pronostic apres therapie d'un cancer de la prostate Withdrawn EP1373899A1 (fr)

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