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WO1998033450A1 - Pronostic pour patients atteints de cancer par determination de l'expression des regulateurs, p27 et cycline e, des cycles cellulaires - Google Patents

Pronostic pour patients atteints de cancer par determination de l'expression des regulateurs, p27 et cycline e, des cycles cellulaires Download PDF

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Publication number
WO1998033450A1
WO1998033450A1 PCT/US1998/001922 US9801922W WO9833450A1 WO 1998033450 A1 WO1998033450 A1 WO 1998033450A1 US 9801922 W US9801922 W US 9801922W WO 9833450 A1 WO9833450 A1 WO 9833450A1
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cyclin
levels
carcinoma
cancer
tumor
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PCT/US1998/001922
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English (en)
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Peggy L. Porter
James M. Roberts
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Fred Hutchinson Cancer Research Center
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Priority to AU63184/98A priority Critical patent/AU724107B2/en
Priority to CA002279361A priority patent/CA2279361A1/fr
Publication of WO1998033450A1 publication Critical patent/WO1998033450A1/fr

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    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/53—Immunoassay; Biospecific binding assay; Materials therefor
    • G01N33/574—Immunoassay; Biospecific binding assay; Materials therefor for cancer
    • G01N33/57407—Specifically defined cancers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B10/00—Instruments for taking body samples for diagnostic purposes; Other methods or instruments for diagnosis, e.g. for vaccination diagnosis, sex determination or ovulation-period determination; Throat striking implements
    • 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
    • G01N33/57415—Specifically defined cancers of breast
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B10/00—Instruments for taking body samples for diagnostic purposes; Other methods or instruments for diagnosis, e.g. for vaccination diagnosis, sex determination or ovulation-period determination; Throat striking implements
    • A61B10/0041—Detection of breast cancer
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B10/00—Instruments for taking body samples for diagnostic purposes; Other methods or instruments for diagnosis, e.g. for vaccination diagnosis, sex determination or ovulation-period determination; Throat striking implements
    • A61B10/0045—Devices for taking samples of body liquids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B10/00—Instruments for taking body samples for diagnostic purposes; Other methods or instruments for diagnosis, e.g. for vaccination diagnosis, sex determination or ovulation-period determination; Throat striking implements
    • A61B10/02—Instruments for taking cell samples or for biopsy
    • A61B10/0233—Pointed or sharp biopsy instruments
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B10/00—Instruments for taking body samples for diagnostic purposes; Other methods or instruments for diagnosis, e.g. for vaccination diagnosis, sex determination or ovulation-period determination; Throat striking implements
    • A61B10/02—Instruments for taking cell samples or for biopsy
    • A61B10/0233—Pointed or sharp biopsy instruments
    • A61B10/0241—Pointed or sharp biopsy instruments for 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
    • G01N2333/435—Assays involving biological materials from specific organisms or of a specific nature from animals; from humans
    • G01N2333/46—Assays involving biological materials from specific organisms or of a specific nature from animals; from humans from vertebrates
    • G01N2333/47—Assays involving proteins of known structure or function as defined in the subgroups
    • G01N2333/4701—Details
    • G01N2333/4739—Cyclin; Prad 1

Definitions

  • This invention provides methods for prognosis and staging in cancer patients involving the measurement in biological samples from cancer patients of the levels of expression of both the cell cycle regulators cyclin E and p27.
  • Cyclin E a regulator of the Gl to S-phase transition in mammalian cells, has been implicated in numerous types of human cancer (Koff et al. (1991); Lew et al. (1991)). Two isoforms of cyclin E, having sizes of 50 and 55 kilodaltons, have been identified in cycling cells (Ohtsubo and Roberts (1993)). Cyclin E is a nuclear protein that attains its maximal level at the entrance to S phase, and then is degraded as S phase progresses (Gong et al. (1994); Ohtsubo et al. (1995)).
  • cyclin E present at this critical stage in the cell cycle would appear to be a factor in a cell's ability to traverse S phase and to subsequently divide.
  • constitutive expression of cyclin E shortens the Gl phase of the cell cycle and promotes an increased rate of cell division, although the cells constitutively expressing cyclin E lack many of the characteristics of tumorigenic cells (Ohtsubo and Roberts (1993)). This latter finding suggests that overexpression of cyclin E alone is not sufficient to cause cancer.
  • Cyclin E and other cyclins as well, manifests its control of the cell cycle by associating in the cell nucleus with other proteins called "cell division kinases" (CDKs) (U.S. Patent No. 5,549,755 (1995)). Association of CDKs with cyclins to form cyclin/CDK complexes results in the activation of the previously dormant kinase activity. Thus, the cyclins often are described as being the regulatory subunits of the CDKs. During the late Gl and early S phases of the cell cycle, cyclin E binds and activates at least two different kinases that belong to the "CDK2" family.
  • Targets for phosphorylation of cyclin E-activated kinase include, for example, cyclin E itself, and histone HI.
  • Levels of the cyclin E/CDK2 polypeptide complexes normally are cell cycle-regulated, and peak in abundance in late Gl phase of the cell cycle in accordance with the peak levels of cyclin E itself.
  • cyclin E is aberrantly expressed in a variety of human tumors (Leach et al. (1993) (cyclin E genes amplified in 2 of 47 colorectal carcinomas); Keyomarsi et al. (1994) (quantitative and qualitative alterations in cyclin E protein production in human breast cancer and leukemia; Garcia-Foncillas, J., et al, (1996) (overexpression of cyclin E associated with decreased survival in nonmetastatic esophageal tumors); Gong et al. (1994) (cyclin E expressed in the wrong phase of the cell cycle in ductal breast carcinoma and colon carcinoma cells); Dutta et al.
  • the p27 protein belongs to this class of cell cycle regulators that, in contrast to the cyclins, inhibit cell division.
  • the class of inhibitors to which p27 belongs acts by inhibiting the activity of the cyclin-dependent kinases, thus are known as the "kip" proteins.
  • p27 is present in high levels in quiescent cells, and declines in proliferating cells in response to mitogenic signals such as growth factors and cytokines (Firpo, E. et al. (1994); Nourse, J., et al. (1994); Coats, S., et al. (1996)).
  • p27-kipl specifically inhibits the kinase activity of the cyclin E/CDK2 complex by binding with cyclin E (Ponce-Castenada et al. (1995); Coats et al. (1996)).
  • Coats et al. demonstrated that enforced expression of p27 arrested the cell cycle in Gl, and that conversely, decreasing the level of p27 with antisense oligonucleotide inhibition resulted in a shortened Gl phase, and an increased rate of cell division.
  • the down regulation of p27 in response to mitogenic signals has been proposed to be a critical step in mediating the response of normal cells to mitogenic stimuli (Coats et al. (1996)).
  • p27 slows cell proliferation by inhibiting CDKs
  • several groups have raised the possibility that p27 alterations could be involved in tumorigenesis.
  • p27 is involved in regulating the cell cycle, but also it has been mapped to the human chromosome arm 12p, which is a site of frequent deletions and rearrangements in a number of human cancers, including germ cell tumors, ovarian teratoma, leukemia, peritoneal mesothelioma, and malignant ovarian neoplasms (Pietenpol et al, (1995); Ponce-Castenada et al. (1995)).
  • tumor progression would involve a process wherein one copy of p27 is first deleted, and the remaining copy is subsequently mutated.
  • Prognostic indicators for cancer are desirable because they provide physicians with a basis for determining the best treatment for individual patients.
  • the prognostic indicators generally relied upon include tumor size, histopathological classification, and the results of lymph node biopsies. Based on these and other cancer-specific criteria, cancers typically are classified into various "stages," generally designated by the roman numerals I, II, III, or IV. In many cases, other indicators have been established whose prognostic value is associated with only one or a limited number of tumor types (McGuire and Clark (1992)). Nonetheless, prognostication of cancer remains imperfect, and many patients continue to be either undertreated or overtreated. Improved prognostic methods can assist physicians in better determining which patients require aggressive treatment, and which ones will thrive with only the minimal degree of therapy, thus improving the average survival of all cancer patients. Summary of the Invention
  • this invention provides methods for determining the prognostic outcome of cancer, and for assigning tumors to various stages of tumor progression. These methods involve obtaining from the patient a biological sample that either contains cancerous tissue, such as a tumor biopsy, or a sample such as blood or urine that contains materials or molecules derived from tumor tissues that have become necrotic or that have otherwise released their contents. The levels of expression of cyclin E and p27 are then determined for these tumor samples. By comparison with a set of standards, the observed levels of expression of cyclin E and p27 in the patient sample are classified as “high,” “intermediate,” or "low”.
  • a low level of cyclin E and a high level of p27 expression indicates a good prognosis, and indicates a low grade of tumor corresponding to the lower stages in tumor progression.
  • Intermediate levels of expression of the two markers will correspond to intermediate stages in progression of the disease.
  • FIGURES 1A-1F illustrate the associations of cyclin E and p27 expression in breast tumor samples and survival of the patients from whom the samples were obtained (Kaplan-Maier plots).
  • the FIGURES show survival in either the total group of women (FIGURES 1A-1C), or in the subset consisting of node-negative women (FIGURES 1D-1F).
  • Each plot shows either the correlation between survival and levels of cyclin E alone (FIGURES 1 A and ID), levels of p27 alone (FIGURES IB and IE), or cyclin E and p27 combined (FIGURES 1C and IF).
  • This invention provides methods for determining the prognostic outcome of cancer and for staging tumors. It has been demonstrated that measuring the levels of expression of cyclin E and biological samples from cancer patients provide a prognostic index having greater predictive value than measurements of either cyclin E or p27 alone. Thus, measurement of these two indicators in the same biological sample provides prognostic information valuable for determining the best therapeutic protocol for treating cancer patients, a group that includes patients suffering from various types of cancer, including sarcoma, melanoma, leukemia, myeloma, and carcinoma, including breast carcinoma, prostate carcinoma, colorectal carcinoma, stomach carcinoma, esophageal carcinoma, bladder carcinoma, cervical carcinoma, lung carcinoma, as well as other cancers.
  • the subject invention thus provides a method for determining the prognostic outcome of cancer that involves measuring the levels of expression of cyclin E and p27 in a tumor sample and comparing the levels observed in the sample with the levels of expression in a set of standards.
  • a tumor sample includes samples derived from any patient suffering from cancer, including those forms of cancer, e.g., leukemia, that are not typically associated with the formation of solid tumor masses. If the patient from whom the tumor sample is taken has, as compared with the standards, a high level of cyclin E expression, and a low or undetectable level of p27 expression, this circumstance indicates that a poor prognostic outcome can be expected for that patient.
  • Cancer patients having a "poor prognostic outcome” are those who are significantly more likely than other patients having the same type of cancer to have a relapse or to die from the cancer at the end of any designated test period. "Significantly more likely” in this context refers to statistical significance, where the relative risk of death (RR) is calculated according to conventional statistical methods. Moreover, the relative levels of cyclin E and p27 can be used to stage cancers as an adjunct or as an alternative to conventional methods for cancer staging.
  • the values for "low,” “intermediate,” or “high” levels of expression are determined by comparison to reproducible standards in which low or high levels of expression have been demonstrated to be present.
  • the tissues used to establish these standards can be derived from the normal tissue found adjacent to tumor tissue in biopsy samples, from normal tissue taken from the same tissue type in non-cancer patients, from normal tissues of other types, or from cultured cells that are determined empirically to express low, intermediate, or high levels of these two prognostic markers.
  • tumor sample may include any tissue or body fluid from a cancer patient and includes either malignant cells or materials or molecules derived from malignant cells.
  • a “tumor sample” includes a body fluid into which the contents of tumor cells have been released (e.g., blood, or could be urine), and which may contain metabolic degradation products derived from the tumor.
  • tumor sample refers not only to tumor biopsy samples, but also to samples of blood, saliva, urine, skin scrapings, or any other tissue derived from the patient's body.
  • Tumor samples can be analyzed by measuring intact mRNA or protein expressed by the cyclin E or p27 genes, including aberrant forms of these proteins, and also can be analyzed by measuring various breakdown products of these molecules that may be present, for example, in blood or urine.
  • cancer patients can now be subdivided into groups having either significantly elevated or significantly reduced risk of mortality based on their levels of expression of cyclin E and p27.
  • these indices are useful in determining which patients suffering from cancer will benefit from more aggressive therapy.
  • Assays for determining levels of cyclin E and p27 in tumor samples include methods for quantifying mRNA specific for these proteins (such as, e.g., Northern blots), methods for direct detection of the proteins (e.g., western blots or immunocytohistological methods), or assays based on detecting functional activities of free cyclin E (e.g., phosphorylase kinase activation) or complex-associated cyclin E (ability to phosphorylate histone HI). Similarly, functional assays for p27 are based on this protein's ability to inhibit cyclin E/CDK kinase activity.
  • the subject invention includes assays for: a) detecting the relative or absolute levels and activities of cyclin E and p27 in tumor samples including nonsynchronized cell populations (e.g., in tumor biopsy specimens or body fluids of cancer patients); and b) assays for determining the levels and activities of cyclin E and p27 in various types of biological samples (i.e., solid tissue samples, primary cultures of tumor cells, blood, urine, saliva, serum, plasma, mucus secretions, CNS fluid, cell extracts, and the like).
  • the levels and activities of cyclin E and p27 expressed in these tumor samples, taken together, provide an improved method of determining the stage and predicting the outcome of cancer in individual patients. Analysis of this pair of markers can be used either as an alternative to present methods of diagnosis, prognosis, and staging, or as an adjunct to extant risk factor analysis.
  • Simultaneous analysis of p27 and cyclin E levels can be used for determining prognosis, i.e., predicting patient survivability and time to recurrence of tumor, for forming a basis for determining if aggressive anti-cancer therapies are appropriate (e.g., chemotherapy or irradiation therapy), for monitoring the effectiveness of ongoing therapy (e.g., by analyzing biopsies taken at various times during treatment), or for staging tumors.
  • prognosis i.e., predicting patient survivability and time to recurrence of tumor
  • aggressive anti-cancer therapies e.g., chemotherapy or irradiation therapy
  • monitoring the effectiveness of ongoing therapy e.g., by analyzing biopsies taken at various times during treatment
  • Stage I Malignant condition often are classified into stages ranging from Stage I to IV. Staging is useful to facilitate planning the most appropriate course of therapy for each patient and for predicting the likely outcome of the disease.
  • Each cancerous condition has its own staging classification, as each cancer is different, but the stages are broadly defined as follows.
  • Stage I is defined usually as cases wherein the cancer is still confined to the organ in which it originated. Such tumors are considered to be operable, and the prognosis is typically favorable.
  • Stage II cancers usually involve some surrounding tissue, while Stage III cancers have invaded the local lymph nodes.
  • Stage IV patients the cancer has metastasized into areas of the body distant from the original site, and organs besides the one in which the cancer originated have become involved.
  • the higher the staging number the more serious the cancer, and the poorer the prognosis.
  • prognostication based on conventional histological staging is imperfect, and physicians usually take other factors into account as well in making decisions regarding treatment.
  • the subject invention offers methods for staging tumors that can improve the physician's ability to predict the course of cancer in individual patients.
  • To establish a correlation between tumor stages and expression of p27 and cyclin E conventionally staged tumors from various types of cancer are analyzed for cyclin E and p27 levels, and thereafter, measurement of these levels can serve as a surrogate, or as an adjunct, to the conventional staging analyses.
  • a tumor sample is obtained from a cancer patient, and the levels of expression of cyclin E and p27 in the tumor sample are assayed. Thereafter, the levels measured in the tumor sample are compared with the levels present in a set of standards whose content of cyclin E and p27 have been established to correspond to the levels found in Stages I, II, III, or IV for the same type of cancer from which the tumor sample is derived.
  • the cancer from which the tumor sample was derived can be assigned a classification based on the correspondence of the levels measured in the sample with the levels present in the standards.
  • the expression of cyclin E and p27 was characterized in breast tumors from a group of 278 young women. Also assayed in these samples were a number of other indicators that had been implicated previously as independent prognosticators of breast cancer. The results, described below in Example 1 , indicated that when the cyclin E and p27 indices were combined, this combination provided a prognostic indicator far better than any one of the indicators taken alone. The superiority of this combined index is apparent from the plots shown in Figures 1 A- IF.
  • Prognosis of breast cancer is important, especially in node-negative patients, because while following excision two-thirds of these women will do well without further adjuvant therapy, the remaining third will experience relapse (Dutta et al. (1995)). Because of the deleterious side effects, aggressive treatment of all node- negative women is not considered worth the risks and side-effects associated with such treatment. However, node-negative women having a poor prognosis could be identified at the time of initial diagnosis, these women could receive the aggressive therapy that would increase their survival.
  • cyclin E levels has recently emerged as being a good prognosticator for breast cancer, and the overexpression of cyclin E protein was shown to be associated with a two-fold greater risk of death (Keyomarsi et al. (1994) (altered expression of cyclin E correlates with increased breast tumor stage and grade); Said and Medina (1995) (increased cyclin E expression in tumorigenic cell lines); Nielsen et al. (1996) (increased cyclin E expression associated with decreased survival of breast cancer patients); Dutta et al. (1995) (elevated cyclin E expression associated with breast cancers having a high proliferative index).
  • Patient population Available for this study were paraffin-embedded primary breast tumor tissue samples, obtained prior to any adjuvant treatment, from a cohort of 1292 women, aged 20 to 44, who were identified through the Cancer Surveillance System (CSS) of western Washington and who were interviewed as part of a ongoing study at the Fred Hutchinson Cancer Research Center. These women were diagnosed between 1983 and 1992. A total of 278 ductal carcinoma samples from this cohort were analyzed. Forty-eight percent of the women from whom these samples were derived were node positive. Information concerning diagnosis date, tumor size, clinical stage, and lymph node status, and deaths was obtained from the CSS. Subjects were followed until the earliest of: their date of death, the date last known to be alive, or the end of the follow-up period. Observations were censored at either the date of last known follow-up or the end date of the follow-up period if death had not occurred.
  • CCS Cancer Surveillance System
  • Each of the tumors analyzed for this study was assigned a histologic grade from I (low) to III (high) according to the Bloom and Richardson grading scheme for invasive ductal carcinoma.
  • Antibodies used for this study included previously characterized affinity purified polyclonal anti-cyclin E (Ohtsubo, M., et al. (1995)), anti-cyclin A (Roberts' lab), and anti-p27 (Nourse, J., et al. (1994)); rabbit polyclonal anti-c-erbB-2 (Dako, Denmark); anti-p53 clone 1801 (Oncogene Science, Uniondale NY); anti-Ki-67 clone MIB-1 (Immunotech, Westbrook ME). Experimental validation of immunostaining with anti-cyclin E antibody was done by constructing cell lines that overexpress cyclin E from a transfected gene.
  • cyclin E immunostaining was compared with western blotting and a direct correspondence between the amount of cyclin E present and the intensity of cyclin E immunostaining was established (Ohtsubo, M., and Roberts, J. (1993)). Tissues from p27 null mice (Fero, M ., et al. (1996)) provided a negative control for the p27 antibody; in the absence of p27, no detectable immunostaining was observed with the anti-p27 antibody.
  • Sections of human tonsil tissue, benign breast epithelium, and invasive ductal carcinoma were subjected to immunohistochemical analyses as described above.
  • human tonsil was immunostained with anti-cyclin E, it was revealed that cyclin E was present in the nuclei of scattered cells of the proliferative germinal center, and was absent from the quiescent mantle zone cells.
  • p27 exhibited the inverse pattern in human tonsil, in that it was absent from the germinal center, and instead was observed predominantly in the quiescent cells of the mantle zone.
  • Different staining patterns for cyclin E and p27 also were observed in benign breast sections, in which cyclin E was absent, and p27 was present in the nuclei of epithelial cells.
  • Breast cancer cells exhibited high levels of cyclin E in a poorly differentiated tumor and, conversely, exhibited high levels of p27 in a well differentiated tumor.
  • cyclin E and p27 were compared in this same group of samples to other tumor characteristics and risk factors (Table 1) and to mortality after a median follow-up of 5.2 years.
  • the relative risks (RR) both univariate and multivariate) of dying and 95% confidence intervals (CI) were estimated using a weighted Cox proportional hazard model, among 237 women for whom information concerning stage, age at diagnosis, tumor size, lymph node status, histologic grade, and assays of cyclin E, p27, Ki-67 proliferation index, p53, and c-erbB-2 were available.
  • Relative risk was determined by the Cox regression model. Ninety-five percent confidence intervals are shown in parentheses.
  • Ki-67 analysis positive tumor nuclei were scored in 4 fields (400X), which were selected to reflect areas of highest proliferation. For this analysis, "low” Ki-67 meant that 0-50% of the cells were positive for this marker, and "high” Ki-67 meant that 51-100% of cells in the observed fields were positive. No significant differences in the results were observed when the cut-off point between high and low values was set at either 25% or 50%.

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Abstract

La présente invention se rapporte à des procédés permettant d'établir un pronostic pour des patients atteints de cancer et de prévoir l'évolution du cancer par analyse de prélèvements de tumeurs visant à déterminer les niveaux de cycline E et de p27-kip1.
PCT/US1998/001922 1997-01-31 1998-01-29 Pronostic pour patients atteints de cancer par determination de l'expression des regulateurs, p27 et cycline e, des cycles cellulaires WO1998033450A1 (fr)

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AU63184/98A AU724107B2 (en) 1997-01-31 1998-01-29 Prognosis of cancer patients by determining expression of cell cycle regulators p27 and cyclin E
CA002279361A CA2279361A1 (fr) 1997-01-31 1998-01-29 Pronostic pour patients atteints de cancer par determination de l'expression des regulateurs, p27 et cycline e, des cycles cellulaires

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Cited By (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1208232A4 (fr) * 1999-06-10 2003-01-15 Sloan Kettering Inst Cancer Marqueurs du cancer de la prostate
US6972170B1 (en) 1997-12-01 2005-12-06 Sloan-Kettering Institute For Cancer Research Markers for prostate cancer
EP1435776A4 (fr) * 2001-09-24 2006-01-25 Univ Pittsburgh Vaccin anticancereux, methodes diagnostiques et reactifs
US7171311B2 (en) 2001-06-18 2007-01-30 Rosetta Inpharmatics Llc Methods of assigning treatment to breast cancer patients
EP1918386A1 (fr) * 2002-03-13 2008-05-07 Genomic Health, Inc. Profilage de l'expression génétique dans des tissus de tumeurs prélevées par biopsie
US7514209B2 (en) 2001-06-18 2009-04-07 Rosetta Inpharmatics Llc Diagnosis and prognosis of breast cancer patients
US7655461B2 (en) 2004-12-07 2010-02-02 University of Pittsbugh — Of the Commonwealth System of Higher Education Therapeutic and diagnostic cloned MHC-unrestricted receptor specific for the MUC1 tumor associated antigen
US8019552B2 (en) 2004-03-05 2011-09-13 The Netherlands Cancer Institute Classification of breast cancer patients using a combination of clinical criteria and informative genesets
US20120035184A1 (en) * 2009-01-29 2012-02-09 Yale University Methods for inducing tumor regression, inhibiting tumor growth, and inducing apoptosis in breast tumors with geranylgeranyltransferase i inhibitors
US8748170B2 (en) 2008-07-25 2014-06-10 University of Pittsburgh—of the Commonwealth System of Higher Education Polypeptides derived from cyclin B1 and uses thereof

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5543291A (en) * 1993-01-29 1996-08-06 Dana Farber Cancer Institute Method of detecting carcinoma
US5672508A (en) * 1996-01-23 1997-09-30 Mitotix, Inc. Inhibitors of cell-cycle progression, and uses related thereto
US5688655A (en) * 1988-02-10 1997-11-18 Ict Pharmaceuticals, Inc. Method of screening for protein inhibitors and activators
US5733920A (en) * 1995-10-31 1998-03-31 Mitotix, Inc. Inhibitors of cyclin dependent kinases

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4980281A (en) * 1988-02-10 1990-12-25 Housey Gerard M Method of screening for protein inhibitors and activators

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5688655A (en) * 1988-02-10 1997-11-18 Ict Pharmaceuticals, Inc. Method of screening for protein inhibitors and activators
US5543291A (en) * 1993-01-29 1996-08-06 Dana Farber Cancer Institute Method of detecting carcinoma
US5733920A (en) * 1995-10-31 1998-03-31 Mitotix, Inc. Inhibitors of cyclin dependent kinases
US5672508A (en) * 1996-01-23 1997-09-30 Mitotix, Inc. Inhibitors of cell-cycle progression, and uses related thereto

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