WO2017079618A1 - Méthodes permettant de déterminer la stratification du risque de cancer lié à la néoplasie intra-épithéliale prostatique de haut grade - Google Patents

Méthodes permettant de déterminer la stratification du risque de cancer lié à la néoplasie intra-épithéliale prostatique de haut grade Download PDF

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Publication number
WO2017079618A1
WO2017079618A1 PCT/US2016/060614 US2016060614W WO2017079618A1 WO 2017079618 A1 WO2017079618 A1 WO 2017079618A1 US 2016060614 W US2016060614 W US 2016060614W WO 2017079618 A1 WO2017079618 A1 WO 2017079618A1
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erg
control sample
compared
expression level
hgpin
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PCT/US2016/060614
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English (en)
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Rajal B. SHAH
Savvas Mendrinos
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Miraca Life Sciences, Inc.
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Publication of WO2017079618A1 publication Critical patent/WO2017079618A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/32—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against translation products of oncogenes
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/53—Immunoassay; Biospecific binding assay; Materials therefor
    • G01N33/574—Immunoassay; Biospecific binding assay; Materials therefor for cancer
    • G01N33/57407—Specifically defined cancers
    • G01N33/57434—Specifically defined cancers of prostate

Definitions

  • Prostate cancer is one of the most common types of cancer that men contract, second only to skin cancer, and is one of the leading causes of cancer death in men.
  • the American Cancer Society estimates that there are approximately 180,000 new cases of prostate cancer per year.
  • PSA prostate-specific antigen
  • DRE digital rectal exam
  • PIN Prostatic intraepithelial neoplasia
  • PIN is a condition in which some prostate cells look and behave differently from typical prostate cells. These cells are typically located in the lining of acini or in the lining of the ducts that carry fluid to the main ejaculatory duct. With PIN, the lining remains intact even though the cells are abnormal, whereas when prostate cancer develops, the epithelial lining is ruptured. PIN can be diagnosed as either low-grade (i.e., LGPIN) or high-grade (i.e., HGPIN). In HGPIN, there is a higher degree of abnormality in the cells. Furthermore, it tends to develop in the peripheral zone of the prostate, which is where most cases of prostate cancer develop. Summary of the Invention
  • a method of determining a cancer risk profile stratification for a subject involves determining an expression level of ERG oncoprotein in high grade prostatic intraepithelial neoplasia (HGPIN) prostate tissue isolated from the subject compared to a control sample, and determining the presence or absence of at least one morphological variable compared to a second control sample, whereby when the expression level of ERG oncoprotein is high compared to the control sample and the at least one morphological variable is present compared to the second control sample, a high cancer risk profile stratification is present, and when the expression level of ERG oncoprotein is low compared to the control sample and the at least one morphological variable is absent compared to the second control sample, a low cancer risk profile stratification is present.
  • HGPIN prostatic intraepithelial neoplasia
  • the at least one morphological variable may include, without limitation, bilaterality, multifocality, greater than 1 core involvement, or cribriform morphology, or any combination thereof.
  • the method may further involve isolating the prostate tissue prior to determining the expression level of ERG as described herein.
  • the method may further involve conducting a prostate biopsy from the subject when a high cancer risk profile stratification is present.
  • the method may further involve treating the subject with a prostate cancer treatment regimen when a high cancer risk profile stratification is present.
  • the expression level of ERG oncoprotein may be determined by immunostaining with a non-human antibody.
  • the non-human antibody may be derived from a rabbit.
  • the non-human antibody may be a rabbit monoclonal antibody.
  • certain steps of the methods disclosed herein may be carried out ex vivo.
  • a method of treating prostate cancer in a subject involves determining an expression level of ERG oncoprotein in HGPIN prostate tissue isolated from the subject compared to a control sample. The method further involves determining the presence or absence of at least one morphological variable compared to a second control sample, and treating the subject with any known prostate cancer treatment regimen when the expression level of ERG oncoprotein is high compared to the control sample and the at least one morphological variable is present compared to the second control sample.
  • the at least one morphological variable may include, without limitation, bilaterality, multifocality, greater than 1 core involvement, or cribriform morphology, or any combination thereof.
  • the method may involve isolating the prostate tissue prior to determining the expression level of ERG as described herein.
  • the method may involve determining the expression level of ERG oncoprotein by immunostaining with a non-human antibody.
  • the non-human antibody may be derived from a rabbit.
  • the non-human antibody may be a rabbit monoclonal antibody.
  • a use of an anti-ERG antibody is disclosed to determine a cancer risk profile stratification in a subject.
  • a high cancer risk profile stratification is present, and when the expression level of ERG oncoprotein is low in the HGPIN prostate tissue compared to the control sample, a low cancer risk profile stratification is present.
  • the use may further involve the use of at least one morphological variable in combination with the anti-ERG antibody to determine the cancer risk profile stratification, wherein when the expression level of ERG oncoprotein is high in the HGPIN prostate tissue of the subject compared to a control sample and the at least one morphological variable is present compared to a second control sample, a high cancer risk profile stratification is present, and when the expression level of ERG oncoprotein is low compared to the control sample and the at least one morphological variable is absent compared to the second control sample, a low cancer risk profile stratification is present.
  • the at least one morphological variable may include, without limitation, bilaterality, multifocality, greater than 1 core involvement, or cribriform morphology, or any combination thereof.
  • the expression level of ERG oncoprotein may be determined by immunostaining with a non-human antibody.
  • the non-human antibody may be derived from a rabbit.
  • the non-human antibody may be a rabbit monoclonal antibody.
  • FIG. 1 depicts a prostate biopsy as described in further detail herein.
  • FIG. 2 depicts luminal epithelial cells as described in further detail herein.
  • FIG. 3 depicts a multivariable analysis as described herein.
  • FIG. 4 depicts a multivariable analysis as described herein.
  • a method of determining a cancer risk profile stratification for a subject is disclosed.
  • the subject may include, without limitation, a mammal.
  • the mammal may include, without limitation, a human.
  • the human subject may include a human male subject.
  • the method involves determining an expression level of ERG oncoprotein in prostate cancer, including without limitation, high grade prostatic intraepithelial neoplasia (HGPIN) prostate tissue isolated from the subject compared to a control sample.
  • ERG expression may be determined at a protein level or, as a non-limiting example, through monitoring mRNA expression.
  • Protein level expression can be monitored, for example, by immunostaining or other methods for determining the level of protein, including, without limitation, Western-blot or Western transfer, ELISA (enzyme-linked immunosorbent assay), competitive EIA (competitive enzyme immunoassay), DAS-ELISA (double antibody sandwich ELISA), immunocytochernical and immunohistochemical techniques, techniques based on the use of protein biochips or microarrays which include specific antibodies or assay s based on colloidal precipitation in formats such as dipsticks.
  • immunostaining or other methods for determining the level of protein including, without limitation, Western-blot or Western transfer, ELISA (enzyme-linked immunosorbent assay), competitive EIA (competitive enzyme immunoassay), DAS-ELISA (double antibody sandwich ELISA), immunocytochernical and immunohistochemical techniques, techniques based on the use of protein biochips or microarrays which include specific antibodies or assay s based on colloidal precipitation in formats such as dipstick
  • the presence or absence of ERG oncoprotein can be determined by way of counting the number of cells that stain positive wherein a positive sample contains 1 positive cell out of approximately 1000 cells; or 1 positive cell out of approximately 900 cells: or 1 positive cell out of approximately 800 cells; or 1 positive cell out of approximately 700 cells; or 1 positive ceil out of approximately 600 cells; or 1 positive cell out of approximately 500 cells; or 1 positive cell out of approximately 400 cells; or 1 positive cell out of approximately 300 cells; or 1 positive cell out of approximately 200 cells; or 1 positive cell out of approximately 175 ceils; or 1 positive cell out of approximately 150 cells; or 1 positive cell out of approximately 125 ceils; or 1 positive cell out of approximately 100 cells; or 1 positive cell out of approximately 90 cells; or 1 positive cell out of approximately 80 cells; or 1 positive cell out of approximately 70 cells; or 1 positive ceil out of approximately 60 ceils; or 1 positive cell out of approximately 50 cells; or 1 positive cell out of approximately 40 cells; or 1 positive ceil
  • Monitoring niRNA expression can be carried out, for example, by Northern blotting, RT-PCR, or gene chip technology and the like.
  • the method further involves determining the presence or absence of at least one morphological variable compared to a second control sample, whereby when the expression level of ERG oncoprotein is high compared to the control sample and the at least one morphological variable is present compared to the second control sample, a high cancer risk profile stratification is present, and when the expression level of ERG oncoprotein is low compared to the control sample and the at least one morphological variable is absent compared to the second control sample, a low cancer risk profile stratification is present.
  • the predictability with which a high or low cancer risk profile stratification is made may be based on the associated P values disclosed herein.
  • the at least one morphological variable may include, without limitation, bilaterality, multifocality, greater than 1 core involvement, or cribriform morphology, or any combination of the foregoing. Determination of the at least one morphological variable can be made without the need for professional skill. For example, determination of the at least one morphological variable can be made by comparing the prostate tissue to well-known predetermined criteria in the second control sample. The method may further involve isolating the prostate tissue prior to determining the expression level of ERG as described herein. Such isolation can be carried out by a prostate biopsy. The method may further involve conducting a subsequent prostate biopsy from the subject when a high cancer risk profile stratification is present. The subsequent prostate biopsy may be used, for example, to diagnose prostate cancer.
  • the method may further involve treating the subject with a prostate cancer treatment regimen when a high cancer risk profile stratification is present. Further, and optionally, the method may involve treating the subject with a prostate cancer treatment regimen following a subsequent prostate biopsy or related diagnosis.
  • the expression level of ERG oncoprotein may be determined by immunostaining with a non-human antibody.
  • the non-human antibody may be derived from a number of species, including, but not limited to, a rabbit. Further, the non-human antibody may be a rabbit monoclonal antibody, as is disclosed in the Examples section detailed herein.
  • certain steps disclosed herein or all of the steps of the methods disclosed herein may be carried out ex vivo.
  • a method of treating prostate cancer in a subject involves determining an expression level of ERG oncoprotein in HGPIN prostate tissue isolated from the subject compared to a control sample. The method further involves determining the presence or absence of at least one morphological variable compared to a second control sample, and treating the subject with a prostate cancer treatment regimen when the expression level of ERG oncoprotein is high compared to the control sample and the at least one morphological variable is present compared to the second control sample.
  • the at least one morphological variable may include, without limitation, bilaterality, multifocality, greater than 1 core involvement, or cribriform morphology, or any combination thereof.
  • the method may involve isolating the prostate tissue prior to determining the expression level of ERG as described herein.
  • the method may involve determining the expression level of ERG oncoprotein by immunostaining with a non-human antibody.
  • the non-human antibody may be derived from a rabbit.
  • the non-human antibody may be a rabbit monoclonal antibody.
  • a use of an anti-ERG antibody is disclosed to determine a cancer risk profile stratification in a subject.
  • the use may further involve the use of at least one morphological variable in combination with the anti-ERG antibody to determine the cancer risk profile stratification, wherein when the expression level of ERG oncoprotein is high in the HGPIN prostate tissue of the subject compared to a control sample and the at least one morphological variable is present compared to a second control sample, a high cancer risk profile stratification is present, and when the expression level of ERG oncoprotein is low compared to the control sample and the at least one morphological variable is absent compared to the second control sample, a low cancer risk profile stratification is present.
  • the at least one morphological variable may include, without limitation, bilaterality, multifocality, greater than 1 core involvement, or cribriform morphology, or any combination thereof.
  • the expression level of ERG oncoprotein may be determined by immunostaining with a non-human antibody.
  • the non-human antibody may be derived from a rabbit.
  • the non-human antibody may be a rabbit monoclonal antibody.
  • PCa refers to prostate cancer
  • ERG refers to the ERG oncoprotein and natural and non- natural variants thereof.
  • one morphological variable includes the clinicopathological parameters disclosed herein.
  • PSA prostate-specific antigen
  • HGPIN refers to high-grade prostatic intraepithelial neoplasia.
  • a prostate biopsy is depicted which contains a focus ofHGPIN demonstrating enlarged nuclei and prominent nucleoli.
  • luminal epithelia cells of HGPIN exhibit strong nuclear ERG over expression (see, for e.g. cells marked 20 in Figure 2).
  • the retained basal cells are highlighted at the periphery of the gland (see, for e.g. cells marked 22 in Figure 2).
  • the mean age was 63 years (range, 46-83).
  • a mean of 2.16 (range, 2 to 5) biopsies were performed with the mean follow up time of 7.5 months (range, 1-63). All 155 patients had at least one repeat biopsy. In addition 24 of 155 patients had more than one repeat biopsy. Means of 12 and 11.8 cores for initial and repeat biopsy were obtained (range, 8-24). Most rebiopsies (62%) were performed in ⁇ 6 months followed by 23% within 7-12 months and 15% > 1 year.
  • Table 1 Univariate analysis of ERG overexpression and various clinicopathological variables in 155 patients with initial HGPIN diagnosis and its predictability of finding prostate cancer at repeat biopsy
  • Table 2 summarizes association of various morphological parameters and subsequent PCa detection in repeat biopsy in relation to ERG expression status.
  • HGPIN positive for ERG and exhibiting bilaterality (83%), multifocality (100%), > 1 core involvement (64%) and cribriform morphology (80%) were associated with very high risk of finding PCa in subsequent biopsy.
  • HGPIN negative for ERG but exhibiting multifocal involvement (45%) and cribriform morphology (67%) continued to show high risk for subsequent PCa detection.
  • the multifocal involvement continued to show significant risk for subsequent PCa detection at repeat biopsy (see: Figure 4 herein).
  • Table 2 Relationship of various morphological parameters with ERG expression and subsequent prostate cancer detection in repeat biopsy
  • Table 3 summarizes characteristics of PCa detected in subsequent biopsies for men with HGPIN in reference to ERG overexpression status.
  • Eight (89%) ERG positive HGPIN had PCa identified at identical site on subsequent biopsy, of which 5 (71%) were ERG positive. Two PCas were ERG negative and PCa focus was not available for ERG in one case.
  • Table 3 Prostate cancer characteristics in repeat biopsy for patients with isolated HGPIN diagnosis stratified based on ERG status
  • ERG expression in HGPIN along with other histological parameters can be utilized effectively to stratify patients into low or high risk groups for having a PCa in repeat biopsy.
  • ERG expressing HGPIN continued to be a significant risk factor for unsampled PCa in repeat biopsy at multivariable analysis.
  • the current study strongly supports the conclusion that patients with ERG- positive HGPIN are more likely to harbor or develop PCa than those with ERG-negative HGPIN.
  • a positive ERG expression especially in the setting of bilateral involvement, multifocality, >1 core involvement and cribriform morphology is associated with a very high risk of cancer detection on subsequent biopsy.
  • focal ERG negative HGPIN involving a single core or two cores can be safely followed up avoiding or delaying biopsy for patients with such a diagnosis.
  • a high risk score can be determined based on an extent of >3 cores or extensive involvement (separated by benign glands) even in the absence of ERG expression.
  • Table 4 Summary of correlation between risk score, extent, and ERG status based on disclosure herein.

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Abstract

L'invention concerne une méthode permettant de déterminer la stratification du profil de risque de cancer chez un sujet. La méthode consiste à déterminer le niveau d'expression de l'oncoprotéine ERG dans un tissu prostatique présentant une néoplasie intra-épithéliale prostatique de haut grade (HGPIN) isolé chez le sujet en comparaison avec un échantillon témoin; et à déterminer la présence ou l'absence d'au moins une variable morphologique en comparaison avec un second échantillon témoin. On est en présence d'une stratification du profil de risque de cancer élevé lorsque le niveau d'expression de l'oncoprotéine ERG est élevé en comparaison avec l'échantillon témoin et que ladite variable morphologique est présente en comparaison avec le second échantillon témoin, et on est en présence d'une stratification de profil de risque de cancer faible lorsque le niveau d'expression de l'oncoprotéine ERG est faible en comparaison avec l'échantillon témoin et que ladite variable morphologique est absente en comparaison avec le second échantillon témoin.
PCT/US2016/060614 2015-11-06 2016-11-04 Méthodes permettant de déterminer la stratification du risque de cancer lié à la néoplasie intra-épithéliale prostatique de haut grade WO2017079618A1 (fr)

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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20090170075A1 (en) * 2004-05-07 2009-07-02 Gyorgy Petrovics Methods of diagnosing or treating prostate cancer using the erg gene, alone or in combination with other over or under expressed genes in prostate cancer
US20130196866A1 (en) * 2011-08-31 2013-08-01 Ventana Medical Systems, Inc. Expression of ets related gene (erg) and phosphatase and tensin homolog (pten) correlates with prostate cancer capsular penetration
US20140370023A1 (en) * 2009-04-29 2014-12-18 The Henry M. Jackson Foundation For The Advancement Of Military Medicine, Inc. Erg monoclonal antibodies

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20090170075A1 (en) * 2004-05-07 2009-07-02 Gyorgy Petrovics Methods of diagnosing or treating prostate cancer using the erg gene, alone or in combination with other over or under expressed genes in prostate cancer
US20140370023A1 (en) * 2009-04-29 2014-12-18 The Henry M. Jackson Foundation For The Advancement Of Military Medicine, Inc. Erg monoclonal antibodies
US20130196866A1 (en) * 2011-08-31 2013-08-01 Ventana Medical Systems, Inc. Expression of ets related gene (erg) and phosphatase and tensin homolog (pten) correlates with prostate cancer capsular penetration

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