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WO2015010596A1 - Procédé de diagnostic pronostique du cancer du sein - Google Patents

Procédé de diagnostic pronostique du cancer du sein Download PDF

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Publication number
WO2015010596A1
WO2015010596A1 PCT/CN2014/082680 CN2014082680W WO2015010596A1 WO 2015010596 A1 WO2015010596 A1 WO 2015010596A1 CN 2014082680 W CN2014082680 W CN 2014082680W WO 2015010596 A1 WO2015010596 A1 WO 2015010596A1
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Prior art keywords
score
breast cancer
staining
cell membrane
cells
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Ceased
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PCT/CN2014/082680
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English (en)
Chinese (zh)
Inventor
孟坤
王兆一
陈凤
白伟
王培培
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Beijing Shenogen Pharma Group Ltd
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Beijing Shenogen Pharma Group Ltd
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    • G01N33/57515—
    • 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
    • G01N2333/705—Assays involving receptors, cell surface antigens or cell surface determinants
    • G01N2333/72—Assays involving receptors, cell surface antigens or cell surface determinants for hormones
    • G01N2333/723—Steroid/thyroid hormone superfamily, e.g. GR, EcR, androgen receptor, oestrogen receptor
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2800/00—Detection or diagnosis of diseases
    • G01N2800/52—Predicting or monitoring the response to treatment, e.g. for selection of therapy based on assay results in personalised medicine; Prognosis

Definitions

  • the invention relates to a method for prognosis diagnosis of breast cancer, belonging to the field of medical diagnosis. Background technique
  • ER-a36 is a novel estrogen receptor discovered in recent years, mainly in the cell membrane and cytoplasm, which can initiate a rapid estrogen signaling pathway.
  • the rapid response of estrogen typically activates, for example, MARK/ERK, phosphatidylinositol-3-kinase, and protein kinase C.
  • MARK/ERK phosphatidylinositol-3-kinase
  • protein kinase C protein kinase C.
  • ER-a36 is highly expressed in breast cancer cells and promotes the proliferation of breast cancer cells.
  • ER-a36 has recently been found to be highly expressed in various tumor cells and plays an important role in the development of tumors.
  • Tamoxifen has been used as a standard drug for endocrine therapy of estrogen receptor (ER-a66)-positive breast tumors for many years. However, most patients with advanced breast cancer eventually have a poor prognosis after receiving tamoxifen. In “Journal of Clinical Oncology”, the title “Expression of ER-a36, a Novel Variant of Estrogen Receptor, and Resistance to Tamoxifen Treatment in Breast Cancer” was published. In this article, it is proposed that in patients with breast cancer who are positive for both estrogen receptors ER-a36 and ER-a66, treatment with tamoxifen leads to a significant decrease in survival.
  • One aspect of the present invention provides a method for prognosis diagnosis of breast cancer, which comprises detecting the expression level of ER-a36 in a tumor specimen of a breast cancer patient, and when the ER-a36 is highly expressed, indicating a poor prognosis of the breast cancer patient.
  • the poor prognosis of the breast cancer patient indicates a breast cancer patient is at risk of breast cancer recurrence and death.
  • the risk of breast cancer recurrence comprises in situ recurrence and metastasis recurrence of breast cancer.
  • the expression level of ER-a36 in the tumor specimen tissue of the breast cancer patient is detected by an immunohistochemical method.
  • ER-a36 is highly expressed such that ER-a36 has an expression value of 5 or more by immunohistochemical scoring criteria.
  • the expression value of ER-a36 is obtained by the following immunohistochemical scoring criteria: cell membrane staining intensity score multiplied by cell membrane staining score + cytoplasmic staining intensity score multiplied by cytoplasmic staining score;
  • the cell membrane staining score is 0% corresponding to the cell membrane staining cell ratio of 0; the cell membrane staining cell ratio 1-24% corresponds to a score of 1, and the cell membrane staining cell ratio is 25-49% corresponding to a score of 2
  • the ratio of cell membrane staining cells to 50-74% corresponds to a score of 3; the ratio of cell membrane stained cells to 75-100% corresponds to a score of 4;
  • the cytoplasmic staining score is 0% corresponding to the proportion of cytoplasmic staining cells; the score corresponding to cytoplasmic staining cells is 1-24%, and the score of cytoplasmic staining cells is 25-49%.
  • the cytoplasmic staining cell ratio of 50-74% corresponds to a score of 3; the cytoplasmic stained cell ratio of 75-100% corresponds to a score of 4.
  • the high expression of ER-a36 indicates that the expression amount of ER-a36 in the tumor tissue of the patient exceeds the expression level of the tumor tissue intermediate cells or the cancer surrounding normal tissues.
  • the tumor specimen tissue is obtained after treatment of the surgical or perforated breast tumor tissue.
  • the antibody that specifically recognizes ER-a36 interacts with the tumor specimen tissue to detect The expression level of ER-a36 in tumor specimen tissues.
  • the ER-a36-recognizing antibody is a murine or rabbit-derived antibody.
  • the tumor specimen tissue contains malignant tumor cells.
  • the breast cancer patient comprises a drug-treated breast cancer patient.
  • said drug-treated breast cancer patient comprises a breast cancer patient treated with tamoxifen.
  • the prognosis diagnosis method for breast cancer of the present invention proves that the detection method of the present invention has high accuracy by detecting the marker ER-a36 in the tumor specimen tissue through more than 1000 clinical cases.
  • the method for prognosis diagnosis of breast cancer of the present invention can help determine the prognosis of breast cancer patients by the expression level of ER-a36 in breast cancer patients or breast cancer patients treated with tamoxifen, and provides guidance for clinical treatment.
  • Figure 1 shows a comparison of overall survival and disease-free survival in patients with positive or negative breast cancer after ER-a36 expression, respectively.
  • Figure 1A shows ER-a36, ER-a66 double positive patients after surgery. Overall survival in patients with ER-a66-positive and ER-a36-negative patients;
  • Figure 1B shows disease-free survival in patients with ER-a66, ER-a36 double-positive and ER-a66-positive, ER-a36-negative patients after surgery
  • Figure 1C shows the overall survival of patients with ER-a66, ER-a36 double-negative and ER-a66-positive ER-a36-negative after surgery;
  • Figure 1D shows ER-a66, ER-a36 after surgery Disease-free survival in negative patients and E-a66-negative, ER-a36-positive patients.
  • Figure 2 shows the effect of tamoxifen on the proliferation of breast cancer cells with different expression of ER-a36, wherein Figure 2A shows that MCF-7 breast cancer cells with high expression of ER-a36 are relatively blank under the action of tamoxifen. The relative growth rate of breast cancer cells in the control group; Figure 2B shows the relative growth rate of MCF-7 breast cancer cells with low expression of ER-a36 relative to the blank control group under the action of tamoxifen.
  • Tumor refers to the abnormal regulation of the clonal dysplasia caused by the loss of normal regulation of the growth of a certain cell in the local tissue at the gene level under various factors. Academics generally divide tumors into benign and malignant categories.
  • patient refers to a patient from China who has undergone radical mastectomy or partial eradication mastectomy.
  • prognosis of breast cancer refers to predicting the condition progression of breast cancer patients.
  • metastasis recurrence means that cancer cells that are identical to the original cancer cells are again found in areas other than the region where the breast cancer was originally diagnosed during the recovery or remission phase of the breast cancer.
  • tumor specimen tissue refers to breast tumor tissue obtained by surgery or perforation, which is then fixed, dehydrated, transparent and immersed in wax, embedded in paraffin, and then paraffin sectioned for tumors for immunohistochemistry. Specimen organization.
  • immunohistochemistry refers to the application of the basic principle of immunology, that is, the principle of specific binding of an antigen to an antibody.
  • the chemical reaction of the coloring agent of the labeled antibody is used to determine the antigen in the tissue cell, and to locate and characterize the antigen. the study.
  • immunohistochemical scoring criteria refers to the first method by immunohistochemistry according to the following formula
  • ER-a36 expression cell membrane staining intensity score multiplied by cell membrane staining score + cytoplasmic staining intensity score multiplied by cytoplasmic staining score;
  • the score is the score of the intensity of staining on the cytoplasm;
  • the cell membrane staining score is 0% corresponding to the cell membrane staining cell ratio, 0; the cell membrane staining cell ratio 1-24% corresponds to a score of 1; the cell membrane staining cell ratio is 25-49%, and the corresponding score is 2
  • the proportion of cell membrane stained cells is 50-74% corresponding to a score of 3; the proportion of cell membrane stained cells is 75-100%, and the corresponding score is 4;
  • the cytoplasmic staining score is 0% corresponding to the proportion of cytoplasmic staining cells; the score corresponding to 1-24% of cytoplasmic staining cells is 1; the ratio of cytoplasmic staining cells is 25-49% corresponding to 2
  • the proportion of cytoplasmic stained cells is 50-74% corresponding to a score of 3; the proportion of cytoplasmic stained cells is 75-100%, and the corresponding score is 4.
  • metastasis refers to the invasion of tumor cells from the primary site into lymphatic vessels, blood vessels or other organs, forming tumors of the same type in the primary site of the tumor, a process known as metastasis.
  • piercing means that a suspicious lesion of the breast (eg, a mass, a thickened area, a calcified foci, etc.) is removed from the breast by means of a hollow needle.
  • a suspicious lesion of the breast eg, a mass, a thickened area, a calcified foci, etc.
  • ER-a36 positive expression of ER-a36 means that the ER-a36 value calculated by the formula (I) is 5 or more by immunohistochemistry.
  • ER-a36 negative expression of ER-a36 means that the ER-a36 value calculated by the formula (I) is less than 5 and does not contain 5 by immunohistochemistry.
  • ER-a66 expression is negative can be determined by immunohistochemistry according to the existing WHO breast cancer scoring standard.
  • malignant tumor cell is a variant cell. Unlike normal cells, it is destroyed by normal tissue cells and destroys the function of normal tissues due to its infinite growth, transformation and metastasis.
  • drug-treated breast cancer patients refers to breast cancer patients who have been treated with breast cancer by oral, intramuscular, or intravenous drug therapy.
  • mouse-derived antibody is an antibody obtained by collecting purified cells from the ascites by transplanting hybridoma cells into the peritoneal cavity of a mouse and producing ascites.
  • rabbit-derived antibody is an antibody obtained by collecting purified cells from the ascites by transplanting hybridoma cells into the abdominal cavity of a rabbit and producing ascites.
  • all survival rate refers to the proportion of patients who survive in a given time period.
  • disease-free survival refers to the proportion of patients who have not relapsed within a specified time period.
  • the ER-a36 antibody provided below includes at least one of SNGmBl antibodies, for example, 2, 3, 4, 5 or all 6 CDR regions.
  • the "SNGmBl antibody” provided herein is a murine monoclonal antibody against ER-a36.
  • the amino acid sequence includes the light chain of SEQ ID: 1 and the heavy chain sequence of amino acid sequence SEQ ID NO: 2.
  • the nucleotide sequences encoding the light and heavy chains of the SNGmB1 antibody are SEQ ID NO: 17 antibody and SEQ ID NO: 19, respectively, and the amino acid sequences of the light and heavy chains are shown below, wherein the CDR regions are italicized and underlined, and The fixed area is an italic shaded portion.
  • amino acid sequence of the SNGmBl heavy chain (SEQ ID NO: 2):
  • the ER-a36 antibody herein comprises SEQ ID NO: 8, (B: heavy chain CDR3 sequence of SNGmBl antibody:).
  • the heavy chain CDR3 region is located at the center of the antigen binding region and is therefore the easiest to bind antigen.
  • the antibody of ER-a36 comprises the heavy chain variable region of the SNGmB1 antibody, ie, the heavy chain SEQ ID NO: 10 ; and/or comprises the light chain variable region of the SNGmB1 antibody, gpSEQ ID NO: 9.
  • the tumor tissue obtained by surgery or perforation is immersed in a fixative, and then the tissue is fully dehydrated with a concentration gradient ethanol.
  • the dehydrated tissue is then paraffin-embedded by xylene transparent and paraffin wax, and the wax block is solidified. After that, cut into pathological sections of 4 ⁇ m thick.
  • the slices were baked in an oven at 65 ° C for 2 hours, soaked in xylene twice for 10 minutes to remove paraffin, then soaked in 100% ethanol for 3 minutes twice, 95% ethanol for 3 minutes and Soak in 75% ethanol for 3 minutes, and finally wash 5 times with phosphate buffer (PBS) for 2 minutes each time.
  • PBS phosphate buffer
  • the antigen was repaired by high pressure repair method, and the section was completely immersed in 1 mmol of disodium edetate (EDTA) pH 8.0 antigen repair solution, heated to boiling in high pressure, and the time was started after the pressure cooker was added to the pressure cooker, 2 minutes 30 After the second, the autoclave was naturally cooled to room temperature, and the sections were taken out, and the phosphate buffer (PBS) was washed 5 times for 2 minutes each time. The sections were placed in a reaction dish containing a freshly prepared peroxidase blocking solution and incubated at 37 ° C for 30 minutes in an oven to eliminate endogenous peroxidase activity.
  • EDTA disodium edetate
  • PBS phosphate buffer
  • phosphate buffer 5% goat serum was added to the tissue area of the immunohistochemical pen for 30 minutes in a 37 ° C oven to block non-specific antigen. Carefully remove and wipe off excess liquid on and around the tissue, add primary antibody working solution (primary antibody is Example 1 antibody, concentration 0.02mg/ml) 4 °C overnight (preferably 16 hours to 18 hours), Rewarrate at room temperature for 30 minutes. Rinse in phosphate buffer (PBS) 5 times for 2 minutes each time. Add appropriate amount of horseradish peroxidase-labeled secondary antibody working solution and incubate at 37 °C for 30 minutes. Rinse the phosphate buffer (PBS) 5 times for 2 minutes each time.
  • ER-a36 of the tumor specimen of the patient was detected by the immunohistochemical routine method using the antibody of Example 1, and the expression value of ER-a36 in each pathological slice was calculated according to the formula (I).
  • ER-a36 expression cell membrane staining intensity score multiplied by cell membrane staining score + cytoplasmic staining intensity score multiplied by cytoplasmic staining score;
  • the cell membrane staining score is 0% corresponding to the cell membrane staining cell ratio of 0; the cell membrane staining cell ratio 1-24% corresponds to a score of 1, and the cell membrane staining cell ratio is 25-49% corresponding to a score of 2
  • the ratio of cell membrane staining cells to 50-74% corresponds to a score of 3; the ratio of cell membrane stained cells to 75-100% corresponds to a score of 4;
  • the cytoplasmic staining score is 0% corresponding to the proportion of cytoplasmic staining cells; the score corresponding to cytoplasmic staining cells is 1-24%, and the score of cytoplasmic staining cells is 25-49%.
  • the proportion of cytoplasmic stained cells is 50-74% corresponding to a score of 3; the proportion of cytoplasmic stained cells is 75-100%, and the corresponding score is 4.
  • the expression of ER-a36 was positive in patients with breast cancer with ER-a36 expression above 5, and the expression of ER-a36 was less than 5 (excluding 5), indicating that the patient's breast cancer ER-a36 expression was negative.
  • Example 4 Examination of the expression of ER-a36 in tumor tissues metastasized from breast cancer patients
  • Experimental method Tumor tissues of breast cancer patients obtained by surgery or perforation were selected, and the patients were determined by the method of epidemic and the method of Example 3. Expression of ER-a36 in breast cancer tissues. And to test whether these patients have lymph node metastasis.
  • Fig. 1A It can be seen from Fig. 1A that, in the ER-a66-positive patients after surgery, the overall survival rate of ER-a36 and ER-a66 positive patients is less than ER-a66-positive, ER with the increase of time after surgery. Survival rate of -a36 negative patients.
  • MCF-7 breast cancer cells were selected and obtained from the American Type Culture Collection (ATCC). Through the gene stabilization technology, the exogenous ER-a36 gene was transferred, and MCF-7 breast cancer cells were highly expressed ER-a36. Tamoxifen was added to the cell culture medium and cultured for 6 days. As can be seen from Fig. 2A, tamoxifen promoted the proliferation of MCF-7 breast cancer cells, and the MCF-7 mammary gland was promoted by tamoxifen. The relative growth rate of cancer cells is much greater than the relative growth rate of MCF-7 breast cancer cells in the blank control group.
  • MCF-7 breast cancer cells not transfected with ER-a36 were selected, which underexpressed ER-a36.
  • Tamoxifen was added to the cell culture medium and cultured for 6 days. As can be seen from Fig. 2B, tamoxifen did not promote the proliferation of MCF-7 breast cancer cells. Under the action of tamoxifen, the relative growth rate of MCF-7 breast cancer cells was smaller than that of the blank control group MCF-7 breast cancer cells.
  • tamoxifen does not inhibit the ER-a36 high expression of breast cancer cells, but promotes the proliferation of ER-a36 breast cancer cells.
  • tamoxifen does not promote proliferation of breast cancer cells with low expression of ER-a36. Therefore, tamoxifen may increase the risk of breast cancer cell proliferation and metastasis if used in the treatment of breast cancer with high expression of ER-a36.

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  • Measuring Or Testing Involving Enzymes Or Micro-Organisms (AREA)

Abstract

La présente invention concerne un procédé de diagnostic pronostique du cancer du sein, comprenant : la mesure de la quantité d'expression de ER-α36 dans du tissu de tumeur d'une patiente atteinte de cancer du sein, où, lorsque ER-α36 a une expression élevée, cela indique que la patiente présente un risque de récidive in situ ou de métastase de cancer du sein. Le procédé de la présente invention a une utilité dans l'orientation d'un pronostic pour une patiente atteinte de cancer du sein.
PCT/CN2014/082680 2013-07-22 2014-07-22 Procédé de diagnostic pronostique du cancer du sein Ceased WO2015010596A1 (fr)

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CN201310306811.X 2013-07-22

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN109596830A (zh) * 2017-12-29 2019-04-09 北京珅奥基医药科技有限公司 用于检测肿瘤组织中ER-α36表达水平的试剂盒

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CN1695057A (zh) * 2002-09-12 2005-11-09 摩诺根公司 基于细胞的疾病检测和鉴别
CN1930188A (zh) * 2004-03-10 2007-03-14 克赖顿大学 雌激素受体和使用方法
CN102285948A (zh) * 2010-06-17 2011-12-21 北京盛诺基医药科技有限公司 四羟基苯并吡喃酮类化合物及其用途
WO2012031027A1 (fr) * 2010-08-31 2012-03-08 Genentech, Inc. Biomarqueurs et procédés de traitement

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1695057A (zh) * 2002-09-12 2005-11-09 摩诺根公司 基于细胞的疾病检测和鉴别
CN1930188A (zh) * 2004-03-10 2007-03-14 克赖顿大学 雌激素受体和使用方法
CN102285948A (zh) * 2010-06-17 2011-12-21 北京盛诺基医药科技有限公司 四羟基苯并吡喃酮类化合物及其用途
WO2012031027A1 (fr) * 2010-08-31 2012-03-08 Genentech, Inc. Biomarqueurs et procédés de traitement

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Title
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SHI, LIANG ET AL.: "Expression of ER-a36, a Novel Variant of Estrogen Receptor a, and Resistance to Tamoxifen Treatment in Breast Cancer", JOURNAL OF CLINICAL ONCOLOGY, vol. 27, no. 21, 20 July 2009 (2009-07-20), XP055248230, DOI: doi:10.1200/JCO.2008.17.2254 *
ZHANG, YANQING ET AL.: "Progress in Research about the Impact of Gene Polymorphisms on Tamoxifen Therapy", CHINESE JOURNAL OF PHARMACOLOGY AND TOXICOLOGY, vol. 26, no. 3, 30 June 2012 (2012-06-30), pages 411 - 414 *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN109596830A (zh) * 2017-12-29 2019-04-09 北京珅奥基医药科技有限公司 用于检测肿瘤组织中ER-α36表达水平的试剂盒

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