WO2019077080A1 - Évaluation du risque de rechute métastatique chez des patients atteints d'un cancer du sein - Google Patents

Évaluation du risque de rechute métastatique chez des patients atteints d'un cancer du sein Download PDF

Info

Publication number
WO2019077080A1
WO2019077080A1 PCT/EP2018/078645 EP2018078645W WO2019077080A1 WO 2019077080 A1 WO2019077080 A1 WO 2019077080A1 EP 2018078645 W EP2018078645 W EP 2018078645W WO 2019077080 A1 WO2019077080 A1 WO 2019077080A1
Authority
WO
WIPO (PCT)
Prior art keywords
bcl
tumor
breast cancer
positive
tumors
Prior art date
Application number
PCT/EP2018/078645
Other languages
English (en)
Inventor
Adrien NOUGAREDE
Ruth RIMOKH
Germain GILLET
Isabelle TREILLEUX
Original Assignee
Universite Claude Bernard Lyon 1
Centre National De La Recherche Scientifique (Cnrs)
Centre Leon Berard
Institut National De La Sante Et De La Recherche Medicale (Inserm)
Hospices Civils De Lyon
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Application filed by Universite Claude Bernard Lyon 1, Centre National De La Recherche Scientifique (Cnrs), Centre Leon Berard, Institut National De La Sante Et De La Recherche Medicale (Inserm), Hospices Civils De Lyon filed Critical Universite Claude Bernard Lyon 1
Publication of WO2019077080A1 publication Critical patent/WO2019077080A1/fr

Links

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
    • G01N33/57415—Specifically defined cancers of breast
    • 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 present invention relates to methods and kits for determining the prognosis of a breast cancer tumor.
  • the methods involve determining the level of expression of the BCL-2 L10 protein in a sample of breast cancer tumor, wherein a BCL-2 L10 positive status of the tumor is correlated with likelihood of metastasis and of relapse/recurrence of the cancer.
  • Cancer is a disease of humans and animals which is commonly fatal, and which is reflected by uncontrolled growth of endogenous cells.
  • cancer is used to denote the formation of malignant tumors, carcinomas and neoplasms.
  • Breast cancer is cancer that develops from breast tissue. Worldwide, breast cancer is the leading type of cancer in women, accounting for 25% of all cases. Outcomes for breast cancer vary depending on the cancer type, the extent of disease, and the age of the patient.
  • the growth of cancers comprises two stages, firstly the local tumor growth and secondly the dissemination of the cancer into diverse parts of the body.
  • Local tumor growth consists of the appearance of a tumor clone from a "transformed" cell, under the action of initiating and promoting carcinogenic agents.
  • Cell proliferation leads to the formation of the tumor.
  • the spread of the cancer from the initial tumor may occur by regional spread and/or by development of secondary tumors referred to as metastases.
  • Cancer prognosis is often determined based on histological and clinical data such as tumor size, invasion of lymph nodes or metastasis. However, this determination is often difficult to make in cancers which are diagnosed at early stages when clinical symptoms and histological data are not available or not evident to read.
  • the size of the resected tumor is a marker of a tumor susceptible to relapse and/or metastase, in particular a tumor size superior to 2 centimeters of diameter is indicative of a higher risk of relapse and/or metastase.
  • Progesterone Receptor PR
  • HER2 Human Epidermal growth factor Receptor 2
  • WO 201 1/007013 describes the prognostic value of ZNF217 expression level, a new marker of "poor" prognosis in breast cancer patients.
  • biomarkers of good/poor prognosis shall be identified in order to characterize, as precisely as possible, the breast cancer tumor of a patient, and therefore to obtain an indication on the likelihood of relapse and/or metastasis of said breast tumor.
  • Such a molecular characterization of a breast cancer tumor would help the clinicians to adapt the treatment and follow-up of the breast cancer patients, in particular after the first line of treatment following the original tumor resection.
  • a molecular characterization of a primary, early-stage breast tumor is in particular of great help for clinicians, who will adapt the treatment strategy in function of the anticipated outcome of the tumor.
  • Apoptosis also referred to as "programmed cell death” plays a pivotal role in numerous biological processes, both normal and pathological. Tumor cells are known to be able to escape apoptosis, by a plurality of molecular processes. Chemotherapeutic treatments are based on the administration of chemical molecules intended to induce apoptosis of cancer cells.
  • anti-apoptotic proteins In cancer cells, overexpression of anti-apoptotic proteins is commonly observed. These anti-apoptotic proteins enable the cancer cells both to evade the organism's endogenous controls, and to resist to chemotherapy drugs intended to induce their cell death.
  • the BCL-2 family comprises regulators of mitochondrial apoptosis, both inducers and inhibitors.
  • the importance of the biological processes controlled by the BCL-2 family members makes them a highly studied protein family.
  • BH domain BCL-2 Homology domains
  • BCL-2 the expression of BCL-2 in 73% of breast cancers seems to be of good prognosis in early stages tumors with estrogen receptor a (ERa) expression, but to be of poorer prognosis in hormone receptor negative breast cancers (Dawson et al., 2010; Honma et al., 2015).
  • ERa estrogen receptor a
  • BCL-2 L10 protein is a member of this anti-apoptotic proteins family.
  • BCL-2 L10 protein was reported to be overexpressed in neoplastic pathologies, such as in breast, prostate and lung cancers, as well as in myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML) (Krajewska et al., 2008).
  • MDS myelodysplastic syndromes
  • AML acute myeloid leukemia
  • BCL-2 L10 protein expression in blood stream tumor cells, from blood samples was also found to be associated with resistance to the chemotherapy drug Azacitidine (Cluzeau et al., 2012; WO 2013/128089).
  • BCL-2 L10 was suspected to be involved in the later stages of breast cancer pathology: the more advanced the tumor, the higher the expression level of BCL-2 L10 protein (Krajewska et al., 2008). Advanced stages of breast cancer are generally characterized by therapeutic failure, tumor relapse and metastatic dissemination.
  • BCL-2 L10 expression level was considered as an indicator of an advanced stage of the tumor, but was not considered as a prognosis marker of the future evolution of a primary breast tumor.
  • the present invention focus on BCL-2 L10 expression level on primary breast tumors only; based on the results obtained for this specific group of tumors, the inventors hereby show that BCL-2 L10 protein expression is a prognosis marker of the evolution of the disease, in particular in terms of distant metastasis free survival (DMFS).
  • DMFS distant metastasis free survival
  • the present invention relates to an unprecedented process comprising detecting BCL-2 L10 protein in samples from a primary breast tumor, identifying said tumor as being BCL-2 L10 positive or negative, to the end of predicting the outcome of said breast tumor, in particular the outcome several years after the characterization of the tumor.
  • the present invention relates to an in vitro process for determining the prognosis of a primary breast cancer tumor in a patient, comprising the following steps: a) Assessing the level of expression of BCL-2 L10 protein in a sample of said breast cancer tumor from said patient;
  • step (c) wherein if said tumor is identified in step (c) as being BCL2-L10 positive, said patient is classified as presenting a shorter distant metastasis free survival (DMFS).
  • DMFS distant metastasis free survival
  • the present invention is specifically related to the detection of BCL-2 L10 protein in tissue samples from primary breast tumors.
  • the present invention is related to the correlation between a primary breast cancer tumor identified as being BCL2-L10 positive, and a high risk of future metastasis dissemination of said tumor.
  • the present invention also relates to an in vitro process for predicting the response of a breast cancer tumor in a patient to a treatment targeting protein BCL-2 L10, comprising the following steps:
  • the present invention also concerns an in vitro process for predicting the response of a solid tumor to a treatment targeting protein BCL-2 L10, comprising the following steps:
  • the present invention also concerns a kit comprising at least one antibody directed to the BCL-2 L10 protein and reactants useful for performing the in vitro processes as described above.
  • DMFS distant metastasis-free survival
  • FIG. 1 Correlation between BCL-2 L10 protein expression and some clinic- pathologic variable factors of breast cancer: age of the patient; menopausal status; tumor size; LN invasion (Lymph Node invasion); SBR grade (Scarff-Bloom- Richardson grade), ER status (Estrogen Receptor status), PR status (Progesterone Receptor status), HER status (Human Epidermal growth factor Receptor 2 status), and Breast cancer subtype (Luminal A, Luminal B, HER2 enriched, or TNBC i.e. Triple-Negative (ER, PR, HER negative) Breast Cancer).
  • LN invasion LN invasion
  • SBR grade Scarff-Bloom- Richardson grade
  • ER status Estrogen Receptor status
  • PR status Progesterone Receptor status
  • HER status Human Epidermal growth factor Receptor 2 status
  • Breast cancer subtype Luminal A, Luminal B, HER2 enriched, or TNBC i.e. Triple-Ne
  • Figure 3 Multivariate analysis of clinical parameters susceptible to predict shorter DMFS in breast cancer: BCL-2 L10 status, ER status, SBR grade III, tumor larger than 2 cm and LN invasion. HR means Hazard Ratio, and CI designates the Confidence Interval. A significant P-value, inferior to 0.1 , is observed for three parameters.
  • the present invention relates to an in vitro process for determining the prognosis of a breast cancer tumor in a patient.
  • a "prognosis" is the likely course and outcome of a disease.
  • the prognosis may include the likelihood of complications of the cancer, of metastasis, of spread, probable outcome of the cancer, likelihood of recovery, overall survival rate and /or overall death rate.
  • a prognosis process allows the prediction / anticipation of particular events in the course of a disease.
  • a prognosis process allows the prediction / anticipation of the outcome of a disease.
  • This information is useful to the patient but also to the physician and/or clinician in determining the most effective course of treatment.
  • a determination of the likelihood for a cancer to relapse or of the likelihood of metastasis can assist the physician and/or clinician in determining whether a more conservative or a more radical therapeutic approach should be taken.
  • the present invention relates to an in vitro process for characterizing a primary breast cancer tumor in a patient, comprising the following steps:
  • the present invention is based on the analysis of a large cohort of breast cancer patients, where BCL-2 L10 is found to be an independent prognosis marker correlated with metastasis dissemination and/or recurrence of the original breast tumors.
  • breast cancer refers to any neoplastic pathology of the breast tissue, and includes all histological and molecular subtypes of breast neoplasia.
  • breast cancer tumor designates the abnormal mass of breast tissue composed of cancer, malignant cells.
  • the present invention concerns an in vitro process for determining the prognosis of both the breast cancer in a patient, and the breast tumor present in the breast tissue of the patient.
  • BCL-2 L10 protein denotes any protein that has been identified as being an isoform or homologue of the human "BCL-2-like 10" protein, registered in GenBank under the accession number AAG00503.1 and having a sequence of 204 amino acids. It is to be noted that BCL-2 L1 0 have other designations in the scientific community, such as BCL- B or Nrh.
  • the level of expression of BCL-2 L10 protein is assessed in a sample of breast cancer tumor from a patient.
  • a sample of breast cancer tumor can be obtained by any means known by those skilled in the art.
  • such sample is obtained after a biopsy, or is part of breast tissue removed during surgery, or is a needle aspirate.
  • the sample typically contains tumor cells.
  • the sample of breast tumor has been previously taken from a patient, the surgical step of obtaining the tumor sample being not part of the in vitro process according to the invention.
  • expression levels of the BCL-2 L10 protein are assessed according to any method known by the skilled persons.
  • a plurality of techniques is available to assess the level of expression of a protein on a tissue sample. For example, the following techniques might be used:
  • Spectrometry methods such as High-Performance Liquid Chromatography (HPLC) and Liquid Chromatography-Mass Spectrometry (LC/MS).
  • HPLC High-Performance Liquid Chromatography
  • LC/MS Liquid Chromatography-Mass Spectrometry
  • Antibody dependent methods such as Enzyme-linked immunosorbent assay (ELISA), Protein immunoprecipitation,
  • Immuno-electrophoresis Western blot
  • Protein immunostaining such as immunohistochemistry and Proximity Ligation Assay (in situ PLA).
  • step (a) is performed using at least one technique chosen among the group consisting of: Western blot, mass spectrometry (LC/MS), ELISA assay, immunohistochemistry, and proximity ligation assay (PLA).]
  • step (a) of the process is performed using at least one technique using at least one antibody.
  • step (a) of the process is performed using an antibody directed to BCL-2 L10, meaning an antibody recognizing and binding specifically the BCL-2 L10 protein.
  • the antibody is directed to the human protein BCL-2 L10.
  • This antibody may be polyclonal or monoclonal.
  • Polyclonal and monoclonal antibodies directed to BCL-2 L10 are commercially available, in particular they may be purchased from the company SIGMA-ALDRICH, for example under the reference HPA04222.
  • the term "reference value” is intended to mean an expression level of BCL-2 L10 protein value, determined on at least one sample of breast cancer tumor whose BCL-2 L10 status is known.
  • said reference value is the mean or the median of several values determined on several tumor samples obtained from a plurality of patients having breast cancer tumors, whose BCL-2 L10 status is known.
  • the reference value is representative of "BCL-2 L10 negative tumors" also designated as “tumors having a BCL-2 L10 negative status”.
  • the BCL-2 L10 protein is undetectable when the techniques for detecting the expression of a protein on a tissue sample are performed.
  • the reference value is representative of "BCL-2 L10 positive tumors", also designated as “tumors having a BCL-2 L10 positive status”.
  • the BCL-2 L10 protein is detected when any of the techniques for detecting the expression of a protein on a tissue sample is performed. When an immunohistochemistry staining is performed, the staining is moderate to strong.
  • the level of expression assessed on a sample of a breast cancer tumor is compared with two reference values.
  • said level of expression assessed on a sample of a breast cancer tumor is compared with two reference values: one reference value representative of "BCL-2 L10 negative tumors" and one reference value representative of "BCL-2 L10 positive tumors".
  • the reference value is a value termed a "threshold” or a "cut-off value, which is determined from reference values representative of BCL-2 L10 positive tumors and from reference values representative of BCL-2 L10 negative tumors.
  • This cut-off reference value is an arbitrary value, representative of the "frontier" between negative and positive status of the tumor regarding BCL-2 L10 expression.
  • a tumor tested according to the process of the invention will be classified as "BCL-2 L10 negative" when the BCL-2 L10 expression level value measured for this tumor is less than the cut-off reference value.
  • a tumor tested according to the process of the invention will be classified as "BCL-2 L10 positive" when the BCL-2 L10 expression level value measured for this tumor is greater than the cut-off reference value.
  • a polyclonal rabbit antibody directed against BCL-2 L10 detectable with commercially available kits, was used in order to determine presence or absence of BCL-2 L10 protein on fixed cells.
  • the staining intensity of cells was classified into three levels:
  • Tumor cells were considered to have negative staining if they had an intensity score of 0 (BCL-2 L10 negative), and were considered to have a positive staining if they had a score of 2 or 3 (BCL-2 L10 positive). In this specific case:
  • a value representative of BCL-2 L10 positive tumors is 2 or 3;
  • a cut-off value representative of the frontier between the two status is 1 .
  • the reference value representative of "BCL-2 L10 positive tumors" is the median level of expression of BCL-2 L10 in breast cancer tumor samples showing moderate or strong staining in immunohistochemistry using an antibody directed to BCL-2 L10.
  • the man skilled in the art is able, when performing an immunohistochemistry process on a tissue sample, to identify the samples showing moderate or strong staining, by comparison with tissue samples showing no staining at all.
  • the level of expression of BCL-2 L10 protein is assessed and compared to a reference value, allowing the identification of the status of the assessed tumor.
  • This molecular characterization of the tumor regarding BCL-2 L10 protein expression will allow those skilled in the art to make prognosis on the evolution of the assessed tumor, and therefore to make prognosis on the evolution of the cancer of the patient.
  • the breast cancer tumor is a primary breast cancer tumor.
  • the phrases "initial tumor”, “original tumor”, “primitive tumor” and “primary tumor” are used interchangeably to designate the first tumor that appears in an organism.
  • “secondary tumors” or “distant tumors” designate metastases, i.e. tumors issued from the migration of cells from the primary tumor.
  • secondary tumors appear most often in the following organs: bone, liver, lung and brain. The sample that is assessed in the process of the invention is therefore issued from a primary breast tumor.
  • the assessed tumor is at an early stage of development.
  • the advantage of the process according to the invention is that determination of the evolution of a breast cancer tumor can be performed even when the tumor is at an early stage of development.
  • the tumor can be a recently-diagnosed tumor; it can also be a tumor classified as being "low grade” (SBR1 ) according to the Scarff-Bloom- Richardson (SBR) system.
  • SBR1 low grade
  • the assessed tumor is a non-metastatic, primary breast cancer tumor.
  • a non-metastatic tumor (or tumor at a non-metastatic stage) is defined as a tumor not capable to spread from the primary site to other sites in the body.
  • the breast cancer tumor that is assessed for BCL-2 L10 status has a size inferior to 2 cm of diameter.
  • the sample that is assessed in the process of the invention is issued from a breast tumor having a size inferior to 2 cm of diameter, at the time it was removed from the body of a patient.
  • the assessed tumor is a primary tumor, at an early stage of development, and having a size inferior to 2 cm of diameter.
  • BCL-2 L10 is an independent marker for the characterization of primary breast tumor
  • the process of the present invention provides prognosis, i.e. the percentage of risk of a certain outcome of the tumor, for a specific primary breast cancer tumor after it has been diagnosed, on the basis of the presence or absence of one marker detected in the primary tumor cells.
  • a measurable parameter allowing to discriminate patients with high and low risk of metastasis is the "distant metastasis free survival" time.
  • DMFS disant metastasis free survival
  • DMFS designates, for a certain percentage of patients free of distant metastasis, the time that has elapsed since a particular event, for example since the date of the diagnosis or the date of the resection of the tumor.
  • the starting point for the measure of the DMFS is the time of the initial diagnosis.
  • BCL-2 L10 positive tumors are correlated with a shorter DMFS in the group of patients bearing these tumors: 80% of BCL-2 L10 negative tumors bearing patients are free of metastasis after 10 years since the initial diagnosis; although 80% of BCL-2 L10 positive tumors bearing patients are free of metastasis 7 years after the initial diagnosis.
  • This result may also be alternatively formulated as "20% of BCL-2 L10 positive tumor bearing patients present metastasis 7 years after the initial diagnosis", or "there is a 20 % risk or more that the breast cancer tumor will metastase within 7 years”.
  • a shorter DMFS designates a DMFS that is shorter than the status-dependent baseline DMFS occurring for a breast tumor; or that is shorter than the DMFS observed for BCL-2 L10 negative tumors bearing patients. Accordingly, if the primary breast cancer tumor is identified in step (c) as being BCL2-L10 positive, said patient is classified as presenting a shorter distant metastasis free survival (DMFS).
  • DMFS distant metastasis free survival
  • the in vitro process according to the invention may also be useful to determine other prognosis, i.e. a risk for other specific events to happen, related to the breast cancer tumors.
  • the breast cancer tumor is identified in step (c) as being BCL2-L10 positive, said tumor is classified as presenting a high risk of metastasis dissemination.
  • Metastasis dissemination refers to the spread of a tumor from the tumor site of origin to additional organs/distal sites in the patient's body, where secondary tumors (metastases) will implant. Metastasis dissemination is the main cause of cancer-related deaths.
  • a high risk of metastasis dissemination designates a risk of occurrence of metastases, which risk is higher than the status- dependent baseline risk of metastases occurring for a breast tumor, taking account of the influence of any treatment, tumor size, proliferation status of the tumor cells, age of the patient, etc.
  • a high risk of metastasis may also designate a risk that is higher than the risk of metastase occurring for a specific group of patients, for example of the group of patients bearing BCL-2 L10 negative tumors.
  • Metastasis risk may also be evaluated as a function of time: risk groups are defined which have higher occurrences of a metastase event as a function of time, for example within the first three years after the first diagnosis, or during years 3 to 5 after the surgical removal of the primary tumor.
  • the primary breast cancer tumor is identified in step (c) as being BCL-2 L10 positive, said tumor is classified as being prone to recur. Otherwise said, if the primary breast cancer tumor is identified as being BCL-2 L10 positive, said BCL-2 L10 positive tumor is classified as having a high risk of reccurence.
  • a high risk of recurrence of the tumor corresponds to a 30%, 40%, 50%, 60%, 70%, 80% or more risk that the tumor will recur in 1 , 2, 3, 4, 5, 6, 7, 8, 9 , 10 or more years from the date when the sample was taken, or from the date of the initial diagnosis.
  • a BCL-2 L10 positive tumor is classified as being prone to recur after a first line of treatment of the tumor, such as surgical treatment, chemotherapy treatment and/or radiotherapy treatment.
  • the breast cancer is classified as having a poor prognosis.
  • a “poor prognosis” designates the likelihood of complications of the cancer, or of metastasis, or of a recurrence, or of a fatal issue of the cancer, said likelihood being higher than the status-dependent baseline likelihood for these adverse events of a breast tumor, or than the likelihood for these events of BCL-2 L10 negative tumors.
  • BCL-2 L10 is an independent marker for prognosis of a primary breast cancer tumor that can be assessed independently from other markers.
  • lymph node (LN) invasion As shown in figure 2, though the presence of BCL-2 L10 significantly correlates with the premenopausal status and larger tumors, no association was observed with lymph node (LN) invasion, Scarff-Bloom-Richardson (SBR) grade, Estrogen Receptor (ER), progesterone receptor (PR), HER2 status or breast cancer subtype.
  • LN lymph node
  • SBR Scarff-Bloom-Richardson
  • ER Estrogen Receptor
  • PR progesterone receptor
  • HER2 status As shown in figure 2, though the presence of BCL-2 L10 significantly correlates with the premenopausal status and larger tumors, no association was observed with lymph node (LN) invasion, Scarff-Bloom-Richardson (SBR) grade, Estrogen Receptor (ER), progesterone receptor (PR), HER2 status or breast cancer subtype.
  • LN lymph node
  • SBR Scarff-Bloom-Richardson
  • BCL-2 L10 status of a primary breast tumor is a molecular feature that is complementary of other features obtained in the implementation of other prognosis processes.
  • BCL-2 L10 positivity is a marker indicative of a shorter DMFS for the patient bearing said BCL-2 L10 positive tumor.
  • BCL-2 L10 status is a good marker of prognosis by itself
  • other marker proteins can be assessed in order to improve the reliability of the prognosis process.
  • expression level and/or activity of proteins involved in the BCL-2 L10 signaling pathway like inositol 1 ,4,5-triphosphate receptors (IP3 receptors) type-l and III, and susbsequent signaling proteins, can be assayed in order to obtain complimentary information relative to the BCL-2 L10 status of a particular tumor.
  • cancer prognosis is often determined based on histological and clinical data such as tumor size, invasion, spread to lymph nodes or metastasis.
  • the malignancy of infiltrating breast cancer may for example be scored according to any appropriate histological grading system.
  • the majority of tumor grading systems currently employed for breast cancer combine nuclear grade, tubule formation and mitotic rate.
  • SBR Scarff-Bloom- Richardson
  • Figure 3 presents a multivariate analysis of clinical parameters susceptible to predict shorter DMFS in breast cancer. It appears that only three parameters are predictive of a shorter DMFS: the BCL-2 L10 status of the tumor, a SBR grade III of the tumor, and the size (diameter) of the tumor larger than 2 cm.
  • the process is combined with at least another prognosis process comprising determining the Scarff Bloom & Richardson grade and/or measuring the size of the tumor.
  • WO 2017/153484 relates to a competitive inhibitor of the binding of the protein BCL-2 L10 to the ligand binding domain of at least one of the IP3R receptors, for its use in the treatment of cancers.
  • the present invention relates to a companion process for predicting the response of a solid tumor to a treatment targeting BCL-2 L10 expression, activity and/or binding capacity to target proteins.
  • the present invention relates to an in vitro process for predicting the response of a solid tumor to a treatment targeting BCL-2 L10 protein, comprising the following steps:
  • a "treatment targeting BCL-2 L10 protein” designates a therapeutic compound having a direct or indirect effect on the activity or expression of BCL-2 L10 protein.
  • predicting the response of a tumor designates the likelihood of a tumor to be sensitive, i.e. responsive, to a specific treatment.
  • the response to a treatment also called the sensitivity to a treatment, can be positive (the treatment is efficient toward the tumor that regress and/or disappear and/or has a lesser agressivity) or negative (the progression of the tumor is not affected by the treatment).
  • a treatment targeting BCL-2 L10 protein relates to a competitive inhibitor of the binding of the protein BCL-2 L10 to the ligand binding domain of at least one of the IP3R receptors.
  • the treatment targeting BCL-2 L10 protein relates to a competitive inhibitor of the binding of the protein BCL-2 L10 to the ligand binding domain of at least one of the receptors IP3R1 and IP3R3.
  • This competitive inhibitor is extensively described in the patent application WO 2017/153484, related to therapeutic peptides for their use in the treatment of cancers expressing BCL-2 L10 protein, and hereby incorporated by reference.
  • the present invention is also related to a method for treating a solid tumor in a patient in need thereof, comprising the following steps:
  • said treatment targeting BCL-2 L10 protein is a competitive inhibitor of the binding of BCL-2 L10 to the ligand binding domain of at least one IP3R receptor.
  • BCL-2 L10 expression has been detected in breast, prostate, lung and gastric cancers.
  • said solid tumor is a breast cancer tumor.
  • Said process for predicting the response and for treating a breast cancer tumor can be applied to all type of breast tumors, such as primary tumors, secondary tumors, early-stage and advanced-stage tumors, non-metastatic and metastatic tumors.
  • kits for characterizing a breast cancer tumor in particular for identifying breast cancer tumors as being "BCL-2 L10 negative” or "BCL-2 L10 positive”.
  • kits for determining the prognosis of a breast cancer tumor in a patient based on the identification of the status of said tumor between "BCL-2 L10 negative” or "BCL-2 L10 positive".
  • kits for characterizing a solid tumor as being "BCL-2 L10 negative” or "BCL-2 L10 positive”.
  • the present invention relates to a kit comprising:
  • the antibody directed to BCL-2 L10 is a polyclonal or monoclonal antibody.
  • the kit may also comprise a positive control, a negative control and any reagents or any devices required to carry out the processes of the invention.
  • the kit of the present invention may also comprise an "invariant" control which can be the level of expression of an housekeeping protein.
  • the invention also encompasses the use of such kit for carrying out the processes of the present invention, and in particular to identify a breast cancer tumor as being "BCL-2 L10 negative” or "BCL-2 L10 positive".
  • LN Axillary lymph node invasion was assessed by sentinel node and/or level I and II axillary dissection and the number of lymph nodes harboring metastasis was determined based on histologic examination. Tumor size was defined as the maximum tumor diameter measured on the tumor specimens
  • HER2 expression was determined using immunohistochemistry and tumors were considered positive if they had 3+ staining by immunohistochemistry or 2+ staining by HER2 amplification detected using FISH.
  • the data exported from the patients' files for analysis included: age, histological subtype, maximum tumor size, number of LNs involved, SBR grade, date of diagnosis, date of relapse, and date of death or last clinical visit.
  • the staining intensity of malignant cells was classified into three levels:
  • tumors were considered to have Negative staining if they had an intensity score of 0 (BCL-2 L10 negative), and were considered to have a Positive staining if they had a score of 2-3 (BCL-2 L10 positive).
  • DMFS distant metastasis-free survival
  • BCL-2 L10 is a novel independent marker of poor prognosis in breast cancer, a predictor of high risk of metastatic dissemination and of the cancer relapse.

Abstract

L'invention concerne un procédé in vitro pour déterminer le pronostic d'une tumeur primaire de cancer du sein chez un patient, comprenant les étapes suivantes : a) évaluer le niveau d'expression de la protéine BCL-2 L10 dans un échantillon de ladite tumeur de cancer du sein dudit patient ; b) comparer ledit niveau d'expression à au moins une valeur de référence choisie parmi (i) une valeur représentative de "tumeurs BCL-2 L10 négatives", (ii) une valeur représentative de "tumeurs BCL-2 L10 positives" et (iii) une valeur de coupure ; c) identifier ladite tumeur comme étant "BCL-2 L10 négative" ou "BCL-2 L10 positive", et si ladite tumeur est identifiée à l'étape (c) comme étant BCL2-L10 positive, classer ledit patient comme présentant une survie sans métastases distantes plus courte (DMFS).
PCT/EP2018/078645 2017-10-19 2018-10-18 Évaluation du risque de rechute métastatique chez des patients atteints d'un cancer du sein WO2019077080A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
EP17306412 2017-10-19
EP17306412.2 2017-10-19

Publications (1)

Publication Number Publication Date
WO2019077080A1 true WO2019077080A1 (fr) 2019-04-25

Family

ID=60201966

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/EP2018/078645 WO2019077080A1 (fr) 2017-10-19 2018-10-18 Évaluation du risque de rechute métastatique chez des patients atteints d'un cancer du sein

Country Status (1)

Country Link
WO (1) WO2019077080A1 (fr)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN115902222A (zh) * 2022-11-04 2023-04-04 迈基诺（重庆）基因科技有限责任公司 一种乳腺癌化疗风险评分模型及其构建方法和系统

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20090275040A1 (en) 2008-04-30 2009-11-05 Burnham Institute For Medical Research Detecting bcl-b expression in cancer and uses thereof
WO2011007013A1 (fr) 2009-07-17 2011-01-20 Centre Leon Berard Znf217 : nouveau biomarqueur pronostique et prédictif des phénotypes récurrents, invasifs et métastatiques du cancer du sein
WO2013128089A1 (fr) 2012-02-28 2013-09-06 Université Nice Sophia Antipolis Test diagnostic de la résistance à l'azacitidine
WO2017153484A1 (fr) 2016-03-11 2017-09-14 Universite Claude Bernard - Lyon 1 Inhibiteurs de l'interaction protéine bcl-2 l10/récepteurs ip3

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20090275040A1 (en) 2008-04-30 2009-11-05 Burnham Institute For Medical Research Detecting bcl-b expression in cancer and uses thereof
WO2011007013A1 (fr) 2009-07-17 2011-01-20 Centre Leon Berard Znf217 : nouveau biomarqueur pronostique et prédictif des phénotypes récurrents, invasifs et métastatiques du cancer du sein
WO2013128089A1 (fr) 2012-02-28 2013-09-06 Université Nice Sophia Antipolis Test diagnostic de la résistance à l'azacitidine
US20150094217A1 (en) * 2012-02-28 2015-04-02 Université Nice Sophia Antipolis Test for diagnosing resistance to azacitidine
WO2017153484A1 (fr) 2016-03-11 2017-09-14 Universite Claude Bernard - Lyon 1 Inhibiteurs de l'interaction protéine bcl-2 l10/récepteurs ip3

Non-Patent Citations (15)

* Cited by examiner, † Cited by third party
Title
"GenBank", Database accession no. AAG00503.1
ADRIEN NOUGAREDE: "Molecular basis of BCL2L10/Nrh oncogenic activity in breast cancer", 18 October 2016 (2016-10-18), XP055452117, Retrieved from the Internet <URL:https://tel.archives-ouvertes.fr/tel-01562339/file/TH2016NOUGAREDEADRIEN.pdf> *
ANONYMOUS: "Breast cancer targeting through inhibition of the endoplasmic reticulum-based apoptosis regulator Nrh/BCL2L10 | Cancer Research", 12 January 2018 (2018-01-12), XP055451371, Retrieved from the Internet <URL:http://cancerres.aacrjournals.org/content/early/2018/01/12/0008-5472.CAN-17-0846.long> [retrieved on 20180215] *
BLOOM HJ; RICHARDSON WW: "Histological grading and prognosis in breast cancer; a study of 1409 cases of which 359 have been followed for 15 years", BR J CANCER, vol. 11, no. 3, September 1957 (1957-09-01), pages 359 - 77, XP055150023
CLUZEAU T ET AL.: "BCL2L10 is a predictive factor for resistance to azacitidine in MDS and AML patients", ONCOTARGET, vol. 3, no. 4, 2012, pages 490 - 501, XP002685820, DOI: doi:10.18632/oncotarget.481
CLUZEAU THOMAS ET AL: "BCL2L10 is a predictive factor for resistance to Azacitidine in MDS and AML patients", ONCOTARGET, IMPACT JOURNALS LLC, UNITED STATES, vol. 3, no. 4, 1 April 2012 (2012-04-01), pages 490 - 501, XP002685820, ISSN: 1949-2553, [retrieved on 20120509], DOI: 10.18632/ONCOTARGET.481 *
DAWSON S-J ET AL.: "BCL2 in breast cancer: a favourable prognostic marker across molecular subtypes and independent of adjuvant therapy received", BR. J. CANCER, vol. 103, no. 5, 2010, pages 668 - 675
DESOUKI M M ET AL: "The genomic relationship between primary breast carcinomas and their nodal metastases", CANCER INVESTIGATION, TAYLOR & FRANCIS INC, US, vol. 29, no. 4, 30 April 2011 (2011-04-30), pages 300 - 307, XP009503503, ISSN: 0735-7907, [retrieved on 20110406], DOI: 10.3109/07357907.2011.568564 *
HATA AN; ENGELMAN JA; FABER AC: "The BCL2 Family: Key Mediators of the Apoptotic Response to Targeted Anticancer Therapeutics", CANCER DISCOV., vol. 5, no. 5, 2015, pages 475 - 487
HONMA N ET AL.: "Differences in clinical importance of Bcl-2 in breast cancer according to hormone receptors status or adjuvant endocrine therapy", BMC CANCER, vol. 15, 2015, pages 698, XP021230556, DOI: doi:10.1186/s12885-015-1686-y
KRAJEWSKA M ET AL.: "Bcl-B expression in human epithelial and nonepithelial malignancies", CLIN. CANCER RES., vol. 14, no. 10, 2008, pages 3011 - 3021, XP055319273, DOI: doi:10.1158/1078-0432.CCR-07-1955
LAKHANI SR; ELLIS 10; SCHNITT SJ; TAN PH; VAN DE VIJVER MJ: "WHO/IARC Classification of Tumours"
M. KRAJEWSKA ET AL: "Bcl-B Expression in Human Epithelial and Nonepithelial Malignancies", CLINICAL CANCER RESEARCH, vol. 14, no. 10, 15 May 2008 (2008-05-15), US, pages 3011 - 3021, XP055319273, ISSN: 1078-0432, DOI: 10.1158/1078-0432.CCR-07-1955 *
TVRDIK D ET AL: "Apoptosis - associated genes and their role in predicting responses to neoadjuvant breast cancer treatment", MEDICAL SCIENCE MONITOR, MEDISCIENCE PUBLIKACJE NAUKOWE, WARZAW, PL, vol. 18, no. 1, 1 January 2012 (2012-01-01), pages BR60 - BR67, XP009503504, ISSN: 1234-1010, [retrieved on 20111222], DOI: 10.12659/MSM.882205 *
YIP KW; REED JC: "Bcl-2 family proteins and cancer", ONCOGENE, vol. 27, no. 50, 2008, pages 6398 - 6406

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN115902222A (zh) * 2022-11-04 2023-04-04 迈基诺（重庆）基因科技有限责任公司 一种乳腺癌化疗风险评分模型及其构建方法和系统

Similar Documents

Publication Publication Date Title
Ni et al. Tenascin-C is a potential cancer-associated fibroblasts marker and predicts poor prognosis in prostate cancer
Aune et al. Increased circulating hepatocyte growth factor (HGF): a marker of epithelial ovarian cancer and an indicator of poor prognosis
US20030224467A1 (en) AIB1 as a prognostic marker and predictor of resistance to endocrine therapy
US20070218512A1 (en) Methods related to mmp26 status as a diagnostic and prognostic tool in cancer management
López-Ruiz et al. One-step nucleic acid amplification (OSNA) for the detection of sentinel lymph node metastasis in endometrial cancer
KR102561377B1 (ko) 마커 분자를 기반으로 화학요법으로 치료되어야 하는 개체를 식별하는 방법 및 관련 용도
Yin et al. The levels of Ki-67 positive are positively associated with lymph node metastasis in invasive ductal breast cancer
Hiraike et al. Expression of DBC1 is associated with nuclear grade and HER2 expression in breast cancer
Di Gioia et al. Serum HER2 supports HER2-testing in tissue at the time of primary diagnosis of breast cancer
Zhao et al. Cortactin is a sensitive biomarker relative to the poor prognosis of human hepatocellular carcinoma
Tanaka et al. Thymidine phosphorylase expression in tumor-infiltrating macrophages may be correlated with poor prognosis in uterine endometrial cancer
Liu et al. Overexpression of lysine-specific demethylase 1 is associated with tumor progression and unfavorable prognosis in Chinese patients with endometrioid endometrial adenocarcinoma
Elkhuizen et al. Isolated late local recurrences with high mitotic count and early local recurrences following breast-conserving therapy are associated with increased risk on distant metastasis
Zhang et al. Prognostic and predictive role of COX-2, XRCC1 and RASSF1 expression in patients with esophageal squamous cell carcinoma receiving radiotherapy
EP2742358A1 (fr) Méthodes de diagnostic du cancer
Xie et al. High cytoplasm HABP1 expression as a predictor of poor survival and late tumor stage in pancreatic ductal adenocarcinoma patients
Corte et al. Cytosolic levels of TFF1/pS2 in breast cancer: their relationship with clinical–pathological parameters and their prognostic significance
Liersch et al. Expression of VEGF-C and its receptor VEGFR-3 in the bone marrow of patients with acute myeloid leukaemia
Kim et al. High expression of urokinase-type plasminogen activator is associated with lymph node metastasis of invasive ductal carcinoma of the breast
Wang et al. High expression of thymosin beta 10 predicts poor prognosis for hepatocellular carcinoma after hepatectomy
Nosaka et al. Cytoplasmic maspin expression correlates with poor prognosis of patients with adenocarcinoma of the uterine cervix
WO2019077080A1 (fr) Évaluation du risque de rechute métastatique chez des patients atteints d&#39;un cancer du sein
Ponz-Sarvisé et al. Differential tumor expression of inhibitor of differentiation-1 in prostate cancer patients with extreme clinical phenotypes and prognostic implications
Zhang et al. Vimentin protein In situ expression predicts less tumor metastasis and overall better survival of endometrial carcinoma
KR102164525B1 (ko) Gdf 15를 포함하는 갑상선 암 진단 또는 갑상선 암 예후 예측용 바이오마커 조성물

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 18785685

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 18785685

Country of ref document: EP

Kind code of ref document: A1