Receptor Discordance in Breast Carcinoma During the Course of Life
Definition:
Receptor discordance refers to changes in the status of hormone receptors (estrogen receptor ERα, progesterone receptor PgR, and HER2) in breast cancer tumors over time or between primary and metastatic sites.
Causes:
Tumor Evolution:
Genetic and epigenetic changes during tumor progression can lead to alterations in receptor status.
Treatment Effects:
Therapies, especially endocrine and targeted therapies, can selectively pressure tumor cells, causing shifts in receptor expression.
Heterogeneity:
Inherent heterogeneity within the tumor can result in subpopulations of cells with different receptor statuses.
Impact on Treatment:
Therapeutic Resistance:
Loss of ERα or PgR can lead to resistance to endocrine therapies.
HER2 discordance affects the efficacy of HER2-targeted treatments.
Treatment Adjustment:
Regular reassessment of receptor status may be necessary to adjust treatment strategies appropriately.
Clinical Implications:
Prognosis:
Receptor discordance is often associated with a poorer prognosis.
Biopsies:
Obtaining biopsies from metastatic sites is crucial for accurate receptor status assessment and effective treatment planning.
Monitoring:
Continuous monitoring of receptor status throughout the disease course can guide personalized therapy adjustments.
Understanding and managing receptor discordance is essential for optimizing treatment outcomes and improving the prognosis for breast cancer patients.
Progesterone receptor (PR) plays an important role in breast cancer progression and response to hormone therapy. PR exists as two isoforms, PR-A and PR-B, which act as transcription factors. PR signaling can occur through both nuclear and non-nuclear pathways. While PR expression correlates with better outcomes from hormone therapy, loss of PR is a mechanism of resistance. Targeting the PR pathway through drugs like anti-RANKL agents may be a preventative strategy, while newer endocrine therapies aim to overcome resistance.
Breast cancer is caused by heterogeneous tumor cells whose behavior depends on biological features. Molecular subtyping through gene expression profiling can classify tumor types, recognize hereditary implications, identify appropriate therapies, determine prognosis, and avoid unnecessary treatment. The major subtypes are luminal A/B, HER2-enriched, and basal-like, which differ in gene expression, sensitivity to therapies, and clinical outcomes. Understanding the molecular biology of breast cancer is crucial for precision medicine approaches to management.
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The document discusses the Epidermal Growth Factor Receptor (EGFR) signaling pathway and its role in regulating cell proliferation. It describes how EGFR activates downstream proteins including RAS, RAF, and MAPK upon ligand binding. Dysregulation of these proteins can lead to cancer. Several FDA-approved targeted cancer drugs work by inhibiting proteins in the EGFR pathway such as tyrosine kinase inhibitors that target EGFR or RAF inhibitors like Vemurafenib for melanoma. Understanding this pathway helps develop new targeted cancer therapies.
Epigenetics is the study of heritable changes in gene expression that do not involve changes to the underlying DNA sequence. These changes can be caused by modifications to DNA and chromatin structure in response to environmental factors. Epigenetic modifications include DNA methylation, histone modifications, and regulation by non-coding RNAs. Changes in epigenetic patterns can lead to changes in gene expression and phenotypic traits, and have been linked to diseases like cancer. While epigenetic changes are heritable, they are reversible and do not permanently alter the DNA sequence like mutations do.
Epidermal growth factor (EGF) is a protein that binds to EGF receptors on epithelial and epidermal cells and initiates the EGF signaling pathway. When EGF binds to EGF receptors, it causes them to dimerize and activate their tyrosine kinase activity, leading to phosphorylation and activation of downstream proteins in the MAPK pathway. Mutations that cause constitutive activation of this pathway can lead to uncontrolled cell growth and cancer. Potential cancer treatments discussed include RGD-based peptides that target the αvβ3 integrin receptor involved in angiogenesis, and a conjugate of low molecular weight heparin and suramin that may inhibit tumor growth by blocking vascular endothelial growth factor (VEGF).
This document discusses epidermal growth factor receptor (EGFR) inhibitors for the treatment of non-small cell lung cancer. It provides background on EGFR expression in various cancers and the role of EGFR in tumor growth. It describes various EGFR inhibitors including cetuximab, gefitinib and erlotinib. It summarizes several clinical trials that evaluated these drugs as monotherapy or in combination with chemotherapy. It discusses ongoing research questions around patient selection, combination/sequencing of therapies, and use of EGFR inhibitors in other cancer types.
Proto-oncogenes are normal cellular genes that encode proteins involved in cell proliferation. When mutated, they become oncogenes that encode constitutively active oncoproteins driving increased cell growth. Proto-oncogenes can encode growth factors, growth factor receptors, signal transducers, transcription factors, or cell cycle regulators. Common mutations include RAS mutations in pancreatic cancer, BRAF mutations in melanoma, PI3K mutations in breast cancer, and MYC translocations in Burkitt's lymphoma. These mutations result in constitutive activation of signaling pathways that drive uncontrolled cell proliferation.
Progesterone receptor (PR) plays an important role in breast cancer progression and response to hormone therapy. PR exists as two isoforms, PR-A and PR-B, which act as transcription factors. PR signaling can occur through both nuclear and non-nuclear pathways. While PR expression correlates with better outcomes from hormone therapy, loss of PR is a mechanism of resistance. Targeting the PR pathway through drugs like anti-RANKL agents may be a preventative strategy, while newer endocrine therapies aim to overcome resistance.
Breast cancer is caused by heterogeneous tumor cells whose behavior depends on biological features. Molecular subtyping through gene expression profiling can classify tumor types, recognize hereditary implications, identify appropriate therapies, determine prognosis, and avoid unnecessary treatment. The major subtypes are luminal A/B, HER2-enriched, and basal-like, which differ in gene expression, sensitivity to therapies, and clinical outcomes. Understanding the molecular biology of breast cancer is crucial for precision medicine approaches to management.
CHEM1110 Chemistry For The Life Sciences I.docxwrite31
The document discusses the Epidermal Growth Factor Receptor (EGFR) signaling pathway and its role in regulating cell proliferation. It describes how EGFR activates downstream proteins including RAS, RAF, and MAPK upon ligand binding. Dysregulation of these proteins can lead to cancer. Several FDA-approved targeted cancer drugs work by inhibiting proteins in the EGFR pathway such as tyrosine kinase inhibitors that target EGFR or RAF inhibitors like Vemurafenib for melanoma. Understanding this pathway helps develop new targeted cancer therapies.
Epigenetics is the study of heritable changes in gene expression that do not involve changes to the underlying DNA sequence. These changes can be caused by modifications to DNA and chromatin structure in response to environmental factors. Epigenetic modifications include DNA methylation, histone modifications, and regulation by non-coding RNAs. Changes in epigenetic patterns can lead to changes in gene expression and phenotypic traits, and have been linked to diseases like cancer. While epigenetic changes are heritable, they are reversible and do not permanently alter the DNA sequence like mutations do.
Epidermal growth factor (EGF) is a protein that binds to EGF receptors on epithelial and epidermal cells and initiates the EGF signaling pathway. When EGF binds to EGF receptors, it causes them to dimerize and activate their tyrosine kinase activity, leading to phosphorylation and activation of downstream proteins in the MAPK pathway. Mutations that cause constitutive activation of this pathway can lead to uncontrolled cell growth and cancer. Potential cancer treatments discussed include RGD-based peptides that target the αvβ3 integrin receptor involved in angiogenesis, and a conjugate of low molecular weight heparin and suramin that may inhibit tumor growth by blocking vascular endothelial growth factor (VEGF).
This document discusses epidermal growth factor receptor (EGFR) inhibitors for the treatment of non-small cell lung cancer. It provides background on EGFR expression in various cancers and the role of EGFR in tumor growth. It describes various EGFR inhibitors including cetuximab, gefitinib and erlotinib. It summarizes several clinical trials that evaluated these drugs as monotherapy or in combination with chemotherapy. It discusses ongoing research questions around patient selection, combination/sequencing of therapies, and use of EGFR inhibitors in other cancer types.
Proto-oncogenes are normal cellular genes that encode proteins involved in cell proliferation. When mutated, they become oncogenes that encode constitutively active oncoproteins driving increased cell growth. Proto-oncogenes can encode growth factors, growth factor receptors, signal transducers, transcription factors, or cell cycle regulators. Common mutations include RAS mutations in pancreatic cancer, BRAF mutations in melanoma, PI3K mutations in breast cancer, and MYC translocations in Burkitt's lymphoma. These mutations result in constitutive activation of signaling pathways that drive uncontrolled cell proliferation.
Cancer genes can be divided into two main classes: oncogenes and tumor suppressor genes. Oncogenes promote cell growth and proliferation when activated by mutations, while tumor suppressor genes normally inhibit cell growth and their inactivation allows for unchecked cell division. Dysfunction of multiple cancer genes is typically required for malignant transformation, as an imbalance between oncogene and tumor suppressor gene activity leads to cancer development. Common oncogenes include ras, myc, and HER2, while tumor suppressor genes include RB, p53, and APC. Mutations in DNA repair genes can also contribute to cancer by allowing genetic errors to persist.
Molecular subtyping of breast cancer through gene expression profiling can identify distinct tumor subtypes with different biological behaviors and responses to therapy. The major subtypes include luminal A/B (ER-positive), HER2-enriched, basal-like (triple-negative), and normal-like. Molecular testing helps determine prognosis, hereditary risk, and appropriate targeted therapies. Hormonal and HER2-targeted therapies are effective treatments for luminal and HER2-positive breast cancers, respectively, while basal-like cancers are more aggressive and difficult to treat.
This document provides an outline on tumor suppressor genes. It discusses several key tumor suppressor genes including p53, Rb, BRCA1/2, APC, PTEN, PPA2, LKB1, p16, WTX, and epigenetic changes. For each gene, it summarizes the associated cancers, functions, and key mechanisms such as phosphorylation, cell cycle regulation, DNA repair, signaling pathways, and chromatin remodeling. It also mentions the roles of miRNAs and how some can act as oncogenes while others like let-7 suppress tumor growth.
Signal transduction proteins and pathways in oncogenesisShashidhara TS
1. The document discusses various signal transduction proteins and pathways that are involved in oncogenesis, including growth factor receptors, Ras, PI3K/Akt, JAK/STAT, and cyclic AMP signaling pathways.
2. Mutations in these proteins and pathways, such as activating mutations in Ras, receptor tyrosine kinases, JAK2, and STATs can lead to constitutive signaling and uncontrolled cell growth.
3. Targeting key nodes in these altered pathways, such as BCR-ABL fusion protein, mutant Ras, PI3K, and JAK2, may provide opportunities for targeted cancer therapies.
Estrogen
Estrogen receptor and signaling pathway
Introduction of cancer and gene involvement
Causes of breast cancer
Type of breast cancer
Different approaches to treat breast cancer
Estrogen receptor antagonism
This document summarizes information about the EGFR gene and the L858R mutation. It discusses how the EGFR gene codes for the epidermal growth factor receptor protein, which plays an important role in cancer signaling pathways. It specifically describes the L858R point mutation in the EGFR gene, which is common in non-small cell lung cancer. This mutation increases the tumor's sensitivity to EGFR inhibitors like gefitinib. Gefitinib is an ATP-competitive inhibitor that binds to the mutated EGFR protein and inhibits its kinase activity, providing a palliative treatment option for cancers with this mutation. A test was later developed to identify patients that may respond to gefitinib based on their tumor's
Stratified Medicine in Cancer: The Role of HistopathologistDr. Shubhi Saxena
This document discusses stratified medicine approaches for cancer treatment. It describes how cellular pathologists classify gene mutations in cancer, including whether they are germline or somatic, synonymous or non-synonymous, activating or inactivating. Certain mutations can predict treatment response or resistance. Key driver mutations are discussed for lung cancer, including EGFR mutations and ALK translocations. EGFR mutant cancers may respond to EGFR tyrosine kinase inhibitors, while ALK rearrangements are targeted by crizotinib. Histopathology plays an important role in mutation detection and molecular testing to guide targeted therapies.
Management of hormonal resistant breast cancer Ahmed Allam
The document discusses endocrine therapy for breast cancer and mechanisms of resistance. It notes that around 60% of ER-positive breast cancer patients benefit from endocrine therapy like tamoxifen. Later studies found aromatase inhibitors and mTOR inhibitors can help overcome resistance. One study showed everolimus plus tamoxifen extended time to progression compared to tamoxifen alone in metastatic breast cancer patients previously treated with aromatase inhibitors.
Tumor suppressor genes help repair damaged DNA and inhibit cell proliferation and cancer growth. They fall into two categories: caretaker genes that maintain genome integrity through DNA repair, and gatekeeper genes that inhibit proliferation or promote death of cells with damaged DNA. Key tumor suppressor genes include p53, Rb, APC, WT1, NF1, VHL, p15, p16, BRCA1, BRCA2, and PTEN. Mutation of both copies of a tumor suppressor gene, as with the two-hit hypothesis for retinoblastoma, can lead to uncontrolled cell growth and cancer development.
This document summarizes key information about tumor suppressor genes. It discusses retinoblastoma, the first tumor suppressor gene identified. It was found that deletion of the RB gene causes retinoblastoma cancer. The document also describes several other important tumor suppressor genes, such as p53, PTEN, Rb, and INK4. It explains how mutations or deletions in these genes can lead to uncontrolled cell growth and cancer development by disrupting cell cycle regulation and apoptosis.
Chemical carcinogenesis involves three main steps: initiation, promotion, and progression. Initiation involves DNA damage from chemical mutagens and fixes mutations irreversibly. Promotion involves selective growth of initiated cells through continuous exposure to tumor promoters. This stage is reversible. Progression results from accumulating mutations during promotion and leads to increased malignancy, invasiveness and metastasis. Inflammation can act at all stages by inducing mutations, stimulating cell growth, and creating an environment conducive to tumor development and spread.
This document discusses hormonal therapy for breast cancer. It notes that around 60-70% of breast cancer patients are estrogen receptor positive. Estrogen receptor positive tumors have a better survival rate than estrogen receptor negative tumors. The document discusses the molecular basis of estrogen receptor signaling and the genomic and non-genomic mechanisms of estrogen action. It describes the different types of hormonal therapies used in breast cancer including selective estrogen receptor modulators, aromatase inhibitors, antiestrogens, LHRH agonists, and progestins. It discusses the application of hormonal therapy in the adjuvant setting for premenopausal and postmenopausal patients.
Breast cancer is the most common female malignancy and is
responsible for about 14% of cancer-related deaths in women
[1]. Triple-negative breast cancer (TNBC), characterized by the
absence of expression of Estrogen Receptor (ER), Progesterone
Receptor (PR), and human epidermal growth factor receptor 2
(HER2), is the most aggressive and deadly subtype of breast cancer
molecular biology and Target therapy in lung cancerRikin Hasnani
This document summarizes molecular biology and targeted therapies in lung cancer. It discusses that lung cancer is a leading cause of cancer death worldwide. Historically, lung cancers were classified by histology alone, but it is now known they are driven by specific mutations. Key driver mutations were discovered in the EGFR, ALK, KRAS genes. These mutations activate intracellular signaling pathways like RAS/RAF/MEK/ERK and regulate cell growth. Targeted therapies like EGFR TKIs erlotinib and gefitinib or the ALK inhibitor crizotinib have significantly improved outcomes for patients with specific driver mutations. However, resistance often develops through secondary mutations like T790M, requiring new
This document discusses pharmacogenetics and how genetic variations can influence individual responses to drugs. It provides definitions and examples of how genes related to drug metabolism and targets can impact drug efficacy and toxicity. Single gene disorders, SNPs, mutations, and inherited conditions are described that influence drug pharmacokinetics and pharmacodynamics. Several clinically applied pharmacogenetic tests are mentioned, such as testing for HLA-B*5701 before prescribing abacavir or DPYD activity before 5-fluorouracil treatment.
This presentation consists of topics related to oncogene, proto oncogene, Tumor suppresor gene, Ras gene family and structure and functions of tumor suppressor gene.
This document summarizes a research article that studied how estrogen receptor beta (ERβ) impacts hormone-induced alternative mRNA splicing in breast cancer cells. The key findings are:
1) Exon skipping was the most common splicing event observed in response to estradiol stimulation.
2) Expression of ERβ significantly affected estrogen-induced splicing in breast cancer cells, modifying some splicing events regulated by ERα alone and inducing new splicing isoforms.
3) ERβ expression was associated with around twice as many splicing events compared to cells lacking ERβ, indicating ERβ has an important role in regulating splicing.
4) Some splicing events were found to be directly regulated by ERβ binding sites near the affected
Breast cancer: Post menopausal endocrine therapyDr. Sumit KUMAR
Breast cancer in postmenopausal women with hormone receptor-positive (HR+) status is a common and complex condition that necessitates a multifaceted approach to management. HR+ breast cancer means that the cancer cells grow in response to hormones such as estrogen and progesterone. This subtype is prevalent among postmenopausal women and typically exhibits a more indolent course compared to other forms of breast cancer, which allows for a variety of treatment options.
Diagnosis and Staging
The diagnosis of HR+ breast cancer begins with clinical evaluation, imaging, and biopsy. Imaging modalities such as mammography, ultrasound, and MRI help in assessing the extent of the disease. Histopathological examination and immunohistochemical staining of the biopsy sample confirm the diagnosis and hormone receptor status by identifying the presence of estrogen receptors (ER) and progesterone receptors (PR) on the tumor cells.
Staging involves determining the size of the tumor (T), the involvement of regional lymph nodes (N), and the presence of distant metastasis (M). The American Joint Committee on Cancer (AJCC) staging system is commonly used. Accurate staging is critical as it guides treatment decisions.
Treatment Options
Endocrine Therapy
Endocrine therapy is the cornerstone of treatment for HR+ breast cancer in postmenopausal women. The primary goal is to reduce the levels of estrogen or block its effects on cancer cells. Commonly used agents include:
Selective Estrogen Receptor Modulators (SERMs): Tamoxifen is a SERM that binds to estrogen receptors, blocking estrogen from stimulating breast cancer cells. It is effective but may have side effects such as increased risk of endometrial cancer and thromboembolic events.
Aromatase Inhibitors (AIs): These drugs, including anastrozole, letrozole, and exemestane, lower estrogen levels by inhibiting the aromatase enzyme, which converts androgens to estrogen in peripheral tissues. AIs are generally preferred in postmenopausal women due to their efficacy and safety profile compared to tamoxifen.
Selective Estrogen Receptor Downregulators (SERDs): Fulvestrant is a SERD that degrades estrogen receptors and is used in cases where resistance to other endocrine therapies develops.
Combination Therapies
Combining endocrine therapy with other treatments enhances efficacy. Examples include:
Endocrine Therapy with CDK4/6 Inhibitors: Palbociclib, ribociclib, and abemaciclib are CDK4/6 inhibitors that, when combined with endocrine therapy, significantly improve progression-free survival in advanced HR+ breast cancer.
Endocrine Therapy with mTOR Inhibitors: Everolimus, an mTOR inhibitor, can be added to endocrine therapy for patients who have developed resistance to aromatase inhibitors.
Chemotherapy
Chemotherapy is generally reserved for patients with high-risk features, such as large tumor size, high-grade histology, or extensive lymph node involvement. Regimens often include anthracyclines and taxanes.
Euthanasia, derived from Greek words meaning "good death," is a complex and controversial ethical and legal issue revolving around the deliberate ending of a person's life to relieve suffering. It is often a topic of intense debate within medical, legal, religious, and ethical circles.
Types of Euthanasia:
Voluntary Euthanasia: This occurs when a competent person makes a voluntary and informed decision to end their life with the assistance of a medical professional or loved one.
Non-voluntary Euthanasia: In this scenario, the decision to end a person's life is made by someone other than the individual, typically when they are unable to make decisions for themselves due to being in a coma or having advanced dementia.
Involuntary Euthanasia: This is the termination of a person's life against their will or without their consent, often performed in situations where the person's suffering is deemed unbearable or where their quality of life is deemed too low by others.
Assisted Suicide: This involves providing a person with the means or information necessary to end their own life, such as prescribing lethal medication, while the individual ultimately carries out the act themselves.
Ethical Considerations:
Autonomy vs. Sanctity of Life: Supporters of euthanasia argue for individual autonomy and the right to die with dignity, while opponents often cite the sanctity of life and the potential for abuse or slippery slope arguments.
Quality of Life: Discussions often revolve around the subjective nature of suffering and the quality of life, with some arguing that euthanasia can alleviate unnecessary suffering, while others raise concerns about the potential devaluation of certain lives.
Medical Ethics: Euthanasia raises questions about the role of healthcare professionals in end-of-life care, the distinction between killing and allowing to die, and the obligations of physicians to relieve suffering while upholding ethical principles.
Legal Status:
The legality of euthanasia varies greatly around the world. Some countries, such as the Netherlands, Belgium, and Canada, have legalized certain forms of euthanasia under strict conditions, while others, including many U.S. states, maintain its illegality. In some regions, there are ongoing debates and court cases seeking to clarify or change existing laws.
Conclusion:
Euthanasia remains a deeply divisive and emotionally charged issue, touching on fundamental questions about life, death, autonomy, and suffering. As medical technology advances and societal attitudes evolve, discussions surrounding euthanasia are likely to persist, challenging individuals, communities, and policymakers to navigate the complexities of this sensitive topic with compassion and integrity.
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Cancer genes can be divided into two main classes: oncogenes and tumor suppressor genes. Oncogenes promote cell growth and proliferation when activated by mutations, while tumor suppressor genes normally inhibit cell growth and their inactivation allows for unchecked cell division. Dysfunction of multiple cancer genes is typically required for malignant transformation, as an imbalance between oncogene and tumor suppressor gene activity leads to cancer development. Common oncogenes include ras, myc, and HER2, while tumor suppressor genes include RB, p53, and APC. Mutations in DNA repair genes can also contribute to cancer by allowing genetic errors to persist.
Molecular subtyping of breast cancer through gene expression profiling can identify distinct tumor subtypes with different biological behaviors and responses to therapy. The major subtypes include luminal A/B (ER-positive), HER2-enriched, basal-like (triple-negative), and normal-like. Molecular testing helps determine prognosis, hereditary risk, and appropriate targeted therapies. Hormonal and HER2-targeted therapies are effective treatments for luminal and HER2-positive breast cancers, respectively, while basal-like cancers are more aggressive and difficult to treat.
This document provides an outline on tumor suppressor genes. It discusses several key tumor suppressor genes including p53, Rb, BRCA1/2, APC, PTEN, PPA2, LKB1, p16, WTX, and epigenetic changes. For each gene, it summarizes the associated cancers, functions, and key mechanisms such as phosphorylation, cell cycle regulation, DNA repair, signaling pathways, and chromatin remodeling. It also mentions the roles of miRNAs and how some can act as oncogenes while others like let-7 suppress tumor growth.
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1. The document discusses various signal transduction proteins and pathways that are involved in oncogenesis, including growth factor receptors, Ras, PI3K/Akt, JAK/STAT, and cyclic AMP signaling pathways.
2. Mutations in these proteins and pathways, such as activating mutations in Ras, receptor tyrosine kinases, JAK2, and STATs can lead to constitutive signaling and uncontrolled cell growth.
3. Targeting key nodes in these altered pathways, such as BCR-ABL fusion protein, mutant Ras, PI3K, and JAK2, may provide opportunities for targeted cancer therapies.
Estrogen
Estrogen receptor and signaling pathway
Introduction of cancer and gene involvement
Causes of breast cancer
Type of breast cancer
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Estrogen receptor antagonism
This document summarizes information about the EGFR gene and the L858R mutation. It discusses how the EGFR gene codes for the epidermal growth factor receptor protein, which plays an important role in cancer signaling pathways. It specifically describes the L858R point mutation in the EGFR gene, which is common in non-small cell lung cancer. This mutation increases the tumor's sensitivity to EGFR inhibitors like gefitinib. Gefitinib is an ATP-competitive inhibitor that binds to the mutated EGFR protein and inhibits its kinase activity, providing a palliative treatment option for cancers with this mutation. A test was later developed to identify patients that may respond to gefitinib based on their tumor's
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This document discusses stratified medicine approaches for cancer treatment. It describes how cellular pathologists classify gene mutations in cancer, including whether they are germline or somatic, synonymous or non-synonymous, activating or inactivating. Certain mutations can predict treatment response or resistance. Key driver mutations are discussed for lung cancer, including EGFR mutations and ALK translocations. EGFR mutant cancers may respond to EGFR tyrosine kinase inhibitors, while ALK rearrangements are targeted by crizotinib. Histopathology plays an important role in mutation detection and molecular testing to guide targeted therapies.
Management of hormonal resistant breast cancer Ahmed Allam
The document discusses endocrine therapy for breast cancer and mechanisms of resistance. It notes that around 60% of ER-positive breast cancer patients benefit from endocrine therapy like tamoxifen. Later studies found aromatase inhibitors and mTOR inhibitors can help overcome resistance. One study showed everolimus plus tamoxifen extended time to progression compared to tamoxifen alone in metastatic breast cancer patients previously treated with aromatase inhibitors.
Tumor suppressor genes help repair damaged DNA and inhibit cell proliferation and cancer growth. They fall into two categories: caretaker genes that maintain genome integrity through DNA repair, and gatekeeper genes that inhibit proliferation or promote death of cells with damaged DNA. Key tumor suppressor genes include p53, Rb, APC, WT1, NF1, VHL, p15, p16, BRCA1, BRCA2, and PTEN. Mutation of both copies of a tumor suppressor gene, as with the two-hit hypothesis for retinoblastoma, can lead to uncontrolled cell growth and cancer development.
This document summarizes key information about tumor suppressor genes. It discusses retinoblastoma, the first tumor suppressor gene identified. It was found that deletion of the RB gene causes retinoblastoma cancer. The document also describes several other important tumor suppressor genes, such as p53, PTEN, Rb, and INK4. It explains how mutations or deletions in these genes can lead to uncontrolled cell growth and cancer development by disrupting cell cycle regulation and apoptosis.
Chemical carcinogenesis involves three main steps: initiation, promotion, and progression. Initiation involves DNA damage from chemical mutagens and fixes mutations irreversibly. Promotion involves selective growth of initiated cells through continuous exposure to tumor promoters. This stage is reversible. Progression results from accumulating mutations during promotion and leads to increased malignancy, invasiveness and metastasis. Inflammation can act at all stages by inducing mutations, stimulating cell growth, and creating an environment conducive to tumor development and spread.
This document discusses hormonal therapy for breast cancer. It notes that around 60-70% of breast cancer patients are estrogen receptor positive. Estrogen receptor positive tumors have a better survival rate than estrogen receptor negative tumors. The document discusses the molecular basis of estrogen receptor signaling and the genomic and non-genomic mechanisms of estrogen action. It describes the different types of hormonal therapies used in breast cancer including selective estrogen receptor modulators, aromatase inhibitors, antiestrogens, LHRH agonists, and progestins. It discusses the application of hormonal therapy in the adjuvant setting for premenopausal and postmenopausal patients.
Breast cancer is the most common female malignancy and is
responsible for about 14% of cancer-related deaths in women
[1]. Triple-negative breast cancer (TNBC), characterized by the
absence of expression of Estrogen Receptor (ER), Progesterone
Receptor (PR), and human epidermal growth factor receptor 2
(HER2), is the most aggressive and deadly subtype of breast cancer
molecular biology and Target therapy in lung cancerRikin Hasnani
This document summarizes molecular biology and targeted therapies in lung cancer. It discusses that lung cancer is a leading cause of cancer death worldwide. Historically, lung cancers were classified by histology alone, but it is now known they are driven by specific mutations. Key driver mutations were discovered in the EGFR, ALK, KRAS genes. These mutations activate intracellular signaling pathways like RAS/RAF/MEK/ERK and regulate cell growth. Targeted therapies like EGFR TKIs erlotinib and gefitinib or the ALK inhibitor crizotinib have significantly improved outcomes for patients with specific driver mutations. However, resistance often develops through secondary mutations like T790M, requiring new
This document discusses pharmacogenetics and how genetic variations can influence individual responses to drugs. It provides definitions and examples of how genes related to drug metabolism and targets can impact drug efficacy and toxicity. Single gene disorders, SNPs, mutations, and inherited conditions are described that influence drug pharmacokinetics and pharmacodynamics. Several clinically applied pharmacogenetic tests are mentioned, such as testing for HLA-B*5701 before prescribing abacavir or DPYD activity before 5-fluorouracil treatment.
This presentation consists of topics related to oncogene, proto oncogene, Tumor suppresor gene, Ras gene family and structure and functions of tumor suppressor gene.
This document summarizes a research article that studied how estrogen receptor beta (ERβ) impacts hormone-induced alternative mRNA splicing in breast cancer cells. The key findings are:
1) Exon skipping was the most common splicing event observed in response to estradiol stimulation.
2) Expression of ERβ significantly affected estrogen-induced splicing in breast cancer cells, modifying some splicing events regulated by ERα alone and inducing new splicing isoforms.
3) ERβ expression was associated with around twice as many splicing events compared to cells lacking ERβ, indicating ERβ has an important role in regulating splicing.
4) Some splicing events were found to be directly regulated by ERβ binding sites near the affected
Breast cancer: Post menopausal endocrine therapyDr. Sumit KUMAR
Breast cancer in postmenopausal women with hormone receptor-positive (HR+) status is a common and complex condition that necessitates a multifaceted approach to management. HR+ breast cancer means that the cancer cells grow in response to hormones such as estrogen and progesterone. This subtype is prevalent among postmenopausal women and typically exhibits a more indolent course compared to other forms of breast cancer, which allows for a variety of treatment options.
Diagnosis and Staging
The diagnosis of HR+ breast cancer begins with clinical evaluation, imaging, and biopsy. Imaging modalities such as mammography, ultrasound, and MRI help in assessing the extent of the disease. Histopathological examination and immunohistochemical staining of the biopsy sample confirm the diagnosis and hormone receptor status by identifying the presence of estrogen receptors (ER) and progesterone receptors (PR) on the tumor cells.
Staging involves determining the size of the tumor (T), the involvement of regional lymph nodes (N), and the presence of distant metastasis (M). The American Joint Committee on Cancer (AJCC) staging system is commonly used. Accurate staging is critical as it guides treatment decisions.
Treatment Options
Endocrine Therapy
Endocrine therapy is the cornerstone of treatment for HR+ breast cancer in postmenopausal women. The primary goal is to reduce the levels of estrogen or block its effects on cancer cells. Commonly used agents include:
Selective Estrogen Receptor Modulators (SERMs): Tamoxifen is a SERM that binds to estrogen receptors, blocking estrogen from stimulating breast cancer cells. It is effective but may have side effects such as increased risk of endometrial cancer and thromboembolic events.
Aromatase Inhibitors (AIs): These drugs, including anastrozole, letrozole, and exemestane, lower estrogen levels by inhibiting the aromatase enzyme, which converts androgens to estrogen in peripheral tissues. AIs are generally preferred in postmenopausal women due to their efficacy and safety profile compared to tamoxifen.
Selective Estrogen Receptor Downregulators (SERDs): Fulvestrant is a SERD that degrades estrogen receptors and is used in cases where resistance to other endocrine therapies develops.
Combination Therapies
Combining endocrine therapy with other treatments enhances efficacy. Examples include:
Endocrine Therapy with CDK4/6 Inhibitors: Palbociclib, ribociclib, and abemaciclib are CDK4/6 inhibitors that, when combined with endocrine therapy, significantly improve progression-free survival in advanced HR+ breast cancer.
Endocrine Therapy with mTOR Inhibitors: Everolimus, an mTOR inhibitor, can be added to endocrine therapy for patients who have developed resistance to aromatase inhibitors.
Chemotherapy
Chemotherapy is generally reserved for patients with high-risk features, such as large tumor size, high-grade histology, or extensive lymph node involvement. Regimens often include anthracyclines and taxanes.
Euthanasia, derived from Greek words meaning "good death," is a complex and controversial ethical and legal issue revolving around the deliberate ending of a person's life to relieve suffering. It is often a topic of intense debate within medical, legal, religious, and ethical circles.
Types of Euthanasia:
Voluntary Euthanasia: This occurs when a competent person makes a voluntary and informed decision to end their life with the assistance of a medical professional or loved one.
Non-voluntary Euthanasia: In this scenario, the decision to end a person's life is made by someone other than the individual, typically when they are unable to make decisions for themselves due to being in a coma or having advanced dementia.
Involuntary Euthanasia: This is the termination of a person's life against their will or without their consent, often performed in situations where the person's suffering is deemed unbearable or where their quality of life is deemed too low by others.
Assisted Suicide: This involves providing a person with the means or information necessary to end their own life, such as prescribing lethal medication, while the individual ultimately carries out the act themselves.
Ethical Considerations:
Autonomy vs. Sanctity of Life: Supporters of euthanasia argue for individual autonomy and the right to die with dignity, while opponents often cite the sanctity of life and the potential for abuse or slippery slope arguments.
Quality of Life: Discussions often revolve around the subjective nature of suffering and the quality of life, with some arguing that euthanasia can alleviate unnecessary suffering, while others raise concerns about the potential devaluation of certain lives.
Medical Ethics: Euthanasia raises questions about the role of healthcare professionals in end-of-life care, the distinction between killing and allowing to die, and the obligations of physicians to relieve suffering while upholding ethical principles.
Legal Status:
The legality of euthanasia varies greatly around the world. Some countries, such as the Netherlands, Belgium, and Canada, have legalized certain forms of euthanasia under strict conditions, while others, including many U.S. states, maintain its illegality. In some regions, there are ongoing debates and court cases seeking to clarify or change existing laws.
Conclusion:
Euthanasia remains a deeply divisive and emotionally charged issue, touching on fundamental questions about life, death, autonomy, and suffering. As medical technology advances and societal attitudes evolve, discussions surrounding euthanasia are likely to persist, challenging individuals, communities, and policymakers to navigate the complexities of this sensitive topic with compassion and integrity.
Management of locally advanced ovarian, fallopian tube, and peritoneal tumors requires a comprehensive and multidisciplinary approach. Locally advanced tumors are those that have spread beyond the ovaries or fallopian tubes and may involve nearby structures, such as the peritoneum or adjacent organs. Here's a brief overview of the management strategies:
Surgery:
Debulking Surgery: The primary treatment for locally advanced tumors involves cytoreductive or debulking surgery. This aims to remove as much of the tumor as possible. Surgeons may perform a total hysterectomy, bilateral salpingo-oophorectomy, and removal of involved peritoneal tissues.
Lymphadenectomy: Lymph node dissection is often done to assess the extent of the disease spread and to remove involved lymph nodes.
Chemotherapy:
Neoadjuvant Chemotherapy: In some cases, chemotherapy may be administered before surgery to shrink the tumor, making surgery more effective.
Adjuvant Chemotherapy: Following surgery, chemotherapy is typically recommended to target any remaining cancer cells. Platinum-based chemotherapy regimens are commonly used.
Targeted Therapies:
PARP Inhibitors: Poly (ADP-ribose) polymerase inhibitors, such as olaparib and niraparib, have shown efficacy in treating ovarian and related cancers with specific genetic mutations, like BRCA mutations.
Immunotherapy:
Checkpoints Inhibitors: Immune checkpoint inhibitors, like pembrolizumab and nivolumab, may be considered in cases with specific molecular profiles.
Radiation Therapy:
External Beam Radiation: In some situations, radiation therapy may be used to target specific areas affected by the tumor.
Clinical Trials:
Participation in clinical trials may be an option for patients with locally advanced disease, offering access to innovative treatments and therapies.
Follow-up Care:
Regular monitoring and follow-up care are crucial to assess treatment effectiveness and detect any signs of recurrence.
Palliative Care:
Palliative care should be integrated into the management plan to address symptom control, improve quality of life, and provide support for both the patient and their family.
A personalized treatment plan should be developed based on the specific characteristics of the tumor, the patient's overall health, and individual factors. Regular communication among a multidisciplinary team, including surgeons, medical oncologists, radiation oncologists, and other specialists, is essential for optimizing the management of locally advanced ovarian, fallopian tube, and peritoneal tumors.
BREAST CANCER: systemic treatment HER 2 Neu pptxDr. Sumit KUMAR
Metastatic breast cancer, specifically HER2-positive subtype, represents an advanced stage of breast cancer characterized by the presence of human epidermal growth factor receptor 2 (HER2) overexpression. HER2-positive breast cancer tends to be more aggressive, but advancements in treatment options have significantly improved outcomes.
Targeted therapies play a crucial role in managing metastatic HER2-positive breast cancer. Trastuzumab (Herceptin) and pertuzumab are monoclonal antibodies that specifically target the HER2 protein, inhibiting its activity and impeding cancer cell growth. These drugs are often used in combination with chemotherapy to enhance their effectiveness.
In addition to trastuzumab and pertuzumab, other HER2-targeted therapies such as ado-trastuzumab emtansine (Kadcyla) and lapatinib may be employed in certain cases. Ado-trastuzumab emtansine is an antibody-drug conjugate that delivers chemotherapy directly to HER2-positive cancer cells, minimizing damage to healthy cells. Lapatinib, on the other hand, is a small molecule inhibitor that blocks HER2 and other related receptors.
Given the chronic nature of metastatic breast cancer, treatment plans are often individualized based on the patient's overall health, specific characteristics of the cancer, and prior treatments. Hormone therapy may also be considered if the cancer is hormone receptor-positive. Clinical trials and ongoing research continue to explore novel treatment options, providing hope for further advancements in managing HER2-positive metastatic breast cancer. Patients are encouraged to work closely with their healthcare team to determine the most appropriate and effective treatment plan tailored to their unique circumstances.
1) Neoadjuvant chemotherapy (NACT) involves administering chemotherapy before surgery to reduce morbidity and mortality from surgery and increase the likelihood of a complete resection of disease.
2) NACT is recommended for patients with clinically unresectable epithelial ovarian cancer or those who are poor surgical candidates due to comorbidities.
3) After 3 cycles of NACT, patient response is evaluated with imaging and surgery is performed if resection is possible; if disease has progressed, further chemotherapy is recommended.
Non-clear cell renal cell carcinoma (RCC) encompasses diverse subtypes, each requiring tailored therapeutic approaches. Papillary RCC may benefit from immunotherapy or vascular endothelial growth factor receptor (VEGFR) inhibitors. Chromophobe RCC often sees mTOR inhibitors or VEGFR inhibitors as initial treatments. For collecting duct and renal medullary carcinomas, cytotoxic chemotherapy is recommended.
Translocation RCC may respond well to lenvatinib plus pembrolizumab, while unclassified RCC patients might consider immunotherapy-based regimens. Sarcomatoid features in non-clear cell RCC lean towards immunotherapy.
Clinical trials are encouraged due to limited high-quality data, emphasizing the need for personalized strategies based on histologic subtypes. Overall, these recommendations aim to optimize outcomes in the diverse landscape of non-clear cell RCC.
Renal cell carcinoma (RCC) often presents with vague symptoms in its early stages, and patients may remain asymptomatic. As the disease progresses, common clinical features may include:
Hematuria: Blood in the urine is a common sign, often presenting as either visible blood or microscopic hematuria.
Flank Pain: Discomfort or pain in the side or lower back, potentially associated with tumor expansion or pressure on surrounding structures.
Palpable Abdominal Mass: A palpable lump or mass in the abdomen may be felt during a physical examination.
Weight Loss and Fatigue: Advanced stages may lead to unintended weight loss and fatigue.
Paraneoplastic Syndromes: Some RCCs produce hormones or cytokines, leading to paraneoplastic syndromes, such as elevated erythropoietin levels causing polycythemia.
Pathology:
Histological Subtypes: Clear cell, papillary, chromophobe, and other rare subtypes exist. Clear cell is the most common and typically associated with worse prognosis.
Genetic and Molecular Alterations: Mutations in tumor suppressor genes (e.g., VHL, PBRM1, BAP1), chromosomal deletions, and alterations in cellular pathways contribute to RCC development.
Tumor Grading: Fuhrman grade and ISUP grading system assess tumor differentiation, with higher grades indicating a poorer prognosis.
Tumor Necrosis: Histologic coagulative tumor necrosis is an independent predictor of outcome.
Imaging:
CT Scan: High-resolution computed tomography (CT) imaging is the primary modality for RCC diagnosis and staging, providing detailed visualization of the tumor, surrounding structures, and potential metastases.
MRI: Magnetic resonance imaging (MRI) offers additional soft tissue contrast and is particularly useful for characterizing renal masses.
Ultrasound: Ultrasound may be used for initial assessment and is effective in detecting solid masses but may have limitations in characterizing complex lesions.
Nuclear Medicine: Positron emission tomography (PET) scans can be used for staging and detecting distant metastases.
Prognosis:
TNM Staging: The tumor, node, metastasis (TNM) staging system stratifies patients based on the extent of disease.
Anatomic Factors: Invasion into the renal vein or inferior vena cava, perinephric fat extension, and involvement of the urinary collecting system impact prognosis.
Histopathological Factors: Clear cell histology, higher tumor grade, and tumor necrosis are associated with a worse prognosis.
Molecular Markers: Various molecular markers, genetic alterations, and gene expression profiles can provide additional prognostic information.
Survival Rates: Prognosis varies widely, with early-stage disease having better survival rates compared to advanced stages. Advances in targeted therapies and immunotherapy have improved outcomes for some patients with advanced RCC.
Osteoradionecrosis is a severe complication arising from head and neck radiotherapy. Mainly affecting the posterior mandible, it often manifests in molars and premolars. Common risk factors include high radiation doses, teeth extractions, and smoking. In the context of treatment, ORN can be categorized into four grades (1-4) based on severity.
Key Points:
Incidence: Occurs in approximately 7.5% of cases, with a median onset time of 8 months post-radiotherapy.
Risk Factors:
Higher incidence with elevated mean radiation doses to the mandible.
Smoking and pre-radiotherapy dental extractions significantly increase the risk.
Treatment Approaches:
Conservative management for early stages.
Surgical interventions include sequestrectomy (Stage 2) and, in severe cases, resection (Stage 3, involving mandibulectomy).
Hyperbaric oxygen therapy may aid in non-healing cases.
Prevention:
Precise dose planning tailored to individual patients crucial for minimizing risks.
Consideration of patient-specific factors, such as smoking and dental history, in treatment planning.
ORN underscores the importance of meticulous treatment planning and individualized approaches to minimize this debilitating complication.
- Borderline ovarian tumors, also known as tumors of low malignant potential, are noninvasive epithelial ovarian neoplasms with an intermediate behavior between benign cystadenomas and invasive carcinomas.
- They account for 14-15% of primary ovarian neoplasms and are most commonly serous histology. The majority are diagnosed at stage I and have an excellent prognosis with five-year survival rates of 99% for stage I disease.
- Treatment involves surgical staging and tumor debulking. For apparent unilateral stage I disease, conservative surgery such as salpingo-oophorectomy may be considered. Bilateral salpingo-oophorectomy is recommended for bilateral tumors. Chemotherapy is not routinely used except in
Definition: Small cell lung carcinoma (SCLC) is a type of lung cancer that typically starts in the bronchi (large airways) and tends to grow and spread quickly. It accounts for approximately 10-15% of all lung cancers.
Characteristics: SCLC is characterized by small, oat-shaped cancer cells that rapidly divide and form large tumors. It is often associated with a history of smoking and has a strong correlation with tobacco exposure.
Aggressive nature: SCLC is considered highly aggressive, with a tendency to metastasize (spread) early to the lymph nodes and other distant parts of the body, such as the liver, bones, and brain. This rapid spread makes early detection and treatment crucial.
Limited and extensive stage: SCLC is classified into two stages: limited stage and extensive stage. Limited stage means the cancer is confined to one side of the chest and potentially adjacent lymph nodes, whereas extensive stage indicates that the cancer has spread beyond the chest to distant organs.
Treatment approach: The treatment of SCLC typically involves a combination of chemotherapy and radiation therapy. Surgery is generally not recommended for SCLC due to its aggressive nature and tendency to spread early. Chemotherapy, often in combination with immunotherapy, is the mainstay of treatment and can help shrink tumors and control the disease.
Prognosis: The prognosis for SCLC is generally poorer compared to non-small cell lung carcinoma (NSCLC) due to its more aggressive behavior and earlier metastasis. However, treatment advances and research efforts continue to improve outcomes for SCLC patients.
Supportive care: As with any cancer diagnosis, supportive care plays a critical role in managing SCLC. This includes addressing symptoms, managing pain, providing emotional support, and ensuring optimal quality of life for patients.
It's important to consult with healthcare professionals for an accurate diagnosis, personalized treatment plan, and ongoing monitoring for individuals suspected or diagnosed with small cell lung carcinoma.
Definition: Peritoneal mesothelioma is a rare cancer that develops in the lining of the abdomen, known as the peritoneum. It is primarily caused by exposure to asbestos fibers.
Symptoms: Common symptoms include abdominal pain, swelling, changes in bowel habits, unexplained weight loss, and fatigue. However, these symptoms can be nonspecific and resemble other gastrointestinal conditions, which can make diagnosis challenging.
Diagnosis: Diagnosis involves a combination of imaging tests, such as CT scans and MRIs, as well as biopsies to confirm the presence of peritoneal mesothelioma. These tests help determine the extent and stage of the disease.
Treatment options: The management of peritoneal mesothelioma often involves a multimodal approach, tailored to the individual case. Treatment options may include surgery, chemotherapy, and heated intraperitoneal chemotherapy (HIPEC).
Surgical interventions: Cytoreductive surgery aims to remove visible tumors from the abdomen, including affected organs and tissues. It is often performed in combination with HIPEC, a procedure where heated chemotherapy drugs are circulated in the abdominal cavity to target any remaining cancer cells.
Chemotherapy: Systemic chemotherapy, given intravenously or orally, may be used before or after surgery to help shrink tumors, kill cancer cells, and prevent their spread. In some cases, intraperitoneal chemotherapy (IPC) may be used instead of HIPEC.
Palliative care: Palliative care focuses on providing relief from symptoms and improving the quality of life for patients. It may involve pain management, nutritional support, and psychological support for both the patient and their loved ones.
Diagnosis: Prompt and accurate diagnosis is crucial. It involves imaging tests such as X-rays, CT scans, and MRIs, as well as biopsies to confirm the presence of pleural mesothelioma.
Treatment options: The management of pleural mesothelioma typically involves a multidisciplinary approach, which may include surgery, chemotherapy, and radiation therapy. The choice of treatment depends on the stage and extent of the disease, as well as the patient's overall health.
Surgical interventions: Surgical options may include pleurectomy/decortication (removal of the affected tissue lining the lungs) or extrapleural pneumonectomy (removal of the affected lung, lining, and nearby structures). These procedures aim to remove as much of the cancerous tissue as possible.
Chemotherapy: Chemotherapy drugs are often used to kill or slow the growth of cancer cells. They can be administered orally or through intravenous infusions. Sometimes, chemotherapy is given before surgery to shrink tumors and after surgery to target any remaining cancer cells.
Radiation therapy: This treatment involves the use of high-energy X-rays or other radiation sources to target and destroy cancer cells. It can be used before or after surgery, or as a standalone treatment to alleviate symptoms and manage the disease.
Palliative care: Palliative care focuses on improving the quality of life for patients by managing pain, reducing symptoms, and providing emotional and psychological support. It can be integrated into the treatment plan at any stage of the disease.
Systemic treatment in advanced hepatocellular carcinoma (HCC) refers to the use of medications or therapies that are administered throughout the body to target cancer cells beyond the liver. HCC is the most common type of liver cancer and often presents at an advanced stage, making systemic therapies crucial in managing the disease.
One of the main categories of systemic treatment for advanced HCC is targeted therapies. Targeted therapies are designed to selectively inhibit specific molecules or pathways involved in tumor growth, thereby blocking the signals that support cancer cell survival and proliferation. Sorafenib and lenvatinib are examples of targeted therapies that have been approved for the first-line treatment of advanced HCC. They target vascular endothelial growth factor (VEGF) receptors, which play a key role in promoting the growth of new blood vessels necessary for tumor growth. By inhibiting these receptors, these drugs can help slow down tumor growth and improve patient outcomes.
In addition to sorafenib and lenvatinib, other targeted therapies have shown promising results in the treatment of advanced HCC. Regorafenib, for instance, is a multi-kinase inhibitor that targets several pathways involved in tumor angiogenesis, cell proliferation, and survival. Cabozantinib is another multi-kinase inhibitor that has been approved as a second-line treatment option for patients who have progressed on or are intolerant to prior systemic therapy. These targeted therapies have demonstrated efficacy in improving overall survival and delaying disease progression in patients with advanced HCC.
Another significant advancement in systemic treatment for advanced HCC is the use of immune checkpoint inhibitors. Immunotherapy has revolutionized cancer treatment in recent years, including for HCC. Immune checkpoint inhibitors, such as nivolumab and pembrolizumab, work by blocking proteins that act as checkpoints on immune cells, such as programmed cell death protein 1 (PD-1) or its ligand (PD-L1). By doing so, these drugs help restore and enhance the immune system's ability to recognize and eliminate cancer cells. Checkpoint inhibitors have shown promising results, with some patients experiencing durable responses and improved overall survival.
Hepatocellular carcinoma (HCC), the most common form of primary liver cancer, presents with various clinical features that can help diagnose and stage the disease. These features, along with imaging studies and laboratory tests, aid in determining the extent and severity of HCC. Here are the key clinical features and staging considerations:
Clinical Features:
Abdominal Pain: HCC can cause pain or discomfort in the upper right abdomen due to liver enlargement or tumor growth.
Jaundice: Yellowing of the skin and eyes (jaundice) may occur when the tumor affects liver function or obstructs the bile ducts.
Weight Loss: Unintentional weight loss may result from factors such as decreased appetite or cancer-related wasting.
Fatigue and Weakness: HCC patients often experience persistent fatigue and generalized weakness.
Loss of Appetite and Nausea: HCC can lead to reduced appetite, resulting in nausea and vomiting.
Abdominal Swelling: Ascites, the accumulation of fluid in the abdomen, may cause abdominal distension and discomfort.
Enlarged Liver: As HCC progresses, the liver may become palpable due to its enlargement and the presence of a tumor.
Staging: HCC staging helps determine the extent and spread of the cancer, guiding treatment decisions. The most commonly used staging system for HCC is the Barcelona
Systemic treatment in advanced hepatocellular carcinoma (HCC) refers to the use of medications or therapies that are administered throughout the body to target cancer cells beyond the liver. HCC is the most common type of liver cancer and often presents at an advanced stage, making systemic therapies crucial in managing the disease.
One of the main categories of systemic treatment for advanced HCC is targeted therapies. Targeted therapies are designed to selectively inhibit specific molecules or pathways involved in tumor growth, thereby blocking the signals that support cancer cell survival and proliferation. Sorafenib and lenvatinib are examples of targeted therapies that have been approved for the first-line treatment of advanced HCC. They target vascular endothelial growth factor (VEGF) receptors, which play a key role in promoting the growth of new blood vessels necessary for tumor growth. By inhibiting these receptors, these drugs can help slow down tumor growth and improve patient outcomes.
In addition to sorafenib and lenvatinib, other targeted therapies have shown promising results in the treatment of advanced HCC. Regorafenib, for instance, is a multi-kinase inhibitor that targets several pathways involved in tumor angiogenesis, cell proliferation, and survival. Cabozantinib is another multi-kinase inhibitor that has been approved as a second-line treatment option for patients who have progressed on or are intolerant to prior systemic therapy. These targeted therapies have demonstrated efficacy in improving overall survival and delaying disease progression in patients with advanced HCC.
Another significant advancement in systemic treatment for advanced HCC is the use of immune checkpoint inhibitors. Immunotherapy has revolutionized cancer treatment in recent years, including for HCC. Immune checkpoint inhibitors, such as nivolumab and pembrolizumab, work by blocking proteins that act as checkpoints on immune cells, such as programmed cell death protein 1 (PD-1) or its ligand (PD-L1). By doing so, these drugs help restore and enhance the immune system's ability to recognize and eliminate cancer cells. Checkpoint inhibitors have shown promising results, with some patients experiencing durable responses and improved overall survival.
Selective alpha1 blockers are Prazosin, Terazosin, Doxazosin, Tamsulosin and Silodosin majorly used to treat BPH, also hypertension, PTSD, Raynaud's phenomenon, CHF
Nutritional deficiency Disorder are problems in india.
It is very important to learn about Indian child's nutritional parameters as well the Disease related to alteration in their Nutrition.
TEST BANK For Brunner and Suddarth's Textbook of Medical-Surgical Nursing, 14...Donc Test
TEST BANK For Brunner and Suddarth's Textbook of Medical-Surgical Nursing, 14th Edition (Hinkle, 2017) Verified Chapter's 1 - 73 Complete.pdf
TEST BANK For Brunner and Suddarth's Textbook of Medical-Surgical Nursing, 14th Edition (Hinkle, 2017) Verified Chapter's 1 - 73 Complete.pdf
TEST BANK For Brunner and Suddarth's Textbook of Medical-Surgical Nursing, 14th Edition (Hinkle, 2017) Verified Chapter's 1 - 73 Complete.pdf
A congenital heart defect is a problem with the structure of the heart that a child is born with.
Some congenital heart defects in children are simple and don't need treatment. Others are more complex. The child may need several surgeries done over a period of several years.
Part III - Cumulative Grief: Learning how to honor the many losses that occur...bkling
Cumulative grief, also known as compounded grief, is grief that occurs more than once in a brief period of time. As a person with cancer, a caregiver or professional in this world, we are often met with confronting grief on a frequent basis. Learn about cumulative grief and ways to cope with it. We will also explore methods to heal from this challenging experience.
Applications of NMR in Protein Structure Prediction.pptxAnagha R Anil
This presentation explores the pivotal role of Nuclear Magnetic Resonance (NMR) spectroscopy in predicting protein structures. It delves into the methodologies, advancements, and applications of NMR in determining the three-dimensional configurations of proteins, which is crucial for understanding their function and interactions.
congenital GI disorders are very dangerous to child. it is also a leading cause for death of the child.
this congenital GI disorders includes cleft lip, cleft palate, hirchsprung's disease etc.
Congestive Heart failure is caused by low cardiac output and high sympathetic discharge. Diuretics reduce preload, ACE inhibitors lower afterload, beta blockers reduce sympathetic activity, and digitalis has inotropic effects. Newer medications target vasodilation and myosin activation to improve heart efficiency while lowering energy requirements. Combination therapy, following an assessment of cardiac function and volume status, is the most effective strategy to heart failure care.
Pharmacology of Drugs for Congestive Heart Failure
Breast cancer :Receptor (ER/PR/HER2 NEU) Discordance.pptx
1. DR SUMIT KUMAR
Assistant professor
NEIGRIHMS, Shillong
? Mechanism
? After neoadjuvant chemotherapy
?After neoadjuvant endocrine therapy
?At the time of recurrence / metastasis
? After neoadjuvant her2 neu inhibitor
2. Prevalence of ERα+ Breast Cancer: ERα+ breast cancer accounts for 75% of all breast cancer cases,
with half also expressing PgR, forming HR-positive breast cancer.
Function of Estrogen Receptors: ERα promotes cancer cell growth through activation of genomic
and non-genomic pathways. ERβ can modulate ERα activity and counteract its effects.
Hormone Receptor (HR) Status: HR status, determined by ERα and PgR expression, is a key
prognostic and predictive factor in breast cancer.
HER2/neu Receptor: HER2/neu is another critical receptor in breast cancer. Overexpression or
amplification of HER2 is found in approximately 15-20% of breast cancers and is associated with
aggressive disease.
Significance of HR and HER2 Status: HR-positive breast cancer is associated with lower
proliferation rates, longer disease-free survival (DFS), and overall survival (OS). HER2-positive
cancers benefit from targeted therapies but are generally more aggressive.
3. Endocrine Therapy (ET): ETs, such as tamoxifen, fulvestrant, and aromatase inhibitors, target ERα
signaling and are standard treatments for HR+ breast cancer.
HER2-Targeted Therapies: HER2-positive cancers are treated with targeted therapies like
trastuzumab and pertuzumab, which specifically inhibit HER2 signaling.
Receptor Discordance: Changes in receptor status (e.g., from HR+ to HR− or HER2− to HER2+) can
occur during disease progression, impacting treatment decisions.
Mechanisms of Discordance: Receptor discordance can result from genetic mutations, epigenetic
modifications, and selective pressure from treatments.
Clinical Impact of Discordance: Regular reassessment of receptor status is essential to guide therapy
adjustments and improve patient outcomes, emphasizing the importance of advanced molecular
profiling to tailor personalized treatment strategies.
7. • Encodes Estrogen Receptor Alpha
(ERα).
• Domains: AF1, DNA-binding (DBD),
Ligand-binding (LBD), AF2, Hinge.
• Binds estrogens (E2), homodimerizes,
and attaches to estrogen-responsive
elements (EREs) to activate gene
transcription.
Genetic Alterations:
• Mutations, deletions, insertions, loss
of heterozygosity (LOH).
• Can lead to functional loss and
therapy resistance.
•Encodes Progesterone Receptor (PgR)
with isoforms A and B.
•PgR expression is regulated by ERα.
• PgR-A: Repressor
• PgR-B: Activator
Genetic Alterations:
• LOH occurs in 18-40% of ERα+ breast
cancers.
• Often leads to loss of PgR expression
8. • Modulation: Cyclic
methylation/demethylation controls ERα
levels.
• Inhibition: Methylation blocks
transcription factors like AP2, preventing
ESR1 transcription.
• Complex Formation: ZEB1 with DNMT3B
and HDAC1 induces hypermethylation and
histone deacetylation, tightening
chromatin and reducing transcription.
•Repression: Loss of ERα signaling
decreases PGR transcription.
•Mechanism: Involves polycomb
repressors, histone deacetylases, and
promoter methylation.
•Impact: Hyper-methylation at key
sites occurs in ~40% of PgR- breast
cancers, leading to loss of PgR
expression.
Epigenetics involves changes in gene expression without altering the DNA sequence, primarily through mechanisms
like DNA methylation and histone modification, which regulate how genes are turned on or off.
These epigenetic changes contribute to hormone receptor loss and breast cancer progression.
9. • Growth factor signaling involves proteins (growth factors) that bind to receptors on the
cell surface, triggering a cascade of intracellular events that promote cell growth,
proliferation, and survival.
• The PI3K/AKT/mTORC1 and MAPK signaling pathways negatively correlate with ERα
expression. Loss of PTEN, an inhibitor of PI3K/AKT/mTORC1, is linked to the loss of ERα
and PgR in breast cancer.
• Around 30-40% of sporadic breast cancers show PTEN loss of heterozygosity (LOH), associated
with higher tumor grades and PgR loss.
with growth factors like IGF-I, EGF, and heregulin downregulates
PGR mRNA and PgR protein in cell lines.
result in MAPK hyperactivation and ERα downregulation.
HER2+ breast cancers express lower ERα levels and show resistance to endocrine
therapies without HER2 inhibition due to HER2-mediated signaling through
PI3K/AKT/mTORC1 and MAPK pathways.
leads to lower ESR1 gene expression in ERα+ PgR− cell
lines, but inhibition of this pathway can restore ERα expression, demonstrating its
reversible nature.
• NFkB, often constitutively active in ERα− breast cancers, correlates with lower ERα levels.
Its activation, possibly due to MAPK hyperactivation or PI3K/AKT/mTORC1 signaling,
further contributes to ERα downregulation.
10. • ESR1 mRNA is 4.3 kb long and contains a 3' untranslated region (UTR) with
AU-rich sequences that promote mRNA degradation.
• Changes in ESR1 mRNA structure can impact the translation of ERα,
though the exact mechanisms are still being studied.
• MicroRNAs (miRNAs) are small RNA molecules that regulate gene
expression. For instance:
• miR-222/221 targets ESR1 mRNA, leading to its degradation. Levels of these miRNAs
are higher in ERα− breast cancer cells compared to ERα+ cells.
• miR-206 and miR-92 also influence ERα and ERβ levels by binding to their respective
mRNA 3' UTRs.
• miR-27a targets ZBTB10, a protein involved in directly regulating ERα expression in
HR+ breast cancer cell lines.
• These miRNAs play a crucial role in fine-tuning ERα expression post-
transcriptionally, contributing to the complex regulation of hormone
receptor levels in breast cancer.
11. :
• ERα undergoes polyubiquitination and subsequent degradation via the ubiquitin
proteasome system (UPS) when bound to estradiol (E2).
• This process is mediated by E2-ERα complex binding to estrogen responsive
elements (EREs), recruiting E3-ubiquitin ligases.
• Selective estrogen receptor degraders (SERDs) like fulvestrant exploit ERα
polyubiquitination for therapeutic benefit in HR+/HER2− breast cancer.
Phosphorylation at specific residues modulates ERα ubiquitination:
• SRC-induced phosphorylation at Y537 residue promotes ERα ubiquitination and
degradation.
• Phosphorylation by GSK3, LMTK3, and ABL stabilizes ERα and enhances its
transcriptional activity.
12. :
• MUC1 stabilizes ERα binding to ERE promoters, enhancing ERα-induced gene
transcription; its knockdown reduces ERα levels in HR+ breast cancer cells.
• PIN1 inhibits ERα degradation by preventing E3 ligase interaction.
• RB protein interacts with ERα to regulate its stability; RB loss correlates with reduced
ERα levels in breast cancer cells.
• HSP90 and p23 chaperones protect ERα from UPS-mediated degradation.
• RNF31 mediates ERα monoubiquitination, stabilizing ERα and enhancing its activity.
• Palmitoylation stabilizes ERα and promotes its localization to the cell membrane,
activating oncogenic signaling.
These diverse post-translational modifications and interactions finely
regulate ERα levels and activity in breast cancer, impacting response to
hormonal therapies and disease progression.
13. Hypoxia in tumors results from rapid growth and poor vascularization.
• It promotes tumor cell growth, alters metabolism, and facilitates metastasis.
• Impact on ERα Expression:
• In HR+ breast cancer:
• Hypoxia reduces ERα protein levels by promoting its degradation via the proteasome.
• HIF-1α, a key regulator in hypoxia, may inhibit ESR1 gene transcription, contributing to
decreased ERα levels (Figure 1).
Research Challenges and Perspectives:
• The relationship between HIF-1α signaling and ERα expression needs
further clarification.
• Understanding hypoxia's influence on ERα sheds light on its role in breast
cancer progression and resistance to therapies.
14. • BRCA1 interacts with RNA polymerase II.
• Activates ESR1 gene transcription by binding to its promoter and recruiting Oct1.
• Loss of BRCA1 function leads to reduced ERα protein levels.
• Despite ERα-positive status, tumors may exhibit lower ERα expression due to
impaired transcriptional activation by BRCA1.
• BRCA1 promotes PgR protein degradation via ubiquitination.
• Induces chromatin silencing at PgR-regulated promoters through the BRCA1/BARD1
complex.
• BRCA gene mutations disrupt normal transcriptional regulation of hormone
receptors.
• Resultant hormone receptor discordance impacts treatment response and tumor
behavior.
15. • Definition: Accumulation of genetic mutations over time leading to the emergence of distinct tumor cell subclones.
• Impact: Results in variability in hormone receptor expression (e.g., ERα, PgR) among tumor cells within the same lesion.
• Changes: Alterations in DNA methylation and histone modifications.
• Effect: Influence gene expression patterns, contributing to phenotypic diversity including hormone receptor status.
• Factors: Variations in oxygen levels (hypoxia), nutrient availability, and pH within the tumor microenvironment.
• Contribution: Influence cellular behavior, survival, and adaptation of different tumor cell populations.
• Presence: Subpopulations of CSCs with self-renewal and differentiation capabilities.
• Role: Contribute to intratumoral heterogeneity by giving rise to diverse progeny with varying hormone receptor expression.
• Spatial Variability: Uneven distribution of tumor cells with different molecular profiles within the tumor mass.
• Temporal Changes: Dynamic alterations in molecular features over the course of tumor progression and treatment.
16. • The transition from HR negative to positive status in breast cancer
management can occur through several mechanisms, although it is generally
less common than the opposite scenario (HR positive to negative).
• some mechanisms that can contribute to this phenomenon:
Definition: Breast tumors are composed of heterogeneous cell populations. During
treatment, some HR-positive cells may survive while HR-negative cells are eliminated.
Mechanism: Chemotherapy or endocrine therapy can exert selective pressure on tumor
cells. HR-positive cells, which may have inherent or acquired resistance mechanisms,
survive treatment while HR-negative cells are eradicated.
Changes: Alterations in DNA methylation patterns or histone modifications.
Effect: These epigenetic modifications can potentially lead to reactivation of HR genes
(ESR1 for ERα or PGR for PgR), thereby switching the phenotype from HR-negative to
HR-positive.
Endocrine Therapy: Treatment with hormonal therapies (e.g., tamoxifen, aromatase
inhibitors) can alter the hormonal environment within the tumor.
Effect: This can influence the expression and activity of hormone receptors in surviving
tumor cells, potentially leading to a change in HR status from negative to positive.
17. Stromal Influences: Changes in the tumor microenvironment, such as interactions with immune cells or
fibroblasts, can impact tumor cell phenotype.
Induction: Certain signals within the microenvironment may induce or suppress the expression of
hormone receptors in tumor cells.
Acquisition of Mutations: Rarely, genetic mutations or alterations may occur during treatment that lead
to activation of HR genes in previously HR-negative cells.
Selective Advantage: Cells with these mutations may gain a growth advantage under the selective
pressure of therapy.
Diverse Cell Populations: Tumors are composed of heterogeneous cell populations with varying
molecular characteristics.
Survival of Subpopulations: HR-positive cells may exist as minor subpopulations within a predominantly
HR-negative tumor mass. Treatment can selectively eliminate HR-negative cells, allowing HR-positive
cells to proliferate and dominate the residual tumor.
Summary: Transition from HR-negative to HR-positive status during breast cancer management is a complex process
involving clonal selection, epigenetic changes, hormonal environment alterations, interactions with the tumor
microenvironment, genetic mutations, and intra-tumor heterogeneity. While less common than the reverse transition,
understanding these mechanisms can inform strategies for monitoring and managing breast cancer, particularly in cases
where HR status conversion impacts treatment decisions.
18. Data Details
Prognostic Impact of HR Loss
Conversion from ERα+ to ERα- status associated with a 48%
increase in risk of death compared to stable ERα+ status (HR
= 1.48, 95% CI 1.08-2.05).
PgR Loss and Clinical Behaviour
Loss of PgR in tumors with high ERα associated with more
aggressive behavior and resistance to SERMs.
Discordance Between Diagnostic and Surgical Samples
Low discordance rates: ERα 1.8%, PgR 15% between core
needle biopsy (CNB) and surgical samples in early-stage
breast cancer.
Discordance in Lymph Node Metastases
Rare discordance: ERα between primary tumors and axillary
lymph node metastases (2/50, 4%).
Technical Challenges in HR Assessment
Variability due to sampling methods (CNB vs. surgical
resection), delays in fixation, and IHC staining
reproducibility.
Standardization of HR Assessment
Improved reliability in determining ERα and PgR status with
standardized IHC techniques.
Impact of Decalcification on HR Assessment
Potential alteration of HR expression in bone metastases
due to decalcification of biopsy samples.
19. • Hormone Receptor (HR) status, including ER and PgR, is crucial in guiding
breast cancer treatment.
• HR status can change between primary and recurrent/metastatic tumors.
• Reassessment of HR status is important to tailor treatment plans and
improve patient outcomes.
• HR discordance rates between primary and recurrent/metastatic breast
cancer:
• ER status conversion: 14-24%
• PgR status conversion: 33%
• Discordance can involve conversion from HR+ to HR- or from HR- to HR+.
20. • HR status should be reassessed at the first recurrence or progression.
• Regular reassessment is recommended during subsequent progressions if clinically
indicated.
• Endocrine Therapy:
• Tamoxifen and aromatase inhibitors can lead to changes in ER and PgR expression.
• Neoadjuvant endocrine therapy may reduce ERα and PgR levels.
• Chemotherapy:
• Anthracyclines and taxanes have been associated with reductions in PgR expression
and changes in ER levels.
• Chemotherapy-induced epigenetic modifications may lead to HR status changes.
21. • Recommend biopsy of at least one metastatic site to reassess HR and HER2
status at first recurrence or progression.
• Suggest reevaluating ER, PgR, and HER2 status at recurrence or metastasis.
• Recommend mandatory reassessment of HR and HER2 status in metastatic
disease.
• Practical Considerations
• Use validated IHC techniques for HR testing.
• Ensure proper tissue handling and fixation.
• A multidisciplinary approach is essential for accurate interpretation and
treatment planning.
22.
23. HER2 Status in Breast Cancer: HER2 status is crucial for determining
treatment strategies and prognosis in breast cancer.
Definition of HER2 Discordance: Change in HER2 status between
primary and recurrent/metastatic tumors.
• Positive to Negative: Loss of HER2 expression in recurrent/metastatic tumors
previously HER2-positive.
• Negative to Positive: Gain of HER2 expression in recurrent/metastatic tumors
previously HER2-negative.
Importance of Discordance
• Impact on Treatment: Changes in HER2 status can lead to different
therapeutic approaches.
• Prognostic Value: Discordance can influence patient outcomes and guide
clinical decisions.
24. Primary mechanisms that can lead to changes in HER2 status from
positive to negative and vice versa
Mechanism Positive to Negative HER2 Neu Negative to Positive HER2 Neu
Tumor Heterogeneity
Loss of HER2 expression in some tumor
regions leading to overall negative status
Gain of HER2 expression in previously
HER2-negative regions
Clonal Evolution
Treatment pressure selecting for clones
without HER2 amplification
Emergence of new clones with HER2
amplification
Epigenetic Changes
DNA methylation silencing HER2 gene
expression
Epigenetic reprogramming leading to HER2
gene expression
Technical Factors
Variability in biopsy sampling, testing
techniques, and tissue handling leading to
misclassification
Initial false-negative result corrected upon
retesting
Genetic Instability
Mutations leading to loss of HER2 gene or
its expression
New mutations activating HER2 gene
Treatment-Induced Changes
Anti-HER2 therapies causing
downregulation or loss of HER2 expression
Other treatments reducing competition,
allowing HER2-expressing cells to
proliferate
Environmental Factors
Changes in tumor microenvironment
inhibiting HER2 expression
Changes in microenvironment favoring
HER2 expression
Loss of HER2 Gene Genetic deletion or loss of the HER2 gene Genetic amplification of the HER2 gene
25. : Reduction in HER2 protein expression while retaining ERBB2 gene amplification.
• Induction by Anti-HER2 Agents: Drugs like trastuzumab cause HER2 internalization and downregulation at
the membrane level.
1. Untreated HER2-Positive Tumors:
• HER2 gene amplification increases receptor expression.
• Promotes dimerization and activation of MAPK and PI3K/AKT/mTOR pathways.
2. Immune Cell Role:
• HER2 downregulation observed with trastuzumab when immune cells are involved.
• Interferon gamma (IFN-γ) from immune cells activates STAT1, leading to HER2 downregulation.
3. Combination Therapies:
• Trastuzumab and pertuzumab dual blockade increases HER2 downregulation.
• ADCs like trastuzumab emtansine (T-DM1) also induce downregulation, possibly leading to resistance.
4. Tyrosine Kinase Inhibitors (TKIs):
• TKIs prevent HER2 internalization, increasing surface HER2 expression.
• Combining TKIs with anti-HER2 antibodies enhances antitumor activity.
26. ?
• Definition: Variability in HER2 expression within different areas of the same tumor.
2009: HER2 heterogeneity defined as 5%-50% tumor cells with:
• Ratio ≥ 2.2 (dual probes) or ≥ 6 HER2 signals/cell (single probes).
2013 Update: Adjusted cut-off to 10% and ratio to 2.0.
1.Filho et al. (2018):
• Evaluated 164 patients treated with T-DM1 and pertuzumab.
• Found 10% of samples were heterogeneous.
• Heterogeneous tumors had no complete response to treatment, while 55% of non-
heterogeneous tumors did.
• Most heterogeneous cases were IHC 2+ and ER-positive.
2.Caswell-Jin et al. (2019):
• Used whole-exome sequencing before and after treatment.
• Found new mutations in post-treatment samples, not present before treatment.
• Indicates resistant cells were selected by the treatment.
27. : HER2-Enriched (HER2-E) to Luminal A after neoadjuvant treatment
Cause: Decreased expression of cell proliferation genes post-treatment exposure
• Initially utilized microarray analysis (400+ genes)
• Currently employs PAM50 classifier for tumor subtyping
:
1. Neoadjuvant Treatment Studies:
• Significant subtype switch observed in many patients across different drug regimens
• HER2-E tumors frequently switch to Luminal A
2. Brasó-Maristany et al.:
• Subtype switch can be reversible after stopping anti-HER2 therapy
3. Pernas et al.:
• In a cohort of 26 patients with residual disease post-treatment:
• 81.8% HER2-E tumors switched to non-HER2-E subtypes
• 7 out of 26 patients converted to HER2-negative status
30. :
• Heterogeneity: I2 = 79%, p < 0.0001
• Primary vs. Distant Metastases: 41 (95% CI: 37–45)
• Primary vs. Loco-regional Relapse: 26 (95% CI: 21–32)
• Heterogeneity: I2 = 77%, p < 0.0001
• Primary vs. Distant Metastases: 10 (95% CI: 7–14)
• Primary vs. Loco-regional Relapse: 6 (95% CI: 3–9)
• IHC and FISH: 10 (95% CI: 7–12)
• IHC Only: 5 (95% CI: 2–8)
• Total Studies: 48
• Total Patients: 9926
31.
32. Implications
• Discordance rates highlight variability in receptor status between primary breast tumors and distant metastases across different sites.
• ER and PR discordance rates were significantly higher in bone and liver metastases compared to CNS metastases.
• HER2 discordance did not show statistically significant differences among the analyzed metastatic sites due to limited data availability.
33. Alterations in ER, PR, and HER2 following NACT vary widely.
• ER changes: 5–23%; PR changes: 14.5–67%.
• HER2 changes less frequently, loss more common than gain.
• Triple negative is most stable;
• ER/HER2-positive show highest change rates.
• Neoadjuvant endocrine therapy less common, PR changes up to 40%.
• Post-NACT ER or HER2 positive can initiate endocrine or anti-HER2 therapy,
but trial evidence is lacking.
34.
35.
36. Study/Trial ER Changes PR Changes
IMPACT Trial
More responders to anastrozole or tamoxifen with
higher baseline ER levels (p = 0.02)
Ellis et al.
No response of ER low expressors to tamoxifen;
some ER low tumors responded to letrozole
Small Study (23 patients)
Minimal to no change in ER status following
anastrozole treatment
Significant reduction in PR expression in 17/18
patients, 11 switched to PR−
National Nagasaki Medical Center
ER expression slightly reduced after NAET in 14.5% of
cases
PR expression loss in 40.1% of cases treated with
NAET vs. 8.2% with NACT
PALLET Trial
Non-significant changes in ER expression after 14
weeks of letrozole or letrozole + palbociclib
Significant reductions in PR expression (geomeans
PR: −96.4% vs. −94.9%)
PROACT Trial
5/40 anastrozole treated and 20/37 tamoxifen
treated tumors switched from ER+ to ER−
16/17 tumors switched from PR+ to PR− with
anastrozole; only 1/11 with tamoxifen
UK Retrospective Study (132 samples)
Only one tumor (0.7%) switched to ER− profile;
minimal changes in Allred score
Highly significant change in PR expression; 12.7%
switched from positive to negative
37. Category Details
Study Design
Retrospective analysis of breast cancer patients undergoing
neoadjuvant dual HER2-targeted therapy
Sample Size 163 female patients
HER2 Status Post-Therapy
- HER2 IHC 3+
36 patients; 12 remained IHC 3+, 9 evolved to IHC 2+ with
amplification, 9 evolved to IHC 2+ without amplification, 4 evolved
to IHC 1+, 2 evolved to IHC 0
- HER2 IHC 2+ with amplification
22 patients; 7 remained IHC 2+ with amplification, 4 evolved to IHC
3+, 4 evolved to IHC 2+ without amplification, 4 evolved to IHC 1+
without amplification, 2 evolved to IHC 1+ with amplification, 1
evolved to IHC 0
- HER2 NR with amplification
3 patients; 2 evolved to IHC 3+, 1 evolved to IHC 2+ without
amplification
Residual HER2 Status Breakdown 36 HER2-positive (59%), 24 HER2-low (36%), 3 HER2-ultralow (5%)
table focusing on the study design, sample size, and HER2 status after dual HER2-targeted therapy:
38. • Discordance in ER, PR, and HER2 status between primary and metastatic breast
cancer lesions is a significant clinical challenge.
• These changes influence treatment decisions and patient outcomes, necessitating
tailored therapeutic strategies.
• Conversion from ER/PR-positive to negative status is associated with reduced
responsiveness to endocrine therapies, impacting treatment efficacy and patient
survival.
• HER2-negative conversions limit the efficacy of HER2-targeted therapies, affecting
treatment outcomes adversely.
• Conversion from negative to positive ER/PR status correlates with improved overall
survival and treatment response.
• Conversely, conversion from positive to negative status may increase mortality risks
due to reduced treatment options and poorer prognosis.
39. • According to NCCN and ESMO guidelines, regular reassessment of ER, PR, and HER2
status is recommended at recurrence or progression to guide treatment decisions
effectively.
• Biomarker testing should be integrated into clinical practice to adapt therapies based
on updated receptor profiles and patient responses.
• Understanding the molecular mechanisms underlying receptor discordance is crucial
for refining treatment strategies and predicting therapeutic outcomes.
• Ongoing research aims to identify biomarkers and develop imaging techniques that
enhance the detection and monitoring of heterogeneous breast cancer subtypes.
• Incorporating advanced diagnostic tools and personalized medicine approaches is
essential for optimizing treatment outcomes and patient care in breast cancer.
• Continued collaboration between clinicians, researchers, and industry stakeholders is
needed to advance precision oncology and improve patient survival.
40.
41. • The ESR1 and PGR promoters undergo cyclic methylation and demethylation of
CpG dinucleotides, modulating ERα and PgR levels in HR+ breast cancer cells.
Methylation of the ESR1 promoter prevents transcription factors like AP2 from
binding, inhibiting ESR1 transcription. Zinc-finger E-box binding homeobox 1
(ZEB1) forms a complex with DNA methyltransferase (DNMT)3B and histone
deacetylase 1 (HDAC1) on the ESR1 promoter, leading to its hypermethylation.
Increased histone deacetylation further limits ESR1 transcription by condensing
nucleosome structure.
• The loss of ERα signaling also represses PGR transcription, involving polycomb
repressors, histone deacetylases, and PGR promoter methylation. Notably, three
methylation-sensitive sites in the PGR CpG islands are unmethylated in normal
breast tissue and PgR+ breast cancers but are hypermethylated in about 40% of
PgR- breast cancers. This hypermethylation is linked to a lack of PgR expression,
highlighting the role of epigenetic changes in hormone receptor loss and breast
cancer progression.
42. • The ESR1 gene on chromosome 6q25.1 encodes the estrogen receptor alpha
(ERα). ERα includes several domains: AF1, DNA-binding domain (DBD),
ligand-binding domain (LBD), AF2, and a flexible hinge domain. ERα binds
estrogens (E2), homodimerizes, and attaches to estrogen-responsive
elements (EREs) to activate gene transcription for cell growth and
proliferation.
• Genetic alterations in ESR1, such as mutations, deletions, insertions, and
loss of heterozygosity (LOH), can affect ERα function. While many alterations
do not cause loss of ERα expression, some, like homozygous deletions or
inactivating mutations, lead to functional loss and therapy resistance.
• The PGR gene on chromosome 11q22-23 encodes the progesterone
receptor (PgR) with isoforms A and B. PgR expression is regulated by ERα,
with PgR-A acting as a repressor and PgR-B as an activator. Genetic
alterations in PGR, including LOH, occur in 18-40% of ERα+ breast cancers
and often lead to loss of PgR expression.
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