Metastatic Breast Cancer, which is classified as Stage IV breast cancer, is the most severe stage of the disease, in which the cancerous cells have spread from the breast tumor and invaded other body regions. Protheragen offers comprehensive services spanning the entire preclinical therapeutics development pipeline for metastatic breast cancer, from target identification and validation to preclinical testing.
Overview of Metastatic Breast Cancer
Metastatic Breast Cancer refers to the most advanced stage of breast cancer, where cancer cells spread from the breast to other organs like the lungs, liver, bones, and brain. This type of cancer is very difficult to control due to its high rate of progression and refractoriness to standard care. Even with remarkable progress in the diagnosis and management of breast cancer, Metastatic Breast Cancer is still one of the most common causes of cancer death in women. The metastatic process consists of a cascade of sophisticated biological activities, which encompasses local invasion, intravasation into blood or lymphatic vessels, circulation, extravasation, and colonization of new remote sites in distant tissues. Comprehending these processes is essential to designing efficient preclinical therapeutics.
Fig.1 The various mechanisms and factors inducing the metastasis of breast cancer. (Park M.,
et al., 2022)
Pathogenesis of Metastatic Breast Cancer
The metastatic cascade of breast cancer is driven by a confluence of genetic, epigenetic, and environmental factors. Key pathogenic mechanisms include:
- Epithelial-Mesenchymal Transition (EMT): EMT, or epithelial-to-mesenchymal transition, entails the loss of epithelial cell characteristics like polarity and intercellular adhesion, along with the gain of migratory and invasive mesenchymal traits. Stem cell-like features are acquired along with therapy resistance due to the action of SNAIL, TWIST, and ZEB, which regulate EMT processes.
- Tumor Microenvironment (TME): The immune components, matrix fibroblasts, and extracellular matrix form the tumor microenvironment (TME), which plays a critical role in the evolution of cancer. Cancer-associated fibroblasts (CAFs) and tumor-associated macrophages (TAMs) are able to enhance the survival, proliferation, and metastatic potential of cancer cells through the secretion of cytokines and other growth factors.
- Epigenetic Changes: Unsurprisingly, metastasis is associated with changes in the epigenome, such as methylation of particular DNA sequences and modification of the associated histones–these processes today are known to change gene expression. One such example involves hypermethylation of suppressor genes, which further fuels cancer development.
- Cancer Stem Cells (CSCs): CSCs, identified by markers like CD44+/CD24-/low and ALDH1, possess self-renewal abilities and survive typical treatments, aiding in metastasis and recurrence.
Diagnostics Development for Metastatic Breast Cancer
Genomic Profiling
The complete examination of genetic changes within cancer cells, which includes mutations, amplifications, and deletions, is termed genomic profiling. The identification of specific genetic changes, such as PIK3CA mutations and BRCA 1/2 mutations, which assist in the customization of therapeutic regimens, is made possible through Next Generation Sequencing (NGS) technologies.
Proteomic Analysis
In cancer cells, proteins are identified and quantified using proteomic methods such as mass spectrometry. This technique assists in the development of protein biomarkers that may signify metastatic diseases and assess the extent of monitoring therapeutic responsiveness. For instance, identification of overexpressed proteins like HER2 aids in the decision-making regarding targeted therapy.
Therapeutics Development for Metastatic Breast Cancer
- Targeted Therapies
MBC has targeted therapies that seek to interrupt particular molecular pathways critical to its development. For instance, the use of trastuzumab and pertuzumab for HER2-positive Metastatic Breast Cancer is a paradigm shift in how Metastatic Breast Cancer is managed. The use of endocrine therapy together with palbociclib and ribociclib as CDK4/6 inhibitors has also markedly improved results in HR positive, HER2-negative Metastatic Breast Cancer.
- Immunotherapies
Both atezolizumab and pembrolizumab are immune checkpoint inhibitors (ICIs) which, along with other immunotherapies, are effective for metastatic breast cancer when used alongside chemotherapy. ICIs destroy the suppressive signals on T cells, which boosts the T cells' ability to recognize and obliterate tumor cells.
Table 1. The FDA-approved drugs for primary and metastatic breast cancer. (Park M., et al., 2022)
| Primary/Metastasis |
Drug Name |
Subtype |
Effect |
| Primary |
Paclitaxel |
Taxanes |
Inhibit the proliferation of cancer cells by promoting the polymerization of microtubules in cells |
| Belinostat |
Histone deacetylase inhibitor (HDACi) |
Epidrug; Treatment of peripheral T-cell lymphoma |
| Tocilizumab (actemra) |
Monoclonal Ab |
IL-6 inhibitors; Inhibit the formation of cancer stem cells in TNBC cells |
| 5-azacitidine |
DNA methyltransferase inhibitor (DNMTi) |
Epidrug; Treatment of myelodysplastic syndrome |
| Metastasis |
Doxorubicin |
Anthracyclins |
Interfering with direct apoptotic effects and DNA local isomerase II action |
| Vorinostat |
Histone deacetylase inhibitor (HDACi) |
Epidrug; Treatment of cutaneous T-cell lymphoma |
| Cyclophosphamide |
Alkylating agents |
Changes in active or inactive metabolites in the body and anticancer effects of phosphoramide mustard |
| Atezolizumab+Paclitaxel |
Monoclonal Ab |
Prolongs progression-free survival in patients with PD-L1-positive breast cancer; Inhibition of metastatic TNBC targeting PD-L1 |
| Zemetostat |
Histone methyltransferase inhibitor (HMTi, EZH1i) |
Epidrug; Treatment of epithelioid sarcoma, relapsed or refractory follicular lymphoma |
| Methotrexate |
Antimetabolites |
Inhibit nucleotide synthesis; increase AICAR concentration |
| Trastuzumab |
Monoclonal antibody |
Targets the HER2/neu receptor on cancer cells |
| Tivozanib |
Tyrosine kinase inhibitor (TKI) |
Inhibitors of VEGF/VEGFR; Inhibits angiogenesis |
| Lapatinib |
Tyrosine kinase inhibitor (TKI) |
Signal transduction inhibitors of epidermal growth factor receptor (EGFR) and human epidermal receptor type 2 (HER2) |
| Pertuzumab |
Monoclonal antibody |
Targets the HER2/neu receptor; induces antibody-dependent cell-mediated cytotoxicity (ADCC) |
| Palbociclib |
Antineoplastic agents |
CDK4/6 inhibitor; prevents cells from moving from the G1 to the S cell cycle phase during division |
| Epirubicin |
Anthracyclines |
An epimer of doxorubicin; blocks the synthesis of nucleic acids and proteins by inserting planar rings between nucleotide base pairs |
Disclaimer: Protheragen focuses on providing preclinical research services. This table is for information exchange purposes only. This table is not a treatment plan recommendation. For guidance on treatment options, please visit a regular hospital.
Our Services
Protheragen offers comprehensive services for the development of diagnostics and therapeutics for metastatic breast cancer. Our services encompass a wide range of preclinical research activities, from target identification and validation to the development of novel biomarkers and therapeutic agents. We leverage cutting-edge technologies and expertise to provide tailored solutions for our clients, ensuring that their research and development efforts are supported by robust scientific data and innovative approaches.
Diagnostics Development
- Karyotype Analysis Service
- Omics Analysis Service
- Biomarker Development Service
- Artificial Intelligence Service
Therapeutic Development
- Anticancer Peptide
- Gene Therapy
- Immunotherapy
- Monoclonal Antibody
- Phytotherapy
- Small Molecule Drug
- Therapeutic Cancer Vaccine
Disease Models
- 4T1 Cell Line Allograft Models
- MDA-MB-231 Line Xenograft Models
- BRCA1 and TP53 Genetically Engineered Mouse (GEM) Models
- Large Animal Models
Protheragen's advantage lies in our ability to provide integrated and customized solutions for the development of diagnostics and therapeutics for metastatic breast cancer. If you are interested in our services, please feel free to contact us.
References
- Park, Misung, et al. "Breast cancer metastasis: mechanisms and therapeutic implications." International journal of molecular sciences 23.12 (2022): 6806.
- Gennari, Alessandra, et al. "ESMO Clinical Practice Guideline for the diagnosis, staging and treatment of patients with metastatic breast cancer☆." Annals of oncology 32.12 (2021): 1475-1495.
All of our services and products are intended for preclinical research use only and cannot be used to diagnose, treat or manage patients.
