Diagram showing most common sites breast cancer spreads to CRUK 169

Metastatic breast cancer, also referred to as

metastases Metastasis is a pathogenic agent's spread from an initial or primary site to a different or secondary site within the host's body; the term is typically used when referring to metastasis by a cancerous tumor. The newly pathological sites, then, ...

, advanced breast cancer, secondary tumors, secondaries or stage IV breast cancer, is a stage of

breast cancer Breast cancer is cancer that develops from breast tissue. Signs of breast cancer may include a lump in the breast, a change in breast shape, dimpling of the skin, milk rejection, fluid coming from the nipple, a newly inverted nipple, or a re ...

where the breast cancer cells have spread to distant sites beyond the

axillary lymph nodes The axillary lymph nodes or armpit lymph nodes are lymph nodes in the human armpit. Between 20 and 49 in number, they drain lymph vessels from the lateral quadrants of the breast, the superficial lymph vessels from thin walls of the chest and th ...

. There is no cure for metastatic breast cancer; there is no stage after IV. Metastases can occur several years after the primary breast cancer, although it is sometimes diagnosed at the same time as the primary breast cancer or, rarely, before the primary breast cancer has been diagnosed. Metastatic breast cancer cells frequently differ from the preceding primary breast cancer in properties such as receptor status. The cells have often developed resistance to several lines of previous treatment and have acquired special properties that permit them to metastasize to distant sites. Metastatic breast cancer can be treated, sometimes for many years, but it cannot be cured. Distant metastases are the cause of about 90% of deaths due to breast cancer. Breast cancer can metastasize anywhere in body but primarily metastasizes to the

bone A bone is a Stiffness, rigid Organ (biology), organ that constitutes part of the skeleton in most vertebrate animals. Bones protect the various other organs of the body, produce red blood cell, red and white blood cells, store minerals, provid ...

lung The lungs are the primary organs of the respiratory system in humans and most other animals, including some snails and a small number of fish. In mammals and most other vertebrates, two lungs are located near the backbone on either side of t ...

s, regional

lymph node A lymph node, or lymph gland, is a kidney-shaped organ of the lymphatic system and the adaptive immune system. A large number of lymph nodes are linked throughout the body by the lymphatic vessels. They are major sites of lymphocytes that inclu ...

liver The liver is a major Organ (anatomy), organ only found in vertebrates which performs many essential biological functions such as detoxification of the organism, and the Protein biosynthesis, synthesis of proteins and biochemicals necessary for ...

and

brain A brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. It is located in the head, usually close to the sensory organs for senses such as vision. It is the most complex organ in a v ...

, with the most common site being the bone. Treatment of metastatic breast cancer depends on location of the metastatic tumors and includes surgery, radiation, chemotherapy, biological, and hormonal therapy. Typical environmental barriers in a metastatic event include physical (a

basement membrane The basement membrane is a thin, pliable sheet-like type of extracellular matrix that provides cell and tissue support and acts as a platform for complex signalling. The basement membrane sits between Epithelium, epithelial tissues including mesot ...

), chemical (reactive oxygen species or ROS,

hypoxia Hypoxia means a lower than normal level of oxygen, and may refer to: Reduced or insufficient oxygen * Hypoxia (environmental), abnormally low oxygen content of the specific environment * Hypoxia (medical), abnormally low level of oxygen in the tis ...

and low pH) and biological (immune surveillance, inhibitory

cytokine Cytokines are a broad and loose category of small proteins (~5–25 kDa) important in cell signaling. Cytokines are peptides and cannot cross the lipid bilayer of cells to enter the cytoplasm. Cytokines have been shown to be involved in autocrin ...

s and regulatory extra-cellular matrix (ECM) peptides) components. Organ-specific anatomic considerations also influence metastasis; these include blood-flow patterns from the primary

tumor A neoplasm () is a type of abnormal and excessive growth of tissue. The process that occurs to form or produce a neoplasm is called neoplasia. The growth of a neoplasm is uncoordinated with that of the normal surrounding tissue, and persists ...

and the homing ability of

cancer Cancer is a group of diseases involving abnormal cell growth with the potential to invade or spread to other parts of the body. These contrast with benign tumors, which do not spread. Possible signs and symptoms include a lump, abnormal b ...

cells to certain tissues. The targeting by cancer cells of specific organs is probably regulated by chemo-attractant factors and adhesion molecules produced by the target organ, along with cell-surface receptors expressed by the tumor cells.

Symptoms

The symptoms produced by metastatic breast cancer vary by the location of the metastases. For instance: * Metastatic disease to the bone causes severe, progressive pain, and, less commonly, pathological fracture,

erythema Erythema (from the Greek , meaning red) is redness of the skin or mucous membranes, caused by hyperemia (increased blood flow) in superficial capillaries. It occurs with any skin injury, infection, or inflammation. Examples of erythema not assoc ...

over the affected bone, and swelling. * Metastatic breast cancer to the brain causes the following symptoms: persistent, progressively worsening headache, visual changes, seizures,

nausea Nausea is a diffuse sensation of unease and discomfort, sometimes perceived as an urge to vomit. While not painful, it can be a debilitating symptom if prolonged and has been described as placing discomfort on the chest, abdomen, or back of the ...

or vomiting,

vertigo Vertigo is a condition where a person has the sensation of movement or of surrounding objects moving when they are not. Often it feels like a spinning or swaying movement. This may be associated with nausea, vomiting, sweating, or difficulties w ...

, behavioral and personality changes, and increased

intracranial pressure Intracranial pressure (ICP) is the pressure exerted by fluids such as cerebrospinal fluid (CSF) inside the skull and on the brain tissue. ICP is measured in millimeters of mercury (mmHg) and at rest, is normally 7–15 Millimeter of mercury, mmHg ...

. * Metastatic disease to the liver causes jaundice, elevated liver enzymes, abdominal pain, loss of appetite, nausea, and vomiting * Metastatic breast cancer to the lung or pleura causes chronic cough,

dyspnea Shortness of breath (SOB), also medically known as dyspnea (in AmE) or dyspnoea (in BrE), is an uncomfortable feeling of not being able to breathing, breathe well enough. The American Thoracic Society defines it as "a subjective experience of brea ...

, abnormal chest X-ray, and chest pain. * Other nonspecific systemic symptoms of metastatic breast cancer include fatigue, malaise, weight loss, and poor appetite. *Sometimes people with metastatic breast cancer do not have any notable changes or symptoms.

Bone

Roughly 70% of all patients living with advanced

have bone metastases Very often bone metastases can be successfully managed for a long time.

Brain

Brain A brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. It is located in the head, usually close to the sensory organs for senses such as vision. It is the most complex organ in a v ...

metastasis Metastasis is a pathogenic agent's spread from an initial or primary site to a different or secondary site within the host's body; the term is typically used when referring to metastasis by a cancerous tumor. The newly pathological sites, then, ...

is observed in 10% of

patients with metastatic properties Many of the

therapies (like targeted

antibodies An antibody (Ab), also known as an immunoglobulin (Ig), is a large, Y-shaped protein used by the immune system to identify and neutralize foreign objects such as pathogenic bacteria and viruses. The antibody recognizes a unique molecule of the ...

) fail to penetrate the

blood–brain barrier The blood–brain barrier (BBB) is a highly selective semipermeable membrane, semipermeable border of endothelium, endothelial cells that prevents solutes in the circulating blood from ''non-selectively'' crossing into the extracellular fluid of ...

, hence allowing for tumor recurrence in the

central nervous system The central nervous system (CNS) is the part of the nervous system consisting primarily of the brain and spinal cord. The CNS is so named because the brain integrates the received information and coordinates and influences the activity of all par ...

Pathophysiology

The main steps involved in the metastatic cascade of a

cell are: *Cell division and growth within the primary

*Invasion of the primary tumor border (

, or BM) and the tissue surrounding the

by the cell *

Intravasation Intravasation is the invasion of cancer cells through the basement membrane into a blood or lymphatic vessel. Intravasation is one of several carcinogenic events that initiate the escape of cancerous cells from their primary sites. Other mechanisms ...

of the circulatory system: the cell enters the bloodstream or lymph channels. *The cell must survive the transit into the new environment, until it ultimately arrests in the microvasculature of the secondary site. *

Extravasation __NOTOC__ Extravasation is the leakage of a fluid out of its container into the surrounding area, especially blood or blood cells from vessels. In the case of inflammation, it refers to the movement of white blood cells from the capillaries to th ...

to a distant site : The cell then invades into the BM of the target tissue. *Proliferation of the cancer cell at the metastatic site *Formation of a

micrometastasis A micrometastasis is a small collection of cancer cells that has been shed from the original tumor and spread to another part of the body through the lymphovascular system. Micrometastases are too few, in size and quantity, to be picked up in a sc ...

inside the secondary site *Progressive colonization, forming a life-threatening metastasis The potential of a tumor cell to metastasize depends on its microenvironment, or “niche” interactions with local factors promoting tumor-cell growth, survival,

angiogenesis Angiogenesis is the physiological process through which new blood vessels form from pre-existing vessels, formed in the earlier stage of vasculogenesis. Angiogenesis continues the growth of the vasculature by processes of sprouting and splitting ...

, invasion and

. This is explained by the

seed and soil A seed is an embryonic plant enclosed in a protective outer covering, along with a food reserve. The formation of the seed is a part of the process of reproduction in seed plants, the spermatophytes, including the gymnosperm and angiosperm pl ...

hypothesis.

Extracellular matrix degradation in cancer

Cell-cell and cell-ECM matrix adhesion, motility, and localised

proteolysis Proteolysis is the breakdown of proteins into smaller polypeptides or amino acids. Uncatalysed, the hydrolysis of peptide bonds is extremely slow, taking hundreds of years. Proteolysis is typically catalysed by cellular enzymes called protease ...

are mediated mainly by

matrix metalloprotease Matrix metalloproteinases (MMPs), also known as matrix metallopeptidases or matrixins, are metalloproteinases that are calcium-dependent zinc-containing endopeptidases; other family members are adamalysins, serralysins, and astacins. The MMPs be ...

s (MMPs). Degradation of the extracellular matrix begins the process of metastasis. The cell develops structures called

invadopodia Invadopodia are actin-rich protrusions of the plasma membrane that are associated with degradation of the extracellular matrix in cancer invasiveness and metastasis. Very similar to podosomes, invadopodia are found in invasive cancer cells and are ...

, which are highly concentrated in several

proteases A protease (also called a peptidase, proteinase, or proteolytic enzyme) is an enzyme that catalyzes (increases reaction rate or "speeds up") proteolysis, breaking down proteins into smaller polypeptides or single amino acids, and spurring the for ...

and have a highly dynamic

actin Actin is a family of globular multi-functional proteins that form microfilaments in the cytoskeleton, and the thin filaments in muscle fibrils. It is found in essentially all eukaryotic cells, where it may be present at a concentration of over ...

cytoskeleton The cytoskeleton is a complex, dynamic network of interlinking protein filaments present in the cytoplasm of all cells, including those of bacteria and archaea. In eukaryotes, it extends from the cell nucleus to the cell membrane and is compos ...

. Mechanisms of

metalloprotease A metalloproteinase, or metalloprotease, is any protease enzyme whose catalytic mechanism involves a metal. An example is ADAM12 which plays a significant role in the fusion of muscle cells during embryo development, in a process known as myogen ...

action in

cell motility Motility is the ability of an organism to move independently, using metabolic energy. Definitions Motility, the ability of an organism to move independently, using metabolic energy, can be contrasted with sessility, the state of organisms th ...

involve: * Proteolytic cleavage of

growth factor A growth factor is a naturally occurring substance capable of stimulating cell proliferation, wound healing, and occasionally cellular differentiation. Usually it is a secreted protein or a steroid hormone. Growth factors are important for regu ...

s, so they are readily available to cells not in direct physical contact * Degradation of the ECM is facilitated by MMPs, so cells can move across tissues into nearby stroma. * Regulated receptor cleavage to modulate migratory signaling Most of these processes require a delicate balance between the functions of matrix metalloproteases (MMPs) or metalloprotease-disintegrins (ADAMs) and natural tissue inhibitors of metalloproteases ( TIMPs). Regulated

is an important mechanism to maintain

homeostasis In biology, homeostasis (British English, British also homoeostasis) Help:IPA/English, (/hɒmɪə(ʊ)ˈsteɪsɪs/) is the state of steady internal, physics, physical, and chemistry, chemical conditions maintained by organism, living systems. Thi ...

. There is increased expression of

protease A protease (also called a peptidase, proteinase, or proteolytic enzyme) is an enzyme that catalyzes (increases reaction rate or "speeds up") proteolysis, breaking down proteins into smaller polypeptides or single amino acids, and spurring the ...

systems in cancer cells, to equip them with the tools necessary to degrade the extracellular matrix and release

s or

transmembrane A transmembrane protein (TP) is a type of integral membrane protein that spans the entirety of the cell membrane. Many transmembrane proteins function as gateways to permit the transport of specific substances across the membrane. They frequentl ...

receptors Receptor may refer to: *Sensory receptor, in physiology, any structure which, on receiving environmental stimuli, produces an informative nerve impulse *Receptor (biochemistry), in biochemistry, a protein molecule that receives and responds to a n ...

. MMP-2 is upregulated in the

, and increased levels of

MMP-1 Interstitial collagenase, also known as fibroblast collagenase, and matrix metalloproteinase-1 (MMP-1) is an enzyme that in humans is encoded by the ''MMP1'' gene. The gene is part of a cluster of MMP genes which localize to chromosome 11q22.3. ...

and MMP-19 are observed in the

. This in turn, upregulates the signaling pathways necessary to provide increased

cell adhesion Cell adhesion is the process by which cells interact and attach to neighbouring cells through specialised molecules of the cell surface. This process can occur either through direct contact between cell surfaces such as cell junctions or indir ...

cell migration Cell migration is a central process in the development and maintenance of multicellular organisms. Tissue formation during embryonic development, wound healing and immune responses all require the orchestrated movement of cells in particular dire ...

, invasion, cancer-

cell proliferation Cell proliferation is the process by which ''a cell grows and divides to produce two daughter cells''. Cell proliferation leads to an exponential increase in cell number and is therefore a rapid mechanism of tissue growth. Cell proliferation re ...

and survival.

Extracellular matrix components

ECM-tumor cell interactions play a critical role in each of the events of the metastatic cascade. Interactions of the

cells with

integrin Integrins are transmembrane receptors that facilitate cell-cell and cell-extracellular matrix (ECM) adhesion. Upon ligand binding, integrins activate signal transduction pathways that mediate cellular signals such as regulation of the cell cycle, ...

fibronectin Fibronectin is a high- molecular weight (~500-~600 kDa) glycoprotein of the extracellular matrix that binds to membrane-spanning receptor proteins called integrins. Fibronectin also binds to other extracellular matrix proteins such as collage ...

laminin Laminins are a family of glycoproteins of the extracellular matrix of all animals. They are major components of the basal lamina (one of the layers of the basement membrane), the protein network foundation for most cells and organs. The laminins ...

collagen Collagen () is the main structural protein in the extracellular matrix found in the body's various connective tissues. As the main component of connective tissue, it is the most abundant protein in mammals, making up from 25% to 35% of the whole ...

hyaluronan Hyaluronic acid (; abbreviated HA; conjugate base hyaluronate), also called hyaluronan, is an anionic, nonsulfated glycosaminoglycan distributed widely throughout connective, epithelial, and neural tissues. It is unique among glycosaminoglycans ...

and

proteoglycan Proteoglycans are proteins that are heavily glycosylated. The basic proteoglycan unit consists of a "core protein" with one or more covalently attached glycosaminoglycan (GAG) chain(s). The point of attachment is a serine (Ser) residue to whic ...

s can contribute to the metastatic process. Some of these proteins are discussed here in relation to breast-cancer metastasis.

Fibrinogen-Integrin

Fibronectin Fibronectin is a high- molecular weight (~500-~600 kDa) glycoprotein of the extracellular matrix that binds to membrane-spanning receptor proteins called integrins. Fibronectin also binds to other extracellular matrix proteins such as collage ...

is an

extracellular This glossary of biology terms is a list of definitions of fundamental terms and concepts used in biology, the study of life and of living organisms. It is intended as introductory material for novices; for more specific and technical definitions ...

glycoprotein Glycoproteins are proteins which contain oligosaccharide chains covalently attached to amino acid side-chains. The carbohydrate is attached to the protein in a cotranslational or posttranslational modification. This process is known as glycos ...

that can bind to

s and other ECM components like

, fibrin and heparan sulphate proteoglycans(HSPGs). Several different

s bind to

. Fibronectin-integrin interactions are important in tumor

, invasion,

and cell proliferation by signaling through

s. Integrin-mediated tumor cell adhesion to ECM proteins can trigger signal transduction and cause upregulation of gene expression, increased tyrosine phosphorylytion of the

focal adhesion kinase PTK2 protein tyrosine kinase 2 (PTK2), also known as focal adhesion kinase (FAK), is a protein that, in humans, is encoded by the ''PTK2'' gene. PTK2 is a focal adhesion-associated protein kinase involved in cellular adhesion (how cells stick to ...

, and activation and nuclear translocation of

mitogen-activated protein A mitogen-activated protein kinase (MAPK or MAP kinase) is a type of protein kinase that is specific to the amino acids serine and threonine (i.e., a serine/threonine-specific protein kinase). MAPKs are involved in directing cellular responses ...

(MAP)

kinase In biochemistry, a kinase () is an enzyme that catalyzes the transfer of phosphate groups from high-energy, phosphate-donating molecules to specific substrates. This process is known as phosphorylation, where the high-energy ATP molecule don ...

Heparanase

Heparanase Heparanase, also known as HPSE, is an enzyme that acts both at the cell-surface and within the extracellular matrix to degrade polymeric heparan sulfate molecules into shorter chain length oligosaccharides. Synthesis and structure The protein ...

cleaves

heparin sulfate Heparan sulfate (HS) is a linear polysaccharide found in all animal tissues. It occurs as a proteoglycan (HSPG, i.e. Heparan Sulfate ProteoGlycan) in which two or three HS chains are attached in close proximity to cell surface or extracellular ma ...

chains of HSPGs, which have an extensive network with several proteins on the cell surface and ECM. The basic HSPG structure consists of a protein core to which several linear

(HS) chains are covalently O-linked; this acts as an assembly of different ECM proteins, including

s, interstitial

s, heparin-binding growth factors,

chemokine Chemokines (), or chemotactic cytokines, are a family of small cytokines or signaling proteins secreted by cells that induce directional movement of leukocytes, as well as other cell types, including endothelial and epithelial cells. In additio ...

s and

lipoprotein A lipoprotein is a biochemical assembly whose primary function is to transport hydrophobic lipid (also known as fat) molecules in water, as in blood plasma or other extracellular fluids. They consist of a triglyceride and cholesterol center, sur ...

s. HSPGs are prominent components of blood vessels. to HS stabilizes

fibroblast growth factor Fibroblast growth factors (FGF) are a family of cell signalling proteins produced by macrophages; they are involved in a wide variety of processes, most notably as crucial elements for normal development in animal cells. Any irregularities in the ...

s (FGFs) and

vascular endothelial growth factor Vascular endothelial growth factor (VEGF, ), originally known as vascular permeability factor (VPF), is a signal protein produced by many cells that stimulates the formation of blood vessels. To be specific, VEGF is a sub-family of growth factors, ...

s (VEGFs) and prevents them from inactivation. HS chains function as low-affinity co-receptors which promote dimerization of FGFs, aids in the sequestration of the

s (GFs) and causes activation of the signaling tyrosine kinase receptors even under low circulating concentrations of growth factors.

expressed by cancer cells participates in

and neovascularization by degrading the

polysaccharide Polysaccharides (), or polycarbohydrates, are the most abundant carbohydrates found in food. They are long chain polymeric carbohydrates composed of monosaccharide units bound together by glycosidic linkages. This carbohydrate can react with wa ...

scaffold of the endothelial BM, thereby releasing angiogenic growth factors from the ECM.

Tenascin

The ECM protein

tenascin C Tenascin C (TN-C) is a glycoprotein that in humans is encoded by the ''TNC'' gene. It is expressed in the extracellular matrix of various tissues during development, disease or injury, and in restricted neurogenic areas of the central nervous sys ...

(TNC) is up-regulated in metastatic breast cancer. TNC is an adhesion-modulating extracellular matrix

. It is highly expressed in tumor stroma and stimulates tumor-cell proliferation. It is hypothesised that TNC stimulates invasion via up-regulation of MMP-1 expression through activation of the

MAPK A mitogen-activated protein kinase (MAPK or MAP kinase) is a type of protein kinase that is specific to the amino acids serine and threonine (i.e., a serine/threonine-specific protein kinase). MAPKs are involved in directing cellular responses to ...

pathway. MMP-1 (

interstitial collagenase Interstitial collagenase, also known as fibroblast collagenase, and matrix metalloproteinase-1 (MMP-1) is an enzyme that in humans is encoded by the ''MMP1'' gene. The gene is part of a cluster of MMP genes which localize to 11q, chromosome 11q22 ...

) cleaves

collagen type I Type I collagen is the most abundant collagen of the human body. It forms large, eosinophilic fibers known as collagen fibers. It is present in scar tissue, the end product when tissue heals by repair, as well as tendons, ligaments, the endomys ...

, II, III, VII and X. Therefore,

over-expression can significantly alter

in the ECM and influence tumor cell migration in cartilaginous tissues.

Endoglin

Endoglin Endoglin (ENG) is a type I membrane glycoprotein located on cell surfaces and is part of the TGF beta receptor complex. It is also commonly referred to as CD105, END, FLJ41744, HHT1, ORW and ORW1. It has a crucial role in angiogenesis, therefore, ...

is a cell-surface disulfide-linked homodimeric

which binds to

integrins Integrins are transmembrane receptors that facilitate cell-cell and cell-extracellular matrix (ECM) adhesion. Upon ligand binding, integrins activate signal transduction pathways that mediate cellular signals such as regulation of the cell cycle, ...

and other RGD ligands and is a co-receptor for

TGF-beta Transforming growth factor beta (TGF-β) is a multifunctional cytokine belonging to the transforming growth factor superfamily that includes three different mammalian isoforms (TGF-β 1 to 3, HGNC symbols TGFB1, TGFB2, TGFB3) and many other sign ...

. Brain-metastatic breast-tumor cells express

endoglin Endoglin (ENG) is a type I membrane glycoprotein located on cell surfaces and is part of the TGF beta receptor complex. It is also commonly referred to as CD105, END, FLJ41744, HHT1, ORW and ORW1. It has a crucial role in angiogenesis, therefore, ...

in large amounts.

-overexpressing cells develop large numbers of invadopodia;

is localized in these structures.

expression in tumor cells contributes to metastasis by upregulating MMP-1 and MMP-19. MMP-19 cleaves components of the

basal lamina The basal lamina is a layer of extracellular matrix secreted by the epithelial cells, on which the epithelium sits. It is often incorrectly referred to as the basement membrane, though it does constitute a portion of the basement membrane. The ba ...

such as

collagen type IV Collagen IV (ColIV or Col4) is a type of collagen found primarily in the basal lamina. The type IV collagen C4 domain, collagen IV C4 domain at the C-terminus is not removed in post-translational processing, and the fibers link head-to-head, rathe ...

laminin 5 Laminins are a family of glycoproteins of the extracellular matrix of all animals. They are major components of the basal lamina (one of the layers of the basement membrane), the protein network foundation for most cells and organs. The laminins ...

nidogen Nidogens, formerly known as entactins, are a family of sulfated monomeric glycoproteins located in the basal lamina of ParaHoxozoa, parahoxozoans. Two nidogens have been identified in humans: nidogen-1 (NID1) and nidogen-2 (NID2). Remarkably, verteb ...

(entactin) and other ECM proteins such as

tenascin Tenascins are extracellular matrix glycoproteins. They are abundant in the extracellular matrix of developing vertebrate embryos and they reappear around healing wounds and in the stroma of some tumors. Types There are four members of the tenasc ...

aggrecan Aggrecan (ACAN), also known as cartilage-specific proteoglycan core protein (CSPCP) or chondroitin sulfate proteoglycan 1, is a protein that in humans is encoded by the ''ACAN'' gene. This gene is a member of the lectican (chondroitin sulfate prote ...

and

. Therefore,

over-expression alters the proteolytic balance of the cells to greater matrix degradation and increased invasive properties of breast cancer.

Mechanisms in bone metastases

The primary extracellular matrix components and cell-surface receptors which aid in

are: ;

Integrin Integrins are transmembrane receptors that facilitate cell-cell and cell-extracellular matrix (ECM) adhesion. Upon ligand binding, integrins activate signal transduction pathways that mediate cellular signals such as regulation of the cell cycle, ...

signalling:

αvβ3 (a cell-surface adhesion molecule) is important for tumor attachment, cell-to-cell communication between the breast tumor cells and the environment in bone,

osteoclast An osteoclast () is a type of bone cell that breaks down bone tissue. This function is critical in the maintenance, repair, and remodeling of bones of the vertebral skeleton. The osteoclast disassembles and digests the composite of hydrated pro ...

bone resorption and

. Integrin-mediated adhesion between

cells and

s in bone

induces

phosphorylation In chemistry, phosphorylation is the attachment of a phosphate group to a molecule or an ion. This process and its inverse, dephosphorylation, are common in biology and could be driven by natural selection. Text was copied from this source, wh ...

extracellular signal-regulated kinases In molecular biology, extracellular signal-regulated kinases (ERKs) or classical MAP kinases are widely expressed protein kinase intracellular signalling molecules that are involved in functions including the regulation of meiosis, mitosis, and p ...

(ERK1/2) in

osteoclasts An osteoclast () is a type of bone cell that breaks down bone tissue. This function is critical in the maintenance, repair, and remodeling of bones of the vertebral skeleton. The osteoclast disassembles and digests the composite of hydrated prote ...

, which in turn induces

differentiation and survival. ;

Cancer Cancer is a group of diseases involving abnormal cell growth with the potential to invade or spread to other parts of the body. These contrast with benign tumors, which do not spread. Possible signs and symptoms include a lump, abnormal b ...

cell-blood

platelet Platelets, also called thrombocytes (from Greek θρόμβος, "clot" and κύτος, "cell"), are a component of blood whose function (along with the coagulation factors) is to react to bleeding from blood vessel injury by clumping, thereby ini ...

interaction: Metastatic breast-cancer cells excrete

lysophosphatidic acid Lysophosphatidic acid (LPA) is a phospholipid derivative that can act as a signaling molecule. Function LPA acts as a potent mitogen due to its activation of three high-affinity G-protein-coupled receptors called LPAR1, LPAR2, and LPAR3 (also kn ...

(LPA) which binds to

on tumor cells, inducing cell proliferation and release of

cytokines Cytokines are a broad and loose category of small proteins (~5–25 kDa) important in cell signaling. Cytokines are peptides and cannot cross the lipid bilayer of cells to enter the cytoplasm. Cytokines have been shown to be involved in autocrin ...

( IL-6 and IL-8, potent bone resorptive agents) and stimulating bone resorption. After the breast-cancer cells have left the primary tumor, they interact with the bone microenvironment and secrete osteolytic factors capable of

formation and bone resorption. Apart from the breast tumor cells, the resident stromal cells also contribute to tumor survival. Growth factors such as

epidermal growth factor Epidermal growth factor (EGF) is a protein that stimulates cell growth and differentiation by binding to its receptor, EGFR. Human EGF is 6-k Da and has 53 amino acid residues and three intramolecular disulfide bonds. EGF was originally descr ...

(EGF),

(FGF) and

transforming growth factor Transforming growth factor (, or TGF) is used to describe two classes of polypeptide growth factors, TGFα and TGFβ. The name "Transforming Growth Factor" is somewhat arbitrary, since the two classes of TGFs are not structurally or genetically rel ...

beta (

TGF-β Transforming growth factor beta (TGF-β) is a multifunctional cytokine belonging to the transforming growth factor superfamily that includes three different mammalian isoforms (TGF-β 1 to 3, HGNC symbols TGFB1, TGFB2, TGFB3) and many other sign ...

) are implicated in the development and progression of metastatic breast cancer. ;Matrix metalloproteinases (MMPs): MMP-2 is the main metalloprotease secreted by breast-cancer cells or induced in the adjacent bone stroma; it plays an important role in the degradation of the extracellular matrix essential for metastasis. Tumor cells use MMP-2 secreted by bone marrow fibroblasts (BMFs). MMP-2 is stored in an inactive conformation in association with the cell surface (or extracellular matrix) of BMFs. Inactive MMP-2 present on the surface of BMFs is displaced by breast-cancer cells. Cancer cells can then use the proteinase to facilitate tissue invasion, which requires the degradation of

connective tissue Connective tissue is one of the four primary types of animal tissue, along with epithelial tissue, muscle tissue, and nervous tissue. It develops from the mesenchyme derived from the mesoderm the middle embryonic germ layer. Connective tiss ...

associated with vascular

s and interstitial connective tissue. MMP-2 is unlike other MMP's as its activity is modulated by metalloproteases called tissue inhibitor of metalloproteases (TIMP) and membrane type 1 MMP (Korhmann et at. 2009)

Mechanism in brain metastasis

The brain is a unique organ for metastasis, since the breast-tumor cells have to pass the

(BBB) to form micrometastases.

CD44

CD44 The CD44 antigen is a cell-surface glycoprotein involved in cell–cell interactions, cell adhesion and migration. In humans, the CD44 antigen is encoded by the ''CD44'' gene on chromosome 11. CD44 has been referred to as HCAM (homing cell adhesi ...

(a cell-surface transmembrane

) is a receptor for

hyaluronic acid Hyaluronic acid (; abbreviated HA; conjugate base hyaluronate), also called hyaluronan, is an anionic, nonsulfated glycosaminoglycan distributed widely throughout connective, epithelial, and neural tissues. It is unique among glycosaminoglycans ...

, involved in

by binding to specific extracellular matrix components. A proposed mechanism for the function of

is to regulate the adhesion of circulating cancer cells in the brain to the

endothelium The endothelium is a single layer of squamous endothelial cells that line the interior surface of blood vessels and lymphatic vessels. The endothelium forms an interface between circulating blood or lymph in the lumen and the rest of the vessel ...

at the secondary site with the help of a hyaluronate matrix ligand or by its cytoplasmic attachments to

-associated proteins of the

merlin Merlin ( cy, Myrddin, kw, Marzhin, br, Merzhin) is a mythical figure prominently featured in the legend of King Arthur and best known as a mage, with several other main roles. His usual depiction, based on an amalgamation of historic and le ...

ezrin Ezrin also known as cytovillin or villin-2 is a protein that in humans is encoded by the ''EZR'' gene. Structure The N-terminus of ezrin contains a FERM domain which is further subdivided into three subdomains. The C-terminus contain an ERM d ...

radixin Radixin is a protein that in humans is encoded by the ''RDX'' gene. Radixin is a cytoskeletal protein that may be important in linking actin to the plasma membrane. It is highly similar in sequence to both ezrin and moesin. The radixin gene has ...

moesin Moesin is a protein that in humans is encoded by the ''MSN'' gene. Moesin (for membrane-organizing extension spike protein) is a member of the ERM protein family which includes ezrin and radixin. ERM proteins appear to function as cross-linkers b ...

family.

Sialyl transferase (glycosylation modifications of gangliosides)

Cell-surface sialylation has been implicated in cell–to-cell interactions, and over-expression of a brain

sialyltransferase Sialyltransferases are enzymes that transfer sialic acid to nascent oligosaccharide. Each sialyltransferase is specific for a particular sugar substrate. Sialyltransferases add sialic acid to the terminal portions of the sialylated glycolipids ...

in breast-cancer cells is a mechanism highlighting the role of cell-surface

glycosylation Glycosylation is the reaction in which a carbohydrate (or ' glycan'), i.e. a glycosyl donor, is attached to a hydroxyl or other functional group of another molecule (a glycosyl acceptor) in order to form a glycoconjugate. In biology (but not al ...

in organ-specific metastatic interactions. Breast-cancer metastasis to the brain involves mediators of

extravasation __NOTOC__ Extravasation is the leakage of a fluid out of its container into the surrounding area, especially blood or blood cells from vessels. In the case of inflammation, it refers to the movement of white blood cells from the capillaries to th ...

through non-fenestrated capillaries, complemented by specific enhancers of BBB-crossing and brain colonization.

Seed and soil hypothesis

The "seed and soil" hypothesis states that specific organs harbor metastases from one type of

by stimulating their growth better than other types of cancer. This interaction is dynamic and reciprocal, since cancer cells modify the environment they encounter. Tumor embolus = seed and Target organ = soil.

Workup

In the detection of bone metastases,

skeletal scintigraphy A bone scan or bone scintigraphy is a nuclear medicine imaging technique of the bone. It can help diagnose a number of bone conditions, including cancer of the bone or metastasis, location of bone inflammation and fractures (that may not be vis ...

(bone scan) is very sensitive and is recommended as the first imaging study in asymptomatic individuals with suspected breast-cancer metastases. X-ray

radiography Radiography is an imaging technique using X-rays, gamma rays, or similar ionizing radiation and non-ionizing radiation to view the internal form of an object. Applications of radiography include medical radiography ("diagnostic" and "therapeut ...

is recommended if there is abnormal radionuclide uptake from the bone scan and in assessing the risk of

pathological fracture A pathologic fracture is a bone fracture caused by weakness of the bone structure that leads to decrease mechanical resistance to normal mechanical loads. This process is most commonly due to osteoporosis, but may also be due to other pathologies ...

s, and is recommended as the initial imaging study in patients with bone pain.

MRI Magnetic resonance imaging (MRI) is a medical imaging technique used in radiology to form pictures of the anatomy and the physiological processes of the body. MRI scanners use strong magnetic fields, magnetic field gradients, and radio waves ...

or the combination

PET-CT Positron emission tomography–computed tomography (better known as PET-CT or PET/CT) is a nuclear medicine technique which combines, in a single gantry, a positron emission tomography (PET) scanner and an x-ray computed tomography (CT) scann ...

may be considered for cases of abnormal radionuclide uptake on bone scan, when radiography does not give an acceptably clear result.

Treatment

Metastasis Metastasis is a pathogenic agent's spread from an initial or primary site to a different or secondary site within the host's body; the term is typically used when referring to metastasis by a cancerous tumor. The newly pathological sites, then, ...

is a complex and interconnected multi-step process. Each step in the process is a potential target for therapies to prevent or reduce

. Those steps which have a good clinical window are the best targets for therapy. Each event in metastasis is highly regulated and requires a synergistic activation of different ECM proteins,

growth factors A growth factor is a naturally occurring substance capable of stimulating cell proliferation, wound healing, and occasionally cellular differentiation. Usually it is a secreted protein or a steroid hormone. Growth factors are important for regu ...

and so on. Although the occasional patient with metastatic breast cancer benefits from surgical resection of an isolated metastasis and most patients receive radiotherapy (often for palliation alone) during the course of their disease, the treatment of metastatic breast carcinoma typically involves the use of systemic therapy. There is no sufficient evidence on the benefits and risks of breast surgery associated with systemic treatment for women diagnosed with metastatic breast cancer.

Chemotherapy

Chemotherapy Chemotherapy (often abbreviated to chemo and sometimes CTX or CTx) is a type of cancer treatment that uses one or more anti-cancer drugs (chemotherapeutic agents or alkylating agents) as part of a standardized chemotherapy regimen. Chemotherap ...

is one of the most important components of therapy for metastatic breast cancer. Therapy of choice is based on three variables; 1. the extent, pattern and aggressiveness at first presentation. 2. what stage of menopause the patient is at. 3. What receptor hormone the tumour has. Observation of metastases provides direct feedback on the effectiveness of the treatment and often a number of chemotherapy agents are tried sequentially to determine one that works. Adding one or more chemotherapy drugs to an established regimen in women with metastatic breast cancer gives greater tumour shrinkage on imaging but also increased toxicity. Combination chemotherapy is often used in patients with metastatic breast cancer. Research suggests no difference in overall survival time between sequential single agent chemotherapy and combination chemotherapy. Sequential single agent chemotherapy may have a more positive effect on progression-free survival. Taxanes are very active in metastatic breast cancer, and abraxane is approved for patients with metastatic breast cancer who either relapsed within six months of adjuvant chemotherapy or failed to respond to combination chemotherapy. This has a higher response rate than solvent-based

paclitaxel Paclitaxel (PTX), sold under the brand name Taxol among others, is a chemotherapy medication used to treat a number of types of cancer. This includes ovarian cancer, esophageal cancer, breast cancer, lung cancer, Kaposi's sarcoma, cervical cancer ...

(15% vs 8%). Abraxane can also deliver a 49% higher dose of medication than solvent-based paclitaxel; however, the side effects are severe and include

chemotherapy-induced peripheral neuropathy Chemotherapy-induced peripheral neuropathy (CIPN) is a nerve-damaging side effect of antineoplastic agents in the common cancer treatment, chemotherapy. CIPN afflicts between 30% and 40% of patients undergoing chemotherapy. Antineoplastic agents ...

. In women with metastatic breast cancer, taxane-containing chemotherapy regimens appear to improve survival and tumour shrinkage and decrease time to progression. Taxanes are associated with increased risk of neuro-toxicity and less nausea and vomiting when contrasted to non-taxane containing regimens.

Vinorelbine Vinorelbine (NVB), sold under the brand name Navelbine among others, is a chemotherapy medication used to treat a number of types of cancer. This includes breast cancer and non-small cell lung cancer. It is given by injection into a vein or by mou ...

is also active in metastatic breast cancer.

Eribulin Eribulin, sold under the brand name Halaven, is an anticancer medication used to treat breast cancer and liposarcoma. The most common side effects include fatigue, nausea, hair loss (alopecia), constipation, certain nerve damage causing weaknes ...

was approved in the US in Nov 2010. A

targeted therapy Targeted therapy or molecularly targeted therapy is one of the major modalities of medical treatment (pharmacotherapy) for cancer, others being hormonal therapy and cytotoxic chemotherapy. As a form of molecular medicine, targeted therapy blocks ...

drug, Kadcyla, was approved in February 2013. This

antibody-drug conjugate Antibody-drug conjugates or ADCs are a class of biopharmaceutical drugs designed as a targeted therapy for treating cancer. Unlike chemotherapy, ADCs are intended to target and kill tumor cells while sparing healthy cells. As of 2019, some 56 phar ...

targets only cancerous cells. It works by only releasing its toxic payload when triggered by a protein found in the cancerous cells in HER2+ breast cancer. It has extremely low side effects using this target therapy method. Platinum-containing chemotherapy regimens are known to be effective for treating a variety of different cancer types. In women with metastatic breast cancer who do not have triple negative disease, there is little or no survival benefit and excess toxicity from platinum-based regimens. However, in women with metastatic triple negative breast cancer, there may be a moderate survival benefit from platinum-based regimens. Antitumour antibiotics are also used in metastatic breast cancer. Antitumour antibiotics work to prevent cancer cells multiplying by damaging them. A meta-analysis has demonstrated that women taking antitumour antibiotics as part of their regimen had an advantage in time to progression and tumour shrinkage, but also increased side effect such as cardiotoxicity, leukopenia and nausea.

Tamoxifen and other anti-estrogens

For estrogen-receptor-positive metastatic breast carcinoma the first line of therapy is often

tamoxifen Tamoxifen, sold under the brand name Nolvadex among others, is a selective estrogen receptor modulator used to prevent breast cancer in women and treat breast cancer in women and men. It is also being studied for other types of cancer. It has b ...

or another anti-estrogen drug unless there are liver metastases, significant lung involvement, rapidly progressive disease or severe symptoms requiring immediate palliation.

Radiotherapy

Radiotherapy is used in the treatment of metastatic breast cancer. The most common reasons for a patient with metastatic breast carcinoma to be treated with radiotherapy are: *

Spinal cord compression Spinal cord compression is a form of myelopathy in which the spinal cord is compressed. Causes can be bone fragments from a vertebral fracture, a tumor, abscess, ruptured intervertebral disc or other lesion. When acute it can cause a medical ...

. Spinal-cord compression is an oncological emergency, as untreated spinal cord compression may cause permanent paralysis or death. In breast cancer, spinal-cord compression occurs when a bone metastasis or spinal metastasis begins to push on the spinal cord this results in inflammation and, if untreated, spinal cord injury. Radiotherapy is an important component of therapy for cord compression secondary to metastatic breast cancer, along with

corticosteroids Corticosteroids are a class of steroid hormones that are produced in the adrenal cortex of vertebrates, as well as the synthetic analogues of these hormones. Two main classes of corticosteroids, glucocorticoids and mineralocorticoids, are involve ...

and

laminectomy A laminectomy is a surgical procedure that removes a portion of a vertebra called the lamina, which is the roof of the spinal canal. It is a major spine operation with residual scar tissue and may result in postlaminectomy syndrome. Depending ...

. *Liver

. Typically, pain from liver metastases responds to chemotherapy and analgesia. However, in cases when chemotherapy is contraindicated or the liver metastases are refractory to chemotherapy (and pain medication fails to provide appropriate

palliation Palliative care (derived from the Latin root , or 'to cloak') is an interdisciplinary medical caregiving approach aimed at optimizing quality of life and mitigating suffering among people with serious, complex, and often terminal illnesses. Wit ...

of liver metastasis-related pain, radiotherapy should be considered; it may relieve pain and shrink the metastases, and perhaps extend survival in a subset of patients with a good response to radiotherapy. *Brain metastases. Brain metastases occur in up to 10–15% of breast-cancer patients, and often (but not always) occur late in the disease. They require urgent treatment; brain metastases may progress rapidly, and can suddenly produce life-threatening complications such as

increased intracranial pressure Intracranial pressure (ICP) is the pressure exerted by fluids such as cerebrospinal fluid (CSF) inside the skull and on the brain tissue. ICP is measured in millimeters of mercury (mmHg) and at rest, is normally 7–15 mmHg for a supine adult. Th ...

herniation of the brain Brain herniation is a potentially deadly side effect of very high pressure within the skull that occurs when a part of the brain is squeezed across structures within the skull. The brain can shift across such structures as the falx cerebri, the te ...

, and

seizures An epileptic seizure, informally known as a seizure, is a period of symptoms due to abnormally excessive or neural oscillation, synchronous neuronal activity in the brain. Outward effects vary from uncontrolled shaking movements involving much o ...

. Radiotherapy is essential in the treatment of

brain metastases A brain metastasis is a cancer that has metastasized (spread) to the brain from another location in the body and is therefore considered a secondary brain tumor. The metastasis typically shares a cancer cell type with the original site of the c ...

from breast cancer, as it halts tumor progression quickly and can induce a response in the majority of patients. *Bone metastases. The bones are a very common site of metastatic disease from breast cancer, and bone metastases can cause severe

pain Pain is a distressing feeling often caused by intense or damaging stimuli. The International Association for the Study of Pain defines pain as "an unpleasant sensory and emotional experience associated with, or resembling that associated with, ...

hypercalcemia Hypercalcemia, also spelled hypercalcaemia, is a high calcium (Ca2+) level in the blood serum. The normal range is 2.1–2.6 mmol/L (8.8–10.7 mg/dL, 4.3–5.2 mEq/L), with levels greater than 2.6 mmol/L defined as hypercalcemi ...

and pathologic fracture. Radiotherapy is indicated to prevent pathologic fracture; it is also part of postoperative treatment following repair of a pathologic fracture. Strontium 89, a

radiopharmaceutical Radiopharmaceuticals, or medicinal radiocompounds, are a group of pharmaceutical drugs containing radioactive isotopes. Radiopharmaceuticals can be used as diagnostic and therapeutic agents. Radiopharmaceuticals emit radiation themselves, which is ...

which is injected into the bloodstream, is under investigation for the treatment of bone metastases from breast cancer; there is evidence that it can relieve pain for up to three months after its administration. It is unknown whether or not it can prevent pathologic fracture, but it should be considered in patients who have three or more sites of painful bone metastases who cannot be treated with external-beam radiotherapy. In some patients with estrogen-receptor-positive breast carcinoma metastatic to the bone only, external-beam radiotherapy followed by tamoxifen or another anti-

estrogen Estrogen or oestrogen is a category of sex hormone responsible for the development and regulation of the female reproductive system and secondary sex characteristics. There are three major endogenous estrogens that have estrogenic hormonal acti ...

may be sufficient to control disease, at least temporarily. In most cases, however, the combination of radiotherapy and hormonal therapy is not enough to maintain disease control, and chemotherapy is needed.

"Alternative" and "complementary" therapies

Some patients with metastatic breast cancer opt to try alternative therapies that are claimed to achieve healing effects similar to scientifically-tested medical approaches, but lack scientific evidence to support those claims. Approaches that are considered alternative therapies when applied to cancer treatment include vitamin therapies, homeopathic treatments, extreme diets, chiropractic treatment and acupuncture. Some alternative treatments are harmful or even life-threatening.

Amygdalin Amygdalin (from Ancient Greek: ' "almond") is a naturally occurring chemical compound found in many plants, most notably in the seeds (kernels) of apricots, bitter almonds, apples, peaches, cherries, and plums. Amygdalin is classified as a cy ...

, an extract derived from apricot kernels, exposes the patient to

cyanide Cyanide is a naturally occurring, rapidly acting, toxic chemical that can exist in many different forms. In chemistry, a cyanide () is a chemical compound that contains a functional group. This group, known as the cyano group, consists of ...

. Bee venom can cause a life-threatening allergic reaction. Severe dietary restrictions such as

Macrobiotic diet A macrobiotic diet (or macrobiotics) is a fad diet based on ideas about types of food drawn from Zen Buddhism. The diet tries to balance the supposed yin and yang elements of food and cookware. Major principles of macrobiotic diets are to reduce ...

s can disrupt the body’s metabolism and cause dangerous weight loss. People should be aware that foods, vitamins, and other treatments may interfere with the effectiveness of surgery, chemotherapy or radiation. It is essential that patients work with their doctors and openly discuss possible effects of any treatment they are considering. Alternative and complementary therapies are not regulated by the U.S. federal government and may lack quality controls. While there is no evidence that any alternative treatments will cure cancer, there are treatments that may alleviate symptoms and improve quality of life for patients. When integrated into a broader medical treatment plan these are sometimes referred to as "complementary" or "integrative" therapies. For example, patients may find hypnosis, massage, meditation, relaxation techniques, tai chi or yoga to be helpful for issues such as stress, pain, nausea, and difficulty sleeping. Gentle exercise and a healthy diet can contribute to overall well-being and quality of life. Some early research suggests that women who refrain from eating for at least 13 hours overnight are less likely to have a cancer recurrence, possibly due to differences in

insulin Insulin (, from Latin ''insula'', 'island') is a peptide hormone produced by beta cells of the pancreatic islets encoded in humans by the ''INS'' gene. It is considered to be the main anabolic hormone of the body. It regulates the metabolism o ...

ketone In organic chemistry, a ketone is a functional group with the structure R–C(=O)–R', where R and R' can be a variety of carbon-containing substituents. Ketones contain a carbonyl group –C(=O)– (which contains a carbon-oxygen double bo ...

glucose Glucose is a simple sugar with the molecular formula . Glucose is overall the most abundant monosaccharide, a subcategory of carbohydrates. Glucose is mainly made by plants and most algae during photosynthesis from water and carbon dioxide, using ...

metabolism. As yet, the effects of nutrition and exercise on cancers are not well understood and some theories are controversial. Patients have been shown to face a greater risk of mortality if they refuse or delay scientifically-proven treatments in favor of alternative therapies. This is also true in the case of complementary therapies. A study published in ''

JAMA Oncology ''JAMA Oncology'' is a monthly peer-reviewed medical journal published by the American Medical Association. It covers all aspects of medical oncology, radiation oncology, and surgical oncology, as well as subspecialties. The journal was establi ...

'' compared the survival of those who used complementary cancer treatments and those who used only the medical cancer treatments recommended by their doctors. They found that those who used complementary treatments during cancer treatment were more likely to refuse some of the conventional cancer treatments their doctors recommended, resulting in a higher risk of dying as compared to those who used no complementary treatments at all. Those most likely to choose complementary treatments were young, affluent, well-educated women with private insurance.

Experimental therapies

Treatment of metastatic breast cancer is currently an active area of research. Several medications are in development or in phase I/II trials. Typically new medications and treatments are first tested in metastatic cancer before trials in primary cancer are attempted. Another area of research is finding combination treatments which provide higher efficacy with reduced toxicity and side effects. Experimental medications: *

sorafenib Sorafenib, sold under the brand name Nexavar, is a kinase inhibitor drug approved for the treatment of primary kidney cancer (advanced renal cell carcinoma), advanced primary liver cancer ( hepatocellular carcinoma), FLT3-ITD positive AML and r ...

a combined Tyrosine protein kinases inhibitor.

Scheduling of drug treatments and impact on results

Scheduling of drug treatments and combination treatment can have substantial impact on treatment efficacy.

Nanotherapies using nanoprobes

Nanomedicine Nanomedicine is the medical application of nanotechnology. Nanomedicine ranges from the medical applications of nanomaterials and BioBrick, biological devices, to Nanoelectronics, nanoelectronic biosensors, and even possible future applicatio ...

is being studied, and there are several developments involving the targeting of

cells using nanoprobes. Some instances where nanoprobes are used to target specific tumor cells (based on the organ to which they have metastasized) are: *

Chlorotoxin Chlorotoxin is a 36-amino acid peptide found in the venom of the deathstalker scorpion (''Leiurus quinquestriatus'') which blocks small-conductance chloride channels. The fact that chlorotoxin binds preferentially to glioma cells has allowed the d ...

(a chemical derived from the

deathstalker scorpion The deathstalker (''Leiurus quinquestriatus'') is a species of scorpion, a member of the family Buthidae. It is also known as the Palestine yellow scorpion, Omdurman scorpion, Naqab desert scorpion and by many other colloquial names, which gene ...

) binds to MMP-2 to cause

endocytosis Endocytosis is a cellular process in which substances are brought into the cell. The material to be internalized is surrounded by an area of cell membrane, which then buds off inside the cell to form a vesicle containing the ingested material. E ...

of the

, thus reducing its activity. Chemically bonded iron-oxide

nanoparticles A nanoparticle or ultrafine particle is usually defined as a particle of matter that is between 1 and 100 nanometres (nm) in diameter. The term is sometimes used for larger particles, up to 500 nm, or fibers and tubes that are less than 1 ...

were coated with about 20 molecules of

chlorotoxin Chlorotoxin is a 36-amino acid peptide found in the venom of the deathstalker scorpion (''Leiurus quinquestriatus'') which blocks small-conductance chloride channels. The fact that chlorotoxin binds preferentially to glioma cells has allowed the d ...

and targeted to brain-metastatic

cells. It was found that nanoprobes reduced brain-metastatic tumors in mice by 98%. * Nanotherapy using

herceptin Trastuzumab, sold under the brand name Herceptin among others, is a monoclonal antibody used to treat breast cancer and stomach cancer. It is specifically used for cancer that is HER2 receptor positive. It may be used by itself or together wi ...

(coated on

gold nanoparticles Colloidal gold is a sol or colloidal suspension of nanoparticles of gold in a fluid, usually water. The colloid is usually either wine-red coloured (for spherical particles less than 100 nm) or blue/purple (for larger spherical particl ...

) has slowed down the growth and invasion of aggressive

breast The breast is one of two prominences located on the upper ventral region of a primate's torso. Both females and males develop breasts from the same embryological tissues. In females, it serves as the mammary gland, which produces and secret ...

tumors in mice. Such therapies, targeted to specific cell types, is hoped to be useful in the future to develop better treatments to prevent or treat

Central nervous system metastases

Clinically symptomatic CNS

are reported in 10–15% of patients with metastatic breast cancer; in large autopsy studies, up to 40% of women who died of metastatic breast cancer were reported to have at least one brain metastasis. CNS metastases are often viewed by patients and doctors as a late complication of metastatic breast cancer for which few effective treatments exist. In most cases, CNS involvement occurs after metastatic dissemination to the bones, liver and/or lungs has already occurred; for that reason, many patients already have refractory, terminal breast cancer by the time they are diagnosed with brain metastases. The diagnosis of brain metastases from breast cancer relies mainly on patient-reported symptoms and neuroimaging. The role of imaging in patients with suspected brain metastases is a very good modality to aid in diagnosis. According to Weil et al., 2005, neuroimaging such as Computed Tomography (CT) and Magnetic Resonance Imaging (MRI) prove to be very effective in the diagnosis of brain and central nervous system metastases. Symptoms of brain metastases from breast cancer are: * new-onset headache * changes in mental status, cognition and behavior *

ataxia Ataxia is a neurological sign consisting of lack of voluntary coordination of muscle movements that can include gait abnormality, speech changes, and abnormalities in eye movements. Ataxia is a clinical manifestation indicating dysfunction of ...

* cranial neuropathy, which may cause

diplopia Diplopia is the simultaneous perception of two images of a single object that may be displaced horizontally or vertically in relation to each other. Also called double vision, it is a loss of visual focus under regular conditions, and is often v ...

and

Bell's palsy Bell's palsy is a type of facial paralysis that results in a temporary inability to control the facial muscles on the affected side of the face. In most cases, the weakness is temporary and significantly improves over weeks. Symptoms can vary fr ...

* vomiting and nausea * deficits in sensation, motor function, and speech Of all brain-metastatic patients, those with a controlled extra-cranial tumor, age less than 65 years and a favorable general performance (

Karnofsky performance status In medicine (oncology and other fields), performance status is an attempt to quantify cancer patients' general well-being and activities of daily life. This measure is used to determine whether they can receive chemotherapy, whether dose adjustment ...

≥70) fare best; older patients with a Karnofsky performance status below 70 do poorly. Effective treatments for brain metastases from breast cancer exist, although symptomatic therapy alone may be chosen for those with poor performance status.

Corticosteroids Corticosteroids are a class of steroid hormones that are produced in the adrenal cortex of vertebrates, as well as the synthetic analogues of these hormones. Two main classes of corticosteroids, glucocorticoids and mineralocorticoids, are involve ...

are crucial to the treatment of brain metastases from any source (including the breast), and are effective in reducing peri-tumoral edema and providing symptomatic relief.

has not been found to be effective in the treatment of brain metastases from breast cancer, due to the inability of most chemotherapeutic agents to penetrate the blood–brain barrier.

Whole-brain radiation Whole brain radiotherapy (WBRT) is a palliative option for patients with brain metastases that alleviates symptoms, decreases the use of Corticosteroid, corticosteroids needed to control tumor-associated edema, and potentially improves overall surv ...

may provide a median survival of 4 to 5 months, which can be further extended by months with

stereotactic surgery Stereotactic surgery is a minimally invasive form of surgical intervention that makes use of a three-dimensional coordinate system to locate small targets inside the body and to perform on them some action such as ablation, biopsy, lesion, injec ...

. Several non-randomized studies have suggested that

may provide a nearly equivalent outcome, compared with surgery followed by whole brain-irradiation. Surgery tends to reduce symptoms quickly and prolong life, with an improved quality of life. Multiple metastases (up to three) may be removed surgically with a risk similar to that of a single lesion, providing similar benefits. Adjuvant radiotherapy follows surgical resection; this combined approach has been shown to prolong median survival up to 12 months, depending on the factors noted above. There is evidence that surgery may be useful in select patients with recurrent brain metastases. Mean survival from diagnosis of a brain metastasis varies between studies, ranging from 2 to 16 months (depending on involvement of the CNS, the extent of the extra-cranial metastatic disease, and the treatment applied). The mean 1-year survival is estimated at 20%. Improvements in the treatment of brain metastases are clearly needed.

References

{{DEFAULTSORT:Metastatic Breast Cancer Breast cancer