Metastatic breast cancer is a complex multi-step process involving the expansion of cancerous cells from the breast to other areas of the body. It is a serious complication of breast cancer, as metastatic disease in breast cancer is often fatal, with treatments mainly limited to palliation.

Breast cancer primarily metastasizes to the bone, lungs, regional lymph nodes, liver and to the brain, with the most common site being the bone. The typical environmental barriers in any metastatic event would include physical (basement membrane), chemical (Reactive oxygen species (ROS), hypoxia and low PH) and biological (immune surveillance, inhibitory cytokines and regulatory Extracellular Matrix (ECM) peptides) components. Organ-specific anatomic considerations can also influence metastasis; these include blood flow patterns from the primary tumor and the homing ability of cancer cells for certain tissues. The targeting by cancer cells of specific organs is likely regulated by chemoattractant factors and adhesion molecules, which are produced by the target organ along with the cell-surface receptors expressed by the tumor cells.

The main steps involved in the metastatic cascade of a cancer cell are:

* The cell division and growth within the primary tumor.
* Invasion of the primary tumor border (basement membrane, referred to as BM) and the local tissue surrounding the tumor by the cell.
* Intravasation 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 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 inside the secondary site.
* Progressive colonization to form a life threatening metastasis.

The potential of a tumor cell to metastasize depends on its microenvironment, or the “niche” interactions with the local factors that promote tumor-cell growth, survival, angiogenesis, invasion and metastasis. This is explained by the theory called the "seed and soil hypothesis".

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 over the affected bone, and swelling.
* Metastatic breast cancer to the brain causes the following symptoms: persistent, progressively worsening headache, visual changes, seizures, nausea or vomiting, vertigo, behavioral and personality changes, and increased intracranial pressure.
* 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, abnormal chest X-ray, and chest pain.
* Other nonspecific systemic symptoms of metastatic breast cancer include fatigue, malaise, weight loss, and poor appetite.

Seed and soil hypothesis

The seed and soil hypothesis states that specific organs harbor metastases from one type of cancer by stimulating their growth better than other types of cancer. This interaction is dynamic and reciprocal, since cancer cells modify the environment they encounter.

Extracellular matrix degradation in cancer

Cell-cell and cell-ECM matrix adhesion, motility, and localised proteolysis are mediated mainly by matrix metalloproteases (MMPs). Degradation of extracellular matrix is the starting process that facilitates metastasis. The cell develops structures called invadopodia, which are highly concentrated in several proteases and have a highly dynamic actin cytoskeleton.

Mechanisms of metalloprotease action in cell motility involve:

* Proteolytic cleavage of growth factors so that they are readily available to cells not in direct physical contact.
* Degradation of the ECM is facilitated by MMPs so that the cells can move across tissues into nearby stroma [disambiguation needed].
* Regulated receptor [disambiguation needed] 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 proteolysis is an important mechanism to maintain homeostasis. There is increased expression of protease systems in cancer cells to equip them with the tools necessary to degrade the extracellular matrix and release several growth factors or transmembrane receptors. MMP-2 is upregulated in the bone, increased levels of MMP-1 and MMP-19 are observed in the brain. This in turn, upregulates the signaling pathways necessary to provide increased cell adhesion, cell motility, cell migration, invasion, cancer cell proliferation and survival.

Bone

Metastasis is the cause of about 90% of deaths due to breast cancer and roughly 70% of all patients dying of breast cancer have evidence of metastatic bone disease. The important extracellular matrix components and cell surface receptors which could help in metastasis are discussed here.

Integrin signalling

Integrin αvβ3, a cell surface adhesion molecule is important for tumor attachment, cell-cell communication between the breast tumor cells and the environment in the bone, osteoclast bone resorption, and angiogenesis. Integrin-mediated adhesion between cancer cells and osteoclasts in bone metastases induces phosphorylation of extracellular signal-regulated kinases (ERK1/2) in osteoclasts, which in turn induces osteoclast differentiation and survival..

Cancer cell-blood platelet interaction

Metastatic breast cancer cells excrete lysophosphatidic acid (LPA) that binds to receptors on tumor cells, inducing cell proliferation and release of cytokines(IL-6 and IL-8, potent bone resorptive agents) and stimulating bone resorption.

After the breast cancer cells have traveled away from the primary tumor, they establish a tight interaction with the bone microenvironment and secrete osteolytic factors capable of osteoclast formation and bone resorption. Apart from the breast tumor cells, the resident stromal cells also contribute to tumor survival. Growth factors like epidermal growth factor (EGF), fibroblast growth factor (FGF), and transforming growth factor beta (TGF-β) 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 [disambiguation needed]; it plays an important role in the degradation of extracellular matrix essential for cancer 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 associated with vascular basement membranes and interstitial connective tissue.

Brain

Brain metastasis is observed in 10% of breast cancer patients with metastatic properties. Many of the breast cancer therapies (like targeted antibodies) fail to penetrate the blood-brain barrier (BBB), hence allowing for tumor recurrence in the Central Nervous System. Brain is a special organ for metastasis as the breast tumor cells have to pass the BBB in order to form micrometastases in the brain.

CD44

CD44, a cell-surface transmembrane glycoprotein is a receptor for hyaluronic acid involved in cell adhesion by binding to specific extracellular matrix components. A proposed mechanism for the function of CD44 may be to regulate the adhesion of circulating cancer cells in the brain to endothelium at the secondary site with the help of hyaluronate matrix ligand or by its cytoplasmic attachments to actin-associated proteins of the merlin/ezrin/radixin/moesin family .
Sialyl transferase (glycosylation modifications of gangliosides)

Cell-surface sialylation has been implicated in cell–cell interactions and overexpression of a brain sialyltransferase in breast cancer cells is a mechanism that highlights the role of cellsurface glycosylation in organ-specific metastatic interactions. Breast cancer metastasis to the brain involves mediators of extravasation through non-fenestrated capillaries, complemented by specific enhancers of blood–brain barrier crossing and brain colonization .

ECM components in breast cancer metastasis

ECM-tumor cell interactions play a critical role in each of the events of the metastatic cascade. Interactions of the breast cancer cells with integrins, fibronectin, laminins, collagens, hyaluronan, proteoglycans which can contribute to the metastatic process. Some of these proteins are discussed here in relevance to breast cancer metastasis.

Fibrinogen - Integrin

Fibronectin is an extracellular glycoprotein that can bind to integrins and other ECM components like collagen, fibrin and Heparan Sulphate ProteoGlycans(HSPGs). Several different integrins bind to fibronectin. Fibronectin-integrin interactions are important in tumor cell migration, invasion, and metastasis and also cell proliferation by signaling through integrins. 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 , activation and nuclear translocation of mitogen-activated protein (MAP) kinases.

Heparanase

Heparanase cleaves heparin sulfate chains of HSPGs which have an extensive network with several proteins on cell surface and ECM. The basic HSPG structure consists of a protein core to which several linear heparin sulfate (HS) chains are covalently O-linked and acts as an assembly of different ECM proteins, including fibronectin, laminins, and interstitial collagens, heparin-binding growth factors, chemokines, lipoproteins.
HSPGs are prominent components of blood vessels.. Binding to HS stabilizes FGFs and Vascular Endothelial Growth Factors (VEGFs) and prevents them from inactivation. HS chains function as low affinity co-receptors that promote dimerization of FGFs, hence helps in the sequestration of the GFs and causes activation of the signaling tyrosine kinase receptors even under low circulating concentrations of the growth factors. Heparanase expressed by cancer cells participates in angiogenesis and neovascularization by degrading the polysaccharide scaffold of the endothelial BM, thereby releasing angiogenic growth factors from ECM.

Tenascin

The ECM protein tenascin C (TNC) is up-regulated in metastatic breast cancer. TNC is an adhesion-modulating extracellular matrix glycoprotein. It is highly expressed in tumor stroma [disambiguation needed] and stimulates tumor cell proliferation. It is hypothsised that TNC stimulates invasion via up-regulation of MMP-1 expression through activation of MAPK pathway. MMP-1 (interstitial collagenase) cleaves collagen type I, II, III, VII and X. Hence, tenascin Coverexpression can significantly alter the collagen in the ECM and influence tumor cell migration in cartilaginous tissues.

Endoglin

Endoglin is a cell-surface disulfide-linked homodimeric glycoprotein which binds to the integrins and other RGD ligands and a coreceptor for TGF-beta. Brain metastatic breast tumor cells express endoglin in large amounts. Endoglin-overexpressing cells develop large numbers of invadopodia and endoglin is localized in these structures. Endoglin-expression in tumor cells contributes to metastasis by upregulating MMP-1 and MMP-19. MMP-19 cleaves components of the basal lamina, such as collagen type IV, laminin 5, nidogen (entactin) and other ECM proteins like tenascin, aggrecan, fibronectin. Hence endoglin-overexpression alters the proteolytic balance of the cells to higher matrix degradation and increased invasive properties of the breast cancer.

Therapies

Metastasis is a complex and interconnected multi-step process. Each step in the process is a potential target for therapies to prevent or reduce metastasis. Those steps which have a good clinical window period are the best targets for therapy. Each event in metastasis is highly regulated and requires a synergistic activation of different ECM proteins, growth factors, etc. 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 has to involve the use of systemic therapy.

Chemotherapy

Chemotherapy is one of the most important parts of therapy for metastatic breast cancer. The Taxenes are very active in metastatic breast cancer, and abraxane, a form of paclitaxel without solvents, is approved for patients with metastatic breast cancer who either relapsed within 6 months of adjuvant chemotherapy or failed to respond to combination chemotherapy, with a higher response rate then solvent-based paclitaxel (15% vs 8%) also, abraxane can deliver a 49% higher dose of medication than solvent based paclitaxel. However, side effects are severe. Also, severe sensory neuropathy can occur in patients treated with abraxane. Combination chemotherapy is often used in patients with metastatic breast cancer, but so far, while some studies have shown that a combination of doxorubicin and paclitaxel improves response rates in metastatic breast cancer over either agent alone, there is no evidence this approach improves overall survival. Xeloda is a new chemotheraputic agent that is approved for colorectal carcinoma and metastatic breast cancer in combination with docetaxel, improved response rates from 22% to 32% when compared to docetaxel alone and overall survival from 11 months to 14 months, a fairly significant benefit. The overall response rate to doxorubicin is 40-50%, which is somewhat lower than the response rate to docetaxel, which has an overall response rate of up to 68%. Also, while doxorubicin is cardiotoxic and is contraindicated in patients with preexisting cardiac disease, docetaxel can be used in those with heart disease, and has slightly less intestinal side effects (mainly a reduction in the incidence of diarrhea. Gemzar is a new antimicrotubule that has been proven to be superior to paclitaxel alone, with an overall response rate of 40% when used in combination with paclitaxel, an 89% improvement in overall response rate when compared with paclitaxel alone (which has a 22% response rate). There was also improved overall survival and time to progression. Vinorelbine is also active in metastatic breast cancer, with an overall response rate of up to 40%. It can also be used following unsuccessful treatment with a taxene or anthracycline, when used in this setting response rates are 15-30%.

Eribulin was approved by FDA in Nov 2010.

Tamoxifen and other anti-estrogens

For estrogen-receptor positive metastatic breast carcinoma, the first line of therapy is often Tamoxifen or another anti-estrogen drug, unless there are liver metastases, significant lung invovlvement, rapidly progressive disease, or severe symptoms requiring immediate palliation. Hormonal therapy should also be used following relapse of an estrogen receptor positive breast carcinoma, because the benefit of further hormonal manipulation in such patients can be as high as 50%.

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 an oncological emergency, as untreated spinal cord compression can causes permanent paralysis or even death. In breast cancer, spinal cord compression occurs when either a bone metastasis or spinal metastasis began to push on the spinal cord, resulting in inflammation, and if untreated, spinal cord injury. Radiotherapy is an important part of therapy for cord compression secondary to metastatic breast cancer, along with corticosteroids and laminectomy.
* Liver metastases. Typically, pain from liver metastases responds to chemotherapy and pain medication. However, in cases when chemotherapy is contraindicated, or the liver metastases are refractory to chemotherapy, and pain medication fails to provide appropriate palliation of liver metastasis related pain, radiotherapy should be considered, as it can be effective in reliving pain and may shrink the metastases, and perhaps even extend survival in a subset of patients who have 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, as brain metastases can progress rapidly, and can suddenly produce life-threatening complications such as increased intracranial pressure, herniation of the brain, and seizures. Radiotherapy is essential in the treatment of brain metastases from breast cancer, as it halts tumor progression quickly and can induce a response in the majority of patients. However, in one small retrospective study of 36 patients with breast cancer metastatic to the brain, despite a high initial response rate of 82%, the duration of the response was very short, with intracranial relapse occurring on average 5.0 months after the end of therapy, and median survival being just 7.9 months. However, it did initially palliate symptoms of the brain metastases, a major objective in terminally ill patients with breast cancer.
* Bone metastases. The bones are a very common site of metastatic disease from breast cancer, and bone metastases can cause severe pain, hypercalicemia, and pathologic fracture. Radiotherapy to areas of painful bone metastases has a symptomatic response rate of more than 75% (however, a symptomatic response only means an improvement in symptoms, not a documented regression of the cancer). Radiotherapy is also indicated to prevent pathologic fracture, as well as part of postoperative treatment following repair of a pathologic fracture. Strontium 89, a radiopharmaceutical that is injected into the bloodstream, is under investigation for the treatment of bone metastases from breast cancer. Currently, there is evidence that it can relieve pain for up to three months after its administration. It is not known 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 may be sufficient to control disease for at least a period of time. In most cases, however, the combination of radiotherapy and hormonal therapy is not enough to maintain disease control, and chemotherapy is needed.

Alternative therapies

Some patients with metastatic breast cancer opt to try alternative therapies, such as vitamin therapy, homeopathic treatments, macrobiotic diet, chiropractic, or acupuncture. There is no evidence that any of these therapies are effective, and they may be harmful, either because patients pass up effective conventional therapies such as chemotherapy or anti-estrogen therapy in favor of alternative treatments, or because the treatments themselves are harmful, as in the case of apricot pit therapy, which exposes the patient to cyanide, or in chiropractic, which can be dangerous to patients with cancer metastatic to the spinal bones or spinal cord. Also, the macrobiotic diet is neither effective nor safe, as it could hypothetically encourage weight loss, owing to the severe dietary restrictions. There is limited evidence acupuncture could relive pain in cancer patients, but data so far is not sufficient to recommend its use outside of clinical trials. Also, there could be a risk of HIV,or hepatitis if needles are not sterilized. Currently, most oncologists discourage alternative breast cancer therapy, because there is no evidence it is effective, it may in some cases be harmful, and it often causes patients to resist the conventional therapies.

Experimental therapies

Treatment of metastatic breast cancer is currently an active area of research. A very promising experimental therapy for breast cancer is Nexavar, a drug already approved for patients with metastatic renal cell carcinoma and hepatocellular carcinoma. In a study of more than 200 patients, those who received Nexavar and the chemotheraputic agent Xeloda had longer time to progression than those who took Xeloda alone, the study said--with the median progression free survival time being 6.4 months in the Xeloda-and-Nexavar group compared to 4.1 months in the Xeloda-alone group.

Nanotherapies using nanoprobes

Recently, nanomedicine has become popular and there are several interesting developments involving the targeting of cancer cells using nanoprobes. Here are a few instances where nanoprobes are used to target specific tumor cells (based on the organ to which they have metastasized):

* Chlorotoxin, a chemical derived from the giant Israeli scorpion, binds to MMP-2 to cause endocytosis of the metalloprotease, thus reducing its activity. Chemically bonded iron oxide nanoparticles were coated with about 20 molecules of chlorotoxin and targeted to the brain metastatic cancer cells. It was found that nanoprobes reduced the brain metastatic tumors in mice by 98%.
* Nanotherapy using antibodies to herceptin coated on gold nanoparticles has showed results of slowing down the growth and invasion of aggressive breast tumors in mice. Such therapies targeted to specific cell types might be useful in the future to develop better treatments to prevent or treat metastasis in breast cancer.

Central nervous system metastases

Clinically symptomatic CNS metastases are reported to occur in 10-15% of patients with metastatic breast cancer, but in large autopsy studies, up to 40% of woman who died of metastatic breast cancer were reported to have at least one brain metastasis. CNS metastases are often viewed by patients and doctors alike 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, and for that reason, many patients already have refractory, terminal breast cancer by the time they are diagnosed with brain metastases. Diagnosis of brain metastases from breast cancer relies mainly on patient reported symptoms and neuroimaging.

Symptoms of brain metastases from breast cancer are:

* new onset headache
* alterations in mental status, cognition, and behavior.
* ataxia
* cranial neuropathy, which can cause diplopia, and bells palsy
* vomiting and nausea
* deficits in sensation, motor function, and speech

Breast cancer involving the CNS is traditionally viewed as a late complication of progressive metastatic disease, for which few effective treatment options exist. For all brain metastatic patients, those with controlled extra-cranial tumor, age less than 65 years, and a favorable general performance (Karnofsky performance status ≥70) fare best whereas older patients with a Karnofsky performance status <70 do poorly. However, effective treatments for brain metastases from breast cancer do exist, although symptomatic therapy alone may be chosen for those with poor performance status. Corticosteroids are crucial in the treatment of brain metastases from any origin-including the breast, and are effective in reducing peri-tumoral edema and providing symptomatic relieve.

Chemotherapy has not been found to be effective in the treatment of brain metastases from breast cancer, due to the inability of most chemotheraputic agents to penetrate the blood brain barrier. Whole brain radiation can provide a median survival of 4 to 5 months, which can be further extended by stereotactic radiosurgery months. Several nonrandomized studies have suggested that stereotactic radiosurgery may provide nearly equivalent outcomes compared to surgery followed by whole brain irradiation. Surgery tends to reduce symptoms quickly and prolong life significantly, with persistent increases in quality of life. Multiple metastases (up to three) can be removed surgically with a risk similar to that of a single lesion, providing similar benefits. At present, adjuvant radiotherapy follows surgical resection because this combined approach has been shown in general to prolong median survival significantly, to 12 months depending on the factors noted above. There is also a growing body of evidence that surgery may be useful in select patients with recurrent brain metastases. Mean survival from diagnosis of a brain metastasis varies between studies but ranges 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.