Metastatic breast cancer, also referred to as advanced breast cancer, secondary tumors, secondaries or stage IV breast cancer, is a stage of breast cancer in which malignant cells arising from breast tissue have spread to distant sites beyond the regional lymph nodes. Stage IV is the most advanced stage of breast cancer. Metastatic breast cancer cannot be cured, but it can be treated to enable women to live longer and to lessen symptoms.
Metastasis 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. A 2021 global metanalysis of over 400 studies suggests that between 6% and 22% of women with breast cancer develop metastases. From 6-10% of women have cancer that has already spread beyond the breast at the time of first diagnosis, referred to as de novo stage IV cancer.
Breast cancer metastases can appear anywhere in the body but most often spread to the bones, lungs, liver, and brain, with the most common site being bone. These distant metastases are the cause of most of the deaths due to breast cancer. Metastatic breast cancer cells frequently differ from the preceding primary breast cancer in ways that permit them to metastasize to distant sites, and may have developed resistance to previous types of treatment. However, they are still breast cancer cells, not bone cancer or lung cancer cells, and are treated as such.
Treatment of metastatic breast cancer depends on location of the metastatic tumors and can include chemotherapy, hormonal therapy. immunotherapy, radiation, and surgery. Subtypes of metastatic breast cancer are associated with varying patterns of occurrence, spread and prognosis. To help determine treatment, tumor biopsy samples are tested for biomarkers that affect cell growth. Tumors containing either estrogen receptors (ER) or progesterone receptors (PR) are called hormone receptor-positive (HR+) and can be treated with hormone therapies. Tumors that contain large amounts of the protein human epidermal growth factor receptor 2 (HER2) can be treated with HER2-targeted therapies. Tumors that do not contain ER, PR, or HER2 are called triple-negative tumors. Triple-negative tumors tend to grow more quickly than other breast cancer types.
Secondary sites and symptoms A diagnosis of metastatic breast cancer is given only when cancer cells have spread to distant sites, beyond the breast and the axillary lymph nodes. The most common distant sites to which breast cancer spreads are the bones, lungs, liver, and brain, but many other sites can also be involved. The symptoms produced by metastatic breast cancer vary by the location of the metastases. Metastatic disease to the bone occurs in roughly 70% of patients with advanced breast cancer. Bone metastasis can cause severe, progressive pain, and, less commonly, pathological fracture, spinal cord compression, and swelling. Metastatic disease to the liver occurs in roughly 50% of patients with advanced breast cancer. Incidence varies widely with subtype, and is reported at 25% for cases of triple-negative breast cancer and 32% for HER2-positive breast cancer. Liver metastasis causes jaundice, abdominal pain, loss of appetite, nausea, itchy skin, rash (sometimes due to treatments) and elevated liver enzymes. Metastatic breast cancer to the lung or pleura may occur in up to 50% of patients with advanced breast cancer. It can cause chronic cough, damage to the lungs and airways, shortness of breath, hemoptysis, pleural effusion, and chest pain. Frequent respiratory tract infection and associated inflammation may increase the risk of cancer cell activity in the lungs. Metastatic breast cancer to the brain is observed in 5–16% of all patients living with breast cancer. Incidence varies widely with subtype: incidence rates are reported at 5–10% for ER+/HER2-negative disease, 25–46% for patients with triple-negative breast cancer, and 30.7–53% for HER2-positive breast cancer. Brain metastasis can cause persistent, progressively worsening headache; changes in cognitive function; sensory or motor deficits (e.g. visual changes such as double vision, blurring vision, seeing flash of lights); seizures; behavioral and personality changes; nausea; vertigo; and increased intracranial pressure. Nonspecific systemic symptoms of metastatic breast cancer also include pain, fatigue, muscle weakness, fibromyalgia, weight loss, and poor appetite. Some people with metastatic breast cancer are asymptomatic and do not have any notable changes or symptoms.
It is also possible to have multiple primary malignancies, distinct cancers that have independent origins rather than being derived from breast cancer. This is rare, and differs from metastatic breast cancer: each primary cancer type will require its own specific treatment.
Pathophysiology Main steps The spreading of a cancer from a primary to a secondary location is called a metastatic cascade. The main steps involved in a metastatic cascade are:
Cell division and growth within the primary tumor Growing into, or invading, nearby normal tissue Moving through the walls of nearby lymph nodes or blood vessels (Intravasation of the circulatory system) Traveling through the lymphatic system and bloodstream to other parts of the body (Transit to a new environment) Stopping in small blood vessels at a distant location, invading the blood vessel walls, and moving into the surrounding tissue (Extravasation to a distant site) Growing in this tissue until a tiny tumor forms (Micrometastasis) Causing new blood vessels to grow, which creates a blood supply that allows the metastatic tumor to continue growing (Progressive colonization of the secondary tumor)
Factors affecting metastasis
The potential of a tumor cell to metastasize to a secondary site depends on the tissue microenvironment of the site and its suitability to be a "niche" for the tumor cell. The "seed and soil" hypothesis implies that specific organs ("soils") may be more likely to stimulate growth and harbor tumor cells from one type of cancer than from others ("seeds"). Interactions between tumor cells and organs may promote tumor-cell homing to a particular organ, cell invasion and metastasis. Interactions between cancer cells and their environment are dynamic and reciprocal, since cancer cells modify the environment they encounter. HR+ breast cancers tend to metastasize to bone (Luminal A) or to bone and liver (Luminal B), HER2 cancers to lung, brain and liver, and triple negative cancers to lung, brain and distant lymph nodes.
The circulation of blood and lymph within the body is also a key element in the metastasis of tumor cells to secondary sites. Breast cancer cells may enter the circulation via the sentinel lymph node or via blood vessels from the primary tumor. A primary tumor requires oxygen and nutrients to survive. It secretes growth factors to stimulate formation of new blood vessels (angiogenesis). New blood vessels are crucial for sustaining the primary tumor, but also provide physical pathways for cancer cells to escape to other sites. Tumor-induced blood vessels tend to be leaky and fragile. Cancer cells can more easily penetrate them (vascular permeability), entering the bloodstream and traveling through it to reach other organs.
To survive the transit to a new environment, a tumor cell needs to pass through physical barriers such as the basement membranes of tissues, and evade chemical and biological protective mechanisms of cells and the innate and adaptive immune systems. The immune system actively works to monitor, recognize, and eliminate tumor cells, to maintain equilibrium and to prevent tumor cells from surviving and escaping.
The mobility of cancer cells can be affected by chemoattractants such as chemokines, with cells moving along a chemical gradient toward an attractant's source. This type of mechanism may enable cancer cells to find a favorable "niche".
Another mechanism involved in cancer metastasis is cell adhesion, the process by which cells attach to each other and their surroundings. This normally supports processes such as wound healing. The protein E-cadherin is important for formation and stability of attachments between cells (cell–cell adhesion), while integrin proteins affect the anchoring of cells to the extracellular matrix that surrounds cells (cell-ECM adhesion). The balance between E-cadherin and integrin is crucial to healthy cell development. Cancerous cells and cell clusters can alter adhesion signaling so that adhesion molecules help them to escape, invade new areas, "stick" to target tissue, and metastasize.
Diagnosis Diagnosis of metastatic breast cancer generally occurs after symptoms of secondary tumors have been reported. X-ray, ultrasound, or magnetic resonance imaging (MRI) may be used to detect suspicious areas of tissue. A biopsy will generally be done to determine whether tissue is benign or malignant. This can determine whether a secondary tumor contains breast cancer cells, and whether those cells differ from the original tumor.
Once a secondary tumor has been confirmed, CT scans or PET scans may be used to assess where and how far the tumor has spread. Bone scintigraphy (bone scan) is a leading technique for assessment of bone metastases.
Blood tests may also be done to look for tumor markers, proteins released by a tumor into the bloodstream. Tumor markers may be useful in assessing progression of a tumor or response to treatment. However, they are not considered conclusive evidence of either the presence or absence of a tumor. Additional blood tests may be done to assess whether organs in the body are functioning properly.
Treatment The focus of treatment in cases of metastatic breast cancer is to enable women to live longer and to lessen the impact of symptoms. While overall female breast cancer incidence rates in the United States have increased by between .5% and 1% per year since 2001, deaths from breast cancer have decreased by between 1.6% and 1.9% per year. Approximately one-third of women with metastatic breast cancer now live 5 years or more after diagnosis.
Metastasis is a complex and interconnected multi-step process. Treatments can target multiple steps in that process. When dealing with early-stage breast cancer, standard treatments tend to be breast-conserving surgery or mastectomy, often with radiotherapy. Chemotherapy may be used to reduce tumor volume before surgery, and systemic therapy may follow. Locally-focused surgery and radiotherapy are less useful once cancer has spread to distant areas. As a result, treatment of metastatic breast cancer tends to rely on systemic therapies which affect the whole body rather than a particular area. Systemic therapies include chemotherapy, hormone therapy, targeted-drug therapy and immunotherapy.
A treatment plan for metastatic breast cancer is individualized to a person based on factors such as: type of primary cancer and previous treatment size, location and number of secondary tumors biochemistry of tumor cells patient age, overall health, and symptoms treatment options and predicted effectiveness treatment risks and possible side effects