Emerging Therapies in Metastatic Breast Cancer

Researchers continue to look for new and better ways to treat advanced breast cancer. Some of the treatments that are being evaluated in clinical trials can be generally grouped into the following categories:

• Targeted therapy, which interferes with specific areas of cancer cells that are involved in the cancer cell’s growth processes
• Immunotherapy, which harnesses the power of the body’s immune system
• Anti-angiogenesis, which blocks the blood supply to the cancer cells

Targeted therapy under investigation for advanced breast cancer

Targeted therapy is a type of treatment that stops or slows breast cancer by interfering with specific areas of cancer cells that are involved in the cancer cell’s growth processes. Also called precision medicine, targeted therapies focus on certain features of cancer cells in an effort to provide treatment for cancer that does less damage to normal cells and causes fewer side effects.^1,2

Some of the targeted therapy areas currently being studied in the treatment of advanced breast cancer include:

• PI3K inhibitors
• Poly (ADP-ribose) polymerase (PARP) inhibitors
• Cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitors

PI3K inhibitors

PI3 kinase (PI3K) is a protein that plays a role in how cells grow and divide. It is estimated that approximately 40% of all advanced breast cancers that are estrogen-receptor positive have a genetic mutation on the gene PIK3CA, which can cause an increase in the activity of PI3K and cause cancer to grow more quickly. PI3K inhibitors block PI3K and can slow or stop the growth of cancer.^3,4 PI3K inhibitors in breast cancer clinical trials have not shown promising results, however. Many of the investigational medicines have shown modest benefit and/or have significant side effects. The research will likely continue in this area, as PI3K is a novel target.⁵

PARP inhibitors

PARP enzymes are important for cellular functions like DNA repair. DNA is replicated any time a cell divides, and the rapid growth of cancer cells creates more opportunities for DNA damage to occur. Damage to the DNA of cells, including cancer cells, can lead to cell death. Normally, cells have multiple ways of repairing any damage that may occur to the DNA. By blocking the PARP repair functionality, PARP inhibitors can limit the cancer cell’s ability to repair the DNA and can lead to the death of cancer cells. Some PARP inhibitors have been approved to treat certain forms of advanced or metastatic breast cancer, and others are being researched.^3,6,7

CDK4/6 inhibitors

CDK4 and CDK6 are proteins that are important during a cell’s growth and replication cycles. In breast cancer cells, CDK4 and CDK6 may be overactive, which may cause the cancer cells to grow uncontrollably. By blocking CDK4/6, CDK4/6 inhibitors can help slow the growth and division of breast cancer cells. Some CDK4/6 inhibitors have been approved for use in the treatment of breast cancer, and others are under investigation.^3,8

Immunotherapy under investigation for advanced breast cancer

Normally, the body’s immune system fights disease and infection. The white blood cells recognize and destroy damaged or diseased cells and foreign invaders, like bacteria and viruses. Cancer cells can often mutate in such a way to avoid detection by the immune system, and they grow out of control. Immunotherapies aim to help the immune system identify and destroy cancerous cells. Several types of immunotherapy are currently being studied for the treatment of advanced breast cancer, including monoclonal antibodies and adoptive cell transfer.^9,10

Monoclonal antibodies are made in the lab to work similarly to how antibodies produced by the bodywork. They can target specific areas of cancer cells and/or the pathway that allows cancer cells to avoid immune system detection, such as blocking the function of specific proteins known as PD-L1 and PD-1. The PD-1 and PD-L1 proteins can help disguise cancer cells from the body’s T-cells (a type of white blood cell) and prevent the T-cells from attacking the cancer cells, allowing cancer to continue to grow and survive. Monoclonal antibodies that target PD-L1 or PD-1 proteins target this pathway and are being studied as a therapy for advanced breast cancer.¹¹

Adoptive cell transfer is an emerging immunotherapy technique that collects and uses the patient’s own immune cells to attack cancer. In one ongoing Phase II clinical trial, researchers are using tumor-infiltrating lymphocytes (TILs), a type of white blood cell. Researchers first identify the specific mutations on the person’s cancer and identify which TILs can recognize them. These cells are removed from the patient’s body and grown in a laboratory to create a large number of them, which can take several weeks. During this time, the patient may be given treatments to reduce their immune cells. The TILs are then given back to the patient, where they can generate an immune response to fight the cancer cells.^9,12

Anti-angiogenesis under investigation for advanced breast cancer

Angiogenesis is the development of new blood vessels. Tumors produce proteins that cause the formation of blood vessels, which supply nutrients to the cancer cells and provide an avenue for cancer to spread to other parts of the body through the bloodstream. Anti-angiogenesis drugs, or angiogenesis inhibitors, block certain proteins involved in the development of blood vessels or affect certain actions of the immune system, which can lead to anti-angiogenesis effects.¹³ Some angiogenesis inhibitors have been approved for use in other cancers and are being studied as a potential treatment for breast cancer.³