What is targeted therapy in the treatment of breast cancer?

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Targeted therapy, also called precision treatment, corresponds to a personalized treatment, according to the type of cancer of the patient, acting on specific molecular targets of the tumor. This recent alternative has greater efficacy and fewer side effects, as it acts specifically on the protein and targets cancer cells, causing less damage to healthy cells, compared to conventional drugs. Targeted therapy acts with the aim of inhibiting the action of cancer cells and reducing tumor growth.

Immunotherapy is a type of biological treatment that aims to boost the immune system so that it can fight infections and other diseases such as cancer.

Immunotherapy includes treatments that work in different ways. Some stimulate the body's immune system in a very general way, while others help the immune system to specifically attack cancer cells.

Targeted therapies differ from standard chemotherapy in several ways:

- They act on specific molecular sites associated with cancer while chemotherapy generally acts on all cells (normal and cancerous) that are in accelerated proliferation.

- Most Target Therapy are cytostatic (ie block tumor proliferation) whereas standard chemotherapy is cytotoxic (ie kill cells).

- Target Therapies are currently the focus of drug development to fight cancer. They are the cornerstone of precision medicine, a form of medicine that uses information about a person's genes and proteins to prevent, diagnose and treat disease.

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What types of immunotherapy?

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The main types of immunotherapy used in cancer treatment include:

Monoclonal antibodies. They are artificial versions of immune system proteins. Antibodies are useful in cancer treatment because they can be designed to attack a very specific part of a cancer cell.

Inhibitors of immune control. These drugs basically eliminate the brakes on the immune system, helping to recognize and attack cancer cells. They are the most used immunotherapeutics today, against different types of cancer

Vaccines. They are normally produced from the patient's own tumor cells or from substances collected from tumor cells. Vaccines used to treat cancer are different from those used to prevent disease.

What are monoclonal antibodies?

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One way the immune system attacks foreign substances in the body is by producing large amounts of antibodies. An antibody is a protein that adheres to another specific protein called an antigen. Antibodies circulate through the body until they find and bind to the antigen. Once turned on, they can recruit other parts of the immune system to destroy the cells that contain the antigen.

Researchers can design antibodies that specifically target a particular antigen, such as that found on cancer cells. From there, several copies of this antibody are made in the laboratory, which are called monoclonal antibodies.

What are the main target therapies used in breast cancer?

• everolimus

• Cicline Route (Palbociclib, Ribociclib and Abemaciclib)

• HER2 (Trastuzumab, Pertuzumab, Lapatinib and TDM1)

• bevacizumab

• Atezolizumab

• olaparib

What is the role of Everolimus in advanced breast cancer?

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Everolimus is a derivative of rapamycin. It is a potent inhibitor of the mTOR pathway (mTOR is a protein with a central role in the growth, proliferation and maintenance of cells, which participates in the formation of two complexes, mTORC1 and mTORC2) and can reverse hormonal resistance. It is believed that an endocrine resistance mechanism would be the aberrant signaling of the PI3K-Akt-mTOR pathway. A substrate of the mTOR complex, called S6-kinase 1, would be responsible for the phosphorylation (and activation) of the estrogen receptor. The drug Everolimus (Afinitor®, Novartis) inhibits mTOR.

The use of aromatase inhibitors, in postmenopausal patients, hormone sensitive (RH positive), leads to high rates of clinical benefit (response and stable disease) and gain in overall survival, being considered the first-line treatment. Unfortunately, not all patients respond (primary resistance) and even those who respond will at some point develop progression (acquired resistance). Other hormone lines can be used in this situation, for example, another class of aromatase inhibitors, tamoxifen or estrogen receptor antagonists (Fulvestrant).

The combination of Everolimus with aromatase inhibitor (Exemestane) was evaluated in a study that showed increased survival for the group treated with the combination.

What is the role of cyclin-dependent kinases in breast cancer?

Cyclin-dependent kinases (CDKs) play an essential role in regulating cell cycle progression, allowing the transition between different phases. Its activation depends on molecules that are synthesized and degraded during the cell cycle – cyclins.

As cell cycle regulators, their inhibition ensures that diseased cells do not enter into cell division, thus preventing them from proliferating and dying, breaking a tumor growth cycle.

To treat this condition, you need to use a targeted therapy known as a CDK inhibitor. This treatment disrupts the activity of cancer cell-promoting enzymes known as cyclin-dependent kinases 4/6 (CDK 4/6).

For now, we have three drugs that work with this objective available on the market. Inhibitors of the enzymes CDK4 and CDK6 are used to treat the most common subtype of breast cancer, called HR+/HER2- (hormone receptor positive/human epidermal growth factor receptor 2 negative).

Among the inhibitors we already have three approved by ANVISA: Palbociclibe, Abemaciclibe and Ribociclibe. Learn more about each of them:

Palbociclib is another example of this therapeutic class, a multiple cyclin kinase inhibitor (CDK4/6), which associated with hormone therapy (letrozole or fulvestrant), in first and second line metastatic in these tumor subtypes, which demonstrated excellent rates of tumor control , and more than doubled, the disease-free lifespan.

Abemaciclib Oral treatment is indicated in combination with an aromatase inhibitor as initial endocrine therapy, in combination with fulvestrant as initial endocrine therapy, or after endocrine therapy in the setting of advanced/metastatic disease. It can also be given alone, after disease progression, after the use of endocrine therapy and prior chemotherapy for metastatic disease.

Ribociclib is a CDK4/6 inhibitor and can be used in patients with HR+/HER2- metastatic breast cancer, associated with an aromatase inhibitor or fulvestrant, in 1st and 2nd lines. Ribociclib treatment in combination with endocrine therapy in premenopausal women has been shown to significantly improve overall survival in this HR+/HER2 negative metastatic disease setting.

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