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

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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.

What are anti HER2 positive drugs?

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HER2 is the abbreviation for “Human Epidermal growth factor Receptor-type 2”, that is, human epidermal growth factor receptor type 2. In normal amounts, this protein plays an important role in the growth and development of a broad category of cells, called epithelial cells. These cells make up the body's inner and outer lining, as well as the glandular tissue. The HER2 gene, responsible for the production of the HER2 protein, is a proto-oncogene. As noted, the HER2 protein has a regulatory role in normally functioning cells. In the breast tissue sample, the increase (or overexpression) of the HER2 receptor (existing in the membrane of tumor cells) or of the HER2/neu gene should be analyzed and investigated. This change corresponds to a specific subtype of breast cancer, currently called HER2 positive breast cancer (HER2+).  The increased expression of HER2 leads to an oncogenic transformation and a more aggressive tumor behavior.

Trastuzumab (HerceptinR)

Trastuzumab was the first monoclonal antibody to be used to block the HER2 pathway. It acts by inhibiting cell proliferation by reducing intracellular signaling mediated by HER, blocks the cleavage of HER2 and prevents activation of its extracellular domain, reducing exacerbated proliferation in these cells. Clinical studies in HER2 positive patients concluded that the use of Trastuzumab in association with chemotherapy is superior to the use of chemotherapy alone, with a significant increase in survival in both metastatic disease and adjuvant.

Lapatinib (TykerbR)

Lapatinib is an inhibitor of HER 1 (EGFR) and HER 2 receptors that acts intracellularly. It is a small molecule that crosses the cell membrane and binds to the intracellular part of the receptor (tyrosine kinase inhibitor), preventing cell proliferation. Lapatinib is currently indicated in combination with Capecitabine in patients with advanced or metastatic breast cancer who have previously progressed with Anthracyclines Taxanes and Trastuzumab.

Lapatinib has also been studied in patients with metastatic disease who have progressed from previous treatments containing Trastuzumab to receive the combination of Trastuzumab with Lapatinib or as monotherapy. The results favored the combination of drugs with a significant increase in the disease-free interval.

Tucatinib is an oral tyrosine kinase inhibitor that is highly selective for the kinase domain of Her2 with minimal inhibition of the epidermal growth factor receptor, which may alter the toxicity profile. In a phase 1b dose-escalation study, Tucatinib in combination with Trastuzumab and Capecitabine demonstrated encouraging antitumor activity in patients with Her2 positive metastatic breast cancer, including those with brain metastases.

Pertuzumab (PerjetaR)

Usually HER2 receptors are dimerized, with HER2 itself or with the other receptors of the HER family (HER1, HER3, HER4). Pertuzumab works by blocking the dimerization of these receptors, and in this way there is an interruption of cell growth and induction of apoptosis (cell death). is the treatment of choice for first-line, metastatic, HER2 positive disease.

T-DM1 (KadcylaR)

T-DM1 (Trastuzumab Entansina) is a conjugated antibody and represents a new approach that confers selectivity on the administration of a highly potent cytotoxic agent. The mechanism of action is twofold: in addition to the biological properties of Trastuzumab, already described, there is an intracellular cytotoxic action with the release of Entansin, through the action of lysosomes. In this way, systemic exposure to DM1 is minimized, which results in much smaller side effects than conventional chemotherapy. This medication is known to be effective in patients with HER2 positive breast cancer in metastatic disease. 

Trastuzumab Deruxtecan (DS-8201)

Trastuzumab Deruxtecan (DS-8201) is a conjugated antibody composed of a monoclonal antibody specific for HER2 with a potent topoisomerase I inhibitor as a cytotoxic drug. Trastuzumab Deruxtecan has shown good results in patients with HER2 positive metastatic breast cancer who have undergone extensive previous therapies

Bevacizumab (AvastimR)

Bevacizumab is a monoclonal antibody that blocks the action of VEGF (vascular endothelial growth factor), that is, it prevents the growth of cancerous vascular cells. Study showed that the use of Paclitaxel plus Bevacizumab prolonged the disease-free interval (but not the overall survival) of patients with metastatic breast cancer, when compared to Paclitaxel

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What are Immune Control Inhibitors for Cancer Treatment?

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An important function of the immune system is its ability to attack normal and abnormal cells in the body. To do this, it uses checkpoints, so-called immune control molecules on immune cells, which need to be turned on (or turned off) to initiate an immune response. In English, they are called check point inhibitors, or checkpoint inhibitors. Cancer cells sometimes use these checkpoints to avoid being attacked by the immune system. Modern immunotherapeutic drugs target these control points, re-establishing the activity of these immune cells to fight cancer cells. These medications have proven to be helpful against many types of cancer in recent years.

What drugs target PD-1 or PD-L1?

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PD-1 is a checkpoint protein in cells of the immune system called T cells. It normally acts as a kind of off switch that prevents T cells from attacking other cells in the body. It does this when it binds to PD-L1, a protein in normal (and cancer) cells. When PD-1 binds to PD-L1, it basically tells the T cell to leave the other cell alone. Some cancer cells have large amounts of PD-L1, which allows them to escape immune attack.

Monoclonal antibodies that target PD-1 or PD-L1 can block this binding and stimulate the immune response against cancer cells. These medications have been shown to be useful in treating various types of cancer.

PD-1 inhibitors. Examples of drugs that target PD-1 include: Pembrolizumab and Nivolumab.

Pembrolizumab is a monoclonal antibody with anti-programmed death 1 (PD-1), shown to have an antitumor activity and mainly low-grade toxic effects in patients with triple negative metastatic breast cancer, especially when used as a first-line treatment

PD-L1 inhibitors. Examples of drugs that target PD-L1 include: Atezolizumab, Avelumab. and Durvalumab.

The application of Atezolizumab together with a chemotherapy agent significantly increased women's survival. Atezolizumab offers an option precisely against the most aggressive subtype of the disease and the one most in need of innovation: the triple-negative breast tumor. The drug is indicated for advanced or metastatic cases of the disease, that is, when it has already spread to other organs.

These drugs have also been shown to be useful in treating a variety of cancers, including bladder cancer, non-small cell lung cancer, and Merkel cell skin cancer. They are also being studied for use against other types of cancer.

One concern with these medications is that the immune system attacks some healthy organs in the body, leading to side effects, which can include fatigue, coughing, nausea, loss of appetite, rash, and itching. Other more serious effects may also occur less frequently, such as problems with the lungs, intestines, liver, kidneys, hormone-producing glands or other organs.

Many other drugs that target PD-1 or PD-L1 are being studied in clinical trials, either alone or in combination with other drugs.

Tucatinib is an oral tyrosine kinase inhibitor that is highly selective for the kinase domain of Her2 with minimal inhibition of the epidermal growth factor receptor, which may alter the toxicity profile. In a phase 1b dose-escalation study, tucatinib in combination with trastuzumab and capecitabine demonstrated encouraging antitumor activity in patients with Her2 positive metastatic breast cancer, including those with brain metastases.