Hormonal Therapy and Breast Cancer

Used to eliminate tumours expressing the ER- and PR-hormone receptors, hormonal therapy blocks the body’s response to hormones or decreases the amount of estrogen in the body. This treatment aims to stop or slow the cancer’s progression. It is often prescribed after surgery and radiation therapy to reduce the risk of recurrence.

There are different types of hormonal therapy, including the following:

Anti-estrogens

  • Tamoxifen (blocks the ER receptor)
  • Fulvestrant (degrades the ER receptor)
  • Aromatase (the key enzyme in estrogen synthesis) inhibitors, such as Letrozole, Anastrozole Exemestane (decrease estrogen levels)
  • Luteinizing hormone-releasing hormone analogues, such as Goserelin, Leuprolide, Buserelin (suppress estrogen production by the ovaries)
  • Oophorectomy (surgery to remove the ovaries, the major estrogen producers): For pre-menopausal women who no longer wish to bear children

Hormonal therapy can cause various side effects, including:

  • Hot flashes
  • Weight gain
  • Decreased libido
  • Osteoporosis (in the case of aromatase inhibitors)
  • Constipation, diarrhea or nausea
  • Reduced fertility
  • Fatigue
  • Vaginal discharge
  • Change in cholesterol levels
  • Hair thinning (in the case of aromatase inhibitors)

Research continues to evaluate the possibility of giving hormonal therapy to women at high risk of breast cancer before cancer develops. The health risks have yet to be assessed.

Targeted therapies

A targeted therapy is a drug that pinpoints specific abnormal molecules within the cancer cells to slow or stop the growth of these cells.

The most commonly used targeted therapy is HER2 inhibitor therapy. Other targets are beginning to be found and are increasingly being used, especially to reduce the risk of recurrence or to treat metastatic cancer that no longer responds to other conventional treatments.

Many targeted drugs are being investigated to improve breast cancer treatment.

HER2-targeted therapies

Therapies targeting the HER2 gene inhibit this receptor and block its ability to proliferate. They are used to destroy tumours with strong HER2 gene expression in order to slow or stop the cancer’s progression. This treatment is often administered after surgery and radiation therapy to prevent the risk of recurrence.

The side effects are usually less severe than for other treatments, since targeted therapies only affect the cancer cells. Side effects of hormonal therapy include:

  • Headaches
  • Fatigue
  • Diarrhea or constipation, nausea and vomiting
  • Mouth sores
  • Infection
  • Red, dry or itchy skin
  • Loss of appetite

Trastuzumab is one such agent. Sometimes this drug may cause heart damage, especially when given in combination with Doxorubicin, a chemotherapeutic agent. Cardiac tests may therefore be recommended before taking Trastuzumab to ensure this treatment will be safe.

Here are some of the available agents in this therapeutic class:

  • Trastuzumab (Herceptin) has been available since the late 1990s and has greatly improved the prognosis of HER2-positive cancers.
  • Pertuzumab (Perjeta) has been used more recently to treat metastatic breast cancer.
  • Trastuzumab Emtansine (Kadcycla) is a newer agent used to treat metastatic breast cancer. It combines Trastuzumab and Emtansine, a chemotherapeutic agent. As a result, the chemotherapy targets cancer cells more precisely.

Research continues to improve HER2-targeting therapy. For example, resistance to Trastuzumab is often observed after one year of use. Treatments to counter this are currently being developed. Also, studies are underway on Pertuzumab and Trastuzumab Emantansin to test their effectiveness in treating early breast cancer and their effect when given in combination with other treatments. New antibodies under investigation (such as Margetuximab) 

Other targeted therapies

Several cellular pathways are involved in the progression of breast cancer. Acting on these pathways may slow or stop the progression of the cancer.

The targeted therapies, other than HER2 inhibitors, are: (liens vers tableaux)

  • Tyrosine kinase inhibitors
  • Cyclin-dependent CDK4 and CDK6 kinase inhibitors
  • PI3K-Akt-mTor intracellular signalling pathway inhibitors

Studies are underway on the use of these drugs for different types and stages of breast cancer. Several drug molecules targeting these pathways are being developed and the efficacy of combinations of different strategies is also being studied.

Targeted therapies under investigation include:

  • Histone deacetylase inhibitors (HDACs) 
  • Steroid sulfatase inhibitors 
  • EGFR inhibitors 
  • Farnesyltransferase inhibitors

Tyrosine kinase is an enzyme activated by receptors in the EGFR family. Tumours with HER2 overexpression have high tyrosine kinase activity. Inhibiting this enzyme can inactivate the HER2 pathway and slow the cancer’s progression. Lapatinib and Neratinib are two agents belonging to this targeted-therapy class.

CDK4 and CDK6 are enzymes involved in the cell cycle and proliferation. Cyclin D1 and CDK4 are overexpressed in 29% and 14% of breast cancers, respectively. This is a promising treatment option for hormone-resistant tumours, since cells need CDK4 and CDK6 to proliferate. Palbociclib (approved for advanced HER2-negative cancers), Ribociclib (also approved for advanced HER2-negative cancers) and Abemaciclib (under study) are in this class of targeted-therapy agents.

PI3K-Akt-mTor are enzymes of a cell-signalling pathway that are activated by receptors in the EGFR family and are involved in cell growth and proliferation. The PI3K-Akt-mTor pathway is overactivated in approximately 70% of breast cancers (enzyme mutations), and sustained activation of this pathway can lead to resistance to treatment.

To produce proteins, DNA is often modified by chemical groupings. One such modification is acetylation, which controls gene expression (the transcription of a gene into a protein) and can cause a protein to be synthesized or not.

HDAC (histone deacetylase) is an enzyme that removes acetyl groups from DNA. This protein is often overexpressed in cancers and causes a misproduction of the proteins involved in the progression of breast cancer.

Like aromatase, steroid sulfatase is an enzyme involved in the synthesis of estrogen. This enzyme is often overexpressed in breast cancers.

Like HER2 activity, the activity of other members of this receptor family (EGFR, HER3 and HER4) may contribute to cell proliferation. Inhibitors of these receptors are currently being investigated.

Farnesylation is a protein modification that activates Ras, an enzyme in a HER2-activated signalling pathway. Blocking farnesyltransferase inhibits Ras and thus slows cell proliferation.

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