Hormonal treatment
Types
surgical | oncology
adjuvant | neo adjuvant | hormonal | chemotherapy | radiotheraphy | follow-up

Hormonal (Endocrine) Manipulation

There are a number of endocrine therapies available today. Endocrine therapy can result in palliation of disease in 50% to 60% of patients with hormone receptor-positive breast cancer.

Manipulation of the endocrine system for the treatment of breast cancer was first used in 1896. Endocrine therapies are directed at either reducing the synthesis of oestrogen or blocking the oestrogen receptor.

Tamoxifen citrate was approved by the US Food and Drug Administration for use in advanced breast cancer in 1978. Selective estrogen receptor modulators (SERMs), as tamoxifen, antagonize estrogen receptor (ER) function by binding competitively to it. Since 1978, more than 40,000 breast cancer patients, most of them postmenopausal, have been treated with tamoxifen, either in the context of clinical research studies or in clinical practice.

Tamoxifen as the standard of care

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SERMS Selective estrogen receptor modulators selectively bind to oestrogen receptors on the surface of breast cancer cells. They prevent oestrogen exerting its stimulatory action on the cancer cells. These drugs block the action of oestrogenic compounds such as 17-β oestradiol and oestrone. Drugs such as tamoxifen and toremifene have some effects that are like oestrogen and some that are antioestrogen. As stated above, these drugs bind to oestrogen receptors on many cells throughout the body. Breast epithelial cells and thus breast cancer cells. Here these drugs inhibit the breast cancer cells. They block the capacity of breast cancer cells to replicate (divide and grow) and invade. They also decrease the risk getting another cancer by 50% in the contralateral (opposite) breast. Lining cells of the uterus - here tamoxifen acts like oestrogen and increases the risk of cancer of the womb. Cells of the heart (coronary artery endothelial cells). Here toremifene and tamoxifen have similar beneficial effects like oestrogen ie reduction in the incidence of ischaemic heart disease (coronary artery disease). Osteoporosis (thin fragile bones) also seems to improve with the antioestrogens.

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Antioestrogens are used in many settings and guises in the treatment of breast cancer. They are primarily used in the treatment of premenopausal women with breast cancer. The biochemical mechanism of action of oestrogen, tamoxifen or toremifene, can be illustrated by studying the following diagramme. Basically when oestrogen attaches to the surface of the breast cancer cell, it influences the genes in the nucleus via the signal transduction pathway. The oncogenes are the initiators of the cancer. The oestrogen hormone is a promoter of the cancer. Together they stimulate the cell, not only to become malignant, but also to grow and metastasise. Toremifene or tamoxifen, by attaching to these receptors, prevents and blocks oestrogen from stimulating the receptors and thus initiating the signal transduction molecular sequence.

Side effects of these SERMS are bothersome hot flashes and vaginal discharge a 2.4 times greater risk of developing invasive endometrial cancer, and thromboembolism.

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Aromatase Inhibitors :Aromatase inhibitors (AIs) work by blocking the enzyme complex responsible for the final step in estrogen synthesis, aromatase, thus preventing the production of the substrate of the Estrogen Receptor. Therefore, unlike tamoxifen, the AIs have no partial agonist activity. An example of non selective aromatase inhibitors is aminoglutethimide. The selective aromatase inhibitors include drugs such as formestane, anastrozole, letrozole, exemestane and fadrozole. In postmenopausal women, all of the third generation AIs suppress circulating estrogen levels by approximately 98%. In contrast to the second generation inhibitors (eg, formestane), they are highly specific with almost no effect on cortisol or aldosterone levels. AIs can be classified by their mechanism of action into steroidal (irreversible, type I) and nonsteroidal (reversible, type II) inhibitors. The inhibitors in clinical use today include the third-generation nonsteroidal agents anastrozole and letrozole and the third-generation steroidal aromatase inactivator exemestane. Their pharmacokinetic profiles are similar, with anastrozole and letrozole having longer half-lives (48 hours) than exemestane (27 hours). All of them are administered orally once daily.

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Side effects of these drugs are joint aches, less hot flushes and weight gain than Tamoxifen.

According to the JCO guidelines adjuvant therapy for postmenopausal women with hormone receptor–positive breast cancer should include an aromatase inhibitor in order to lower the risk of tumor recurrence. Neither the optimal timing nor duration of aromatase inhibitor therapy is established. Aromatase inhibitors are appropriate as initial treatment for women with contraindications to tamoxifen.

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For all other postmenopausal women, treatment options include 5 years of aromatase inhibitors treatment or sequential therapy consisting of tamoxifen (for either 2 to 3 years or 5 years) followed by aromatase inhibitors for 2 to 3, or 5 years. Patients intolerant of aromatase inhibitors should receive tamoxifen.

Luteinizing Hormone-Releasing Agonists:
These drugs suppress ovarian function to a degree similar to surgical ablation. These drugs reduce the release of oestrogen by providing constant high levels of pituitary – releasing hormone receptors and shutting down gonadotropin production.