Anti-oestrogens

Question 1

What are hormones?

Answer 1

Hormones are substances which function as chemical messengers in the body. They affect the actions of cells and tissues at various locations in the body and often reach their targets through the bloodstream.

Question 2

Where are oestrogen and progesterone produced?

Answer 2

They are produced by the ovaries in premenopausal women and by some other tissues including fat and skin in both premenopausal and postmenopausal women and men. Oestrogen promotes the development and maintenance of female sex characteristics and the growth of lone bones. Progesterone plays a role in the menstrual cycle and pregnancy.

Question 3

How does oestrogen and progesterone promote growth of breast cancers?

Answer 3

Hormone sensitive breast cancer cells contain receptors which become activated when hormones bind to them. The activated receptors cause changes in the expression of specific genes which can stimulate cell and tumour growth.

Question 4

What is hormone therapy?

Answer 4

Hormone therapy slows or stops the growth of hormone sensitive tumours by blocking the body’s ability to produce hormones or by interfering with effects of hormones on breast cancer cells. Tumours that are hormone insensitive do not have hormone receptors and do not respond to hormone therapy.

Question 5

How are breast cancer cells which contain hormone receptors detected?

Answer 5

By performing a biopsy and testing the sample. If the tumour cell contains oestrogen receptors the cancer is called oestrogen receptor positive. If the tumour cell contains progesterone receptors the cancer is called progesterone receptor positive.

Question 6

What are breast cancers which lack oestrogen or progesterone receptor?

Answer 6

Oestrogen receptor negative. They are oestrogen insensitive, meaning they do not use oestrogen to grow. Breast tumours that lack progesterone receptors are called progesterone receptor negative. Breast tumours that lack both oestrogen and progesterone receptors are called hormone receptor negative.

Question 7

How do protein receptors relate to cancer?

Answer 7

Some breast cancers have high numbers of receptors for the protein HER2. They are HER2 positive breast cancers.

Question 8

What is a treatment for HER2 positive breast cancer?

Answer 8

Herceptin – Trastuzumab.

Question 9

What are the type of hormone therapies used for cancer?

Answer 9

Blocking ovarian function.
Blocking oestrogen production.
Blocking oestrogen effects.

Question 10

How does blocking ovarian function work?

Answer 10

Ovaries are the main source of oestrogen in premenopausal women, oestrogen levels in these women can be reduced by eliminating or suppressing ovarian function. Blocking ovarian function is called ovarian ablation.
Ovarian ablation can be done surgically to remove the ovaries or by radiation treatment. This is permanent.
Ovarian function can be suppressed by drugs called gonadotropin releasing hormone agonists which interfere with signals from the pituitary gland that stimulate the ovaries to produce oestrogen eg Zoladex.

Question 11

How can oestrogen function be blocked?

Answer 11

Aromatase inhibitors block the activity of aromatase which the body uses to make oestrogen in the ovaries and other tissues. They are used in menopausal women because the ovaries in premenopausal women produce too much aromatase for the inhibitors to block effectively. Examples are Arimidex and Femara.

Question 12

What is the function of aromatase?

Answer 12

To produce oestrogen by aromatising androgens. Aromatase is capable of catalysing the aromatisation of 6 membered ring. Aromatase converts androstenedione to oestrogen and testosterone to oestradiol.

Question 13

How can the effects of oestrogen be blocked?

Answer 13

By using selective oestrogen receptor modulations which bind to oestrogen receptors and prevent oestrogen from binding.
By using Faslodex which binds to the oestrogen receptor and functions as an oestrogen antagonist. It has no oestrogen agonist effect and when it binds to the receptor, the receptor is targeted for destruction.

Question 14

What are the main ways that hormone therapy is used to treat hormone sensitive breast cancer?

Answer 14

Adjuvant therapy for early-stage breast cancer.
Treatment of advanced or metastatic breast cancer.
Neoadjuvant treatment of breast cancer.

Question 15

What is adjuvant therapy for early-stage breast cancer?

Answer 15

Women who receive 5 years of adjuvant therapy with tamoxifen have reduced risk of breast cancer recurrence. It is used for post-menopausal and premenopausal women with ER positive early stage breast cancer and the aromatase inhibitors anastrozole and letrozole are approved for this use in postmenopausal women.
Exemenstane is approved for adjuvant treatment of early stage breast cancer in postmenopausal women who have received tamoxifen previously.

Question 16

What is the treatment for advanced or metastatic breast cancer?

Answer 16

Hormone therapy is a treatment option for ER positive breast cancer that has come back into the breast, chest wall or nearby lymph.
Tamoxifen and toeremifene are approved for the treatment of metastatic breast cancer. Fulvestrant is approved for postmenopausal women with metastatic ER positive breast cancer which has spread after treatment with other antioestrogens.
Aromatase inhibitors anastrozole and letrozole are approved for the use in postmenopausal women as initial therapy for metatsic or locally advanced hormone sensitive breast cancer. They are used to treat post menopausal women with advanced breast cancer whose disease has worsened after treatment with tamoxifen.
Some women are treated with combination of hormone therapy and targeted therapy eg lapatinib is used in combination with aromatase inhibitor to treat hormone receptor positive, HER2 positive metastatic breast cancer in postmenopausal women.

Question 17

What is neoadjuvant treatment of breast cancer?

Answer 17

It is used to reduce the size of a breast tumour to allow breast conserving surgery. Neoadjuvant hormone therapy with aromatase inhibitors can be effective in reducing the size of breast tumours in postmenopausal women. The result in premenopausal women are less clear because only a few small trials involving relatively few premenopausal women have been conducted.

Question 18

Can hormone therapy be used to prevent breast cancer?

Answer 18

Yes. A trial found that tamoxifen taken for 5 years reduced the risk of developing invasive breast cancer by around 50% in postmenopausal women who were at an increased risk.
Two aromatase inhibitors – exemestane and anastrazole have been found to reduce the risk of breast cancer in postmenopausal women at increased risk of the disease. Women who took exemestane were 65% less likely than those who took placebo to develop breast cancer.

Question 19

What are the side effects of hormone therapy?

Answer 19

They depend on the drug or the type of treatment. The benefits and harms of taking hormone therapy should be carefully weighted.
Hot flashes, night sweats, vaginal dryness are common side effects. It also disrupts the menstrual cycle in premenopausal women.

Question 20

What other drugs affect hormone therapy?

Answer 20

Antidepressant SSRIs inhibit CYP2D6 which plays a role in the use of tamoxifen by the body because it metabolises it into metabolites which are more active than tamoxifen itself. This slows the metabolism of tamoxifen and reduces the effectiveness.
Patients should be switched from SSRI to a weaker inhibitor to CYP2D6 eg sertraline, venlafaxine or citalopram. Postmenopausal women should take an aromatase inhibitor instead of tamoxifen.