Breast cancer

Question 1

Estrogen receptor

Answer 1

• activated upon binding estrogen
• gene expression induced by binding to Specific DNA Sequences called Estrogen Response Elements
• Estrogen-induced gene products increase cell proliferation, resulting in breast cancer

Question 2

Important estrogen regulated genes

Answer 2

• Progesterone receptor
• Cyclin D1
• c-myc
• TGF-alpha

Question 3

Major treatment approaches for breast cancer

Answer 3

• Surgery
• Radiation therapy
• Chemotherapy
• Endocrine therapy

Question 4

Endocrine therapy

Answer 4

• cornerstone of breast cancer treatment
• therapy results in ovarian suppression, blocking estrogen production by enzymatic inhibition and inhibiting estrogen responses

Question 5

Hormonal control of target tissues

Answer 5

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Question 6

What is the major source of estrogen biosynthesis in pre-menopausal women?

Answer 6

Ovaries

Question 7

Ovarian ablation

Answer 7

Carried out by:

• Surgical oophorectomy
• Ovarian irradiation

-major problems with these procedures are morbidity and irreversibility=overcome by designing treatments to produce medical ovarian ablation

Question 8

LHRH agonists

Answer 8

• Luteinising Hormone Releasing Hormone agonists
• reversible and reliable medical ovarian ablation
• bind to LHRH receptors in pituitary leading to receptor down-regulation and LH release suppression and ovarian function inhibition (including estrogen production)
• examples include Goserelin, Buserelin, Leuprolide and Triptorelin

Question 9

Aromatase inhibitor target sites

Answer 9

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Question 10

LHRH agonist target site

Answer 10

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Question 11

Antiestrogens target site

Answer 11

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Question 12

Breast cancer risk factors

Answer 12

• early age of onset of menarche (first occurrence of menstruation)
• late age of menopause
• age at first full-term pregnancy
• some forms of contraceptive pill
• Hormone Replacement Therapy (HRT)
• Obesity
• Diet, physical activity, height, medication (aspirin)

Question 13

Breast cancer screening

Answer 13

• mammography to screen all women 50-64 years old who are registered with a GP in the UK
• screening age being extended to 70 years old across the country
• each patient asked to attend test once every 3 years
• > 70% of women attend breast screening appointments=more than 1,200,000 women screened for breast cancer each year
• only 6/100 are asked to go back for more tests
• > 90% of breast tumours are first spotted by women themselves

Question 14

Patient history of breast cancer

Answer 14

1) lump detected (self examination/GP)
2) referred to hospital
3) examined by surgical team (mammogram, FNA)
4) surgery performed (lumpectomy/mastectomy)
5) tumour examined pathologically (ER/PR)
6) see physician for first time

Question 15

Problems with using Tamoxifen in breast cancer prevention

Answer 15

• increase incidence of endometrial cancer
• stroke
• deep vein thrombosis
• cataracts

Question 16

Overcoming problems with Tamoxifen

Answer 16

Prevention trials are being conducted with:

• Raloxifene/ Faslodex (SERM)
• Aromatase inhibitors

Question 17

Aromatase inhibitors

Answer 17

• in postmenopausal women, the major source of estrogen derives not from ovaries but from enzymatic conversion of adrenal hormones Androstenedione (A) and to a lesser extent, Testosterone, to Estrogen=occurs at extra-adrenal or peripheral sites (fat, liver and muscle)
• enzymatic conversion catalysed by aromatase enzyme complex

Question 18

Aromatase

Answer 18

• consists of a complex containing a cytochrome P450 heme containing protein and the flavoprotein NADPH cytochrome P450 reductase
• catalyses 3 separate steroid hydroxylations involved in androstenedione conversion to estrone
• aromatase can metabolise androstenedione (produced by adrenal glands)=leads to estrone sulphate production which is circulated in plasma

Question 19

Type I aromatase inhibitors

Answer 19

-mechanism-based/suicide

Question 20

Type II aromatase inhibitors

Answer 20

-competitive

Question 21

Progestins in breast cancer

Answer 21

• progesterone is the dominant naturally occurring progestin
• poor absorption of progesterone=overcome with some synthetic derivative progestins
• progestin response in the human breast=complex and influences both proliferation and differentiated function
• progestins used in endocrine treatment of uterine and breast cancer with clinically proven antineoplastic properties
• progestin therapy for metastatic breast cancer=used principally as second or third line therapy following selective estrogen
• principal progestin used for metastatic breast cancer has been megestrol acetate

Question 22

Estrogen receptors in breast cancer

Answer 22

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Question 23

Estrogens and anti-estrogens

Answer 23

• Tamoxifen=competitive inhibitor of estradiol binding to ER
• antiestrogens negate stimulatory effects of estrogen=block ER causing cell to be held at G1 phase of cell cycle
• Tamoxifen=endocrine treatment of choice for metastatic disease in postmenopausal patients (~1/3 patients respond)
• few side effects reported=hot flushes (29% reported) most commonly reported during Tamoxifen therapy

Question 24

Tamoxifen

Answer 24

• Selective estrogen receptor modulators (SERMs)
• estrogenic effects in bone
• estrogenic effects in the cardiovascular system
• Anecdotal reports associating the administration of Tamoxifen for advanced breast cancer with subsequent thromboembolic episodes
• Tamoxifen is known to produce endometrial thickening, hyperplasia and fibroids following several years of therapy

Question 25

Estrogen desirable effects

Answer 25

• improves cognitive function (brain)
• programs glands to produce milk (breast)
• lowers cholesterol, reduces atherosclerosis and heart attacks (liver and heart)
• programs uterus to nourish a foetus (uterus)
• maintains density to help prevent bone loss (bone)

Question 26

Estrogen negative effects

Answer 26

• promotes breast cancer (estrogen)
• increases thromboembolism (liver)
• promotes endometrial cancer (uterus)

Question 27

Tamoxifen desirable effects

Answer 27

• reduces breast cancer (breast)
• lowers cholesterol, reduces atherosclerosis and heart attacks (liver and heart)
• maintains density to help prevent bone loss (bone)

Question 28

Tamoxifen negative effects

Answer 28

• increases vasomotor symptoms (hypothalamus)
• increases cataracts (eye)
• increases thromboembolism (liver)
• promotes endometrial cancer, fibroids, polyps and vaginal discharge (uterus)