clinical oncology 4: breast cancer

Question 1

epidemiology of breast cancer:

Answer 1

• 1/5 cancer deaths in women
• 1 in 9 females develop breast cancer
• incidince rising (55,000 women a year diagnosed in UK)
• mortality decreasing (as a result of early Dx, chemo/radiotherapies + hormonal treatments)

Question 2

what are the risk factors for breast cancer?

Answer 2

• early menarche
• late menopause
• age at first full term pregnancy
• contraceptive pill
• HRT
• obesity
• diet, physical activity, heart and meds

Question 3

what is the screening program for breast cancer?

Answer 3

mammography every 3 years between the ages of 50 & 64

• 6/100 need more tests
• 90% cancers first spotted by women themselves

Question 4

what is the cellular organisation of the mammary gland?

Answer 4

layer of myoepithelial cells (making contact with basement membrane) around luminal cells

Question 5

what is the pathogenesis of breast tumours?

Answer 5

luminal epithelial cells become cancerous -> proliferate within basement membrane (carcinoma in situ) -> break through basement membrane + spread

Question 6

what are the main types of breast cancer?

Answer 6

infiltrating ductal carcinoma (account for 80%, show no special histological structure) infiltrating lobular carcinomas (5-15%)

Question 7

what happens when oestrogen binds to the human oestrogen receptor?

Answer 7

formation of intracellular complex -> enters nucleus -> binds to ‘response elements’ on DNA -> induce gene expression

Question 8

what are some examples of important oestrogen regulated genes?

Answer 8

• progesterone receptor (PR)
• cyclin D1
• c-myc
• TGF-α

Question 9

what percentage of breast cancers are oestrogen receptor positive?

Answer 9

80%

• sample stained with antiboidies against HER
• around 70% of breast cancers overexpress ER

Question 10

what are the surgical treatment options for breast cancer?

Answer 10

mastectomy: removal of breast
lumpectomy: removal of tumour + margin of tissue

Question 11

what are the basic mechanisms of endocrine therapies for breast cancer?

Answer 11

• ovarian suppression
• blocking oestrogen by inhibiting enzymes
• inhibiting oestrogen response

Question 12

what is ovarian ablation?

Answer 12

elimination of ovarian source of oestrogen via surgical oophrectomy / irradiation or medial methods that avoid morbidity and irreversibility

Question 13

how do LHRH agonists work?

Answer 13

bind to pituitary LHRH receptors -> cause down-regulation and suppression of LH release -> inhibit ovarian function
eg goserelin, triptorelin

Question 14

how do anti-oestrogens work?

Answer 14

act as competitive inhibitors of oestradiol binding to ERs -> negate stimulatory effects of oestrogen -> holds cell at G1 phase of cell cycle
eg tamoxifen

Question 15

what is tamoxifen?

Answer 15

competitive inhibitor of oestradiol

Question 16

when is tamoxifen used?

Answer 16

in metastatic disease of post-menopausal patients

• 1/3 respond (reducing reccurence by 1/2 and mortality by 1/3)
• few side effects reported (most commonly hot flushes in 30%)

Question 17

what are SERMs?

Answer 17

selective oestrogen receptor modulators

eg tamoxifen

Question 18

what are the positive and negative effects of tamoxifen?

Answer 18

positive:
- breast (reduces breast cancer)
- liver & heart (lowers cholesterol, reduces atherosclerosis & heart attacks)
- bone (maintains density)

negative:
- hypothalamus (increases vasomotor symptoms)
- eye (increases cataracts)
- liver (increases thromboembolism)
- uterus (promotes endometrial cancer, fibroids, polyps & vaginal discharge)

Question 19

what does aromatase do?

Answer 19

catalyses 3 separate steroid hydroxylations involved in conversion of androstenedione to oestrone
- major source of post-menopausal oestrogen is adrenal androgens converted to oestrogens in extra-adrenal sites eg fat/liver/muscle by aromatase complex

Question 20

what are the types of aromatase inhibitors?

Answer 20

type 1: irreversible suicide inhibitors - initially compete with natural substrate but upon binding, the enzyme acts on substrate to yield reactive alkylating species -> forms covalent bonds near active site to inactivate it
eg exomestane -> significant decrease in oestrogen plasma concentration

type 2: bind reversibly to active site to reduce product formation eg anastrozole -> suppresses plasma oestrogen

Question 21

what effect does progesterone have on breast cancer?

Answer 21

influences proliferation & differentiated function