Cancer 12 - Breast cancer

Question 1

Breast cancer is the leading female cancer. How come the mortality rate has decreased in breast cancer

Answer 1

1. Early diagnosis
2. Chemo/radiotherapies
3. Hormonal therapies

Question 2

What is the only organ that develops post natally.

Answer 2

Breast.

It develops into fatty and glandular structures in puberty to produce milk for neonates.

Any part of breast/mammary gland can give rise to tumours

Majority of breast cancers arise from ductal epithelial tissue

Question 3

There are 2 layers of epithelial cells that surround breast lumen. Describe them

Answer 3

1. Inner epithelial layer - luminal epithelial cells - have receptors that respond to hormone therapy - 90% of breast cancers occur here
2. Myoepithelial cells - occur more deep - contact basement membrane - they contract and push substances out of the luminal cells into lumen.

NB - there are fatty stromal cells between tubules

Question 4

Describe the progression of normal breast to malignant breast cancer

Answer 4

1. Benign/carcinoma in situ - luminal cells proliferate but my-epithelium not breached - precancerous state.

Subsequent cancer can be crudely divided as:

2. Lobular carcinoma - tumour cells adopt tubular like arrangement - no myoepithelial cells present anymore. Cells behave relatively normal

Or

3. Medullary carcinoma - tumour cells have hormones/peptides. Look neuroendocrine in origin

or

4. Infiltrating/invasive ductal carcinoma (IDC) - they have no special histological structure. Immunohistochemical staining (antibodies) against Human Oestrogen receptor (ER) is informative

Can classify tumours based on degrees of ER expression

Question 5

80-90% of breast cancers are Oestrogen receptor positive, meaning

Answer 5

They grow in response to oestrogen

Question 6

The oestrogen receptor is cytosolic and ligand activated transcription factor. How does it work

Answer 6

1. Oestrogen is lipophilic - passes through cell membrane and binds ER (displaces HSP)
2. 2x activated ERs dimerise –> enters nucleus (oestrogen bound) –> locates specific DNA sequences (oestrogen response elements)
3. Oestrogen induced gene products increase cell proliferation –> resulting in breast cancer

Question 7

Name 4 important oestrogen regulated genes

Answer 7

1. Progesterone receptor - if you find PR activity, shows that ER activated
2. Cyclin D1
3. C-myc (apoptosis regulation)
4. TGF-a (growth factor)

Question 8

Why is dimerisation of the ERs important

Answer 8

The response element is present in 2 halves –> each half of the dimer will bind to half of response element

Question 9

1/3 of PREMENOPAUSAL women respond to which treatment?

Answer 9

Oophorectomy - remove main source of oestrogen

Question 10

Paradoxically, giving High-dose oestrogen seems to cause breast tumour regression in post-menopausal women - why

Answer 10

If overstimulate tumour –> ER down regulated –> no longer as responsive to oestrogen

Cons - poor tolerance –> eventual resistance and metastasis

Question 11

ER is over expressed in most breast cancers, and the presence of ER is indicative of a better prognosis. Increased ER indicates a worse prognosis in?

Answer 11

Men

Question 12

What are the major treatment approaches to breast cancer

Answer 12

1. Surgery
2. Radiation therapy
3. Chemotherapy
4. Endocrine therapy - can be adjuvant therapy if after surgery, or non-adjuvant if before surgery to shrink size of tumour

Question 13

The basis for endocrine therapy of breast cancer is inhibiting oestrogen action in the breast. How

Answer 13

1. Ovarian suppression
2. Blocking oestrogen production by enzymatic inhibition
3. Inhibiting oestrogen responses

Question 14

Aside from the ovaries, where else is oestrogen made?

Answer 14

In the adrenal glands –> from androgens via aromatase

i.e. inhibit aromatase –> prevent conversion of androgens into oestrogens

Question 15

Ovarian ablation therapy aims to eliminate the ovaries (major source of oestrogen production in pre-menopausal women). How

Answer 15

1. Surgical oophorectomy
2. Ovarian irradiation

But these had major problems - morbidity and irreversibility.

SO, “medical ovarian ablation” developed - more pharmaceutical –> LHRH AGONIST

LHRH agonist binds to LHRH receptor in pituitary gland —> leads to receptor downregulation and suppression of LH release and inhibition of ovarian function –> minimal oestrogen production.

Benefit is that LHRH agonist is reversible and controllable through pregnancy.

e.g. LHRH agents = goserelin, Mbuserelin, leuprolide, triptorelin

Question 16

LHRH agonists, aromatase inhibitors and anti-oestrogens can be given for breast cancer therapy. How do antioestrogens work

Answer 16

They essentially block ER in mammary gland.

Antioestrogens negate stimulatory effects of oestrogen by blocking ER –> cells effectively held at G1 of cell cycle

1. Tamoxifen = competitive inhibitor of ER. Non-steroidal anti-oestrogen. Endocrine treatment of choice for metastatic disease in postmenopausal women. Few SEs (hot flushes and cataracts most common),

Tamoxifen is a SERM (Selective ER modulator)

Weirdly, tamoxifen has oestrogenic effects in bone (i.e. acts as an agonist in bone) - so no osteoporosis

Tamoxifen is also oestrogenic in CVS - good.

Undesirably - tamoxifen = endometrial thickening, hyperplasia and fibroids.

But tamoxifen may reduce incidence of contralateral breast cancer

Question 17

Aside from tamoxifen, what other anti-oestrogens are there?

Answer 17

1. Toremifene - structural derivative of tamoxifen with similar effects
2. Faslodex (SERM) = it is a PURE anti-oestrogen (i.e. anti-oestrogen in all tissues - 2nd line must be carefully managed). May offer advantages over tamoxifen - decreasing tumour cell invasion and decreasing endometrial carcinoma
3. Raloxifene - used for osteoporosis treatment in post-menopausal women. Agonist in bone but no activity in breast / uterus

Question 18

What are the problems associated with using Tamoxifen prophylactically

Answer 18

1. increased risk of endometrial cancer
2. Stroke
3. DVT
4. Cataracts

Question 19

Postmenopausally, major oestrogen source = conversion of adrenal hormones (androstenedione + testosterone) to Estrone, via CYP450 enzymes. Explain how aromatase inhibitors work

(side note - oestrogen in blood often circulates with sulphate)

Answer 19

Conversion of adrenal hormones to oestrogen occurs extra-adrenally or peripheral sites e.g. fat, liver, muscle.

Conversion catalysed by aromatase complex - contains CYP450 enzymes.

2 types of aromatase inhibitors:

1. Irreversible (suicide inhibitor) - competes with androstenedione/testosterone for active site of aromatase complex - enzyme acts on inhibitor, yielding a reactive alkylating species —> forms covalent bonds near/at active site —> enzyme irreversibly inactivated. e.g. Exemestane
2. Reversible (competitive inhibitors) - more commonly used, e.g. anastrozole. Binds reversibly to active site and prevents oestrogen formation for only as long as its bound to active site.

Aromatase inhibitors = front line therapy, well tolerated

Question 20

How are progestins used in breast cancer

Progestin = agonist for PR, NOT ANTAGONIST

Answer 20

Progestins given —> overstimulate PR –> receptor down regulation –> tumour cells don’t respond to progesterone –> less/no growth

Progestins used in breast and uterine cancer

2nd/3rd line therapy for breast cancer

Main progestin used = Megestrol acetate

Question 21

Significant proportion of breast cancers and all metastatic cancers become resistant to?

Answer 21

Endocrine therapies

They may continue to demonstrate responsiveness to ER therapy

Question 22

What is the biggest lifetime risk for breast cancer?

Answer 22

Lifetime exposure to oestrogen

Also other risks e.g. BMI (more fat = more conversion of androgen to oestrogen)

Question 23

What are the molecular subtypes of breast cancers?

Answer 23

ER positive (2 subtypes) - can be divided into Luminal B/C, Luminal A

ER negative (3 subtypes) - can be divided into Basal like, ErbB2 +ve, Normal like. (Basal like can be further subdivided - metaplastic/medullary/mucinous, etc)