12: Breast Cancer

Question 1

Epidemiology

Answer 1

Leading female cancer
1 in 5 cancer deaths in women
1 in 8 women will develop during lifetime (UK/USA)
Incidence is RISING but mortality is FALLING
(early diagnosis, chemo/radio/hormonal therapy)

Question 2

Pathophysiology

Answer 2

Carcinoma
Most breast cancer arises from ductal cells
Hyperproliferation of luminal cell -> benign in situ carcinoma -> invasive breast cancer
Most are invasive DUCTAL carcinomas (80%)

Check for Estrogen receptor (ER) levels using antibodies against it
About 80% of breast cancers are Estrogen positive

Estrogen positive indicates GOOD prognosis for women

Question 3

How does ER induce cancer?

Answer 3

Estrogen (steroid hormone) is lipid soluble so goes across cell membrane
Binds to ER (transcription factor)
Goes to nucleus
Binds to estrogen response elements in DNA Upregulation of gene expression
Products formed increase cell proliferation leading to cancer

Question 4

What are some important estrogen regulated genes?

Answer 4

Progesterone receptor
Cyclin D1
c-myc
TGF-a

ALL involved in cell growth/survival

Question 5

What are the types of endocrine therapy?

Answer 5

Ovarian suppression
Enzymatic inhibition of estrogen production
Inhibiting estrogen responses

Question 6

Why do we use endocrine therapy?

Answer 6

It is an adjuvant therapy (like chemo/radiotherapy)

It is to minimise the risk of the spread of tumour cells after surgery

Question 7

Mechanisms of ovarian suppression?

Answer 7

LHRH AGONISTS (not antagonists) are reliable and reversible

• Bind to LHRH receptors and OVERSTIMULATE them
• Leads to receptor down-regulation and negative feedback causes suppression of LHRH
• Shuts down ovaries

Question 8

Examples of LHRH agonists

Answer 8

Goserelin, Leuprolide

Question 9

How do we inhibit estrogen action?

Answer 9

Anti-estrogens:

Tamoxifen = Selective Estrogen Receptor Modulator (SERM)
Competitive inhibitor of estrogen receptor
Causes cell to be held at G1 phase

Tamoxifen is drug of choice for post-menopausal
Side effect: hot flushes

Question 10

What are other positive effects of Tamoxifen

Answer 10

Tamoxifen has ESTROGENIC effects in bone and CVS

Estrogen important in bone maintenance in premenopausal women
Estrogen lowers LDL/raises HDL cholesterol

Reduces incidence of contralateral breast cancer by a third

Question 11

Side effects of Tamoxifen

Answer 11

Endometrial thickening

Question 12

Tamoxifen in breast cancer prevention?

Answer 12

38% reduction in overall incidence
Problems: increased incidence of endometrial cancer, stroke, DVT, cataracts
Hence trials are being done with other SERMs like Raloxifene

Question 13

How do we inhibit estrogen production?

Answer 13

Aromatase inhibitors
Most estrogen is derived from conversion of androstendione (and some testosterone) to E2
This occurs peripherally and is catalysed by aromatase

Question 14

What types of aromatase inhibitors are there?

Answer 14

Type 1 = suicide inhibitors, irreversible. Causes formation of covalent bonds in active site and inactivates aromatase

Type 2 = Competitive inhibitors, reversible.

Question 15

Another drug used in breast cancer?

Answer 15

Progestins given at high dose degrades progesterone receptors on tumour cells

Question 16

Why do a lot of patients on endocrine therapy go into relapse?

Answer 16

They develop RESISTANCE

Question 17

Risk factors of breast cancer?

Answer 17

Exposures to oestrogen
Late menopause
Hormone replacement therapy
Obesity, diet, physical activity

Question 18

Screening?

Answer 18

All women between 50 and 64 who are registered with a GP in the UK (being extended to 70)

Patient tested every 3 years

Question 19

Treatment for ER negative?

Answer 19

Chemotherapy