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Cancer > 12. Breast cancer > Flashcards

12. Breast cancer Flashcards

1
Q

What proportion of cancer deaths in women if caused by breast cancer?

A

1/5

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2
Q

How is breast cancer incidence and mortality changing?

A
  • Incidence rising

* Mortality falling (early diagnosis)

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3
Q

What type of therapy has the biggest impact on breast cancer?

A

Hormonal therapies

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4
Q

What type of breast cancer is the most common?

A

Carcinoma (tumour of epithelial cells)

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5
Q

Which gland is the only organ to develop post-natally?

A
  • Mammary gland

* Initially present as a rudimentary gland, then growth is driven by hormonal changes

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6
Q

What cells line the lumen in the mammary gland?

A 
• Ring of epithelial cells 
• 2 layers
• Second layer of epithelial cells = myoepithelial cells 
- can contract
- these make contact with the BM
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7
Q

Which cells produce milk?

A

Luminal cells

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8
Q

Which cells make the milk-producing cells release it into the duct?

A

Myoepithelial cells squeeze the luminal cells to release milk

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9
Q

Is it harder to treat epithelial or myoepithelial tumours?

A

Myoepithelial

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10
Q

What percentage of luminal cells can respond to oestrogen?

A
  • 10-20%

* These cells have receptors to respond to steroid hormones, particularly oestrogen

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11
Q

What is it called when there is a local proliferation of cells that are luminal, they don’t break away and there is no loss of myoepithelial cells?

A

Benign in situ carcinoma
• easily diagnosed as non-cancer
• however, it’s a precursor state for the development of cancer

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12
Q

What is lobular carcinoma?

A
  • Cancer cells try to form tube-like structures, but fail
  • Some indication that they try to retain the ability to behave like a normal luminal epithelial cell
  • But no myoepithelial cells present
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13
Q

What is medullar carcinoma?

A
  • Look nothing like breast cancer cells or epithelial cells

* Packed full of vesicles that are rich in neuro-endocrine peptides and hormones

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14
Q

What is a major staining method for the identification of breast cancer and what can this tell us?

A
  • Immunohistochemical staining using antibodies against the human oestrogen receptor (ER) (using an antibody)
  • Allows classification based on level of ER expression (nothing to very high)
  • About 80% of breast cancers are ER positive - so 80% are treatable
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15
Q

What percentage of breast cancers does infiltrating ductal carcinoma (IDC) account for?

A

Almost 80%

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16
Q

What happens to breast tissue after the loss of ovarian function during menopause and how is this significant in treatment options?

A

• Atrophy of the breast tissue - no breast cancer

  • Therefore, ovariectomy has been proposed as a treatment for breast cancer
  • Ovariectomy in pre-menopausal women has resulted in disease regression
  • Oestrogen on the other hand has been shown to stimulate breast cancer so this makes sense
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17
Q

Which lifetime oestrogen related risk factors can contribute to the risk of breast cancer?

A
  • Age of onset of menarche (first menstrual cycle)
  • Age to first full-term pregnancy (early pregnancy is protective)
  • Some contraceptive pills
  • Some hormone-replacement therapies
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18
Q

Which part of the cell is the oestrogen receptor located in?

A

Cytoplasm (but it is a ‘nuclear receptor’)

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19
Q

What is the oestrogen receptor bound to?

A
  • Heat-shock 90 protein
  • This is displaced when the oestrogen binds
  • Allows the receptor to dimerise
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20
Q

How does the oestrogen receptor induce gene expression?

A
  • Binds to specific DNA sequences called oestrogen response elements
  • Increases cell proliferation and cell survival
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21
Q

Why is it so easy for oestrogen to cross the cell membrane?

A

Very lipophilic molecule

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22
Q

What type of receptor is the progesterone receptor?

A

Nuclear receptor

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23
Q

What is the relation between the progesterone receptor and oestrogen?

A
  • The PR is a very strongly oestrogen-regulated gene in the mammary gland
  • Where PR is expressed, the ER is working
  • Can be used in a test to see if the ER is working in a tumour
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24
Q

Apart from the PR, which other genes are affected by oestrogen in breast cancer cells and what do they do?

A
  • Cyclin d1 - regulator of the cell cycle
  • C-myc - regulation of apoptosis
  • TGF-alpha - GF that directly influences cellular growth
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25
Q

Why does high-dose therapy with synthetic oestrogens cause breast tumour regression in post-menopausal women?

A

• Negative feedback - less receptors
• Degradation of the receptor due to too much oestrogen
• Cells no longer express ER, so cannot be driven with oestrogen
- tumour regression

26
Q

Why is the use of synthetic oestrogens not a good treatment option?

A
  • Can lead to metastasis - tumour becomes incurable
  • Resistance often follows remission
  • Drugs must be given in high dose - many side effects
27
Q

How responsive are ER-positive and negative cancers in the use of anti-oestrogens?

A
  • ER +ve - 70%

* ER -ve - 5-10%

28
Q

How does an increased level of ER expression affect the prognosis in male breast cancer?

A

Worse prognosis

29
Q

What is the primary treatment option for breast cancer?

A

Surgery

30
Q

What do surgeons also tend to remove during surgery, apart from the tumour itself?

A

Sentinel lymph nodes under the arm

31
Q

What treatment are patients often offered before surgery?

A

Endocrine therapy to shrink the size of the tumour (rare now due to early detection)

(example of neo-adjuvant therapy)

32
Q

When is endocrine therapy most often given?

A

• After surgery (adjuvant therapy)
• During surgery some cancer cells may break off and travel in the blood, or they may be left behind
- so endocrine treatment helps in this event

33
Q

Which hormones regulate oestrogen production?

A

• Peptide gonadotrophin hormones FSH + LH
- from pituitary gland
• Pituitary is regulated by GnRH
- from hypothalamus
• Androgenic steroids can be converted to oestrogens (aromatisation)
- in pre/post-menopausal women

34
Q

What is ovarian ablation?

A
  • Suppression of ovaries to stop them from producing oestrogen
  • Surgical oophorectomy - removal
  • Ovarian irradiation - destroy thecal cells
35
Q

What are the problems with ovarian ablation?

A
  • Morbidity and irreversibility

* Lost fertility

36
Q

How can the problems of ovarian ablation be overcome

A
  • Medical ovarian ablation using LHRH agonists
  • Bind to LHRH receptors in the pituitary
  • Leads to LHRH receptor down-regulation and suppression of LH release
  • This causes inhibition of ovarian function
37
Q

Are the effects of medical ovarian ablation with LHRH agonists reversible?

A

Yes, ovarian function and fertility is restored when coming off treatment

38
Q

Can women have children during treatment with LHRH agonists?

A

Yes

39
Q

What can we prescribe to block the effect of oestrogen on cancer in post-menopausal women?

A
  • Aromatase inhibitors

* Anti-oestrogens

40
Q

What does tamoxifen do?

A
  • Anti-oestrogen
  • SERM - selective oestrogen receptor modulator
  • Competitive inhibitor oestradiol binding to the ER
  • Causes the cell to be held at G1 - cell will die
  • Endocrine treatment of choice for metastatic disease in post-menopausal patients
  • 1/3 respond
  • Few side effects
41
Q

What is the effect of tamoxifen on bone?

A
  • Oestrogenic effects

* Therefore it doesn’t cause osteoporosis like most long-term anti-oestrogens

42
Q

What effect does oestrogen have on cholesterol and why is this significant for post-menopausal women?

A
  • Lowers LDL
  • Raises HDL
  • Removal of this effect causes post-menopausal women to be at the same risk for CHD as men
43
Q

What is the effect of tamoxifen on the CVS?

A
  • Oestrogenic effects

* Therefore it doesn’t increase the CV effects like most long-term anti-oestrogens

44
Q

What is a SERM?

A
  • Selective oestrogen receptor modulator
  • Acts different on different oestrogen receptors
  • Some can only target the mammary gland to effect the tumour
45
Q

What are the unwanted effects of tamoxifen?

A
  • Association with thromboembolic episodes
  • Endometrial thickening (risk of cancer)
  • Hyperplasia
  • Fibrosis
46
Q

What are the advantages and disadvantages of Fulvestrant (anti-oestrogen)?

A
  • Pure anti-oestrogenic - many side effects

* However, it decreases tumour cell invasion well and decreases the stimulation of endometrial carcinoma

47
Q

What is raloxifene?

A
  • Anti-tumour agent
  • SERM - acts in the bone
  • Used in the treatment of osteoporosis in post-menopausal women
48
Q

How useful has tamoxifen been in breast cancer prevention?

A
  • 38% decrease in incidence
  • No effect on ER negative incidence
  • No association between prevention and age

Therefore, it promotes prevention

49
Q

Give 4 problems associated with the use of tamoxifen in prevention

A
  • Endometrial cancer risk
  • Stroke
  • DVT
  • Cataracts
50
Q

What has been done to overcome the problems associated with the use of tamoxifen in prevention?

A

Trials being conducted with
• Raloxifene/Faslodex (SERM)
• Aromatase inhibitors

51
Q

What is, and describe, the major source of oestrogen in post-menopausal women?

A
  • Conversion of adrenal hormones Androstenedione (and testosterone to a lessor extent)
  • Occurs at extra-adrenal or peripheral sites e.g. fat, muscle and liver
  • Catalysed by the aromatase enzyme complex
52
Q

What does aromatase consist of?

A
  • Complex containing a CYP450 heme containing protein

* Also flavoprotein NADPH CYP450 reductase

53
Q

What type of reactions and how many reactions does aromatase catalyse?

A

Three separate hydroxylations involved in the conversion of androstenedione to oestrone

54
Q

Where is androstenedione produced?

A

Adrenal glands

55
Q

Oestrone sulphate is produced by the metabolism of what?

A

Androstenedione by aromatase

56
Q

What 2 types of drugs can inhibit the activity of aromatase?

A
  • Type I - mechanisms-based, or suicide, inhibitors - irreversible
  • Type II - competitive inhibitors - reversible
57
Q

Describe type I aromatase inhibitors

A
  • Initially compete with the natural substrate for binding to the active site
  • The enzymes then acts on the inhibitor to yield reactive alkylating species
  • These form covalent bonds at/near the active site
58
Q

Describe type II aromatase inhibitors

A
  • Bind reversibly to the active site of the enzyme

* Prevent product formation only as long as the inhibitor occupies the catalytic site

59
Q

How are progestins useful in cancer treatment?

A

• Response in the breast is complex, but it influences proliferation and differentiation function
• Used in endocrine treatment of uterine and breast cancer - anti-neoplastic properties
• Second/third-line therapy for metastatic breast cancer
e.g. megestrol acetate

60
Q

What type of treatment do all patients with metastatic disease become resistant to?

A

Endocrine therapy

61
Q

How do ER-positive tumours become resistant to endocrine therapy and how can this be overcome?

A
  • Mutation of ER

* Continue with this therapy, but with additional therapeutic agents

62
Q

What the the UK breast-cancer screening programme involve?

A
  • Mammography for women between 50-60yrs who are registered with a GP
  • Age being extended to 70
  • Attendance every 3 years
  • More than 90% are spotted by women themselves

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